Classic features of thyroid storm are indicative of a sudden and severe exacerbation of thyrotoxicosis, with fever, marked tachycardia, tremor, nausea and vomiting, diarrhea, dehydration, restlessness, extreme agitation, delirium or coma. Fever is typical and may be higher than 105.8 oF (41 oC). Patients may present with a true psychosis or a marked deterioration of previously abnormal behavior. Sometimes thyroid storm takes a strikingly different form, called apathetic storm, with extreme weakness, emotional apathy, confusion, absent or low fever

Signs and symptoms of decompensation in various organ systems may be present. Delirium is one example. Congestive heart failure may also occur, with peripheral edema, congestive hepatomegaly, and respiratory distress. Marked sinus tachycardia or tachyarrhythmias, such as atrial fibrillation, are common. Liver damage and jaundice may derive from congestive heart failure or 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 clinical picture may be masked 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 may occur in patients with toxic nodular goiter1 . In the past, death was the usual final outcome of thyroid storm2 . In a large series reported in 1969, three-fourths of patients with thyroid storm died3 . These patients typically were malnourished, had severe thyrotoxicosis, and had coincident serious disease, such as heart failure4. In later series mortality was 30-75%1,5 . At present, although still life-threatening, death from thyroid storm is rarer if it is promptly recognized and aggressively treated in an intensive care unit6 .

In Nelson and Becker's series reported in 19693 , there were 21 cases of thyroid storm among 2,329 admissions due to thyrotoxicosis (about 1%). Other series, which included all cases with fever of 38.3 oC or more in the postoperative period, reported an incidence of thyroid storm as high as 10% of patients operated on4 . Few patients are now seen with the classic pattern of thyroid storm, but patients are occasionally encountered with marked accentuation of symptoms of thyrotoxicosis in conjunction with infection. Most recent reports described single cases. The incidence of thyroid storm currently is very low.

Thyroid storm classically began a few hours after 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 current standards. Exacerbation of thyrotoxicosis is still seen in patients sent too soon to surgery, but it is unusual in the antithyroid drug-controlled patient. Thyroid storm occasionally occurs in patients operated on for some other illness while severely thyrotoxic. Severe exacerbation of thyrotoxicosis is rarely seen following 131-I therapy for hyperthyroidism; some of these may be defined as thyroid storm7.

Thyroid storm appears most commonly following infection3, which seems to induce an escape from control of thyrotoxicosis. Pneumonia, upper respiratory tract infection, enteric infections, or any other infection can cause this condition. Pathophysiology is incompletely understood8 . Interestingly, serum free T4 concentrations were higher in patients with thyroid storm than in those with uncomplicated thyrotoxicosis, while serum total T4 levels did not differ in the two groups9 , suggesting that events like infections may decrease serum binding of T4 and cause a greater increase in free T4 responsible for storm occurrence.

The decreased incidence of thyroid storm can be largely attributed to improved diagnosis and therapy. In most cases, thyrotoxicosis is recognized early and treated by measures of predictable therapeutic value. Patients are routinely made euthyroid before thyroidectomy or 131-I therapy. Using thionamides preoperatively, thyroid glands have only minimal amounts of stored hormones, thus minimizing thyroid hormone release due to manipulation. Postoperative storm, formerly the most frequent kind of storm, has now been largely eliminated. 131-I is increasingly being used as a first-line treatment of hyperthyroidism (Chapter 10 and Chapter 17), but thyroid storm is rarely seen after this treatment, due to adequate medical pretreatment, and only isolated cases have been reported 10,11 .

Diagnosis of thyroid storm is made on clinical grounds and involves the usual diagnostic measures for thyrotoxicosis. There are no distinctive laboratory abnormalities. Free T4 and, if possible, free T3 should be measured. T3 may rarely be normal or even decreased because of coexisting nonthyroidal illness12 . Electrolytes, blood urea nitrogen (BUN), blood sugar, liver function tests, and plasma cortisol should be monitored.

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

It should be noted 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 used13. If the thyrotoxic patient is untreated, an antithyroid drug should be given. PTU, 150-250 mg every 6 hours should be given, if possible, rather than methimazole, since PTU also prevents peripheral conversion of T4 to T3, thus more rapidly reduces circulating T3 levels. Methimazole (15-25 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 suppository14 . An hour after thiocarbamide has been given, iodide should be administered. A dosage of 100 mg twice daily is more than sufficient. Unless congestive heart failure contraindicates it, propranolol or other blocking agents 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 131-I or immediate thyroidectomy should be deferred until euthyroidism is restored. Other supporting measures should fully be exploited, including sedation, oxygen, treatment for tachycardia or congestive heart failure, rehydration, multivitamins, occasionally supportive transfusions, and cooling the patient to lower body temperature down. Antibiotics may be given on the presumption of infection while results of culture are awaited.

