Graves disease (GD) is the most common autoimmune disorder with the main target of the immune system being the thyroid-stimulating hormone (TSH) receptor of the thyrocyte (1,2). In contrast to most autoimmune diseases that cause targeted tissue damage, the deleterious immunologic response in GD results in thyrocyte stimulation and over production of thyroid hormones (3). Thyroid eye disease (TED) is the most common extrathyroidal manifestation of GD (4,5). The extrathyroidal manifestations of GD occur from cross-reaction between activated lymphocytes and cells expressing the TSH and possibly other surface receptors (6). Although the pathogenesis of TED is not clearly understood, most researchers now agree that the orbital fibroblast is the primary point of attack of the immune reaction (7–11). TED may develop before or concomitantly with Graves hyperthyroidism, but in 60% of cases it follows (ranging from months to years) the diagnosis of systemic GD (12,13).
PREVALENCE AND NATURAL HISTORY OF THYROID EYE DISEASE
The occurrence of clinically evident TED in patients with GD varies greatly from 13% to 69% (14). In a nonintervention, prospective study from a single referral center, over an 8-year period, 346 patients were recruited to determine the prevalence and natural history of TED (15). At presentation, 73.7% of patients had no clinical evidence of TED, 20.2% had mild TED, 5.8% had moderate-to-severe TED, and 0.3% had dysthyroid optic neuropathy. Of the 194 patients who did not have TED on presentation, after 18 months, 87.1% continued to have no TED, 10.3% developed mild TED, and only 2.6% developed moderate-to-severe TED. Interestingly, of the 43 patients with mild TED on presentation, 58.1% improved spontaneously and only 2.4% progressed to moderate-to-severe TED.
Patients with TED present in 2 distinct phases conceptualized by Rundle curve (Fig. 1) (16,17). The active inflammatory phase is characterized by periorbital erythema and edema, conjunctival chemosis, orbital inflammation and congestion, associated with eyelid retraction, proptosis, and diplopia. The active inflammatory phase is frequently mild and self-limited and often requires only supportive intervention (e.g., artificial tears, sunglasses) (18). The inflammatory phase is typically followed after a variable period (between 6 and 24 months) by a quiet, minimally inflammatory chronic fibrotic phase associated with orbital fibrosis, glycosaminoglycan deposition, and enlarged extraocular muscles. The chronic fibrotic phase results in similar clinical findings (i.e., eyelid retraction, proptosis, and diplopia) to the active inflammatory phase (17).
Treatment of TED has relied on a shotgun approach of general inflammatory suppression with corticosteroids and orbital radiotherapy (ORT) during the active phase and surgical correction of the anatomic sequelae during the chronic phase. As with other autoimmune diseases, a more contemporary approach to TED focuses on targeted therapies directed at blocking the production or interfering with the activity of specific pro-inflammatory cytokines, manipulating the development, proliferation, and function of specific subtypes of B and T cells and inhibiting adipogenesis (19–21). In TED, such therapies will only be effective in the active inflammatory phase of the disease. Because of the broad clinical overlap of the active and fibrotic phases, it is important to identify, through improved classification schemes, where a patient is situated in the evolution of their disease.
CLASSIFICATION SCHEME AND CLINICAL ASSESSMENT OF THYROID EYE DISEASE
There has been great deal of discussion regarding the classification and assessment of TED for both clinical and research purposes (17,22–26). Given the emerging emphasis on a focused immunosuppression and immunomodulation approach to autoimmune diseases in general, and TED in particular, any such classification or assessment scheme must not only be reproducible but it must be able to accurately score the severity and activity of the inflammatory phase of the disease (27). In 1969, Werner devised the clever mnemonic NO SPECS (No signs and symptoms, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle involvement, Corneal involvement, and Sight loss), which was the basis of the ophthalmology index for many decades (28–31). Although this classification has been used to document disease severity (its original intention was to summarize the overall [active and chronic] clinical manifestations of TED), it does not adequately identify patients in the active phase of disease (22). Since the development of NO SPECS, a number of other classification and assessment schemes have been developed including VISA (Vision, Inflammation, Strabismus, and Appearance) (32), CAS (Clinical Activity Score) (24,33), and the EUGOGO (European Group On Graves' Orbitopathy) system (34) (See Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A100). These scoring systems assess inflammatory signs in an attempt to identify patients in the active phase who are most likely to respond to treatment.
