The Thyroid and its Diseases
	Chapter 12                                                          HOME Graves' Disease: Complications Revised 25 November 2003 by Dr. Georg Henneman	Downloads

THYROID STORM

Thyroid storm is a sudden, life-threatening exacerbation of thyrotoxicosis. In its pure form the manifestations are due simply to the action of excess thyroid hormone. In recent years, thyroid storm, defined in this manner, has become rare, largely because of earlier recognition of the disease, better pre- and postoperative medical management, and possibly improved nutrition. Acute exacerbations of the symptoms of thyrotoxicosis induced by intercurrent illness, especially infection, are still seen occasionally. Whether or not these should be considered examples of thyroid storm is a question of semantics, but they are indeed life threatening, and constitute a major therapeutic challenge. Thyroid storm in the past most frequently followed surgery, but now it is usually a complication of the untreated. or poorly trea. disease, rather than a postoperative complication.

Clinical pattern

The classic findings in thyroid storm suggest a sudden and severe exacerbation of hyperthyroidism. There is fever, rapid tachycardia, tremor, nausea and vomiting, diarrhea, dehydration, and delirium or coma. Fever is perhaps the most characteristic feature; the temperature may rise above 105.8^oF (41^oC). Occasionally, patients have a true toxic psychosis or a marked deterioration in previously abnormal behavior. Sometimes thyroid crisis takes a strikingly different form, which has been called apathetic storm. This condition is characterized by extreme weakness, emotional apathy and sometimes confusion. The wild delirium and agitation of the classic victim of thyroid storm are missing, and fever, if present, does not rise so high.

Signs and symptoms of decompensation in various organ systems may be present. Delirium is one example. Congestive heart failure may occur, with edema, congestive hepatomegaly, and respiratory distress. Extreme tachycardia or atrial fibrillation is common. Liver damage and jaundice may occur from congestive heart failure or possibly from a direct action of thyroid hormone on the liver coupled with malnutrition (Chapter 10). Fever and vomiting may produce dehydration and prerenal azotemia. Abdominal pain may be a prominent feature. The temperature may rise alarmingly, perhaps because the usual thermal controls have broken down in a manner similar to that occurring in the heat stroke. Frequently the clinical picture is clouded by a secondary infection such as pneumonia, a viral infection, or infection of the upper respiratory tract. Death may be caused by cardiac arrhythmia, congestive heart failure, hyperthermia, or other unidentified factors.

Storm is typically associated. with Graves' disease, but it has also been repor. in patients with toxic nodular goiter. ¹ In years past, death was the final outcome of storm with awesome regularity.² In an unusually large series repor. in 1969, three-fourths of the patients with thyroid storm succumbed to their disease.³ These patients typically were nutritionally depleted., had severe thyrotoxicosis, and had coincident serious disease, such as cardiac decompensation. In later series the mortality has been 30-75%.^1,4 At present, although still life-threatening, death from thyroid storm becomes rare provided that prompt recognition and aggressive treatment is initially in an intensive care unit.⁵

Incidence

In Nelson and Becker's series reported. in 1969 ³ there were 21 cases of storm among 2,329 thyrotoxic admissions. Reports from other clinics, which included all cases manifesting febrile reactions of 38.3oC or more in the postoperative period, set the incidence of storm as high as 10% of patients opera. on.⁴ Few patients are now seen who fit the classic pattern of storm, but patients are occasionally encountered with marked accentuation of the symptoms of thyrotoxicosis in conjunction with infection. Most reports in the literature in recent years have been accounts of single cases. The incidence of thyroid storm is very low at present.

