Chapter 36
Thyroid Orbitopathy
Susan M. Tucker, Nancy A. Tucker and John V. Linberg
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Thyroid orbitopathy represents an organ-specific autoimmune process that is usually associated with thyroid disease. Although Parry, Graves, and von Basedow are all credited with reporting the association between toxic goiter and ophthalmopathy in 1825, 1835, and 1840, respectively,1–3 a much earlier description of goiter with exophthalmos exists from 12th century Persian writings.4 A variety of terms have been used to describe the constellation of eye findings that can occur in patients with thyroid disease: thyroid orbitopathy, dysthyroid orbitopathy, thyroid ophthalmopathy, Graves' ophthalmopathy, infiltrative ophthalmopathy, thyroid eye disease, endocrine ophthalmopathy, endocrine exo-phthalmos, and malignant exophthalmos. We prefer the term thyroid orbitopathy (TO) because the disease is known to occur in conditions other than Graves' disease, and the orbit is the primary site of involvement.

Graves' disease is the most common thyroid abnormality associated with TO, but other disorders of the thyroid can have similar ocular manifestations. These include Hashimoto's thyroiditis, thyroid carcinoma, primary hyperthyroidism, and primary hypothyroidism.5–7 Approximately 25% to 50% of patients with Graves' disease have or will develop clinically apparent TO,8,9 although fewer than 5% of patients with Graves' disease have severe ophthalmopathy.10 However, subclinical orbital alterations can be detected on ultrasonography or computed tomography (CT) in the majority of patients.11,12 Of those patients with TO, approximately 10% are clinically euthyroid,13 but the majority of these patients have laboratory evidence of thyroid autoimmune disease, including TSH receptor antibodies (TRAb), antithyroglobulin, and/or antimicrosomal (also called antithyroid peroxidase) antibodies, negative TRH test, or negative T3 suppression test.6,13,14 Of patients with euthyroid orbitopathy, approximately 25% will develop thyroid dysfunction at 1 year and 50% at 5 years.7 In general, patients with euthyroid Graves' disease tend to have less severe orbitopathy.15

In 70% to 85% of patients, eye signs develop within 18 months of the detection of the thyroid disease.13,16 The onset of TO is, however, unpredictable and can precede or occur many years after the diagnosis of Graves' disease.17 Thyroid orbitopathy is usually a slow, progressive disease that may have a fluctuating course over months to several years before undergoing a gradual and often incomplete regression.18

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Overall, TO has an incidence rate of 16 females and 2.9 males per 100,000 population per year.7 Bimodal peak incidence rates for women occur from ages 40 to 44 years and 60 to 64 years; for men from ages 45 to 49 years and 65 to 69 years.7 There appears to be an increased prevalence of thyroid disease in smokers, for whom the relative risk of developing TO is twice as high as it is for nonsmokers.19 The reason for this difference is not known, but one possibility is that the decreased immunosuppression in smokers may allow greater expression of autoimmune processes. Other theories, which have been postulated to explain this association include orbital hypoxia, the effects of thiocyanate, increased circulating thyroglobulin levels leading to higher levels of thyroid antigen release, nicotine leading to adrenergic stimulation of the thyroid gland, direct irritative effects, and localized changes in the orbital circulation.20,21

There is some genetic predisposition; the concordance level is 50% in identical twins and 30% in nonidentical twins. Also, there is an increased prevalence of HLA-B8 and HLA-DR3 in Caucasians,22 HLA-DRW6 in African Americans,23 and HLA-B35 in Japanese patients with Graves' disease.24 These HLA associations, however, are of no predictive value for the development of orbitopathy in patients with Graves' disease. In keeping with its probable underlying autoimmune nature, patients with TO may have other organ-specific or generalized autoimmune disorders, such as diabetes mellitus, Addison's disease, vitiligo, pernicious anemia, or myasthenia gravis.25

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Although a number of important details in the complex pathogenesis of TO have been clarified in recent years, the precise nature of this autoimmune process and the source of the offending antibodies are still poorly understood and largely speculative.

Current understanding of this autoimmune process in the pathogenesis of thyroid orbitopathy is the result of developments that have occurred over the past 50 years. Historically, before an underlying autoimmune etiology was suspected, overactivity of the thyroid gland was thought to be due to increased thyroid-stimulating hormone (TSH, thyrotropin). Once assays were available for TSH, however, TSH was found to be low in most patients with Graves' disease. In 1956, Adams and Purves26 isolated a factor in the serum of patients with Graves' hyperthyroidism that caused stimulation of the animal thyroid gland. This factor was very similar to TSH but had a longer half-life, and was therefore called long-acting thyroid stimulator (LATS). In 1964, Kriss et al.27 showed that LATS had the structure of an IgG immunoglobulin, and its action could be neutralized by thyroid tissue, indicating that it was an antibody. Further experiments have shown that hyperthyroidism in Graves' disease is due to the binding of stimulatory autoantibodies to the TSH receptor (TSAb) on thyroid follicular cells.8

In contrast, the pathophysiology of TO is less well understood. Circulating antibodies against proteins contained in eye muscle (63 kDa and 64 kDa) and retro-orbital fibroblasts (23 kD) are frequently detected in sera of patients with TO, but they lack tissue and disease specificity.28 Most investigators agree that these antibodies are produced secondary to the disease process and are probably not involved as primary autoimmune targets. Several investigators have examined the TSH receptor as a possible orbital autoantigen, however, there currently exists little evidence to directly link this receptor in the pathogenesis of TO. Although in several studies the level of TSH receptor antibodies (TSAb) has been correlated with the degree of ophthalmopathy (eyelid swelling, proptosis, and extraocular muscle involvement),29,30 other studies have found no such association.31,32 Insulin-like growth factor 1 (IGF-1) receptor, which is highly expressed in Graves' fibroblasts, may be another possible autoantigen.33 However, the identity of the relevant self-antigen remains to be determined.

Although the relative contribution of cellular and humoral immunity to the pathogenesis of TO remains uncertain, it is likely that both are important for full clinical expression and propagation of the autoimmune process within the orbit.34 Orbital fibroblasts appear to have a central role in the pathogenesis of TO through mechanisms that are not completely understood but which are likely mediated by cytokines.8,34,35 Orbital fibroblasts have been shown to have distinct phenotypic properties, with the ability to activate a diverse array of immunocompetent cells with the release of such chemoattractants as the cytokine IL-16 and the chemokine RANTES.36 These chemoattractants may orchestrate T lymphocyte infiltration of many tissues, including the thyroid.36 Activated endomysial fibroblasts also then produce glycosaminoglycans (mostly hyaluronan) and collagen, causing edema and fibrosis.8 Additionally, a subpopulation of orbital fibroblasts appears capable of undergoing adipocyte differentiation in vitro, which contributes to the orbital volume augmentation.37

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The predominant orbital pathology is inflammation of the orbital soft tissues and the interstitial connective tissue of the extraocular muscles. This immune-mediated inflammation consists mostly of lymphocytes, plasma cells, and a scattering of mast cells.38,39 These inflammatory changes differ from the more exuberant lymphocytic infiltration of the orbital fat, extraocular muscles, and their tendinous insertions seen in idiopathic orbital inflammatory disease.40 Also, eosinophils and germinal centers with follicles, such as may be found in other noninfectious orbital inflammations, are typically absent in thyroid orbitopathy.38 In the latter stages of TO, interstitial fibrosis results in muscle atrophy and degeneration.41

The inflammatory process involves the endomysial connective tissue, and other orbital structures are affected to a lesser extent. The lacrimal gland typically shows a mild mononuclear cell infiltration and interstitial edema, with mild fibrosis and atrophy of acinar structures.41 Similarly, in the contiguous orbital fat, there is only a small amount of inflammation.41 The tendinous insertions onto the globe and the optic nerve meninges generally show no inflammation at all.

The increased orbital volume is due to the accumulation of glycosaminoglycan, in which hyaluronan predominates, and collagen in the connective tissues of the extraocular muscles (not the myocytes themselves) and the orbital fat compartments, and de novo adipogenesis in these tissues.8 The hydrophilic glycosaminoglycan macromolecules result in an osmotic accumulation of water within the perimysial and retro-ocular connective tissues. Impaired venous drainage from the orbit may also contribute to the increased orbital volume. In particular, enlargement of the superior rectus muscle may reduce venous outflow by compressing the superior ophthalmic vein.

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Attempts have been made to classify the various manifestations of thyroid orbitopathy. Werner42 introduced the NOSPECS classification system in 1963. The first version did not allow for quantitation of the severity of ophthalmopathy and was therefore updated by the American Thyroid Association in 1977 by devising an ophthalmopathy index scoring system to allow improved evaluation of the severity of the ophthalmopathy within each class (Table 1).43 In 1989 Bartalena et al.44 proposed a newer classification system in which the index scoring system was modified to place more significance on the vision-threatening manifestations of thyroid orbitopathy. Bartalena et al. proposed that the scores in each class could be mathematically added to arrive at a final ophthalmopathy score for each patient.


TABLE 1. Classification and Grading of Thyroid Orbitopathy

Class Grade Mnemonic Suggestions for Grading
0 NNo physical signs or symptoms
1 OSigns only
2 SSoft tissue involvement
 0  Absent
 A  Minimal
 B  Moderate
 C  Marked
3 PProptosis of 3 mm or more
 0  Absent
 A  3–4 mm
 B  5–7 mm
 C  8 mm or more
4 EExtraocular muscle involvement
 0  Absent
 A  Limitation of motion at extremes of gaze
 B  Evident restriction of motion
 C  Fixation of globe
5 CCorneal involvement
 0  Absent
 A  Punctate lesions
 B  Ulceration
 C  Necrosis or perforation
6 SSight loss (due to optic nerve)
 0  Absent
 A  20/20–20/60
 B  20/70–20/200
 C  Worse than 20/200


We believe that the NOSPECS classification is a helpful mnemonic for medical students and beginning ophthalmology residents as a reminder of the various manifestations of thyroid orbitopathy. Otherwise, classification systems should be discouraged because patients usually do not fit into a single class; there is often not an orderly progression from one class to the next; the use of Snellen visual acuity alone to assess optic nerve involvement is inadequate; the classification is not helpful in making treatment decisions, and the classification has almost no prognostic value. Even as a means of standardizing the results of clinical trials, comparing the final ophthalmopathy score of one patient with that of another is difficult to interpret. We believe it is better to carefully document and follow each manifestation of a given patient's thyroid orbitopathy and base treatment decisions, accordingly.

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The clinical manifestations of thyroid orbitopathy are due to inflammation, edema, and fibrotic changes within the soft tissues of the orbit, resulting in enlargement of retrobulbar tissues and restriction of extraocular muscle motion45 (Figs. 1 and 2). Although asymmetric eye involvement is quite common, unilateral eye disease occurs in only 5% to 14% of patients with TO.11,46

Fig. 1 Typical clinical presentation of moderate thyroid orbitopathy, showing axial proptosis, eyelid retraction, prolapse of orbital fat, conjunctival chemosis, and prominent vessels over the horizontal rectus muscle insertions.

Fig. 2 Patient with severe thyroid orbitopathy, showing marked eyelid retraction, strabismus, conjunctival chemosis, injected vessels, and exophthalmos.


Thyroid orbitopathy is the most common cause of both unilateral and bilateral proptosis in adults. Exophthalmos, defined as measurement of 2 mm or more above normal limit (upper normal limit of globe protrusion in Caucasians is 20 mm; African Americans, 22 mm; and individuals of Japanese descent, 18 mm),43,47,48 occurs in 20% to 30% of patients with Graves' disease and in 40% to 70% of patients with TO.46 The proptosis is bilateral in 80% to 90% of affected individuals,46 but it may be asymmetric (Fig. 3). Thyroid orbitopathy results in an axial proptosis as the muscle and connective tissue volume behind the eye increases; displacement of the globe in any other direction is suggestive of another diagnosis. When the pressure within the retrobulbar tissues exceeds the forces counteracting proptosis, the rare complication of subluxation of the globe anterior to the eyelid may occur.

