Concise Review invited by Shunichi Yamashita; Reviewing Editor: Luca Persani

The authors declare no conflict of interest for this paper

Correspondence to: Yuji Hiromatsu, Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 830-0011 Japan. E-mail: yuji@med.kurume-u.ac.jp

ABSTRACT
Magnetic resonance imaging (MRI) can visualize the inflamed lesions of Graves’ orbitopathy (GO). Parasagittal, transverse and coronal sections of T1-weighted, T2-weighted and short inversion time inversion recovery (STIR) images can correlate clinical manifestations with the location of the inflamed lesions. In addition, the measurement of T2 relaxation time or signal intensity ratio of the enlarged muscles in T2-weighted fat suppression images or STIR images provide a precise quantitative evaluation of disease activity and may predict the outcome of immunosuppressive therapy for GO. MRI has potential in the evaluation of new drugs for GO. Therefore, we recommend MRI as a useful tool for the management of GO.

Introduction
Graves’ orbitopathy (GO) is an autoimmune disorder frequently associated with autoimmune thyroid diseases. GO is clinically relevant in 25–50% of patients with Graves’ disease and in 2% of patients with chronic thyroiditis (1–5). At the onset of ophthalmopathy, 90% of GO patients have hyperthyroidism and the rest have either euthyroidism or hypothyroidism. It often develops concomitantly with hyperthyroidism, but it may precede or follow hyperthyroidism (4). GO is usually bilateral, but it can be asymmetric or unilateral in 15% of patients (5). Sight is threatened in 3–5% of GO patients and, thus, requires urgent treatment (4).
Histological studies showed that extraocular muscles are widely separated by lymphocytic infiltrations and amorphous accumulation of glycosaminoglycans in the active stage. There are also lymphocytic infiltrations in the expanded fat tissue and lacrimal glands. In the inactive stage, atrophy and fibrosis of muscle bundles are evident. Although there is increasing evidence that the thyrotropin receptor may be the primary autoantigen in GO, and insulin-like growth factor-1 receptor and other antigens shared between the thyroid and orbit are hypothesized as important autoantigens in GO, the precise mechanisms of the development of GO are still unclear (3). The mechanism of the frequent association of GO with Graves’ disease also remains unclear. The underlying genetic factors for susceptibility to GO have not been fully elucidated.
As various sites are involved in GO, various symptoms and signs are observed (6) (Fig. 1). In most cases, the diagnosis of GO is obvious: lid retraction combined with unilateral or bilateral proptosis in a person with a history of hyperthyroidism or hypothyroidism. However, in unilateral or unusual cases, orbital imaging is necessary for accurate diagnosis. Orbital imaging, such as magnetic resonance imaging (MRI), computed tomography (CT) and echography, show enlargement of the extraocular muscles, an increase in orbital fat tissue volume and enlargement of the lacrimal glands (7). In addition, orbital imaging reveals abnormalities in 90% of patients with Graves’ disease.
Recently, the European Groups on Graves’ Orbitopathy (EUGOGO) published recommendations for the assessment of GO using the clinical activity score (CAS) and ophthalmologic examination (8,9). In North America, the International Thyroid Eye Disease Study Group proposed the VISA (Vision-Inflammation-Soft tissue-Activity) scoring system for the assessment of GO (10). According to EUGOGO’s recommendation, in their combined thyroid eye clinics, clinicians first assign their GO patients to “sight-threatening”, “moderate-to-severe” or “mild” categories, and then determine whether or not the disease is active using CAS. If CAS is more than 3, immunosuppressive therapy is recommended for the treatment of GO (8).
In Japan, orbital MRI has been widely used to assess the activity and severity of GO, since we established the usefulness of MRI using short inversion time inversion recovery (STIR) images or T2 relaxation time (11–18). In this review, we examine the value of MRI for diagnosis and management of GO and for assessment of disease activity and severity, as well as allowing visualization of the involved lesions.


Fig. 1. Orbital lesions and clinical manifestations in Graves’ orbitopathy. (modified from ref. # 6)

Magnetic resonance imaging
Our currently used MRI protocols for GO patients are: 1) T1-weighted image of the transverse, coronal and parasagittal sections; 2) T2-weighted fat suppression image or STIR image of the transverse, coronal and parasagittal sections; and 3) measurement of T2 relaxation time of the enlarged rectus muscles or signal intensity ratio in the coronal T2-weighted fat suppression image, or STIR image. The protocols should be adjusted for each machine.