Cause

Thyroid storm classically began a few hours after a thyroidectomy performed on a patient prepared for surgery by potassium iodide alone. Many such patients were not euthyroid and would not be considered appropriately prepared for surgery by contemporary standards. Exacerbations of thyrotoxicosis are still seen in patients taken too soon to surgery but are unusual in the antithyroid drug-controlled patient. Thyroid storm occasionally occurs in patients opera. on for some other illness while severely thyrotoxic. Severe exacerbations of thyrotoxicosis are seen rarely following 131I therapy; some of these may merit the term storm.⁶

As reported. in the series of Nelson and Becker,³ thyroid storm appears most commonly following infection, which seems to induce an escape from control of the thyrotoxicosis. Pneumonia, upper respiratory tract infection, enteric infections, or any other infection can produce an acute exacerbation of the symptoms of thyrotoxicosis. The pathophysiology is incompletely understood.⁷ A finding of possible significance is an elevated. free T4 in patients with thyroid storm while total T4 levels were similar as compared with patients with uncomplicated. thyrotoxicosis.⁸

These data suggest that events like infection may decrease serum binding of T4 resulting in increase in free T4 that may play a role in the precipitation of the storm.

The decreased incidence of thyroid storm can be largely attributed. to the improved methods of diagnosis and therapy available today. In most cases, thyrotoxicosis is recognized before extreme debilitation occurs and is treated. by measures of predictable therapeutic value. Patients are routinely made euthyroid before surgery or treatment with 131-I. Under present-day therapy, using thiocarbamides, the glands have only minimal amounts of stored hormone, in contrast to the iodized gland facing the surgeons of six decades ago. Postoperative storm, formerly the most frequent kind of storm, has now been largely eliminated.

I-131 is increasingly being used as a first line of treatment of hyperthyroidism (Chapt.10 and17), but thyroid storm is rarely seen after this form of treatment, due to proper medical pre-treatment, and only isolated. cases have been reported.^9,9a

Diagnosis

The diagnosis of thyroid storm is made entirely on clinical grounds and involves the usual diagnostic measures for thyrotoxicosis. There are no distinctive laboratory abnormalities. Total and free T4 and if possible total T3 should be measured. T3 may rarely be normal or even decreased because of co-existing non-thyroidal illness.¹⁰ Electrolytes, blood urea nitrogen (BUN), blood sugar, liver function tests, and plasma cortisol should be monitored.

Therapy

It should be emphasized that a thyroid storm is a major medical emergency that has to be treated. in an intensive care unit (Table 12-1).

It should be no. that if any possibility is present that orally given drugs will not be appropriately absorbed (e.g. due to stomach distention, vomiting, diarrhea or severe heart failure), the intravenous route should be used. If the patient has not been under prior treatment, an antithyroid drug should be given. PTU, 150-250 mg every 6 hours should be given, if possible, in preference to methimazole, since PTU prevents peripheral conversion of T4 to T3. Since peripheral formation of T3 is a major source of the hormone, PTU more rapidly reduces the circulating level of T3 and thus aids recovery. Methimazole (15 mg every 6 hours) can be given orally, or if necessary, the pure compound can be made up in a 10 mg/ml solution for parenteral administration. Methimazole is also absorbed when given rectally in a suppository.¹¹ An hour after thiocarbamide has been given, iodide should be administered. A dosage of 0.1g twice daily is more than sufficient. Unless congestive heart failure contraindicates it, propranolol or other beta blocker should be given at once, orally or parenterally in large doses, depending on the patient's clinical status. Permanent correction of the thyrotoxicosis by either radioactive iodide or immediate surgery should be deferred. Other supporting measures should be fully exploited. These include the use of sedation, oxygen, treatment for tachycardia or congestive heart failure, rehydration, multivitamins, occasionally supportive transfusions, and cooling the patient to bring the temperature down to a reasonable level. An antibiotic may be given on the presumption of infection while the results of culture are awaited.