The adrenal gland may be limited in its ability to increase steroid production during thyrotoxicosis15 . If there is any suspicion of hypoadrenalism, hydrocortisone (100-200 mg/day) or its equivalent should be given. The dose can rapidly be reduced when the acute process subsides. Pharmacological doses of glucocorticoids (2 mg dexamethasone every 6 h) acutely depress serum T3 levels by reducing T4 to T3 conversion. This effect of glucocorticoids is beneficial in thyroid storm and supports their routine use in this clinical setting. Propranolol controls tachycardia, restlessness, and other symptoms16,17 .

Usually rehydration, repletion of electrolytes, treatment of concomitant 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 value18 . Peritoneal dialysis can remove circulating thyroid hormone, and plasmapheresis can do likewise, but at the expense of serum protein loss. Orally administered ion-exchange resin19 (20-30g/day as Colestipol-HCl) can trap hormone in the intestine and prevent recirculation. These treatments are rarely needed.

Antithyroid treatment should be continued until euthyroidism is achieved, when a final decision regarding antithyroid drugs, surgery, or 131-I therapy can be made.

Data on the incidence of GO are limited21. In a population-based setting in USA, an adjusted rate of 16 cases per 100.000 per year in women and 2.9 cases per 100.000 in men was reported22. Clinical evident ocular manifestations are present in about 50% of Graves’ patients, but subclinical abnormalities can be demonstrated (e.g., by CT or MRI of the orbit23, or by measurement of intraocular pressure in upward gaze24) also in the majority of the remaining 50%. GO is severe and potentially sight-threatening in 3-5% of cases25. Ocular involvement is in most cases bilateral, although often asymmetrical, but it may be unilateral in up to 15% of cases20. The onset of GO apparently has a bimodal peak in the fifth and seventh decades of life, but eye disease may occur at any age22. It is more frequent in women, but men tend to have a more severe disease26,27, as suggested by a decrease in the female/male ratio from 9.3 in mild GO, to 3.2 in moderately severe GO, and 1.4 in severe GO27.

There is a close temporal relationship between the onset of GO and the onset of hyperthyroidism. In approximately 85% of cases GO and hyperthyroidism occur within 18 months of each other25,26, although GO may both precede (about 20% of cases) or follow (about 40% of cases) the onset of hyperthyroidism25,26.

The natural history of GO is poorly understood. However, in a longitudinal cohort study, spontaneous amelioration was observed in two thirds of cases, while ocular involvement did not change with time in 20% and progressed in 14%28. It is worth noting that GO seems to be less frequent than in the past. A review of the first 100 consecutive patients seen at the same joint thyroid-eye unit in 1960 and 1990 revealed a decrease in the proportion of Graves’ patients with clinical relevant GO from 57% to 32%29; likewise, a reduction in the proportion of severe forms of GO compared to milder forms was observed29, likely reflecting an earlier diagnosis and treatment of both hyperthyroidism and orbitopathy. The latter finding is, however, controversial, since in a recent multicenter study carried out by the European Group on Graves’ Orbitopathy (EUGOGO), 40% of GO patients had mild disease, 33% had moderate GO, and 28% had severe eye disease30. It should be noted that these figures may have been influenced by the fact that EUGOGO centers are all referral centers where it is likely to see more complicated cases of GO.

An important epidemiologic feature of GO is its relation with cigarette smoking31. The prevalence of smokers among Graves’ women with orbitopathy is much higher than that in Graves’ women apparently without GO or in normal controls (Figure 1)32. Smoking is a predictor of Graves’ hyperthyroidism, with a hazard ratio of 1.93 in current smokers, 1.27 in ex-smokers, and 2.65 in heavy smokers33. In a case-control study, the odds ratio of cigarette smoking for Graves’ hyperthyroidism without GO was 1.7, but raised to 7.7 for Graves’ disease with GO34. Whether passive smoking may have the same impact as active smoking is unsettled; however, in a recent European survey of GO in childhood, the highest prevalence of Graves’ children with GO was found in countries where the prevalence of smokers among teenagers was also highest: since >50% of children were <10 years of age, it is likely that passive smoking rather than active smoking influenced GO occurrence35. Mechanisms whereby smoking may affect the development and course of GO are unclear. In addition to direct irritative effects and modulation of immune reactions in the orbit36, smoking was associated with an increase in the orbital connective tissue volume as assessed by MRI37, and with an increased adipogenesis and hyaluronic acid production in in vitro cultured orbital fibroblasts38.