Fig. 3 Patient with very asymmetric thyroid orbitopathy. Left eye shows proptosis and marked inferior rectus restriction, while right eye demonstrates normal motility on upgaze.

The increased orbital volume is usually due to both extraocular muscle and orbital fat expansion; however, patients younger than 40 years of age are more likely to exhibit orbital fat enlargement in the absence of muscle enlargement, whereas patients over 70 years are more prone to severe, fusiform muscle enlargement without significant changes in orbital adipose tissue volume.49 Forbes et al.11 reported enlargement of the fat compartment in 46% of patients with TO, whereas 8% had increased fat compartments with normal muscle volumes (Fig. 4).

Fig. 4 Axial CT scan of patient with thyroid orbitopathy, extreme proptosis, and no clinical evidence of optic neuropathy. Note the increase in orbital fat volume without significant extraocular muscle enlargement. In this case axial proptosis has allowed spontaneous decompression of increased orbital volume.


In the inflammatory stage, careful examination of these patients may reveal eyelid edema or a fine tremor of gently closed eyelids. Von Graefe's sign is the lag of the downward movement of the upper eyelid on slow downgaze. Early eyelid lag is best detected by having the patient hold a fixation target at arm's length high above the head; the patient maintains fixation as he or she slowly lowers the target.

Thyroid orbitopathy is the most common cause of upper eyelid retraction, which may be accentuated by the coexistence of exophthalmos. Eyelid retraction is the most common sign of TO, present in 75% of patients at diagnosis and occurring at some point in the clinical course in more than 90% of patients.7 Upper eyelid retraction may be due to adrenergic overaction of the Müller's muscle, fibrosis and functional shortening of the levator muscle, and/or overaction of levator-superior rectus muscle complex, secondary to fibrosis of the inferior rectus muscle.50 With minimal eyelid retraction, a misdiagnosis of ptosis of the opposite eyelid can be made. The upper eyelid retraction in Graves' disease has a characteristic temporal flare, with a greater amount of sclera visible laterally as compared with medially. This may occur, in part, because the eye in primary position looks away from the orbital axis and projects more lateral sclera.51 The lower eyelid retraction may result from similar changes in the capsulopalpebral fascia (Fig. 2).


Thyroid disease should be considered in all cases of adult-onset strabismus. Using sensitive measurement techniques, such as ultrasound, CT, and MRI, extraocular muscle enlargement has been noted in 60% to 98% of patients with Graves' disease,46 and restrictive extraocular myopathy occurs in approximately 42% of patients with TO.52 The most common motility abnormality is limitation of elevation owing to fibrosis of the inferior rectus muscle, which results in diplopia on upgaze (Fig. 3). The second most common muscle to be involved clinically is the medial rectus, followed by the superior rectus/levator complex, and finally the lateral rectus.53,54 Some studies have found the medial rectus muscle to be more frequently involved than the inferior rectus,12,55 and one study found the superior rectus muscle to be most frequently involved.56 Isolated muscle enlargement usually involving the inferior rectus muscle may occur in a small percentage of patients and often remains monomuscular.57 This differs from monomuscular myositis, which most commonly involves the medial rectus.58 The mechanisms underlying disproportionate involvement of the extraocular muscles are poorly understood. It may, in part, be due to the well-developed connective tissue system around the inferior oblique and inferior rectus muscles, which also have the greatest number of septal connections with the adjacent periorbit.59

The increased intraocular pressure measured during upgaze in patients with thyroid orbitopathy is a normal phenomenon exaggerated by thyroid orbitopathy and other infiltrative and congestive orbital processes.60 When restriction of the inferior rectus muscle occurs, the intraocular pressure may increase by 6 mm Hg or more in upgaze as compared with primary gaze. It is often not an indicator of early disease because it occurs infrequently in patients with minimal eye findings.60 Significant reduction in intraocular pressure has been reported following decompression surgery and botulinum A toxin injections into the inferior rectus muscle.61,62


Although still speculative, a primary lacrimal gland dysfunction with an altered rate of tear production or a change in the protein composition of tears may be present in patients with thyroid orbitopathy.63


Corneal involvement due to exposure keratitis may result from proptosis, upper eyelid retraction, lower eyelid retraction, lagophthalmos, or a combination of these. Exposure keratitis may range from minimal staining of the lower cornea to severe keratitis and even corneal ulceration. Superior limbic keratitis (SLK) may exist, especially when upper eyelid retraction is present. SLK may be a prognostic marker for severe TO: in a study of 57 patients with SLK by Kadrmas et al.,64 16/33 (48.5%) had severe enough orbitopathy to require orbital decompression.

Conjunctival chemosis and injection of the conjunctival and episcleral vessels overlying the insertions of the extraocular muscles can be seen in the inflammatory stage of TO.


The prevalence of optic neuropathy with visual loss in patients with thyroid orbitopathy is less than 5%.65 Optic neuropathy is, however, the most common cause of blindness secondary to thyroid orbitopathy. Left untreated, as many as 21% of patients develop an irreversible deficit in visual acuity.65–67 Its onset is often insidious and may be masked by other symptoms. These patients are usually older (ages 50 to 70), have a later onset of thyroid disease, and more often have diabetes.65,68 The ratio of women to men is widely variable among reported series; in a large retrospective study of 215 patients with optic neuropathy, the ratio of women to men was 2.4:1.69 Optic neuropathy is usually bilateral, but up to one-third of cases may be unilateral.65,68

Most cases of optic neuropathy are due to compression of the optic nerve by the enlarged extraocular muscles at the orbital apex (Fig. 5). Patients with compressive optic neuropathy have a more symmetric involvement of the extraocular muscles as compared with most patients with thyroid disease.65 Although patients with optic neuropathy usually have proptosis, optic neuropathy can occur without significant proptosis in patients whose orbital septum efficiently limits anterior globe displacement, despite increased retrobulbar pressure. Very rarely, optic neuropathy can occur without significant muscle enlargement. In these cases, it is postulated that a short optic nerve is being stretched or the optic nerve is being compressed by surrounding orbital fat.49 These cases are so rare that optic neuropathy in the absence of muscle enlargement or proptosis should be investigated thoroughly to rule out other etiologies.

Fig. 5 A. Axial CT scan of a patient with compressive optic neuropathy. Note that position of globe shows only mild proptosis, and orbital fat is not increased in volume. The posterior portion of the extraocular muscles is markedly enlarged, compressing the optic nerve. B. Coronal CT scan of the orbital apex in the same patient clearly shows displacement of orbital fat by enlarged muscles. The apex is “crowded,” consistent with clinical findings of optic neuropathy.

Although a history of decreased vision should be carefully sought, it is important to realize that optic neuropathy can occur in a significant number (18%) of patients with visual acuities in the range of 20/20 to 20/25 6/6 to 6/7.5 [Metric equivalent given in parentheses after Snellen notation]).68 An afferent pupillary defect is present in 35%.68 An abnormal disc (either swollen or pale) is seen in only 53%. Visual field defects are present in 66%.68 In a large retrospective study of 291 eyes with visual field defects from optic neuropathy, 49% were inferior, 37% were central or cecocentral, 12% showed generalized depression, 1% had superior depression, and 1% had bitemporal depression.69 The Farnsworth-Munsell 100-hue color vision test is a sensitive indicator of optic nerve dysfunction, but pseudoisochromatic screening procedures (e.g., Ishihara plates) rarely identify an acquired color defect, unless optic neuropathy is severe.68 The pattern reversal VEP is very sensitive at detecting early optic neuropathy and may be a useful means of following patients after treatment.

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When the ophthalmologic signs and symptoms raise a suspicion of underlying thyroid disease, the systemic thyroid status should be assessed. This includes a history pertaining to weight loss, increased appetite, heat intolerance, difficulty sleeping, weakness of the limb girdle muscles, and mood changes. The thyroid gland should be palpated to detect an enlargement. Less commonly, infiltrative dermopathy characterized by pretibial myxedema and thyroid acropathy characterized by clubbing and subcutaneous fibrosis of the fingers may be seen. Laboratory tests should be ordered to confirm a suspected thyroid abnormality. All patients with newly diagnosed thyroid disease should be referred to an endocrinologist or internist for management and follow-up of the systemic thyroid status.

Some patients with thyroid orbitopathy may initially present with nonspecific complaints, such as eyelid fullness, ocular irritation, or lacrimation and the diagnosis of thyroid orbitopathy may not be suspected. These clinical presentations are most often not thyroid related and may be caused by dry eye, lacrimal outflow obstruction, or a variety of primary abnormalities of the eyelid, conjunctiva, or cornea. In these situations a high index of suspicion is required to search for clinical evidence of thyroid disease, followed by appropriate laboratory investigations. The ophthalmologist's examination must be directed toward the detection of subtle signs of thyroid orbitopathy.

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In patients with suspected Graves' disease, laboratory tests can be used to detect hyperthyroidism. Thyroid stimulating hormone immunoradiometric assay (TSH-IRMA, sensitive TSH, sTSH) reliably separates normal from hyperthyroid states. It is the most useful first-line test of thyroid function in patients with thyroid disease. It is so consistent, sensitive, and reliable that it renders the TRH stimulation test almost obsolete in the diagnosis of hyperthyroidism.70 One of the few remaining indications for the TRH stimulation test is in the detection of hyperthyroidism in hospitalized patients with severe thyroidal illness.71 A general strategy for laboratory testing is to first obtain results of the TSH-IRMA. If this is normal, then the patient is said to be euthyroid. In patients with suspected thyroid orbitopathy, further testing for antibodies is then indicated. If the TSH-IRMA value is elevated, or undetectable, then overt hypothyroidism or hyperthyroidism can be distinguished from subclinical disease by measuring the free T4. Some clinicians, therefore, routinely initially order the free T4 test along with the TSH-IRMA to avoid the delay and inconvenience of the stepwise approach to diagnosis.

Three antibodies can currently be measured using standard techniques: thyrotropin receptor antibodies, antimicrosomal antibodies, and antithyroglobulin antibodies. In Graves' disease, thyrotropin receptor antibodies are present in 85% to 95% of patients with untreated Graves' hyperthyroidism and in approximately 50% of patients with euthyroid Graves' disease. Antimicrosomal antibodies are found in 60% of patients, and antithyroglobulin antibodies are present in approximately 30% of patients.70,72 When these tests are positive they help support a diagnosis of autoimmune thyroid disease. Thyrotropin receptor antibody levels are also helpful in pregnant women because of the predictive value of an increased thyrotropin receptor antibodies for neonatal Graves' disease in the infant, irrespective of the mother's thyroid status.72

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Ultrasonography can detect early thyroid disease in patients with equivocal laboratory tests; however, its usefulness depends on the skills and experience of the ultrasonographer. Most patients with Graves' disease, even those without overt eye findings, have ultrasonographic evidence of extraocular muscle involvement.73 This test may also be helpful in distinguishing between active and inactive disease; there is a lower internal reflectivity of the extraocular muscles in active as compared with inactive disease.74 Ultrasonography is, however, less suited than CT to assessing muscle thickness at the orbital apex.
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CT is not necessary in most patients who present with a clinical picture and supporting laboratory evidence of Graves' disease. It is, however, indicated when optic neuropathy is suspected, before orbital decompression, to examine the anatomic relationship of the orbit to both the sinus cavities and the cribriform plate, in patients with atypical proptosis or motility disturbances; or instead of ultrasonography to detect early thyroid orbitopathy in patients with equivocal results of laboratory tests. Like ultrasonography, CT allows reliable identification of even minimal enlargement of the recti muscles.40 Of those patients with clinical unilateral thyroid orbitopathy, CT will detect subclinical enlargement of the extraocular muscles on the contralateral side in 50%.75

The most characteristic CT finding in thyroid orbitopathy is enlargement of the extraocular muscles, which is usually bilateral and symmetric and has a fusiform configuration, with sharply defined borders and sparing of the tendinous insertions. Atypical cases with tendon involvement and blurred muscle margins have been described.75

The pattern of muscle enlargement on CT parallels that seen clinically. The inferior rectus is the most commonly involved, followed by the medial rectus, superior rectus, and lateral rectus. Other findings include proptosis and anterior prolapse of the orbital septum due to excessive orbital fat and muscle swelling (see Fig. 4).76 Also, lacrimal gland enlargement and bone remodeling without erosion can occur.75 Patients at risk for developing optic neuropathy may also have severe apical crowding, a dilated superior ophthalmic vein, and anterior displacement of the lacrimal gland.68 Of these, apical crowding is the most sensitive indicator for the presence of optic neuropathy (Fig. 5A).56 Both axial and coronal CT cuts should be obtained; the coronal plane is needed to assess the enlargement of the extraocular muscles at the apex (see Fig. 5B).