TREATMENT OF ACTIVE THYROID EYE DISEASE
There is no consensus as to the best treatment strategy for TED. Management of active TED requires a comprehensive and multimodality approach in which the ophthalmologist and endocrinologist work as a team to develop a specific plan of care (34,35). As mentioned above, the decision to initiate treatment requires a careful analysis of the patient's ophthalmic status (severity) and determination of whether the patient is in the active or chronic phase of the disease (Fig. 1B). Specific questions to be addressed include:
1. How active and severe is the TED?
2. What TED risk factors can be modified or treated?
3. What is the best management strategy for the Graves hyperthyroidism?
4. What is the optimum treatment for the TED?
Modifiable Risk Factors for Development or Progression of Thyroid Eye Disease
There are many risk factors that can affect the development or progression of TED (Fig. 2) (36). Some of these, such as age, gender, ethnicity, genetics, and thyrotropin receptor antibody status, are not modifiable (37,38). Others, such as smoking and thyroid status, can be modified with a potential favorable impact on the course of the disease (4,38).
There is strong clinical evidence that cigarette smoking is associated with and adversely affects the development, progression, and management of TED (39). In a case–control study of 450 thyroid patients (with 400 controls), smoking cigarettes increased the risk of TED by 7-fold (40). Smoking has been associated with more severe and progressive TED (34), worsening of TED after radioactive iodine (RAI) treatment (41), and lessening the beneficial effects of immunosuppressive therapy (38,42).
As with the cessation of smoking, it is important to achieve and sustain a euthyroid state in patients with TED (38). Prummel et al (43) found that patients with hyperthyroidism or hypothyroidism had a greater eye severity score than euthyroid patients, which translated to an odds ratio of 2.8. It has also been shown that restoring euthyroidism can improve TED (44).
Treatment of Hyperthyroidism
There are 3 main treatment options for patients with Graves hyperthyroidism: antithyroid drugs, thyroidectomy, and RAI treatment (45). Each of these modalities has been studied in terms of the influence on the development and worsening of TED.
The thionamides (propylthiouracil, methimazole, and carbimazole) lower thyroid hormone production by inhibiting the iodination of thyroglobulin and ultimately the production of thyroxine (T4) and thriiodothryronine (T3) (46). Several studies have shown that antithyroid drugs do not adversely affect TED (34,47,48). Bartalena et al (49) studied the effect of methimazole on the development and progression of TED. Of the 148 patients treated with methimazole, 95% had no change in TED status, 3% improved, and only 3% worsened.
The effect of thyroidectomy on the course of TED remains unclear (34). Marcocci et al (50) performed a case–control study in which 30 patients with either no or mild TED treated with near total thyroidectomy were compared with 60 patients treated with methimazole. One patient (3.3%) in the thyroidectomy group had new or worsening TED compared with 2 patients (3.3%) in the methimazole group. The authors concluded that near-total thyroidectomy did not have an effect on TED. In a meta-analysis of 3 randomized clinical trials involving total thyroidectomy vs subtotal thyroidectomy (51), no difference was found between these 2 surgical procedures on the development or worsening of TED (52–54).
Radioactive Iodine Treatment
In 1967, Kriss et al (55) were the first to report the effect of RAI treatment on TED. Since then many retrospective reports have shown a negative effect of RAI treatment on TED (56,57). Approximately 15% of patients may experience new onset or worsening of TED after RAI treatment (See Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A101) (34,49,58–62). Prophylactic treatment with oral prednisone during and for several weeks following RAI treatment may significantly reduce the risk of the development or progression of TED (49,59,63,64). Although the exact pathomechanism of TED development or worsening after RAI treatment is not precisely known, it has been suggested that there is a change in thyroid autoimmunity with the production of TSH receptor antibodies due to the release of thyroid antigens as the result of RAI-induced tissue damage (17,56).