Clinical manifestations of GO reflect the enhanced orbital volume, due to an increase in retroocular fibroadipose tissue and swelling of extraocular muscles39. Orbital tissues, including muscles, are infiltrated by inflammatory cells, including lymphocytes, mast cells, and macrophages. Proliferation of orbital fibroblasts and adipocytes, both in the retroocular space and in the perimysial space, is also associated with an increased production of glycosaminoglycans, which are the ultimate responsible for edematous changes both in the connective tissue and the muscles, owing to their hydrophilic nature. The relative contribution of the increase in fibroadipose tissue volume and extraocular muscle swelling is not always the same, and a predominance of either component may be observed in different patients with similar clinical features40. Because the orbit is a rigid, bony structure anteriorly limited by the orbital septum, the increased orbital volume deriving from cell proliferation, inflammatory infiltration and edema, results into enhanced intraorbital pressure, forward displacement of the globe (proptosis or exophthalmos), extraocular muscle dysfunction causing diplopia and/or strabismus, soft tissue changes with periorbital edema, conjunctival hyperemia and chemosis. If proptosis, which can be considered a form of spontaneous decompression, is severe, subluxation of the eye may occur. Proptosis is responsible for corneal exposure which may be particularly dangerous at night for the incomplete eyelid closure (lagophthalmos), and may result into sight-threatening corneal ulceration. The enlarged muscle volume may cause optic nerve compression (dysthyroid optic neuropathy), especially if the orbital septum is tight and proptosis is minimal. Optic nerve compression is particularly evident at the orbital apex and may be responsible for sight loss. Orbital inflammation and related anatomical changes may cause venous and lymphatic congestion that contribute to periorbital edema and chemosis. With time inflammation subsides and muscle fatty degeneration and fibrosis may contribute to further extraocular muscle restriction and strabismus, which, at this stage, can only be corrected by surgery.

Although it is widely accepted that GO is an autoimmune disorder, its pathogenesis is not completely clear. A still leading pathogenic hypothesis, based on the link between thyroid disease and eye disease41, is that autoreactive T lymphocytes directed against one or more antigens shared by thyroid and orbit infiltrate the orbital tissue and the perimysium of extraocular muscles. Recruiting of T cells to the orbit may be facilitated by adhesion molecules42. Following shared antigen(s) recognition, facilitated by HLA class II antigen expression on antigen-presenting cells, CD4+ T lymphocytes secrete cytokines which amplify the immune response by activating either CD8+ T lymphocytes or autoantibody-producing B cells43, and by stimulating orbital fibroblast proliferation44. Analysis of T-cell clones from GO orbital tissues has shown both Th1 cytokine (interleukin-2, interferon-gamma, tumor necrosis factor-alpha) and Th2 cytokine (interleukin-4, interleukin-5, interleukin-10) secretory profiles, possibly related to different stages of the disease, with Th1 cytokines predominating early and Th2 cytokines late in the course of GO45. Cytokines produced by T cells, macrophages and fibroblasts perpetuate the ongoing inflammatory process through several mechanisms, including induction of expression of HLA class II antigens, heat-shock proteins, CD40, prostaglandins, adhesion molecules, proliferation of fibroblasts, differentiation of preadipocyte fibroblasts into adipocytes, and stimulation of fibroblasts to synthesize and secrete glycosaminoglycans40,43. The observation that immunoglobulins G from GO patients induce glycosaminoglycan synthesis in their orbital fibroblasts through the IGF-I receptor might suggest that the latter may represent a possible pathway in GO pathogenesis46. Increased adipogenesis in the orbit of GO patients might be related to overexpression of adipocyte-related genes, such as secreted frizzled-related protein-1, PPAR-, adiponectin47, and immediate early genes which act as triggers of the subsequent transcriptional cascade leading to adipocyte phenotype48. Interestingly, ligands of PPAR gamma, such as rosiglitazone, have been shown to stimulate adipocyte differentiation in orbital tissue in culture49; in addition, progression of GO has been reported in a patient submitted to rosiglitazone treatment for diabetes mellitus type 250. The role of PPAR-gamma agonists in GO pathogenesis is, however, not unequivocal, since in GO orbital fibroblasts and preadipocytes in culture rosiglitazone suppresses the release of IFN-gama-inducible chemokine CXCL10, which plays an important role in the initial phases of autoimmune thyroid disorders51.