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Although more expensive than CT, magnetic resonance imaging (MRI) is the preferred imaging modality for delineating subtle compressive optic neuropathy. MRI using 1.5 tesla units and orbital surface coils provides optimal spatial resolution of the orbit. MRI may also be useful in distinguishing between active and inactive disease by recognizing the increased fluid associated with inflammation: extraocular muscles that have acute inflammation have longer T2 relaxation times owing to the higher water content.77–79 However, this is not widely used because it is difficult to perform and time-consuming and may be of limited use in the decision of whether or not to apply immunosuppression therapy.77,78
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A visual field should be performed in all patients suspected to have optic neuropathy and is useful when following patients after initiation of treatment.
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Most patients with thyroid orbitopathy present with typical signs and symptoms of bilateral eyelid retraction and proptosis that are almost pathognomonic of thyroid orbitopathy. In these patients the diagnosis is easily made and confirmed through laboratory testing. Occasionally, however, a patient with thyroid orbitopathy may be misdiagnosed.

Clinical presentations in which the possibility of thyroid orbitopathy is often overlooked include ocular irritation, lacrimation, and minimal eyelid retraction in early thyroid orbitopathy. Thyroid orbitopathy may also mask as a superior oblique palsy or be confused with the motility disturbances seen in myasthenia gravis. When thyroid orbitopathy presents as an acute orbital inflammation, it must be distinguished from myositis, orbital cellulitis, or scleritis. Myositis is more likely to be unilateral, involving a single muscle, with tendon involvement revealed by ultrasonography or CT. The differentiation between myositis and thyroid muscle enlargement on CT may, however, be difficult because the tendon swelling in myositis is not a consistent finding and because multiple muscles may be affected.75 Unlike thyroid orbitopathy, myositis most commonly involves the medial rectus (57%), followed by the lateral rectus (36%).80

The differential diagnosis of proptosis includes orbital neoplasms, orbital myositis, granulomatous processes (e.g., sarcoidosis, Wegener's granulomatosis), orbital cellulitis or abscess, vascular lesions (carotid-cavernous fistulas), and miscellaneous causes, such as lithium therapy, cirrhosis, and amyloidosis.

The differential diagnosis of eyelid retraction includes neurologic disorders, such as midbrain disease (e.g., Parinaud's syndrome), hydrocephalus, aberrant regeneration of cranial nerve 111, sympathomimetic drugs, cirrhosis, and postoperative after ptosis repair or eyelid reconstruction. Pseudo-retraction occurs with ptosis in the normal-appearing contralateral eyelid, exophthalmos, and unilateral high axial myopia.

The differential diagnosis of extraocular muscle enlargement includes primary or local tumor invasion (including lymphoma, rhabdomyosarcoma, meningioma), myositis, metastatic tumor, and vascular abnormalities, such as carotid-cavernous fistula, infection, and acromegaly.

Primary and metastatic tumors usually involve a single muscle and produce a nodular muscle enlargement with sharp borders and frequent bony changes. A carotid-cavernous fistula will have a prominent vascular channel within the orbit, including an enlarged superior ophthalmic vein, and uniform, moderate enlargement of the horizontal recti, especially the medial rectus.40 Infectious cases usually demonstrate unilateral, single muscle enlargement, blurred margins, tendon involvement, and contiguous soft tissue changes. Acromegaly results in bilateral enlargement of all recti, may involve the insertions, and shows mild enlargement of the optic nerve sheaths without vascular distension.

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The management of thyroid disorders necessitates both treatment of the systemic thyroid disease and management of the TO. Although the treatment of the systemic thyroid dysfunction will be initiated and followed by the collaborating endocrinologist, it is important for the ophthalmologist to have a general knowledge of the treatment options available.

The emphasis of the ophthalmologist's clinical evaluation should be to detect ocular involvement that requires either medical or surgical intervention. The clinical examination should include: (1) testing for the best corrected visual acuity, (2) color vision testing, (3) examination for an afferent pupillary defect, (4) extraocular muscle motility examination, (5) measurement of the lid fissure height in primary gaze, (6) measurement of upper and lower scleral show, (7) exophthalmometry to detect proptosis, (8) slit-lamp biomicroscopy to assess the tear film and fluorescein pattern, and (9) fundus examination to detect optic disc swelling or pallor.


Natural History

The mortality from untreated Graves' disease is 10% to 30%, and morbidity can occur from cardiovascular and neuropsychiatric complications.81 Treatment of thyroid dysfunction is therefore recommended. The three modes of therapy are medication, iodine-131 (131I), and surgery.82–84 In the United States the majority of patients are treated with 131I, whereas in Europe medications are more often used as the first line of therapy.85

Medical Therapy

The antithyroid drugs, methimazole and propylthiouracil (PTU), will restore euthyroidism within a few weeks by inhibiting the thyroid's ability to produce hormones.86 Carbimazole is used in Europe and is converted in vivo to the active metabolite methimazole. With the proper dosage, symptoms can be controlled within a few weeks.72 Drug therapy needs to be continued until clinical remission and normalization of circulating thyroid hormones is obtained. Unfortunately, permanent remission after drug therapy can be obtained in less than 50% of the patients,72 and some studies show a long-lasting remission in no more than 25% of unselected patients.87 The chance of long-lasting remission is improved with larger doses of medication and low levels of dietary iodine. Antithyroid drugs do have adverse side effects, such as rash, arthralgias, leukopenia, and agranulocytosis.72,88 The reported incidence of agranulocytosis is 0.1% to 0.5% and is thought to be immunologically mediated. PTU can also cause hepatitis and a lupus-like syndrome.88 Because PTU does not cross the placental barrier as readily as methimazole, it is the medication of choice during pregnancy.


131I, the standard radionuclide for therapy, has been shown to be reliable and safe.85 The use of 131I therapy in children is controversial but is most likely safe.72 In women of childbearing age, a negative pregnancy test should be documented before administering 131I. 131I is given by mouth either in liquid or capsule form and works by emitting β particles that are locally destructive to the thyroid gland. After the treatment, most patients improve by 6 to 8 weeks, with the rate of recovery being dependent on the dose given, the size of the thyroid gland, and the severity of the hyperthyroidism. 131I therapy can be repeated, but no earlier than 3 months after initial therapy.72 Hypothyroidism may occur as early as 12 weeks after 131I therapy; when large doses are used, 90% or more are hypothyroid by 1 year after treatment.89 Most therapists have now concluded that cure of hyperthyroidism with a single therapy is desirable. Hypothyroidism is easy to diagnose and treat and more acceptable than persistent hyperthyroidism. Aside from hypothyroidism, there are no significant side effects from 131I therapy. There is no evidence that 131I therapy in Graves' disease will increase risks of developing thyroid cancer, leukemia, reproductive or congenital abnormalities in patients, or thyroid damage in patients' offspring.85


Subtotal thyroidectomy, popular a few decades ago, is no longer routinely advisable owing to the risk of complications arising from surgery and the relative merits of other therapeutic alternatives.72 There are instances, however, when surgery should be considered first, such as in pregnant patients in whom immediate control of hyperthyroidism is mandatory, in patients with large toxic nodular goiter and pressure symptoms, or in the presence of a nodule suspicious for malignancy. Surgery usually brings about a euthyroid state within 4 to 12 weeks.72 Before surgery, the patient should be treated with standard antithyroid medications and inorganic iodine to make the thyroid gland less vascular and easier to resect. Significant complications of surgery include death, recurrent laryngeal nerve damage (1%–2%), and hypoparathyroidism (1%–2%).90


Natural History

The course of ophthalmopathy tends to be one of rapid progression, peaking after a relatively short interval (6–24 months), followed by a prolonged plateau phase and then a gradual, often incomplete regression of eye findings.18,67 On occasion, the progressive course may be more prolonged. Hales and Rundle91 followed 104 patients and showed that approximately 50% with previously conspicuous eye changes still had obvious ophthalmopathy an average of 15 years later. Perros et al.92 longitudinally studied 59 patients with mild to moderately severe TO who had not received immunosuppression or surgical treatment and found 64% spontaneously improved after a median of 12 months, whereas progression was observed in 13.5%. Bartley et al.52 found that 89 of 120 patients (74%) with TO required either no treatment or only supportive measures, whereas 24 patients (20%) underwent one or more surgical procedures. Eyelid retraction and exophthalmos are the most likely signs to persist. Eyelid retraction resolves in only 40% to 45% of affected patients,16,91 and less than 10% of patients show an improvement in exophthalmos.91,93

Effect of Treatment of Systemic Disease on Orbitopathy

It is unclear whether the specific method of treatment has an effect on the onset or progression of orbitopathy. Although a number of large retrospective studies have reported no significant influence on the course of TO,94–96 others report exacerbation of TO after 131I therapy compared to patients treated with an antithyroid drug or thyroidectomy.97,98 In their prospective study, Tallstedt et al.97 found that eye disease developed or progressed in 35% of those treated with radioactive iodine, in 16% of patients treated with subtotal thyroidectomy, and in 10% of patients treated with antithyroid drugs. Bartalena et al.98 showed a worsening of orbitopathy in 15% treated with radioiodine and 3% on methimazole. When prednisone was given during the administration of 131I at a dose of 30 mg daily for 1 month there was no worsening of mild orbitopathy.98 A combined group of 50 patients from two prospective studies showed no significant risk for radioiodine-induced initiation or progression of TO.55,99

There are a number of factors, including duration of disease, previous history of treatment, 131I dose, and promptness of correction of hypothyroidism resulting from 131I therapy100 that may be responsible for these conflicting results. Euthyroidism seems to be an important factor in the outcome of ophthalmopathy after therapy, whatever the mode of treatment chosen to attain it.99 However, the mechanism by which hypothyroidism or TSH elevation accelerates TO has not been elucidated. It may be that 131I or thyroidectomy causes a treatment-related release of thyroid antigens and activation of the autoimmune response, and that prednisone may help to suppress this autoimmune response. Because we still do not know enough about risk factors in the deterioration of ocular signs, possible approaches in patients with significant preexisting TO include using antithyroid drugs rather then 131I therapy, considering thyroidectomy or treating with a 3-month course of steroids after 131I is given.


For mild disease, treatment consists of elevating the head of the bed, sleeping supine, lubricating the cornea with eye drops, and wearing dark glasses for outside activities. Patients should be advised to stop smoking because this habit has been associated with orbitopathy.101 For moderate to severe orbitopathy in which the patient presents with orbital inflammation, increasing proptosis, exposure symptoms, and generalized orbital discomfort, immunosuppression in the form of corticosteroids, radiation, and immunomodulators may be given. Medical treatment is most effective in the early inflammatory phase before extensive fibrosis of extraocular muscles and orbital connective tissue has occurred. The aim of treatment is to protect the cornea, shrink orbital tissues, and reduce periorbital edema.