Relationship between clinical manifestations and MRI
As mentioned above, patients with GO show a variety of symptoms and signs. The NOSPECS classification (19) has been used for long periods and is now outdated as a means of assessing patients with GO in clinical studies. However, it is still useful as a reminder of the clinical features that should be assessed.

Class 0: No physical signs or symptoms
More than a half of patients with Graves’ disease do not have evident ophthalmopathy. Villadolid et al.(17) reported that 71% of patients with untreated Graves’ disease without symptoms or signs of ophthalmopathy had enlargement of the extraocular muscles. Similar results were reported by Enzmann et al. (20) using CT. Therefore, subclinical involvement of the extraocular muscles is common in GO and is termed “occult thyroid eye disease” (21,22). Although we do not know who will develop overt ophthalmopathy, we recommend MRI for patients with symptoms such as sensation of grit, light sensitivity, photophobia, excess eye-watering and blurring of vision, but no signs by ophthalmological examination. These symptoms may be initial symptoms during early GO. Future studies are indicated to clarify the factors associated with susceptibility to GO. It is important to control thyroid function in euthyroidism and abstain from tobacco smoking at this stage. Fig. 2A and 2B show T1-weighted images of the parasagittal section of orbital MRI in 2 patients with class 0.

Class I: Only signs, no symptoms (upper lid retraction, staring, and eyelid lag
Lid retraction has been observed in 58–79% of GO patients (23,24). The sympathetic nerve stimulation associated with hyperthyroidism causes contraction of Müller’s muscles, resulting in lid retraction. In this condition, it is important to achieve and maintain euthyroidism and guanethidine may alleviate lid retraction. However, two-thirds of patients may not respond to guanethidine. MRI reveals the enlargement of the “levator palpebrae superioris” (LPS) muscle and/ or “superior rectus”(SR) muscle (Fig. 2C, 2D). In patients with von Graefe’s sign, MRI reveals the enlargement of the LPS muscle and/ or other extraocular muscles. Unilateral eye changes occur in 15% of patients with GO. In patients with unilateral lid retraction, enlargement of the LPS muscle and/or SR muscle are observed in the affected eye. Local injection of glucocorticoids (25,26), or botulinum toxin (27,28), or systemic administration of glucocorticoids indicated in those patients. MRI therefore aids treatment decision-making.

Fig. 2 Orbital MRI (T1-weighted parasagittal sections) in 4 patients. A: Patient without signs, or symptoms; MRI indicates no enlargement of muscles; B: Patient without signs, or symptoms; MRI reveals the enlargement of superior and inferior rectus muscles; C: Patient with Dalrymple sign, von Graefe’s sign and proptosis; MRI reveals the enlargement of levator palpebrae superioris muscle; D: Patient with Dalrymple sign; MRI shows the enlargement of superior and inferior rectus muscles. Arrows indicate the lesions. (modified from Hiromatsu Y, Nippon Naika Gakkai Zasshi. 2010; 99:755-62, 2010).

Class II: Soft tissue involvement (symptoms and signs)
Lid swelling is frequently observed in 47%–68% of patients (23,24), and conjunctival injection and edema are observed in 32% of GO patients. MRI reveals the accumulation of fat tissue in the upper and lower eyelids (Fig. 1C, 1D).

Class III: Proptosis
Proptosis is seen in 24% of untreated patients with Graves’ disease and in 74%–85% of GO patients (23,24). Proptosis is usually accompanied by lid retraction (46%), lid swelling (19%), or both (16%). MRI reveals two types of exophthalmus. One is a result of the increase in fat tissue volume, and the other arises from enlargement of the extraocular muscles. The former type is observed in young female patients, the latter is more dominant in older male patients. In patients with the former type of exophthalmus, orbital fat decompression surgery is indicated in the inactive stage. The latter type of exophthalmus is classified as class IV. MRI can visualize the proptosis in transverse and parasagittal sections.



Fig. 3. Orbital MRI before steroid pulse therapy for patients with diplopia. A: Patient with diplopia; MRI reveals the enlargement of superior and inferior rectus muscles, proptosis and the accumulation of fat tissue in the eyelids B: Another patient with diplopia; upper snapshot, coronal section of T1-weighted image; lower snapshot, coronal section of STIR image Open circles shows the area where the signal intensity is measured. 1, orbital connective tissue; 2, eye muscle; 3, cerebral substantia alba.(modified from ref. # 11).