The nature of autoantigen(s) shared by thyroid and orbit is still unclear52. Because Graves’ hyperthyroidism is caused by TSH-receptor (TSH-R) antibodies (TRAb), TSH-R might be a plausible candidate autoantigen. TSH-R expression has been shown in the orbital tissue of GO patients, both at the mRNA and protein levels53, 54; however, TSH-R is also expressed in several other tissues not involved in Graves’ disease and orbitopathy55, and, although at lower levels, in normal orbital fibroadipose tissue samples and cultures56. On the other hand, BALB/c mice injected with spleen cells primed either with a TSH-R fusion protein or with TSH-R cDNA developed thyroiditis with blocking-type TRAb, but also showed orbital pathological changes (lymphocytic and mast cell infiltration, edema, presence of glycosaminoglycans) similar to those seen in human GO57. In addition, one study showed a correlation between GO activity, as assessed by the Clinical Activity Score, and TRAb58. Thus, although evidence is not conclusive, TSH-R may have a role in GO pathogenesis. Other autoantigens have been proposed as putative shared antigens, including several eye muscle antigens59, acetylcholine receptor, thyroperoxidase, thyroglobulin60, alpha-fodrin61 (Table 2), but their true role is, to say the least, uncertain52.

The role of genetic factors in the pathogenesis of GO is not very well defined, and no striking differences have been observed between Graves’ patients with or without associated GO62. An association between GO and Major Histocompatibility Complex (MHC), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or intercellular adhesion melecule 1 gene polymorphisms has been looked for63-65, but results are not unequivocal. GO likely stems from a complex interplay between endogenous factors and exogenous (environmental) risk factors 21,36. The latter are probably more important and include cigarette smoking, thyroid dysfunction, and, in a subset of patients, radioiodine therapy for Graves’ hyperthyroidism21,36. The relationship between cigarette smoking and GO has been discussed above (see paragraph on Epidemiology). Both hyperthyroidism66,67 and hypothyroidism68 seem to influence negatively the course of the orbitopathy. TRAb are independent risk factors for GO and can help to predict severity and outcome of eye disease69. Radioiodine therapy for Graves’ hyperthyroidism is associated with GO progression in about 15% of cases, although this effect may be transient70,71. This effect is more frequently observed in patients who already have GO prior to radioiodine therapy, smoke, have high TRAb levels, or whose post-radioiodine hypothyroidism is not promptly corrected by L-thyroxine replacement therapy21,36. Radioiodine-associated progression of GO can be prevented by a short course of prednisone71,72. Neither thyroidectomy nor antithyroid drugs influence the course of the orbitopathy73. The above observations have important practical implications in terms of GO prevention (Table 3), because GO patients should be urged to refrain from smoking, their thyroid dysfunction (both hyper- and hypothyroidism) should be promptly corrected, and, in case of radioiodine therapy, a short course of oral prednisone should be administered21,36.

Signs & Symptoms. Clinical features of GO include soft tissue changes, proptosis, extraocular muscle dysfunction, corneal abnormalities, and optic nerve involvement (Figures 2-5). The NOSPECS classification (Table 4) is a useful memory aid of GO abnormalities74. Recommendations for GO assessment in clinical practice have recently been reviewed by EUGOGO75. Soft tissue changes include eyelid edema and periorbital swelling, eyelid erythema, conjunctival hyperemia and chemosis, inflammation of the caruncle or plica: their assessment and grading can be done with the aid of an atlas76, which can be downloaded from EUGOGO website ( www.eugogo.org). Proptosis, i.e., protrusion of the eye (exophthalmos), is usually measured by Hertel exophthalmometer; normal values are usually less than 20 mm, but vary with race, age, gender, degree of myopia, and should be established in each center or institution. Extraocular muscle dysfunction is responsible for diplopia (double vision), which can be subjectively defined as intermittent (i.e., present only when fatigued or when first waking), inconstant (i.e., present only at extremes of gaze), or constant (i.e., present also in reading positions and primary gaze); objective assessment of extraocular muscle functioning can be done by several methods, including measurent of ductions in degrees75,76. Palpebral aperture may be increased due to several factors, including upper and/or lower lid retraction, proptosis. Lid retraction and proptosis are responsible for corneal exposure, which may lead to corneal epithelium damage (punctate keratopathy), corneal ulceration and perforation. The incomplete eye closure at night (lagophthalmos) and the absence of Bell’s phenomenon (no upward eye rotation on attempted eye closure) are risk factors for corneal damage75,76. Intraocular pressure is often increased, particularly in upward gaze24, but this abnormality rarely progresses to true glaucoma. Dysthyroid optic neuropathy, due to optic nerve compression at the orbit apex by swollen extraocular muscles, or, less frequently, to optic nerve stretching in cases of marked proptosis or eye subluxation, is a sight-threatening expression of GO. It can be diagnosed by fundoscopy showing disc swelling, reduced visual acuity, abnormal color vision test, contrast sensitivity, perimetry, visual-evoked potentials, and pupillary responses75,76.