Corticosteroids are a valuable temporizing measure but rarely provide the final resolution of eye disease. They are believed to work by altering cell-mediated immune response and diminishing the production of mucopolysaccharides by the orbital fibroblasts.102,103 Improvement of soft tissue involvement occurs in approximately 60% of patients with acute congestive orbitopathy, but, unfortunately, the orbitopathy often worsens when the dosage is reduced or discontinued.104,105 Zgliczynski et al.106 found that 31 of 53 (58%) patients relapsed during the first year of follow-up. Corticosteroids do not have as much of an effect on diplopia, and no significant effect on proptosis.104 Traditionally, a “short burst” of high-dose corticosteroids has been given, usually in the range of 60 to 120 mg/day of oral prednisone. Improvement in subjective symptoms, such as pain and tearing usually occurs first, often as early as 24 to 48 hours, followed by improvement in soft tissue congestion and muscle function over a period of days to weeks.107,108 The dose is then tapered to the minimum level required to prevent a flare-up of ocular signs and symptoms. If after 3 weeks on oral prednisone there are no clinical signs of improvement, it is unlikely that treatment will succeed, and the dosage should be quickly tapered. Perhaps the most common error in the clinical management of thyroid eye disease is the long-term use of corticosteroids without a worthwhile response.

High doses of intravenous methylprednisolone in “pulse” therapy form have been described for TO in small, uncontrolled studies. Ohtsuka et al.109 treated 41 patients with intravenous methylprednisolone (1 g/day × 3 days × 3 times) followed by 3-month oral prednisone therapy. They found improvement in muscle hypertrophy but minimal effect on ocular motility and no significant effect on proptosis. In a subsequent study, this same group found no benefit of adjuvant orbital irradiation with pulse intravenous steroids compared to pulse intravenous steroids alone.110 Macchia et al.111 compared 25 patients given biweekly intravenous injections of 1 g of methylprednisolone for 6 weeks, to 26 patients treated with oral prednisone for 4 to 6 months. They found that all patients showed significant improvement in signs and symptoms of orbital inflammation and a “slight improvement in proptosis and diplopia.” Kauppinen-Makelin et al.112 also found intravenous methylprednisolone pulse therapy and oral prednisone to be equally effective in improvement of soft tissue activity scores for 18 and 15 patients, respectively. However, they found that the intravenous pulse therapy group required additional forms of therapy at 3 months less frequently than the oral steroid group. Controlled, randomized studies are required to elucidate the exact role of pulse intravenous steroid therapy for TO.

Side effects of corticosteroids include diabetes, depression, hypertension, weight gain, peptic ulceration, infection, and avascular necrosis of the hip. Intravenous methylprednisolone can also cause cardiac arrhythmias, seizures, hypersensitivity reactions, psychiatric disorders, severe hepatitis, and intractable hiccups.113–115

Other Medical Therapies.

There are no sufficient data to determine whether a variety of other immunosuppressive agents, such as cyclosporine, cyclophosphamide, or methotrexate, will be useful as single therapies.116–120 They may, however, find a place as corticosteroid-sparing agents. Cyclosporine as monotherapy is less effective than prednisone,105 but the combin-ation appears more effective than does prednisone alone.105,121 Other investigational therapies that also require further study include potent long-acting somatostatin analogs (octreotide, lanreotide, and SOM 230) that suppress insulin-like growth factor in extraocular muscles and fat cells,122 bromocriptine,123 pentoxifylline (which inhibits cytokine-induced glycosamino-glycan synthesis by orbital fibroblasts in vitro),124 or antioxidants (allopurinal and nicotinamide).125,126 Intravenous immunoglobulin,127 plasmapheresis,129,130 and low-voltage electric therapy131 have been reported but have no established roles as treatment modalities.

Future therapies aimed more specifically at fibroblast processes may include treatment with cytokine antagonists, cyclooxygenase-2 inhibitors, or agents which may inhibit adipogenesis.8,122

Orbital Irradiation.

The role of radiation therapy in the treatment of congestive orbitopathy has yet to be well defined. The rationale for the use of radiation therapy is presumed reduction or elimination of radiosensitive pathogenic orbital lymphocyte, although this has not been conclusively demonstrated. It is also thought that the glycosaminoglycan production by fibroblasts is reduced, thereby reducing orbital edema, orbital tension, and conjunctival injection.132

The literature consists of mostly retrospective studies that have not been controlled for other prior or concurrent treatments, the natural history of improvement, or objective quantifiable measures of outcome. It is therefore not surprising that a varied spectrum of reported benefit from orbital irradiation exists from none32,110,133,134 to overall good response in 60% to 70% of patients.132,135,136 Teng et al.137 reviewed 20 patients receiving 20 to 24 Gys irradiation and noted that 35% showed soft tissue improvement within 3 weeks of treatment; proptosis decreased in only four patients and with one exception ophthalmoplegia did not improve.137 A retrospective study be Van Ruyen et al.138 of 90 patients with signs and symptoms of Graves' ophthalmopathy less than 1 year, treated with 20 Gy orbital irradiation found no improvement in proptosis and an improvement of only 1-degree elevation and abduction 3 months after radiotherapy; and an improvement of 4-degree elevation and abduction in a subgroup of 14 patients with more than 10-degree restricted eye motility.

The majority of the small prospective studies performed show minimal, if any, benefit from orbital irradiation. A prospective, double-masked, randomized clinical trial examined 42 patients with onset of eye symptoms ranging from 0.2 to 16 years (median 1.3 years), showed no clinical or statistically significant difference between 20 Gy irradiated orbits and untreated orbits at 6 months.139 Nineteen of these patients were previously treated with steroids, two patients within 30 days of irradiation. They found no difference between those with symptoms less than 1.3 years (about 50%) versus those with symptoms greater than 1.3 years. In a 3-year follow-up of this study, no delayed benefit was observed.32 Maalouf et al.133 prospectively studied oculomotor disorders in 15 patients treated with 20 Gy and found no change in amplitude of range of motion or thickness of the extraocular muscles 3 months after radiotherapy. In a prospective study of 33 patients with TO treated with 20 Gy in 10 sessions, Wilson and Prochera140 found significant improvement in soft-tissue signs, mean of 6-degree improvement in supraduction, mean of two prism diopters improvement in horizontal and of four prism diopters in vertical strabismus. However, only 35% avoided eye muscle surgery.140 Prummel et al.141 performed a double-blind randomized trial comparing 28 patients treated with 20 Gy irradiation and placebo capsules to 28 patients receiving a 3-month course of oral prednisone and sham irradiation. A successful outcome was obtained in 50% of both groups. The improvement mostly involved soft-tissue changes and eye-muscle motility: mean elevation in responders to radiotherapy increased from 18.5 degrees at baseline to 21.8 degrees at 24 weeks. There was no change in proptosis or eye-muscle enlargement in either group.141 In a double-blind randomized clinical trial of 30 patients with moderately severe TO receiving 20 Gy/10 fractions radiotherapy versus 30 patients sham-irradiated, there was improvement in upgaze and field of binocular single vision, but only 25% of the irradiated patients were spared from additional strabismus surgery.134 There was no reduction of proptosis, eyelid retraction, or eyelid swelling.134

When orbital irradiation is given, most radiotherapists use a protocol modified from Donaldson et al. (132). A total of 20 Gy to orbital structures is given in 10 sessions over a 2-week period. Megavoltage, highly collimated X-ray beams from a linear accelerator are aimed via a lateral port to give a maximum dose to the retro-ocular tissues but at negligible risk to the lens and retina. Lower doses of 10 Gy given in 10 fractions of 1 Gy have been shown to be both equally effective as 20 Gy142 and not as effective as 24 Gy of radiation143; however these data are difficult to interpret until the exact role of irradiation is established. Improvement has been reported 2 weeks to 3 months after radiation therapy but can continue for as long as 1 year.132,137,144,145 The contraindications to radiation therapy include orbital fibrotic changes and limited expertise with ocular radiation. Because of an increased potential for radiation vasculopathy, relative contraindications to radiation therapy include systemic vascular disease, concomitant chemotherapy, and previous ocular or brain irradiation. Previous concerns that orbital radiotherapy would increase orbital fibrosis, making subsequent surgery to the ocular muscles more difficult, have proved to be unfounded.132,144 Infrequent but potentially sight-threatening side effects of radiation therapy, such as dry eye, cataract, radiation retinopathy, and radiation neuropathy, can occur.146–148 Although cases of secondary malignancy have not been published after orbital irradiation for TO, latency periods of decades are possible, and a theoretic risk of 1.2% has been postulated.149

Although several studies have shown the combination of irradiation with high doses of oral systemic corticosteroids to be synergistic,82,150 other investigators have not demonstrated an increased response rate over that reported with irradiation alone.103,144


Natural History.

The natural history of vision in patients with optic neuropathy has not been outlined conclusively, and, therefore, there are no definite guidelines regarding optimum therapy. Compressive optic neuropathy can cause permanent visual loss. Pooled data from the literature regarding the outcome of untreated optic neuropathy in 32 patients with Graves' disease show persistent impairment of visual acuity (20/100 or less) in one-fifth of patients, 5 of whom developed near or total blindness.65–67 In a series by Trobe et al.65 seven untreated eyes with optic neuropathy with acuity of 20/40 or better and minimal visual field defects were followed. Resolution of the neuropathy was documented in four eyes (57%) within 6 to 12 months, and no change was observed in three eyes (43%) with up to 15 months of follow-up.

Treatment options for compressive optic neuropathy include high doses of corticosteroids, irradiation, and orbital decompression. Data compiled from case reports and small series suggest that visual functions improve within days for about 82% of patients receiving surgical decompression, in 1 week for about 94% given intravenous pulses of methylprednisolone, in 1 to 2 weeks for about 73% treated with oral prednisone, and in 1 to 3 months for about 79% receiving radiotherapy.151 Some patients require only one of these modalities, whereas other patients need combined therapies. If corticosteroids are given, the dose is as described earlier for acute congestive ophthalmopathy. In approximately one-half of patients with compressive optic neuropathy treated with corticosteroids, there is an excellent initial response. Symptoms recur, however, in 50% to 55% of patients when corticosteroid doses are tapered.69,152 Methylprednisolone pulse therapy over 3 days followed by oral prednisone, and/or irradiation may be beneficial for dysthyroid optic neuropathy,153 but controlled studies are required to determine the role of pulse intravenous steroids. A retrospective review of compressive optic neuropathy showed that only 1 of 29 (3%) patients treated with radiotherapy required surgical decompression compared with 6 of 16 (37%) treated with corticosteroids.154 Hurbli et al.136 found that 8 of 14 patients (57%) with thyroid optic neuropathy improved or stabilized after 20 Gy irradiation, but 4 had recurrences within 5 months. They found that maximal response ranged from 1 to 12 months, with a mean of 5.6 months.136 If there are no signs of improvement in visual function within 3 weeks65 of high doses of corticosteroid therapy, orbital irradiation or surgical decompression should be considered.66 Radiation therapy, however, must be administered in fractionated doses, which delays its beneficial effect. For this reason, if visual dysfunction progresses while the patient is on corticosteroids, surgical decompression is usually recommended, if the patient is a surgical candidate.

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Orbital decompression may be indicated fairly urgently for compressive optic neuropathy and exposure keratitis with corneal ulceration. Otherwise, it is best to wait until the stable phase of the disease when considering it to relieve the diffuse pressure and discomfort of the tight post-inflammatory orbit and cosmesis for disfiguring exophthalmos. However, some patients have a prolonged inflammatory course, and they may be willing to accept the increased unpredictability of surgery even though they are not in the postinflammatory phase, to allow them to work and function properly.