The adrenal gland may be limited. in its ability to augment steroid production during thyrotoxicosis.¹² If there is any suspicion of hypoadrenalism, hydrocortisone (100-200 mg/day) or its equivalent should be given. The dose can be rapidly reduced when the acute process subsides. Pharmacological doses of steroids (2 mg dexamethasone every 6 h) acutely depress serum T3 levels in normal subjects and in Graves' disease patients by reducing T4 to T3 conversion. This effect of steroids is beneficial in thyroid storm and supports the routine use of corticosteroids. Propranolol may not reverse the metabolic insults of thyrotoxicosis but does dramatically suppress tachycardia, restlessness, and other symptoms.^13,14

Usually rehydration, repletion of electrolytes, treatment of coincident disease such as infection, and specific agents (antithyroid drugs, iodine, propranolol, and corticosteroids) produce a marked improvement within 24 hours. A variety of additional approaches have been reported, but indications for their use are not well defined. For example, oral gallbladder contrast agents such as ipodate and iopanoic acid in doses of 1-2 g, which inhibit peripheral T4 to T3 conversion, may have value.¹⁵ Peritoneal dialysis can remove circulating thyroid hormone, and plasmapheresis can do likewise, but at the expense of serum protein loss. Orally administered ion-exchange resin¹⁶ (20-30g/day as Colestipol-HCl) can trap hormone in the intestine and prevent recirculation. Probably these treatments will rarely be needed.

The antithyroid treatment should be continued until euthyroidism is achieved, at which point a final decision regarding antithyroid drugs, surgery, or 131I therapy can be made.

GRAVES’ OPHTHALMOPATHY (GO)

Two types of manifestations may occur in GO: (1) functional abnormalities due to hyperactivity of the sympathetic nervous system, produced by the thyrotoxicosis, and (2) infiltrative lesions involving the contents of the orbit. Only the infiltrative type has a serious prognosis. Two classifications of eye signs are being used to date. The first one is depicted. in Table 12-2.

Table 12-2.

Criticism has been raised with regard to this NOSPECS mnemonic (composed of the first character describing each grade. See the table ). The criticism basically states that although NOSPECS is "an ingenious catchy memory aid for medical students who have forgotten how to examine a Graves' eye" it is insufficient in that it is directed. towards the mean status of the eye so that it is impossible, using this index, to evaluate isolated. components separately. In other words, although the NOSPECS index does not reflect it, important and essential components of the eye complex may have improved or deteriorated.. For this reason it was proposed that data should be provided separately and not put together in an overall index.¹⁹ Others on the basis of the same criticism proposed a modification of NOSPECS.²⁰ In order to be able to assess treatment of active inflammatory ophthalmopathy and also to predict therapeutic outcome and to select patients for surgical or non-surgical treatment, they introduced the clinical activity score (CAS).²¹ (Table 12-3)

This scoring system was shown to have a high predictive value for therapeutic outcome of immunosuppressive treatment of infiltrative ophthalmopathy.²²

SIGNS AND SYMPTOMS

Noninfiltrative Ophthalmopathy

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.²³ This 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

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 .

1. Edema of the orbital contents. The lids and periorbital tissues are irritated. injec., and characteristically swollen and puffy. The lids may be erythematous. The swollen lids usually feel firm and do not pit. There is chemosis, and edema of the scleral conjunctiva. Edematous conjunctiva may even protrude beyond the palpebral fissure. Associated. with this condition may be excessive lacrimation and photophobia. The lacrimal gland may be almost totally destroyed by the infiltrative lesion. Nevertheless epiphora is typical. Eye pain, irritation, and "grittiness" of the eyes are common complaints.

2. Protrusion of the globe. It is unusual for the anterior border of the cornea to protrude normally more than 18 mm beyond the lateral margin of the orbit. If measurements with the Leudde or Hertel exophthalmometer show that the globe is 2 or 3 mm beyond this limit, then true proptosis is present (normal limits may be race-dependent). Associated. with this condition, and responsible for the edema and exophthalmos, is an increase in the volume of extra-ocular orbital contents including fatty tissue and muscles. The lacrimal gland may be enlarged and palpable, and even visible. Prolapse of the globe beyond the orbital fissure in rare extreme proptosis may permit a startling closure of the lids behind the globe.