Symptoms of GO (Table 5) include, in addition to changes in ocular appearance related to periorbital swelling and proptosis, excess lacrimation, photophobia, grittiness, pain in or behind the eyes, either spontaneous or with eye movements, diplopia of different severity with or without strabismus, blurred vision, which may clear with blinking (due to excessive lacrimation) or covering one eye (reflecting extraocular muscle impairment), or may persist (probably reflecting optic neuropathy, particularly if associated with gray areas in the field of vision). In addition to reduced visual acuity, optic nerve involvement can be heralded by decreased color perception. Diplopia may be absent if extraocular muscle involvement is symmetrical in both eyes.

Clinical manifestations of GO have a profound negative impact on quality of life and daily activities of affected individuals77. By the use of general health-related quality of life (HRQL) questionnaires, such as the SF-36 or its shorter forms, it was shown that GO is associated with significant changes in several functions, including physical functioning, role functioning, social functioning, mental health, general health perception, and bodily pain78. Interestingly, these changes in HRQL parameters were similar to those found in patients with inflammatory bowel disorders, and even more marked than those observed in patients with diabetes mellitus, heart failure or emphysema78. Since HRQL questionnaires are broad and may not address items speficic for a given disease, a GO-speficic quality of life (GO-QoL) questionnaire was developed and validated in clinical studies77,79-81. This questionnaire (dowloadable from EUGOGO website at www.eugogo.org) is composed of 16 questions, 8 concerning the consequences of diplopia and decrased visual acuity on visual functioning, and 8 regarding the consequences of changes in physical appearance on social functioning77. The Go-QoL is a useful tool for self-assessment of treatment outcomes for GO82.

Activity & Severity. Definition of GO severity is somehow arbitrary and may reflect different views20,30. According to the most recent EUGOGO definition30, mild GO is characterized my minimal to moderate soft tissue swelling, proptosis <25 mm, no or intermittent diplopia, no corneal or optic nerve involvement; moderate (or moderately severe) GO by marked soft tissue swelling, and/or proptosis >25 mm, and/or inconstant diplopia, and/or punctate corneal staining, with no evidence of optic neuropathy; severe GO by constant diplopia and/or optic neuropathy (Table 6). A value of 25 mm proptosis is probably too high for mild GO, since it is 9 mm above the median value and 7 mm above the upper normal limit in normal controls, at least in Italy20, and also the NOSPECS classification indicated a value of 24 mm as indicative of moderate (or moderately severe) proptosis74. Independently of this argument, clinical optic neuropathy, constant diplopia, as proposed by EUGOGO30, but also marked proptosis are, taken individually, sufficient to define GO as severe, but GO may be defined as severe also if less marked degrees of each feature are present at the same time20 (Table 7). Assessment of severity is particularly relevant to decide on whether a given patient should be treated by aggressive treatments (either medical or surgical) or simply by local or general supportive measures (see below).The other important feature of GO is its activity. Although, as stated above, GO natural history is not completely understood, it is commonly accepted that GO undergoes an initial phase of activity, characterized by progressive exacerbation of ocular manifestations until a plateau phase is reached; GO then tends to remit spontaneously, but remission is invariably partial. In the inactive phase (burnt-out GO), only residual ocular manifestations are present (e.g., proptosis, strabismus due to muscle fibrotic changes), but inflammation has subsided and it is unlikely that it may flare up. It is unknown how long this process takes to be completed, but it is widely believed that it takes between 6 months and two years. Recognition of the different phases of the disease is important, because active disease, basically characterized by the presence of inflammation, can respond to immunosuppressive treatments, which are largely ineffective when GO is burnt-out. Different indicators have been proposed to assess GO activity, including short duration of treatment (<18 months), positivity of octreoscan, decreased extraocular muscle reflectivity at orbital ultrasound, prolonged T2 relaxation time at MRI, increased urinary glycosaminoglycan levels, but they lack sufficient specificity and accuracy83. A useful tool to assess GO activity is represented by the Clinical Activity Score (CAS), which can be calculated very easily and is recommended by EUGOGO in the assessment of GO in routine clinical practice, in specialist multidisciplinary clinics, and for clinical trials75. In its original formulation84 it included 10 items, which were subsequently reduced to 7 when revised by an ad hoc Committee of the four sister thyroid societies85 (Table 8). If one point is given to each item when present, CAS, which basically reflect eye inflammation, may range from 0 (absent activity) to 7 (maximal activity); GO is generally defined active if CAS is >3.