Bony orbital decompression for TO was first reported by Dollinger155 in 1911, using the lateral orbitotomy approach of Kronlein. Since then, many different techniques involving one to four orbital walls have been described156–161 (Fig. 6). Walsh and Ogura162 popularized a transantral approach in the mid 1950s to remove the floor and medial orbit, which became the standard of care for orbital decompressions for many years. The transorbital (via fornix or eyelid) approach to inferior and medial wall decompression became the most common approach used by ophthalmologists in the mid-1980s and early 1990s.163–167 The medial wall can also be approached transcaruncular or via an endoscopic endonasal approach. Removal of the lateral wall, popular in the early 1900s, showed resurgence of interest in the 1980s, with reports of extended lateral wall removal.161,168 The addition of a lateral wall advancement,169 with outward rotation of the lateral orbital wall, had the advantage of further increasing both the orbital volume and simultaneously improving upper eyelid retraction. The current popular techniques are deep lateral bony removal and the “balanced” orbital decompression with symmetrical decompression of the medial and lateral walls with preservation of the orbital floor to minimize complications involving muscle imbalance.170,171 The deep lateral bony decompression involves removing the posterior lateral wall overlying the temporal loose dura, including the deep portion or “trigonal bone” of the greater wing of sphenoid, which has a highly vascular marrow space.161,168,171,172 The deep lateral wall can be assessed through a coronal, lateral cutaneous or lateral transconjunctival approach. The mean retroplacement of the globe with isolated deep lateral decompression is approximately 3.5 mm (range 0.5 to 6 mm), with a two-wall decompression is about 5 mm (range 3–8 mm), and with a three-wall technique the range is between 5 and 10 mm.152,167,171,173–176 It is important to remember, however, that proptosis and vision improvement are, to a great extent, independent of each other. Visual rehabilitation depends on removal of bone at the orbital apex.

Fig. 6 Orbital bony anatomy: frontal bone (blue); greater wing of sphenoid (light green); lesser wing of sphenoid (dark green); zygoma (pink); maxilla (yellow); lacrimal bone (purple); ethmoid bone (orange); palatine bone (pale blue). AE=anterior ethmoidal foramina; PE=posterior ethmoidal foramina; OC=optic canal; SOF=superior orbital fissure; IOF=inferior orbital fissure; LSF=lacrimal sac fossa; IF=infraorbital foramen; ZF=zygomaticofacial foramen. Dotted lines demarcate deep lateral wall removal (which includes the greater wing of sphenoid from the edge of the SOF to IOF), areas of medial wall, and floor removal. The entire lateral orbital call can be removed (x-line) and advanced with a vulgus rotation. Removal of medial wall should not extend above the anterior and posterior ethmoidal foramina, which denote the level of the cribriform plate. When the floor and medial wall are removed, a strut of bone as depicted can be left to minimize postoperative ocular motility problems. Very little additional decompression is obtained by removal of the floor lateral to the infraorbital groove. For maximal apical decompression, palatine bone can be removed up to the optic canal (x-line).

In a large retrospective study of 205 eyes with visual acuity of 20/40 or worse from optic neuropathy, acuity improved following transantral decompression of the medial wall and floor by three Snellen lines or more in 110 (54%), and visual field defects resolved in 120/291 (41%) and improved in 126/291 (43%).69 Two percent of patients lost more than three Snellen lines of visual acuity after orbital decompression.69 In a retrospective review, 25 of 28 (89%) undergoing endoscopic and transconjunctival medial wall and floor decompression for CON showed improvement, with 43% having greater than six lines of vision improvement.177 In a retrospective study of 33 patients undergoing translid inferior and medial wall decompression for optic neuropathy, visual acuity improved and remained stable in 58%, visual improved but was then followed by subsequent deterioration in 36%, and in 2/33 patients vision deteriorated and did not improve. Visual function stabilized within 12 months of surgery in 76% and within 18 months in 91% of patients.178

There is no doubt that decompression can cause or worsen muscle imbalance, and, therefore, orbital decompression, if required, should precede any strabismus surgery. Various factors may influence the incidence and severity of postoperative strabismus: preoperative myopathic state, the degree of “apical crowding,” asymmetric herniation of orbital contents after orbital decompression, and variations in surgical techniques. Rates of new onset of postoperative diplopia in primary position are between 30% and 65% with the transantral approach,179,180 although this may be greatly reduced by incising periorbita in the anterior–posterior direction from the equator of the globe and perpendicular to this anteriorly59 or by not incising the anterior periorbita at all.181 Leaving the medial orbital strut of bone at the maxillary-ethmoid junction also minimizes diplopia182 (Fig. 6). Compared with transantral decompression, a lesser incidence of iatrogenic diplopia is observed after coronal or transorbital orbital decompressions.175 New onset of postoperative diplopia in primary position is between 5% and 25% with the transorbital approach to the removal of the medial wall and floor173,183,184 and 9% to 20% after coronal decompression.173,175 Patients with restricted ocular motility preoperatively are more likely to have postoperative diplopia; in a series of patients undergoing transconjunctival orbital floor and transcutaneous medial wall decompressions, Nunery176 found 4% (1/25) patients without preoperative diplopia or abnormal versions develop postoperative diplopia compared with 61% (22/36) patients developing new or worsening of diplopia in primary position with preoperative restrictive motility loss and diplopia within 20 of primary position. Reports of new onset of diplopia after balanced medial and lateral decompression with or without orbital fat removal range from 0%185 to 18%.186,187 Resolution of preexisting diplopia after orbital decompression has been reported in up to one-third of patients.173,188

Reported complications following decompression surgery include infraorbital nerve anesthesia, which resolves in most patients within 4 to 6 months; anesthesia in the distribution of the zygomaticotemporal and zygomaticofacial nerves; cerebrospinal fluid leaks, most of which seal spontaneously; intracranial bleeding, meningitis, nasolacrimal duct obstruction; and 1% loss of vision.69,160,171,189,190


Orbital fat decompression was first proposed by Crawford191 in 1973 to relieve the apical compression on the nerve by the enlarged extraocular muscles. This technique was then ignored until a resurgence of interest followed Olivari's192 reported series in 1991. Intraconal fat can be removed between the lateral and inferior rectus muscles and if needed from the superomedial and inferomedial compartments. Retrospective studies reporting removal of 3 to 12 mL of intraconal and extraconal fat show mean reductions of proptosis of 5 to 6 mm (range 1–12 mm).193,194 Reported rates of de nova diplopia are varied. In a retrospective study of 1000 orbits of 511 patients, 4% developed de novo diplopia, preexisting diplopia was “cured” in 64% of patients, and improvement was seen in 17% of patients.194 Ferreira et al.195 reported on 73 patients with an average removal of 7.6 mL of eyelid plus orbital fat per side: seven patients suffered temporary diplopia and one patient developed permanent diplopia. Adenis et al.193 studied 41 orbital fat decompressions with a mean retrieval of 7.31 mL (range 3.25–12 mL) of intraconal and extraconal fat and reported that 3 of 9 patients developed de novo diplopia, whereas 5 of 14 patients with preexisting diplopia “improved.”

Rare reported complications include pupillary abnormalities from injury to the ciliary ganglion, orbital hematoma, supraorbital nerve paresis, and upper eyelid malposition.193,194

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When surgical correction is indicated, a planned approach is required to optimize functional and cosmetic results. The order of correction is important: if orbital decompression is indicated, it should be performed first, followed by extraocular muscle surgery. Eyelid surgery should follow completion of orbital or extraocular muscle surgery. Because specific surgical techniques are covered extensively elsewhere, they will not be discussed in this chapter.

A major source of morbidity in thyroid orbitopathy, and the most frequent problem associated with orbital decompression surgery, has been strabismus. In patients with relatively minimal degrees of ocular misalignment, diplopia can be avoided with a compensatory head posture, Fresnel plastic press-on prisms, or temporary occlusion. Unfortunately, there is significant image degradation with larger prisms used, limiting their usefulness. If there is marked asymmetry in ocular deviation in different fields of gaze, prisms are also less effective. In some cases during the inflammatory period, use of in-tramuscular botulinum toxin has shown some efficacy.196–198

Extraocular muscle surgery should be postponed until the muscles are no longer inflamed and the deviation has remained stable for at least 6 months, although successful results have been reported during active TO in selected patients with marked disability.199 Secondary strabismus repair after orbital decompression can be addressed earlier, possibly as soon as a few months after surgery.200 Globe ptosis should be ruled out in cases of motility disturbance after orbital decompression surgery, because an orbital implant may be required.165 Most commonly, a tight inferior rectus muscle needs to be recessed. One must remember that recessing the inferior rectus may produce or aggravate preexisting lower eyelid retraction. The adjustable suture technique of strabismus repair gives the best results.201,202 Surgery should aim for monocular vision in primary and reading positions. A number of series have demonstrated that very few patients with severe thyroid myopathy revert to binocular vision in all fields of gaze after surgical repair.203 Often multiple procedures on more than one muscle are necessary, even in expert hands, to achieve optimal results.203,204

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As with other thyroid eye problems, eyelid retraction may improve with time, however 55% to 60% of patients will have persistent eyelid retraction.7,91 Surgical correction of eyelid abnormalities should be performed only after orbital or extraocular muscle surgery because these operations may change eyelid position. For example, inferior rectus muscle restriction may cause upper eyelid retraction because of the superior rectus/levator palpebrae overaction against the restriction. Specific techniques for repair of eyelid retraction are discussed in other chapters.
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Thyroid orbitopathy is a complex and poorly understood inflammatory disease that causes a wide variety of clinical problems. Clinical management is often frustrating for both the physician and the patient, because no immediate or dramatic cure exists. Each treatment modality has significant side effects and complications, and treatment decisions are rarely easy.

The ophthalmologist's first task, after establishing the diagnosis, is to begin the lengthy process of patient education. It is difficult for patients to grasp the fact that regulation of their thyroid dysfunction will not cure the eye disease. Thyroid eye disease often strikes otherwise healthy adults in the midst of their professional, social, and family responsibilities and causes both visual problems and profound cosmetic disfigurement. A general health-related quality-of-life questionnaire demonstrates that TO patients have a lower quality-of-life than do patients with diabetes mellitus or chronic inflammatory bowel disease.205 Long-term psychologic sequelae of TO are notable; despite treatment, more than one-third of patients are dissatisfied with their ultimate appearance.52 Since we have no “ready cure,” it is extremely important that the physician provide education and emotional support as the patient comes to grips with the chronic nature of the disease. It is helpful to emphasize that although no immediate remedy is available, the patient is not doomed to a “life sentence.” With medical and surgical treatment, given at appropriate times, patients with thyroid orbitopathy can be restored to normal function and appearance in most cases (Figs. 7 and 8). Unfortunately, the process required to reach this goal is usually lengthy and presents one of the most difficult challenges in the clinical practice of ophthalmology.

Fig. 7 A. Patient with onset of thyroid orbitopathy after hyperthyroidism who presented with visual loss, proptosis, strabismus, and eyelid retraction. B. Two years later the patient has excellent vision and normal appearance. Her treatment included prednisone, orbital decompression, strabismus repair, and eyelid surgery.

Fig. 8 A. Patient with axial proptosis from increased orbital fat volume, eyelid retraction, and exposure keratopathy. B. Postoperative following bilateral orbital fat decompressions alone.