Class IV: Extraocular muscle involvement
About 22% of patients with GO suffer from diplopia (23). Enlargement of the inferior rectus muscle causes restriction of motion in upward gazing, and vertical deviation of the affected eye (Fig. 3A). The enlarged eye muscle is no longer able to lengthen. In most GO patients, several rectus muscles are affected to various degrees. Therefore, MRI is useful to evaluate the orbital lesions in GO.

Class V: Corneal involvement
When the cornea cannot be protected by the closed eye, stippling of the cornea and ulceration may occur. Although punctuate staining is seen in 10%–17% of patients, the incidence of sight-threatening ulceration was <2% a century ago, and is probably lower now (5).
Class VI: Sight loss (optic nerve involvement)
Optic nerve involvement, so-called dysthyroid optic neuropathy, is observed in 3–7% of GO patients (8,24). Papilledema, papillitis and optic nerve atrophy are the main findings in this stage. MRI shows narrowing of apical crowding as a result of the enlargement of all rectus muscles, which compress the optic nerve. Intravenous injection of methylprednisolone is urgently indicated. If an improvement of sight is not obtained within 2 weeks, decompression surgery is warranted.

Differential diagnosis
In most cases, the diagnosis of GO is obvious: lid retraction combined with unilateral or bilateral proptosis in a person with a history of hyperthyroidism or hypothyroidism. Euthyroidism does not exclude GO. When the diagnosis is uncertain in atypical cases, orbital imaging is warranted. Myasthenia gravis, orbital myositis, carotid-cavernous fistula, orbital tumors and progressive external ophthalmoplegia should be ruled out.

Disease severity
The severity of disease should be assessed by measuring lid aperture, swelling and redness of the eyelids, redness and edema of the conjunctivae, inflammation of the caruncle or plica, exophthalmos, diplopia, eye muscle involvement, corneal involvement and optic nerve involvement, etc (8). Three classes of disease are described below (see also Fig. 4):
1) “Sight-threatening” GO
Dysthyroid optic neuropathy or corneal breakdown is sight-threatening and requires immediate treatment (8). Deterioration of vision, changes in intensity or quality of color vision, or disk swelling on fundoscopy, or if there is orbital subluxation, corneal opacity, or lagophthalmos with visible cornea, urgent referral is important.
2) “Moderate-to-severe” GO
For patients without sight-threatening GO, but whose eye disease has a marked impact on daily life, the risks of immunosuppression (if active) or surgical intervention (if inactive) are justified. Patients with moderate-to-severe GO usually have any one or more of the following: lid retraction ≥2 mm, moderate or severe soft tissue involvement, exophthalmos ≥3 mm above normal for race and gender, inconstant or constant diplopia, moderate corneal involvement.

3) “Mild” GO
In patients whose features of GO have only a minor impact on daily life, immunosuppressive or surgical treatment is not justified (8). Making treatment decisions requires detailed assessment of the eyes, understanding of the natural history of the disease, insight into the impact of GO on individual patients, and appreciation of the efficacy and side effects of therapies.