Diagnosis of GO is usually easy on clinical grounds and by careful ophthalmological examination. Although not necessary in most Graves’ patients, CT scan or MRI of the orbit confirm diagnosis by showing enlarged extraocular muscles (without involvement of the tendon) and/or increased orbital fibroadipose tissue86. Modest extraocular muscle enlargement and increased fibroadipose tissue volume are often found in Graves’ patients without clinical manifestations of ocular involvement. Orbital imaging is very useful to detect signs of optic nerve compression, which support the diagnosis of optic neuropathy. Imaging is required in asymmetrical or, particularly, unilateral forms of GO, to rule out that proptosis, periorbital swelling, inflammation, or diplopia be due to disorders other than GO. The latter include primary or metastatic orbital tumors, vascular abnormalities (e.g., carotid-cavernous sinus fistula, carotid aneurysm, cavernous sinus thrombosis, subarachnoid hemorrhage, subdural hematoma), granulomatous disorders. Occasionally, angiograms or venograms may be required for diagnosis. Octreoscan may be useful to identify patients with active GO86, but its role in clinical practice is limited, also in view of its high cost.

Management of GO is based on a multidisciplinary approach which involves endocrinologists, ophthalmologists, orbit surgeons, radiologists and radiotherapists. In a recent survey of GO management based on a questionnaire distributed among members of the European Thyroid Association, European Society of Ophthalmic Plastic and Reconstructive Surgery, and European Association of Nuclear Medicine, 96% of responders stated that a multidisciplinary setting for GO management is valuable, although 21% of patients were in the end not treated in a multidisciplinary setting87. The therapeutic approach to a GO patient should be based on both severity and activity of the disease, the former being the feature to assess first (Figure 2)

Mild GO. Most patients have mild (nonsevere) GO, which does not require particularly aggressive treatments and often is self-limiting20,88. If GO activity is modest, simple local measured can be suggested to obtain symptomatic relief until GO is burnt-out (Table 9). Photophobia can be mitigated by sunglasses; grittiness due to corneal exposure can be controlled by artificial tears and topical lubricants, particularly indicated in the presence of lagophthalmos; the latter may require taping the eyelids shut at night; eyelid retraction can be controlled (with a variable degree of success) by -blocking drops (useful for the increased intraocular pressure) or by botulinum toxin injections89; elevation of the bed may be helpful to reduce periorbital swelling due to congestion; mild diplopia often is controlled by prisms (if they are tolerated) 20. Reassurance is an important issue, and the patient must be informed that his/her eye disease is unlikely to progress to more severe forms, usually stabilizes, and often ameliorates spontaneously. Control of thyroid dysfunction is fundamental, because progression often is associated with hyper- or hypothyroidism21,36; refrain from smoking is also essential, because it is associated with a decreased chance of developing proptosis and diplopia90, and decreases the likelihood to develop severe GO34. Patients who do not succeed to quit smoking by themselves, should be helped by professional stop-smoking clinics, organizations, groups, where they can receive counseling, behavioral therapies, pharmacological treatments.

Moderate-to-severe GO. Management of moderate-to-severe GO depends not only on severity, but also on activity of the orbitopathy (Figure 6; Table 10). Medical treatment is likely to be beneficial in patients with active GO, with florid signs and symptoms of inflammation, recent-onset extraocular muscle dysfunction, recent progression of the ocular abnormalities as a whole. On the contrary, in long-standing GO, with chronic proptosis and residual, stable diplopia and/or strabismus, but no no evidence of inflammation, medical treatment has little chances to produce favorable effects, and the surgical, rehabilitative approach is preferable20. Dysthyroid optic neuropathy, the most severe expression of the orbitopathy, is a clinical, sight-threatening emergency, which requires immediate treatment. If there is no response to medical treatment (high-dose intravenous glucocorticoids), orbital decompression is warranted20,30.