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1. Parry CH: Collections from the Unpublished Medical Writings, vol. 11. London: Underwoods, 1825

2. Graves RJ: Newly observed affection of the thyroid gland in females. London Med Surg J 7:516–517, 1935

3. von Basedow K: Exophthalmos durch hypertrophic des zellgewebes in der augenhohle. Wochens Ges Heilkd 13:197, 1840

4. Elgood C (ed):Medicine in Persia. New York: Hoeber, 1934

5. Fries PD: Thyroid dysfunction: Managing the ocular complications of Graves' disease. Geriatrics 47:58–60, 1992

6. Salvi M, Zhang Z-G, Haegert D, et al: Patients with endocrine ophthalmopathy not associated with overt thyroid disease have multiple thyroid immunological abnormalities. J Clin Endocrinol Metab 70:89–94, 1990

7. Bartley GB, Fatourechi V, Kadrmas EF, et al: The incidence of Graves' ophthalmopathy in Olmsted County, Minnesota. Am J Ophthalmol 120:511–517, 1995

8. Bahn RS: Clinical review 157. Pathophysiology of Graves' ophthalmopathy: The cycle of disease. J Clin Endocrinol Metab 88:1939–1946, 2003

9. Burch HB, Wartofsky L: Graves' ophthalmopathy: Current concepts regarding pathogenesis and management. Endocr Rev 14:747–793, 1993

10. Kriss JP: Pathogenesis and treatment of Graves' ophthalmopathy. Thyroid Today 7:1–9, 1984

11. Forbes G, Gorman CA, Brennan MD, et al: Ophthalmopathy of Graves' disease: Computerized volume measurements of the orbital fat and muscle. Am J Neuroradiol 7:651–656, 1986

12. Chang TC, Huang KM, Chang TJ, et al: Correlation of orbital computed tomography and antibodies in patients with hyperthyroid Graves' disease. Clin Endocrinol (Oxf) 32:551–558, 1990

13. Marcocci C, Bartalena L, Bogazzi F, et al: Studies on the occurrence of ophthalmopathy in Graves' disease. Acta Endocrinol (Copenh) 120:473–478, 1989

14. Kalman K, Leovey A, Kelenhegyi C, et al: Euthyroid infiltrative ophthalmopathy: Clinical-immunological characteristics. Acta Med Hung 46:101–108, 1989

15. Prummel MF, Wiersinga WM, Mourits MP, et al: Effect of abnormal thyroid function on the severity of Graves' ophthalmopathy. Arch Intern Med 150:1098–1101, 1990

16. Bartley GB, Fatourechi V, Kadrmas EF, et al: The chronology of Graves' ophthalmopathy in an incidence cohort. Am J Ophthalmol 121:426–434, 1996

17. Tamai H, Nakagawa T, Ohsako N, et al: Changes in thyroid functions in patients with euthyroid Graves' disease. J Clin Endocrinol Metab 50:108–112, 1980

18. Gorman CA: The presentation and management of endocrine ophthalmopathy. Clin Endocrinol Metab 7:67–96, 1978

19. Tellez M, Cooper J, Edmonds C: Graves' ophthalmopathy in relation to cigarette smoking and ethnic origin. Clin Endocrinol (Oxf) 36:291–294, 1992

20. Christensen SB, Ericsson UB, Janzon L, et al: Influence of cigarette smoking on goiter formation, thyroglobulin, and thyroid hormone levels in women. J Clin Endocrinol Metab 58:615–618, 1984

21. Ericsson U-B, Lindgärde F: Effects of cigarette smoking on thyroid function and the prevalence of goitre, thyrotoxicosis and autoimmune thyroiditis. J Intern Med 229:67–71, 1991

22. Kahaly G, Moncayo R, Stover C, et al: Relationship of eye muscle antibodies with HLA phenotypes and thyroid-stimulating immunoglobulins in endocrine orbitopathy. Res Exp Med 191:137–144, 1991

23. Sridama V, Hara Y, Fauchet R, et al: HLA immunogenic heterogeneity in black American patients with Graves' disease. Arch Intern Med 147:229–231, 1987

24. Kawa A, Nakamura S, Nakazawa M, et al: HLA-B35 and B5 in Japanese patients with Graves' disease. Acta Endocrinol (Copenh) 86:754–757, 1977

25. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 325:599–605, 1991

26. Adams DD, Purves HD: Abnormal responses in the assay of thyrotropin. Proc Univ Otago Med Schove 34:11–12, 1956

27. Kriss JP, Pleshakov V, Chien JR: Isolation and identification of the long-acting thyroid stimulator and its relation to hyperthyroidism and circumscribed pretibial myxedema. J Clin Endocrinol Metab 24:1005–1028, 1964

28. Gunji K, Kubota S, Stolarski C, et al: A 63 kDa skeletal muscle protein associated with eye muscle inflammation in Graves' disease is identified as the calcium binding protein calsequestrin. Autoimmunity 29:1–9, 1999

29. Noh JY, Hamada N, Inoue Y, et al: Thyroid-stimulating antibody is related to Graves' ophthalmopathy, but thyrotropin-binding inhibitor immunoglobulin is related to hyperthyroidism in patients with Graves' disease. Thyroid 10:809–813, 2000

30. Gerding MN, van der Meer JWC, Broenink M, et al: Association of thyrotrophin receptor antibodies with the clinical features of Graves' ophthalmopathy. Clin Endocrinol 52:267–271, 2000

31. Morris JCIII , Hay ID, Nelson RE, et al: Clinical utility of thyrotropin-receptor antibody assays: Comparison of radioreceptor and bioassay methods. Mayo Clin Proc 63:707–717, 1988

32. Gorman CA, Garrity JA, Fatourechi V, et al: The aftermath of orbital radiotherapy for Graves' ophthalmopathy. Ophthalmology 109:2100–2107, 2002

33. Weightman DR, Perros P, Sherif IH, et al: Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmology. Autoimmunity 16:251–257, 1993

34. Heufelder AE: Pathogenesis of Graves' ophthalmopathy: Recent controversies and progress. Eur J Endocrinol 132:532–541, 1995

35. De Carli M, D'Elios MM, Mariotti S, et al: Cytolytic T cells with Th1-like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves' ophthalmopathy. J Clin Endocrinol Metab 77:1120–1124, 1993

36. Pritchard J, Horst N, Cruikshank W, et al: Igs from patients with Graves' disease induce the expression of T cell chemoattractants in their fibroblasts. J Immunol 168:942–950, 2002

37. Sorisky A, Pardasani D, Gagnon A, et al: Evidence of adipocyte differentiation in human orbital fibroblasts in primary culture. J Clin Endocrinol Metab 81:3428–3431, 1996

38. Jakobiec FA, Bilyk JR, Font RL: Orbit. In: Spencer WH (ed): Ophthalmic Pathology: An Atlas and Textbook, vol 4, 4th ed. Philadelphia WB Saunders, 1996:2438–2933

39. Tallstedt L, Norberg R: Immunohistochemical staining of normal and Graves' extraocular muscle. Invest Ophthalmol Vis Sci 29:175–184, 1988

40. Trokel SL, Jakobiec FA: Correlation of CT scanning and pathological features of ophthalmic Graves' disease. Ophthalmology 88:553–564, 1981

41. Campbell RJ: Immunology of Graves' ophthalmopathy: Retrobulbar histology and histochemistry. Acta Endocrinol 121(suppl 2):9–16, 1989

42. Werner SC: Classification of the eye changes of Graves' disease (Editorial). J Clin Endocrinol Metab 29:982–984, 1969

43. Werner SC: Modification of the classification of the eye changes of Graves' disease: Recommendations of the Ad Hoc Committee of the American Thyroid Association (Letter). J Clin Endocrinol Metab 44:203–204, 1977

44. Bartalena L, Marcocci C, Bogazzi F, et al: A new ophthalmopathy index for quantitation of eye changes of Graves' disease. Acta Endocrinol 121(suppl 2):190–192, 1989

45. Gorman CA: The measurement of change in Graves' ophthalmopathy. Thyroid 8:539–543, 1998

46. Wiersinga WM, Smit T, van der Gaag R, et al: Clinical presentation of Graves' ophthalmopathy. Ophthalmic Res 21:73–82, 1989

47. Migliori ME, Gladstone GJ: Determination of the normal range of exophthalmometric values for black and white adults. Am J Ophthalmol 98:438–442, 1984

48. Amino N, Yuasa T, Yabu Y, et al: Exophthalmos in autoimmune thyroid disease. J Clin Endocrinol Metab 51:1232–1234, 1980

49. Anderson RL, Tweeten JP, Patrinely JR, et al: Dysthyroid optic neuropathy without extraocular muscle involvement. Ophthalmic Surg 20:568–574, 1989

50. Hamed LM, Lessner AM: Fixation duress in the pathogenesis of upper eyelid retraction in thyroid orbitopathy. A prospective study. Ophthalmology 101:1608–1613, 1994

51. Lemke BN: Anatomic considerations in upper eyelid retraction. Ophthal Plast Reconstr Surg 7:158–166, 1991

52. Bartley GB, Fatourechi V, Kadrmas EF, et al: Long-term follow-up of Graves ophthalmopathy in an incidence cohort. Ophthalmology 103:958–962, 1996

53. Coleman DJ, Jack RL, Franzen LA, et al: High resolution B-scan ultrasonography of the orbit. Eye changes in Graves' disease. Arch Ophthalmol 88:465–471, 1972

54. Fells P, Kousoulides L, Pappa A, et al: Extraocular muscle problems in thyroid eye disease. Eye 8:497–505, 1994

55. Gupta MK, Beham JP, Sheeler LR, et al: Effect of 131Iodine therapy on the course of Graves' ophthalmopathy: A quantitative analysis of extraocular muscle volumes using orbital magnetic resonance imaging. Thyroid 11:959–965, 2001

56. Nugent RA, Belkin RI, Niegel JM, et al: Graves orbitopathy: Correlation of CT and clinical findings. Radiology 177:675–682, 1990

57. Prummel MF, Bakker A, Wiersinga WM, et al: Multi-center study on the characteristics and treatment strategies of patients with Graves' orbitopathy: The first European group on Graves' orbitopathy experience. Eur J Endocrinol 148:491–495, 2003

58. Weinstein GS, Dresner SC, Slamovits TL, et al: Acute and subacute orbital myositis. Am J Ophthalmol 96:209–217, 1983

59. Koornneef L: Eyelid and orbital fascial attachments and their clinical significance. Eye 2:130–134, 1988

60. Spierer A, Eisenstein Z: The role of increased intraocular pressure on upgaze in the assessment of Graves' ophthalmopathy. Ophthalmology 98:1491–1494, 1991

61. Kikkawa DO, Cruz RCJr , Christian WK, et al: Botulinum A toxin injection for restrictive myopathy of thyroid-related orbitopathy: Effects on intraocular pressure. Am J Ophthalmol 135:427–431, 2003

62. Ohtsuka K: Intraocular pressure and proptosis in 95 patients with Graves' ophthalmopathy. Am J Ophthalmol 124:570–572, 1997

63. Khalil HA, de Keizer RJ, Kijlstra A: Analysis of tear proteins in Graves' ophthalmopathy by high performance liquid chromatography. Am J Ophthalmol 106:186–190, 1988

64. Kadrmas EF, Bartley GB: Superior limbic keratoconjunctivitis. A prognostic sign for severe Graves' ophthalmopathy. Ophthalmology 102:1472–1475, 1995

65. Trobe JD: Optic nerve involvement in dysthyroidism. Ophthalmology 88:488–492, 1981

66. Day RM, Carroll FD: Optic nerve involvement associated with thyroid dysfunction. Arch Ophthalmol 67:289–297, 1962

67. Henderson JW: Optic neuropathy of exophthalmic goiter (Graves' disease). Arch Ophthalmol 59:471–480, 1958

68. Neigel JM, Rootman J, Belkin RI, et al: Dysthyroid optic neuropathy. The crowded orbital apex syndrome. Ophthalmology 95:1515–1521, 1988

69. Soares-Welch CV, Fatourechi V, Bartley GB, et al: Optic neuropathy of Graves' disease: Results of transantral orbital decompression and long-term follow-up in 215 patients. Am J Ophthalmol 136:433–441, 2003

70. Gorman CA: Temporal relationship between onset of Graves' ophthalmopathy and diagnosis of thyrotoxicosis. Mayo Clin Proc 58:515–519, 1983

71. Spencer CA: Clinical utility and cost-effectiveness of sensitive thyrotropin assays in ambulatory and hospitalized patients. Mayo Clin Proc 63:1214–1222, 1988

72. Yeh SD: Symptoms, diagnosis and treatment of thyroid disease. Compr Ther 17:12–18, 1991

73. Shammas HJF, Minckler DS, Ogden C: Ultrasound in early thyroid orbitopathy. Arch Ophthalmol 98:277–279, 1980

74. Forrester JV, Sutherland GR, McDougall IR: Dysthyroid ophthalmopathy: Orbital evaluation with B-scan ultrasonography. J Clin Endocrinol Metab 45:221–224, 1977