Disease activity
1) Clinical activity score
The CAS was proposed as a measure of disease activity by EUGOGO (8). CAS is calculated according to the presence or absence of the seven characteristic symptoms and signs (painful oppressive feeling in or behind the orbit, gaze-evoked pain, eyelid swelling, eyelid erythema, conjunctival redness, chemosis, caruncle or plica swelling). A CAS with 0 to 2 characteristics indicates inactive GO, and with 3 to 7 characteristics indicates active GO. The score has been shown to be predictive of a patient’s response to immunosuppressive therapy. Mourits et al.(29) reported that GO patients whose CAS was over 4 of 10 points had a good response to glucocorticoid therapy. However, 10 of 28 patients whose CAS was 3 points or less also responded to immunosuppressive therapy (30). A recent study in Japan showed that two of eight GO patients whose CAS was 0 had active GO according to orbital MRI (31). Thus they hypothesized that MRI is more sensitive for detection of disease activity than CAS alone. Therefore, we recommend orbital MRI for assessment of GO.
2) T2 relaxation time and signal intensity ratio assessed by orbital MRI
Just et al.(32) reported that a long T2 time in the extraocular muscles before treatment was associated with a good response to orbital radiation. We reported that STIR imaging was useful for predicting the outcome of immunosuppressive therapy (11) (Fig. 3B). In 23 patients, we found a positive predictive value of 69% and a negative predictive value of 86% (11). Yokoyama et al. (18) reported that a homogeneously high signal intensity in T2 images was associated with a good response to methylprednisolone pulse therapy. Since then several reports have confirmed these findings. Thus, MRI seems a promising modality to detect disease activity. There are correlations between CAS and signal intensity ratio in STIR (33) and TIRM (turbo inversion recovery magnitude) sequences in T2-weighted and fat-suppressed images (34) and T2 relaxation time (31). Therefore, we recommend MRI as a useful tool for GO management.
There are some criticisms that MRI is not suitable for the assessment of GO because of the high cost, poor reproducibility of T2 relaxation times, and the dependence of T2 relaxation times on specific MRI equipment in different institutions. However, we recommend evaluating the disease activity by selecting either T2 relaxation time or signal intensity ratio in STIR in each institute. The good negative predictive value should be confirmed in a larger study.


Fig. 4. Management of Graves’ orbitopathy. We recommend that MRI should be considered to all the GO patients in the specialized center. It helps the diagnosis of GO (severity and activity) and the decision making of management of GO. Rehabilitative surgery includes orbital decompression, squint surgery, lid lengthening, and blepharoplasty/browplasty. i.v.GCs, intravenous glucocorticoid; OR, orbital radiotherapy; DON, dysthyroid optic neuropathy. (modified from ref. #8)

Treatment of hyperthyroidism
Because uncontrolled thyroid function is more likely to be associated with severe GO than patients with euthyroidism, all patients with GO should be treated promptly to restore and maintain euthyroidism (Fig. 4). Anti-thyroid drugs and thyroidectomy do not affect the course of GO, whereas radioiodine treatment is associated with a small risk of exacerbation of the disease (35,36). Development or exacerbation of GO after radioiodine therapy has been reported in randomized controlled trials (RCTs). In one RCT, radioiodine therapy caused progression of GO in about 15% of patients, whereas anti-thyroid drugs did not modify the natural course of GO (36). Risk factors for progression of GO after radioiodine therapy for hyperthyroidism include cigarette smoking (37), severe hyperthyroidism (free thyroxine >5 nmol/L), high levels of thyrotropin-receptor antibodies (38), and uncontrolled hypothyroidism. In two RCTs concomitant treatment of high risk patients with oral prednisolone prevented progression and ameliorated the preexisting GO. The risk of exacerbation of pre-existing GO after radioiodine therapy is negligible as long as post-radioiodine hypothyroidism is avoided with levothyroxine (39).