Glucocorticoids are the mainstay in the medical treatment of GO20,91-93. They have been used for decades because of their anti-inflammatory effects, but also because they exert immunosuppressive actions useful to control the course of the orbitopathy20,91-94. The latter include interference with the function of T and B lymphocytes, decreased recruitment of neutrophils and macrophages, down-regulation of adhesion molecules, inhibition of cytokine secretion, inhibition of glycosaminoglycan secretion20,91-93. Locally (subconjunctivally or retrobulbarly) given glucocorticoids are less effective than systemically given glucocorticoids20,91-93, although favorable responses in terms of improvement of diplopia and reduction in extraocular muscle dysfunction have been reported with in a recent randomized clinical trial of periocular injections of triamcinolone acetate95. Glucocorticoids have for a long time been given orally, but high doses are required, treatment lasts for several months, recurrences are frequent upon drug tapering or withdrawal, side effects (particularly Cushing’s syndrome) are frequent20,91-93. In the last 20 years the intravenous route has become the most commonly used96. Intravenous glucocorticoids are more effective, with a rate of favorable responses of about 80-90% versus 60-65% with oral glucocorticoids96, and better tolerated than oral glucocorticoids97. Glucocorticoids are most effective on soft tissue, inflammatory changes, recent-onset extraocular muscle dysfunction, and dysthyroid optic neuropathy, whereas proptosis and long-lasting eye muscle impairment are less responsive20. However, it should be noted that severe liver damage, heralded by a marked rise in serum concentrations of hepatic enzymes, was noted in 7 of about 800 treated patients (approximately 0.8%), three of whom died98. The causes of this hepatotoxicity are unclear, but might include direct liver toxicity of glucocorticoids, precipitation of virus-induced hepatitis, sudden reactivation of the immune system upon drug withdrawal leading to autoimmune hepatitis96. The cumulative dose of glucocorticoids might also be important, since no cases of liver damage were reported in a recent randomized clinical trial in which lower, but equally highly effective, doses of glucocorticoids were employed99. Accordingly, the current recommendation is that the cumulative dose of glucocorticoids should not be higher that 4.5-6 grams96. The early response (or lack of response) to first-week with intravenous glucocorticoids may be of help to predict long-term treatment outcome100.

Orbital radiotherapy is the other non-surgical mainstay in the management of GO20,93. The rationale for its use and the indications are quite similar to those of glucocorticoids; in addition, irradiation exploits the radiosensitivity of T lymphocytes which infiltrate the orbit101. Irradiation is currently carried out by linear accelerators, using a cumulative dose of 20 Gray fractionated in 10 daily 2-Gray doses over a 2-week period103, although other regimens (and lower doses) might be equally effective104. Favorable responses are observed in about 60% of treated patients102. Recent years have witnessed a lively debate on the true effectiveness of orbital radiotherapy104, and, compared to a previous survey of 1996, a recent questionnaire-based survey promoted by EUGOGO in Europe, showed that, among treatments for moderate-to-severe GO, there was greater use of steroids and lesser use of irradiation87. However,the results of several randomized studies confirmed, with one exception, its efficacy103,105-108. In addition, orbital radiotherapy is a safe procedure devoid of relevant short-term and long-term side effects or complications109,110. Preexistent retinopathy associated with diabetes mellitus or hypertension represents a contraindication to its use109,110. As for glucocorticoids, orbital radiotherapy is mostly effective on soft tissue inflammatory changes and recent-onset extraocular muscle dysfunction102. Orbital radiotherapy can be used either alone or in combination with glucocorticoids20. The association exploits the prompter effect of glucocorticoids and the more sustained action of irradiation; in two randomized prospective studies, combined therapy proved to be more effective than either treatment alone111,112.

Among other medical treatments recently proposed, particular attention was given to somatostatin analogs, octreotide and lanreotide. Their use in GO was supported by the observation that somatostatin receptors are expressed on the surface of both orbital fibroblasts113 or orbital lymphocytes114 from GO patients, and that positivity of orbital octreoscan could predict subsequent GO response to immunosuppressive therapy86. After an initial optimism based on the positive results of small and often uncontrolled studies115, four recent randomized and controlled clinical trials have shown that both octreotide and lanreotide have only marginal and clinically poorly relevant effects on GO116-119; accordingly, their use is presently not justified120,121. Whether novel somatostatin analogs currently under investigation, such as SOM230, may be more effective remains to be demonstrated. Cyclosporine, used in GO for its immunosuppressive properties, has been reported in only two randomized and controlled studies122,123 . Cyclosporine has a lower efficacy than glucocorticoids as a single-agent therapy, although a combination of both drugs might be more effective than either treatment alone122,123. Thus, the use of cyclosporine might be maintained in patients who are relatively resistant to glucocorticoids in whom persistent GO activity warrants continuing medical intervention. Side effects of cyclosporine are not negligible and should be carefully considered. Intravenous immunoglobulins (IVIGs) have been reported to have favorable effects on GO in some studies, but not in others20; only two studies were randomized. Thus, IVIGs use is currently not recommended, also in view of their high cost and the possible risk deriving from the use of plasma-derived products20.