75. Rothfus WE, Curtin HD: Extraocular muscle enlargement: A CT review. Radiology 151:677–681, 1984

76. Shah KJ, Dasher BG, Brooks B: Computed tomography of Graves' ophthalmopathy. Diagnosis, management and posttherapeutic evaluation. Clin Imaging 13:58–61, 1989

77. Ott M, Breiter N, Albrecht CF, et al: Can contrast enhanced MRI predict the response of Graves' ophthalmopathy to orbital radiotherapy? Br J Radiol 75:514–517, 2002

78. Prummel MF, Gerding MN, Zonneveld FW, et al: The usefulness of quantitative orbital magnetic resonance imaging in Graves' ophthalmopathy. Clin Endocrinol 54:205–209, 2001

79. Just M, Kahaly G, Higer HP, et al: Graves' ophthalmopathy: Role of MR imaging in radiation therapy. Radiology 179:187–190, 1991

80. Patrinely JR, Osborn AG, Anderson RL, et al: Computed tomographic features of nonthyroid extraocular muscle enlargement. Ophthalmology 96:1038–1047, 1989

81. Weetman AP: Overview of Graves' autoimmune disease. In Dutton JJ, Haik BG (eds): Thyroid Eye Disease: Diagnosis and Treatment. New York: Marcel Dekker, 2002:97–106

82. Schaaf L, Rominger-Seyrich D, Grossmann E, et al: Reduction by orbital radiation of cumulative doses of gluco-corticosteroids in patients with Graves'-Basedow ophthalmopathy. Dev Ophthalmol 20:155–158, 1989

83. Beck RW, DiLoreto DA: Treatment of Graves' ophthalmopathy (Letter). N Engl J Med 322:1088–1089, 1990

84. Solomon B, Glinoer D, Lagasse R, et al: Current trends in the management of Graves' disease. J Clin Endocrinol Metab 70:1518–1524, 1990

85. Dunn JT: Thyroglobulin, hormone synthesis and thyroid disease. Eur J Endocrinol 132:603–604, 1995

86. Weetman AP, McGregor AM, Hall R: Evidence for an effect of antithyroid drugs on the natural history of Graves' disease. Clin Endocrinol (Oxf) 21:163–172, 1984

87. Orgiazzi J: Management of Graves' hyperthyroidism. Endocrinol Metab Clin North Am 16:365–389, 1987

88. Meyer-Gessner M, Benker G, Lederbogen S, et al: Antithyroid drug-induced agranulocytosis: Clinical experience with ten patients treated at one institution and review of the literature. J Endocrinol Invest 17:29–36, 1994

89. Scott GR, Forfar JC, Toft AD: Graves' disease and atrial fibrillation: The case for even higher doses of therapeutic iodine-131. Br Med J 289:399–400, 1984

90. Wade JS, Goodall P, Deane L, et al: The course of partial parathyroid insufficiency after thyroidectomy. Br J Surg 52:497–503, 1965

91. Hales IB, Rundle FF: Ocular changes in Graves' disease. A long-term follow-up study. Q J Med 29:113–126, 1960

92. Perros P, Crombie AL, Kendall-Taylor P: Natural history of thyroid associated ophthalmopathy. Clin Endocrinol 42:45–50, 1995

93. Hamilton HE, Schultz RO, DeGowin EL: The endocrine eye lesion in hyperthyroidism. Its incidence and course in 165 patients treated for thyrotoxicosis with iodine-131. Arch Intern Med 105:675–685, 1960

94. Calissendorff BM, Söderström M, Alveryd A: Ophthalmopathy and hyperthyroidism—a comparison between patients receiving different antithyroid treatments. Acta Ophthalmol 64:698–703, 1986

95. Sridama V, DeGroot LJ: Treatment of Graves' disease and the course of ophthalmopathy. Am J Med 87:70–73, 1989

96. Bartley GB, Fatourechi V, Kadrmas EF, et al: The treatment of Graves' ophthalmopathy in an incidence cohort. Am J Ophthalmol 121:200–206, 1996

97. Tallstedt L, Lundell G, Torring O, et al: Occurrence of ophthalmopathy after treatment for Graves' hyperthyroidism. The Thyroid Study Group. N Engl J Med 326:1733–1738, 1992

98. Bartalena L, Marcocci C, Bogazzi F, et al: Use of corticosteroids to prevent progression of Graves' ophthalmopathy after radioiodine therapy for hyperthyroidism. N Engl J Med 321:1349–1352, 1989

99. Manso PG, Furlanetto RP, Wolosker AMB, et al: Prospective and controlled study of ophthalmopathy after radioiodine therapy for Graves' hyperthyroidism. Thyroid 8:49–52, 1998

100. Tallstedt L, Lundell G, Blomgren H, et al: Does early administration of thyroxine reduce the development of Graves' ophthalmopathy after radioiodine treatment? Eur J Endocrinol 130:494–497, 1994

101. Shine B, Fells P, Edwards OM, et al: Association between Graves' ophthalmopathy and smoking. Lancet 335:1261–1263, 1990

102. Sergott RC, Felberg NT, Savino PJ, et al: Graves' ophthalmopathy: Immunologic parameters related to corticosteroid therapy. Invest Ophthalmol Vis Sci 20:173–182, 1981

103. Sisson JC, Vanderburg JA: Lymphocyte-retrobulbar fibroblast interaction: Mechanisms by which stimulation occurs and inhibition of stimulation. Invest Ophthalmol Vis Sci 111:15–20, 1972

104. Wiersinga WM, Smit T, Schuster-Uittenhoeve ALJ, et al: Therapeutic outcome of prednisone medication and of orbital irradiation in patients with Graves' ophthalmopathy. Ophthalmologica 197:75–84, 1988

105. Prummel MF, Mourits MP, Berghout A, et al: Prednisone and cyclosporine in the treatment of severe Graves' ophthalmopathy. N Engl J Med 321:1353–1359, 1989

106. Zgliczynski S, Jastrzebska H, Górowski T, et al: Treatment of severe Graves' ophthalmopathy: a three-stage management: Corticotherapy, retrobulbar irradiation, and transantral decompression. Acta Endocrinol 121(suppl 2):169–178, 1989

107. Apers RC, Oosterhuis JA, Bierlaagh JJ: Indications and results of prednisone treatment in thyroid ophthalmopathy. Ophthalmologica 173:163–167, 1976

108. Ivy HK: Medical approach to ophthalmopathy of Graves' disease. Mayo Clin Proc 47:980–985, 1972

109. Ohtsuka K, Sato A, Kawaguchi S, et al: Effect of high-dose intravenous steroid pulse therapy followed by 3-month oral steroid therapy for Graves' ophthalmopathy. Jpn J Ophthalmol 46:563–567, 2002

110. Ohtsuka K, Sato A, Kawaguchi S, et al: Effect of steroid pulse therapy with and without orbital radiotherapy on Graves' ophthalmopathy. Am J Ophthalmol 135:285–290, 2003

111. Macchia PE, Bagattini M, Lupoli G, et al: High-dose intravenous corticosteroid therapy for Graves' ophthalmopathy. J Endocrinol Invest 24:152–158, 2001

112. Kauppinen-Makelin R, Karma A, Leinonen E, et al: High-dose intravenous methylprednisolone pulse therapy versus oral prednisone for thyroid-associated ophthalmopathy. Acta Ophthalmol Scand 80:316–321, 2002

113. Shipley ME, Bacon PA, Berry H, et al: Pulsed methylprednisolone in active early rheumatoid disease: A dose-ranging study. Br J Rheumatol 27:211–214, 1988

114. Chikanza C, Fernandes L: Arrhythmia after pulse methylprednisolone therapy. Br J Rheumatol 30:392–393, 1991

115. Schonwald S: Methylprednisolone anaphylaxis. Am J Emerg Med 17:583–585, 1999

116. Utech C, Wulle KG, Panitz N, et al: Treatment of Graves' ophthalmopathy with new immunosuppressive agents. Dev Ophthalmol 20:94–99, 1989

117. Weetman AP, McGregor AM, Ludgate M, et al: Cyclosporin improves Graves' ophthalmopathy. Lancet 2:486–489, 1983

118. Bigos ST, Nisula BC, Daniels GH, et al: Cyclophosphamide in the management of advanced Graves' ophthalmopathy. Ann Intern Med 90:921–923, 1979

119. Perros P, Weightman DR, Crombie AL, et al: Azathioprine in the treatment of thyroid-associated ophthalmopathy. Acta Endocrinol 122:8–12, 1990

120. Kahaly G, Lieb W, Muller-Forell W, et al: Ciamexone in endocrine orbitopathy. A randomized, double-blind, placebo-controlled study. Acta Endocrinol 122:13–21, 1990

121. Kahaly G, Pitz S, Muller-Forell W, et al: Randomized trial of intravenous immunoglobulins versus prednisolone in Graves' ophthalmopathy. Clin Exp Immunol 106:197–202, 1996

122. Wiersinga WM, Prummel MF: Graves' ophthalmopathy: A rational approach to treatment. Trends Endocr Met 13:280–287, 2002

123. Kolodziej-Maciejewska H, Peterski Z: Positive effect of bromocriptine treatment in Graves disease orbitopathy. Exp Clin Endocrinol 86:241–242, 1985

124. Balazs C, Kiss E, Farid NR: Inhibitory effect of pentoxifylline on HLA-DR expression and gylcosaminoglycan synthesis of retrobulbar fibroblasts induced by interferon gamma. Acta Microbiol Immunol Hung 44:173–179, 1997

125. Bartalena L, Pinchera A, Marcocci C: Management of Graves' ophthalmopathy: Reality and perspectives. Endocr Rev 21:168–199, 2000

126. Bouzas EA, Karadimas P, Mastorakos G, et al: Antioxidant agents in the treatment of Graves' ophthalmopathy. Am J Ophthalmol 129:618–622, 2000

127. Antonelli A, Saracino A, Alberti B, et al: High-dose intravenous immunoglobulin treatment in Graves' ophthalmopathy. Acta Endocrinol 126:13–23, 1992

128. Kelly WF, Longson D, Smithard D, et al: An evaluation of plasma exchange for Graves' ophthalmopathy. Clin Endocrinol 18:485–493, 1983

129. Glinoer D, Schrooyen M: The treatment of severe Graves' ophthalmopathy with plasma exchange and immunosuppression. Acta Endocrinol (Copenh) 121:149–153, 1989

130. Zielinski CC, Weissel M, Muller C, et al: Long-term follow-up of patients with Graves' orbitopathy treated by plasmapheresis and immunosuppression. Dev Ophthalmol 20:130–138, 1989

131. Fakhri O: The use of low voltage electric therapy in the treatment of Graves' ophthalmopathy. Int Ophthalmol 15:201–203, 1991

132. Donaldson SS, Bagshaw MA, Kriss JP: Supervoltage orbital radiotherapy for Graves' ophthalmopathy. J Clin Endocrinol Metab 37:276–285, 1973

133. Maalouf T, George JL, Angioi-Duprez K, et al: Effects of orbital radiotherapy on extraocular muscles in Graves' ophthalmopathy. Orbit 15:25–32, 1996

134. Mourits MP, van Kempen-Harteveld ML, García MBG, et al: Radiotherapy for Graves' orbitopathy: Randomised placebo-controlled study. Lancet 355:1505–1509, 2000

135. Bartalena L, Marcocci C, Chiovato L, et al: Orbital cobalt irradiation combined with systemic corticosteroids for Graves' ophthalmopathy: Comparison with systemic corticosteroids alone. J Clin Endocrinol Metab 56:1139–1144, 1983

136. Hurbli T, Char DH, Harris J, et al: Radiation therapy for thyroid eye diseases. Am J Ophthalmol 99:633–637, 1985

137. Teng CS, Crombie AL, Hall R, et al: An evaluation of supervoltage orbital irradiation for Graves' ophthalmopathy. Clin Endocrinol 13:545–551, 1980