Treatment of ophthalmopathy
1) Glucocorticoids
Patients with sight-threatening dysthyroid optic neuropathy require immediate treatment, usually with high-dose intravenous glucocorticoid agents (8). A common initial regimen is the administration of 1g of methylprednisolone intravenously for 3 consecutive days. If there is little or no improvement after 1 to 2 weeks, patients should promptly undergo surgical orbital decompression. There was no significant difference in outcome between decompression performed as first-line treatment, and initial treatment with intravenous glucocorticoids followed by oral prednisone (40).
Systemic administration of glucocorticoids is also indicated in moderate-to-severe and active GO (41). In a placebo-controlled, randomized trial, intravenous glucocorticoids (four cycles of methylprednisolone at a dose of 500 mg for 3 consecutive days at 4-week intervals) were effective in treating inflammatory changes and ocular movements in five of six patients as compared with one of nine patients who received placebo (42). In RCTs, intravenous therapy results in a higher rate of favorable responses than oral therapy and is better tolerated, with a reduced risk of the development of cushingoid features (43,44). However, severe and acute liver damage has been reported during intravenous glucocorticoid therapy (45–47). The risk of life-threatening liver failure has been reported with very high cumulative doses in 0.8% of patients. Therefore, EUGOGO recommends that the total cumulative dose of methylprednisolone should not exceed 8 g in one course of therapy (8,48). There is no consensus regarding the optimal dose and schedule. Thus, intravenous glucocorticoid therapy should be given only with close monitoring in specialized centers. All the patients should be closely followed for other potential adverse effects of glucocorticoid treatment (e.g., hypertension, hyperglycemia, electrolyte abnormalities, gastric ulcer and infections).
2) Orbital radiotherapy
Orbital radiotherapy is also useful for GO. In open trials about 60% of patients have had overall favorable responses to orbital irradiation (4). A common cumulative dose of radiation is 20 Gy per eye, given in 10 sessions over a 2-week period. An alterative regimen of 1 Gy per week over a 20-week period was equally effective and better tolerated (49). A lower dose (10 Gy) may be as effective as the standard 20 Gy regimen. Although one RCT has questioned the efficacy of orbital irradiation (50), a recent review of 18 studies (8 cohort and 10 RCT) showed that orbital radiotherapy is effective treatment for GO and the combination of orbital radiotherapy with intravenous methylprednisolone is more effective than either modality alone (51). Diabetes mellitus and severe hypertension are relative contraindications for orbital irradiation, because they increase the risk of retinopathy. Although the risk of tumors secondary to orbital irradiation is extremely small, orbital irradiation should be avoided in patients younger than 35 years of age because of the potential long-term carcinogenic effects (8).
3) Surgery
Orbital decompression is required for sight-threatening dysthyroid optic neuropathy if high dose glucocorticoids do not ameliorate this condition within 1 to 2 weeks. Orbital decompression is also required for imminent corneal breakdown, if local measures and eyelid closure do not provide rapid, substantial improvement. Orbital CT is the modality of choice to plan orbital decompression surgery because CT can provide precise imaging of the orbital apex and especially of the osseous structures.
Rehabilitative surgery is indicated for moderate-to-severe GO in the inactive stage. EUGOGO recommends that rehabilitative surgery should be performed in patients who have had inactive GO for at least 6 months, and surgical management should proceed in the following sequence: orbital decompression, then squint surgery, and then lid lengthening with or followed by blepharoplasty/browplasty, since the side effects of each step can interfere with the subsequent step (8).

Treatment of mild GO
EUGOGO recommends that simple measures and watchful waiting are appropriate for the majority of patients with mild GO, because glucocorticoids are rarely justified in mild GO as the risks outweigh the benefits (8). In a minority of patients with mild GO, whose quality of life is profoundly affected, glucocorticoid therapy is indicated. Although GO is a self-limiting disease, new efficacious drugs with minimal side effects are warranted. Antioxidants, such as selenium and pentoxifylline may be beneficial candidates for mild GO (52, 53). Parasagittal MRI provides information on eyelids and LPS and RS muscles, which is useful for planning therapy such as local injection of a glucocorticoid or botulinum toxin.

Other possible pharmacologic treatment
Randomized trials have not shown a benefit of somatostatin analogs (octreotide and lanreotide) for GO (54). The efficacy of the new somatostatin analog, SOM230, which has a relatively broad spectrum of activity, has not yet been evaluated. Cyclosporine was less effective than oral glucocorticoids in a randomized trial but may help to reduce the dose of glucocorticoids. Preliminary data suggest that immunomodulatory drugs such as rituximab (anti-CD20) (55–57) and etanercept (inhibitor of tumor necrosis factor-)(58) may be beneficial for GO. In an open-label study, rituximab showed better outcomes and fewer adverse effects than intravenous steroid treatment. Randomized, controlled trials are required to evaluate the role of rituximab in the treatment of GO.

Conclusions
Patients with GO should be evaluated in a specialist center or by both an endocrinologist and ophthalmologist experienced in the management of this disorder. Orbital MRI provides useful information regarding the inflamed lesions in the orbit, especially in extraocular muscle involvement and optic nerve involvement. Both T2 relaxation time and signal intensity ratio in STIR images indicate the activity of the lesion. Furthermore, MRI can visualize the inflamed lesion in the orbit. Thus, MRI is useful for decision-making regarding immunosuppressive therapy and prompt surgery for GO. It is also useful for predicting the outcome of immunosuppressive therapy. It may also provide a rationale to select new drugs for GO. Although there are some limitations in MRI, because of the reproducibility of the T2 relaxation time, cost and availability in some countries, we recommend that MRI should be considered for assessment of GO in specialized clinics.

Acknowledgements
This work is supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.

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