Orbital decompression is, with glucocorticoids and orbital radiotherapy, a milestone in the management of GO. It is aimed at increasing the space available for the increased orbital content by removing part of the bony walls of the orbit and/or the orbital fibroadipose tissue20. It is indicated in patients who have impending sight loss due to optic neuropathy and do not respond promptly to intravenous glucocorticoids124. Other important indications for decompressive surgery are represented by corneal damage due to eyeball exposure in patients with marked proptosis, or by recurrent subluxation of the globe, which may stretch the optic nerve and cause sight loss. In recent years, thanks to the improved surgical techniques and the diminished surgical risk, the indications for orbital decompression have expanded, including also correction of residual cosmetic problems125,126. Several techniques of orbital decompression are available, aimed at removing part of one, two, three or four orbital walls (floor, roof, lateral wall, medial wall) as well as part of the retroorbital fibroadipose tissue. The different surgical options should be discussed with the patient, as well possible complications of the procedure, particularly the de novo occurrence or worsening of diplopia, particularly frequent after extensive removal of the orbital floor127. Removal of fibroadipose tissue can be done together with or without bone removal, but removal of fat alone is associated with a lower reduction of proptosis20.

Rehabilitative surgery includes surgery for strabismus or eyelid retraction. Extraocular muscle surgery is aimed at correcting residual diplopia after medical and/or surgical treatment of GO. Timing of surgery is crucial, because it should not be performed when GO is active, but when it has been inactive for 6 months20. The goal of eye muscle surgery is to align the eyes, avoiding abnormal head posture and restoring single binocular vision in primary and reading positions; multiple operations may be required to achieve this goal. Eyelid surgery may rarely be an emergency procedures in patients with exposure keratitis and corneal ulcerations, but it usually is carried our to correct eyelid malposition after medical treatment or orbital decompression. Eyelid surgery usually constitutes the last step of rehabilitation.

Thyroid ablation. The question of whether in a patient with the orbitopathy, Graves’ hyperthyroidism should be treated by non-ablative (i.e., thionamides) or ablative (i.e., radioiodine therapy, thyroidectomy, both) therapy is unanswered128. Supporters of thyroid ablation justify this approach by mentioning the pathogenic link between thyroid and orbit: removal of thyroid-orbit shared antigen(s) and autoreactive T lymphocytes might be beneficial to the eye129; supporters of non-ablative thyroid treatment suggest that control of thyrotoxicosis by antithyroid drugs may be associated with a reduction of autoimmune phenomena which might be reflected by an amelioration of ocular conditions; furthermore, once triggered, GO might proceed independently of thyroid treatment130. Two retrospective studies showed that total thyroid ablation (thyroidectomy followed by radioiodine therapy, as in thyroid cancer) was associated with an improvement of clinical GO131,132. A recent randomized, controlled clinical trial demonstrated that, as compared to total thyroidectomy alone, total thyroid ablation is followed by a better outcome of GO in patients given intravenous glucocorticoids133. Probably this is not enough to support total thyroid ablation in all patients with clinically relevant GO; however, current evidence justifies it in GO patients in whom thyroidectomy is the treatment of choice for their hyperthyroidism.

Future perspectives. GO is only partially preventable, but environmental factors play an important role in its pathogenesis21,36. Accordingly, preventive measures, including refrain from smoking, control of thyroid dysfunction, and a cautious use of radioiodine therapy should be adequately applied21,36 (Table 3). However, this is not enough. Our better understanding of GO pathophysiology has led to unraveling immunologic mechanisms responsible for its occurrence and progression39-41.

As a consequence, it is possible that in the future, immunotherapy can be developed for Graves’ disease and, in particular, for the orbitopathy134. In this regard, attention has recently been focused on rituximab, a chimeric murine-human monoclonal antibody targeting the CD-20 antigen expressed on the B lymphocyte surface; rituximab kills CD-20+ cells by several mechanisms, and for this reason it has been used successfully in the treatment of non-Hodgkin lymphomas, but also of several autoimmune disorders134. A possible role of rituximab has been postulated for Graves’ disease135,136, but this remains to be established. This drug has been used in a limited number of GO patients137-139; preliminary results seem encouraging, but confirmation by large, randomized clinical trials is warranted134. The same considerations can be made for etanercept, which is an anti-TNFalpha monoclonal antibody, and, in a small, open and uncontrolled study was reported to have beneficial effects on GO140. Whether other immunotherapies, e.g., with CTLA-4 Ig, PPAR gamma-antagonists, IL-1 receptor antagonists, might have a role in the management of GO presently remains purely speculative134. The contribution of oxygen reactive species to the changes occurring in the orbit of GO patients141 supported the hypothesis that antioxidants might play a role in GO management. Insofar only two small, non-randomized studies are available on the use of pentoxifylline, and nicotinamide or allopurinol, showing some effects of these drugs142,143; EUGOGO is currently carrying out a large multicenter, randomized, placebo-controlled study on the effects of pentoxifylline or selenium in mild GO, the results of which should be available in one year.