138. van Ruyven RLJ, van den Bosch WA, Mulder PGH, et al: The effect of retrobulbar irradiation on exophthalmos, ductions and soft tissue signs in Graves' ophthalmopathy: A retrospective analysis of 90 cases. Eye 14:761–764, 2000

139. Gorman CA, Garrity JA, Fatourechi V, et al: A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy. Ophthalmology 108:1523–1534, 2001

140. Wilson WB, Prochoda M: Radiotherapy for thyroid orbitopathy. Effects on extraocular muscle balance. Arch Ophthalmol 113:1420–1425, 1995

141. Prummel MF, Mourits MP, Blank L, et al: Randomised double-blind trial of prednisone versus radiotherapy in Graves' ophthalmopathy. Lancet 342:949–954, 1993

142. Kahaly GJ, Rösler H-P, Pitz S, et al: Low-versus high-dose radiotherapy for Graves' ophthalmopathy: A randomized, single blind trial. J Clin Endocrinol Metab 85:102–108, 2000

143. Nakahara H, Noguchi S, Murakami N, et al: Graves ophthalmopathy: MR evaluation of 10 Gy versus 24 Gy irradiation combined with systemic corticosteroids. Radiology 196:857–862, 1995

144. Kriss JP, Petersen IA, Donaldson SS, et al: Supervoltage orbital radiotherapy for progressive Graves' ophthalmopathy: Results of a twenty-year experience. Acta Endocrinol 121:154–159, 1989

145. Leone CR: The management of ophthalmic Graves' disease. Ophthalmology 91:770–779, 1984

146. Kinyoun JL, Kalina RE, Brower SA, et al: Radiation retinopathy after orbital irradiation for Graves' ophthalmopathy. Arch Ophthalmol 102:1473–1476, 1984

147. Brown GC, Shields JA, Sanborn G, et al: Radiation retinopathy. Ophthalmology 89:1494–1501, 1982

148. Nygaard B, Specht L: Transitory blindness after retrobulbar irradiation of Graves' ophthalmopathy. Lancet 351:725–726, 1998

149. Snijders-Keilholz A, De Keizer RJW, Goslings BM, et al: Probable risk of tumour induction after retro-orbital irradiation for Graves' ophthalmopathy. Radiother Oncol 38:69–71, 1996

150. Marcocci C, Bartalena L, Bogazzi F, et al: Orbital radiotherapy combined with high dose systemic glucocorticoids for Graves' ophthalmopathy is more effective than radiotherapy alone: Results of a prospective randomized study. J Endocrinol Invest 14:853–860, 1991

151. Wiersinga WM, Prummel MF: An evidence-based approach to the treatment of Graves' ophthalmopathy. Endocrinol Metab Clin North Am 29:297–319, 2000

152. Panzo GJ, Tomsak RL: A retrospective review of 26 cases of dysthyroid optic neuropathy. Am J Ophthalmol 96:190–194, 1983

153. Guy JR, Fagien S, Donovan JP, et al: Methylprednisolone pulse therapy in severe dysthyroid optic neuropathy. Ophthalmology 96:1048–1053, 1989

154. Kazim M, Trokel S, Moore S: Treatment of acute Graves' orbitopathy. Ophthalmology 98:1443–1448, 1991

155. Dollinger J: Die Druckentlastung der augenhöhle durch entfernung der äuberen orbitalwand bei hochgradigem exophthalmus (morbus Basedowii) und konsekutiver Hornhauterkrankung. Deutsche Medizin Wochenschr 41:1888–1890, 1911

156. Long JC, Ellis GD: Temporal decompression of the orbit for thyroid exophthalmos. Am J Ophthalmol 62:1089–1098, 1966

157. Berke RN: A modified Krönlein operation. Trans Am Ophthalmol Soc 51:193–231, 1953

158. Naffziger HC: Progressive exophthalmos following thyroidectomy: Its pathology and treatment. Ann Surg 1994:582–584, 1931

159. Hirsch O: Surgical decompression of malignant exophthalmos. Arch Otolaryngol 51:325–334, 1950

160. Ogura JH, Lucente FE: Surgical results of orbital decompression for malignant exophthalmos. Laryngoscope 84:637–644, 1974

161. Kennerdell JS, Maroon JC: An orbital decompression for severe dysthyroid exophthalmos. Ophthalmology 89:467–472, 1982

162. Walsh TE, Ogura JH: Transantral orbital decompression for malignant exophthalmos. Laryngoscope 67:544–568, 1957

163. Anderson RL, Linberg JV: Transorbital approach to decompression in Graves' disease. Arch Ophthalmol 99:120–124, 1981

164. Carter KD, Frueh BR, Hessburg TP, et al: Long-term efficacy of orbital decompression for compressive optic neuropathy of Graves' eye disease. Ophthalmology 98:1435–1442, 1991

165. Long JA, Baylis HI: Hypoglobus following orbital decompression for dysthyroid ophthalmopathy. Ophthal Plast Reconstr Surg 6:185–189, 1990

166. Scherer H: Orbital decompression surgery. Dev Ophthalmol 20:169–172, 1989

167. McCord CD: Current trends in orbital decompression. Ophthalmology 92:21–33, 1985

168. Hurwitz J, Rosenstock T: Management of inadequate transantral orbital decompression with extended lateral orbitotomy. Can J Ophthalmol 18:194–196, 1983

169. Wulc AE, Popp JC, Bartlett SP: Lateral wall advancement in orbital decompression. Ophthalmology 97:1358–1369, 1990

170. Leone CR, Piest KL, Newman RJ: Medial and lateral wall decompression for thyroid ophthalmopathy. Am J Ophthalmol 108:160–166, 1989

171. Goldberg RA, Kim AJ, Kerivan KM: The lacrimal keyhole, orbital door jamb, and basin of the inferior orbital fissure. Arch Ophthalmol 116:1618–1624, 1998

172. Tessier P: Expansion chirurgicale de l'orbite. Ann Chir Plast 14:207–214, 1969

173. Lyons CJ, Rootman J: Orbital decompression for disfiguring exophthalmos in thyroid orbitopathy. Ophthalmology 101:223–230, 1994

174. ünal M, Ileri F, Konuk O, et al: Balanced orbital decompression combined with fat removal in Graves' ophthalmopathy. Ophthal Plast Reconstr Surg 19:112–118, 2003

175. Paridaens D, Hans K, van Buitenen S, et al: The incidence of diplopia following coronal and translid orbital decompression in Graves' orbitopathy. Eye 12:800–805, 1998

176. Nunery WR, Nunery CW, Martin RT, et al: The risk of diplopia following orbital floor and medial wall decompression in subtypes of ophthalmic Graves' disease. Ophthal Plast Reconstr Surg 13:153–160, 1997

177. Schaefer SD, Soliemanzadeh P, Della Rocca DA, et al: Endoscopic and transconjunctival orbital decompression for thyroid-related orbital apex compression. Laryngoscope 113:508–513, 2003

178. Hutchison BM, Kyle PM: Long-term visual outcome following orbital decompression for dysthyroid eye disease. Eye 9:578–581, 1995

179. Garrity JA, Fatourechi V, Bergstralh EJ, et al: Results of transantral orbital decompression in 428 patients with severe Graves' ophthalmopathy. Am J Ophthalmol 116:533–547, 1993

180. Tallstedt L, Papatziamos G, Lundblad L, et al: Results of transantral orbital decompression in patients with thyroid-associated ophthalmopathy. Acta Ophthalmol Scand 78:206–210, 2000

181. Seiff SR, Tovilla JL, Carter SR, et al: Modified orbital decompression for dysthyroid orbitopathy. Ophthal Plast Reconstr Surg 16:62–66, 2000

182. Goldberg RA, Shorr N, Cohen MS: The medial orbital strut in the prevention of postdecompression dystopia in dysthyroid ophthalmopathy. Ophthal Plast Reconstr Surg 8:32–34, 1992

183. Mourits MP, Koornneef L, Wiersinga WM, et al: Orbital decompression for Graves' ophthalmopathy by inferomedial, by inferomedial plus lateral, and by coronal approach. Ophthalmology 97:636–641, 1990

184. Linberg JV, Anderson RL: Transorbital decompression. Indications and results. Arch Ophthalmol 99:113–119, 1981

185. White WA, White WL, Shapiro PE: Combined endoscopic medial and inferior orbital decompression with transcutaneous lateral orbital decompression in Graves' orbitopathy. Ophthalmology 110:1827–1832, 2003

186. Kacker A, Kazim M, Murphy M, et al: “Balanced” orbital decompression for severe Graves' orbitopathy: Technique with treatment algorithm. Otolaryngol Head Neck Surg 128:228–235, 2003

187. Shepard KG, Levin PS, Terris DJ: Balanced orbital decompression for Graves' ophthalmopathy. Laryngoscope 108:1648–1653, 1998

188. Goldberg RA, Weinberg DA, Shorr N, et al: Maximal, three-wall, orbital decompression through a coronal approach. Ophthalmic Surg Lasers 28:832–843, 1997

189. Gorman CA, DeSanto LW, MacCarty CS, et al: Optic neuropathy of Graves' disease. Treatment by transantral or transfrontal orbital decompression. N Engl J Med 290:70–75, 1974

190. Colvard DM, Waller RR, Neault RW, et al: Nasolacrimal duct obstruction following transantral-ethmoidal orbital decompression. Ophthalmic Surg 10:25–28, 1979

191. Crawford BA: Thyroid optic neuropathy: To decompress or not? Aust J Ophthalmol 1:6–11, 1973

192. Olivari N: Transpalpebral decompression of endocrine ophthalmopathy (Graves' disease) by removal of intraorbital fat: Experience with 147 operations over 5 years. Plast Reconstr Surg 87:627–641, 1991

193. Adenis JP, Robert PY, Lasudry JGH, et al: Treatment of proptosis with fat removal orbital decompression in Graves' ophthalmopathy. Eur J Ophthalmol 8:246–252, 1998

194. Olivari N: Thyroid-associated orbitopathy: Transpalpebral decompression by removal of intraorbital fat. Experience with 1362 orbits in 697 patients over 13 years. Exp Clin Endocrinol Diabetes 107:S208–S211, 1999

195. Ferreira MC, Tuma PJr , Costa MP, et al: Surgical treatment of endocrine exophthalmos by removal of orbital fat: Clinical experience. Rev Hosp Clín Fac Med 57:217–222, 2002

196. Dunn WJ, Major MC, Arnold AC, et al: Botulinum toxin for the treatment of dysthyroid ocular myopathy. Ophthalmology 93:470–475, 1986

197. Lyons CJ, Vickers SF, Lee JP: Botulinum toxin therapy in dysthyroid strabismus. Eye 4:538–542, 1990

198. Biglan AW, Burnstine RA, Rogers GL, et al: Management of strabismus with botulinum A toxin. Ophthalmology 96:935–943, 1989

199. Coats DK, Paysse EA, Plager DA, et al: Early strabismus surgery for thyroid ophthalmopathy. Ophthalmology 106:324–329, 1999

200. Boergen KP: Surgical repair of motility in Graves' orbitopathy. Dev Ophthalmol 20:159–168, 1989

201. Gardner TA, Kennerdell JS: Treatment of dysthyroid myopathy with adjustable suture recession. Ophthalmic Surg 21:519–521, 1990

202. Lueder GT, Scott WE, Kutschke PJ, et al: Long-term results of adjustable suture surgery for strabismus secondary to thyroid ophthalmopathy. Ophthalmology 99:993–997, 1992

203. Scott WE, Thalacker JA: Diagnosis and treatment of thyroid myopathy. Ophthalmology 88:493–498, 1981

204. Nguyen VT, Park DJJ, Levin L, et al: Correlation of restricted extraocular muscle motility in surgical management of strabismus in Graves' ophthalmopathy. Ophthalmology 109:384–388, 2002

205. Gerding MN, Terwee CB, Dekker FW, et al: Quality of life in patients with Graves' ophthalmopathy is markedly decreased: Measurement by the medical outcomes study instrument. Thyroid 7:885–889, 1997

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