The patient or friends usually note these abnormalities as an increased prominence of the eyes or a "staring" or "wild" expression. Occasionally there is a severe pain behind the eyes. Exophthalmos causes the exposed conjunctivae to be more readily irritated. by all noxious agents. If the lids fail to close completely over the cornea while the patient sleeps, development of ulceration is a hazard.

3. Infiltration of the extraocular muscles. The muscles become infiltrated, inflamed, and enlarged. Inflammation of the muscles gives rise to an important and characteristic sign that we find helpful in differentiating the ophthalmopathy of Graves' disease from other causes of exophthalmos. The insertion of the swollen lateral rectus is often visible as a beefy red area at the inner and outer canthus when the patient turns the eye laterally or medially. Normally the muscle insertion is barely visible and is pale pink. In tumors or other retrobulbar lesions, this change in muscle insertion is not seen. The muscle enlargement can be recognized by ultrasound or, more certainly, by computed. tomography (CT) or MRI scanning. The enlargement is almost pathognomonic of Graves' disease.

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 disease²⁴. 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.

Pathology

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-g 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 (Mimura, LY; Villares, SMF; Monteiro, MLR; Guazzelli, IC; Bloise, W.                Peroxisome proliferator-activated receptor-g gene expression in orbital adipose/connective tissues is increased during the active stage of Graves’ ophthalmopathy.        Thyroid    13            845          2003).

Cause and PathGOenesis

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.²⁷ The specific antigen however is at present still not certain, but increasing evidence points to the TSH receptor ( see 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.⁴⁸ GO 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.⁴⁹ All had positive tests in at least one of the assays. Clinically apparent ophthalmopathy occurs in 25 - 50% of patients with hyperthyroid Graves' disease.^50-52 When 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.^53a The 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 lymphocytes⁵⁴. 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.⁴⁴ These antibodies were sometimes devoid of any cross reactivity with thyroid cell consitutents⁵⁵, were not directly related to TSAb activity in patients serum,⁵⁶interacted with some unique eye muscle determinants not present in the skeletal muscle⁵⁷, were found to bind to retroocular fibroblasts⁵⁸ and apart from binding to retroocular muscle displayed cytotoxic activity.⁵⁹ Promising 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.64 However 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.70 In a recent 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 a serious candidate as the 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 (33,34). 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 (35,36). 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, TGFß, RANTES, and prostaglandin E₂ (PGE₂), that help to attract T cells by stimulating the expression of certain adhesion molecules17

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.^85,86 In 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 type⁸⁷.

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.^90-92 Smoking is a predisposing factor for Graves' ophthalmopathy^93-95. Smoking increased the risk of Graves' ophthalmopathy about 7 times⁹⁶, 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. The relationship to smoking has been related to the fact that extraocular muscle fibroblasts were shown to be stimulated by hypoxia in vitro.⁹⁷ Cultured 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. Cawood et al report that exposure of orbital fibroblasts from patients with GO and control subjects to cigarette smoke extract in vitro lead to increased production of hyaluronic acid and adipogenesis. Adipogenesis was also augmented by IL-1, and the two agents were synergistic.(Cawood TJ, Moriarty P, O'farrelly C, O'shea D. Smoking and Thyroid-Associated Ophthalmopathy: A Novel Explanation of the Biological Link.J Clin Endocrinol Metab. 2007 Jan;92(1):59-64. Epub 2006 Oct 17)  Whether this interesting in vitro observation has any relevance to the situation in vivo, is another question.Other predisposing factors for the development of ophthalmopathy or worsening of eye symptoms may include thyroidectomy⁹⁸ or treatment with radioactive iodine for Graves' hyperthyroidism, although the effect on eye signs by RAI is still being deba.^99,100 Release 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

Fig 12-2 Thyroid Eye Disease (with permission from ref 80c)