All patients with TED should be counseled on risk modification, particularly smoking cessation. Although corticosteroids and ORT reduce the active inflammatory symptoms, there is no proven role for these modalities in reducing the risk of disease progression in patients with mild TED (65). Preservative free artificial tears and moisture chambers are very helpful for dry eyes and corneal exposure. Sunglasses can improve photosensitivity. Fresnel prisms (or monocular occlusion) can resolve double vision. Eyelid retraction can be temporarily treated with the injection of botulinum toxin into the levator superioris and Müller muscle complex (66–68).
The most common current treatment strategies for active moderate-to-severe TED involve corticosteroids and ORT.
Corticosteroids are the most often used therapy for TED. However, the precise dosage, duration, preparation, and route (intravenous [IV], oral [PO], or periocular) of administration remain a matter of opinion and debate (17,69,70). In most cases, corticosteroid use is reserved for patients with active moderate-to-severe TED and dysthyroid optic neuropathy (16,66,71). The response rate with PO corticosteroids is less than IV corticosteroids (60% vs 80%, respectively) (17,72,73). Pooled data have shown that patients who received IV corticosteroids compared with PO corticosteroids fared better in terms of double vision, ocular motility, and proptosis, with fewer side effects (72). To date, there have been only 4 randomized clinical trials that have compared the efficacy of PO corticosteroids with IV corticosteroids (See Supplemental Digital Content, Table E3, http://links.lww.com/WNO/A102) (74–78).
Based on a review of the literature, Zang et al (78) recommend a 12-week course of IV methylprednisolone (0.5 g as a single dose per week for 6 consecutive weeks followed by 0.25 g as single dose per week for 6 consecutive weeks, not to exceed a total of 8 g) for patients with active moderate-to-severe TED. EUGOGO performed a multi-center, randomized, double-blinded trial to access the efficacy and safety of 3 different cumulative doses (2.25, 4.98, and 7.47 g) of IV methylprednisolone over a 12-week period in patients with active moderate-to-severe TED. The 7.47 g group had the greatest positive short-term response in terms of CAS. This benefit did not persist at 24 weeks and was associated with a slightly higher rate of adverse events compared with the lower doses (79). Oral and IV corticosteroid treatment can be associated with significant hepatic, metabolic, cardiovascular, and cerebrovascular side effects and in some cases death. Patients must be monitored carefully with the benefits weighed against the risks (80).
Intravenous corticosteroids can be highly effective in reversing the visual loss due to dysthyroid optic neuropathy and should be instituted before considering alternative therapy, such as orbital decompression (16,66,81,82). The use of corticosteroids concurrently with ORT has been found to be more efficacious than ORT alone (see below) (17,72,73). Some patients can have worsening orbital inflammation during or after ORT, which can be suppressed with a short course of corticosteroids (83).
Selenium, through its effects from selenoproteins, plays an important role in cell development and proliferation, oxidative stress protection, and production of T3. Since selenium acts as a potent antioxidant, and oxygen free radicals contribute to the orbital inflammatory process, theoretically it could be of some therapeutic benefit in TED (84,85). In a randomized, double-blinded, placebo controlled trial of mild TED, the overall ophthalmic outcome was better in the selenium (100 μg twice daily) group compared with the placebo group (P = 0.01) (86). TED improved in 61% of the selenium group and 36% of the placebo group. TED worsened in 7% of the selenium group and 26% of the placebo group (selenium compared with placebo, P = 0.01). Although there were no adverse drug reactions in any patients taking selenium, concerns of selenium toxicity include the increased risk of diabetes mellitus, glaucoma, and neurotoxicity (87–89).
ORT can be effective in TED with an overall response rate of 60% (34,90). However, there remains much debate over the role of ORT in TED (91). The impediment to a general consensus of ORT in TED derives from the paucity of randomized clinical trials, nonstandardized clinical measures and outcomes, conflicting study results, and heterogeneity of study design and patient populations (See Supplemental Digital Content, Table E4, http://links.lww.com/WNO/A103). In general, ORT has been shown to improve ocular motility and possibly periocular soft tissue changes but not the degree of proptosis (92,93). ORT has not been shown to decrease the risk of disease worsening in patients with mild TED (94,95).
Three randomized controlled trials compared ORT with sham (94,96,97). Gorman et al (97) found no difference in the treatment effect between ORT and sham, but Mourits et al (96) found that ORT was superior to sham. Prummel et al (94) reported that ORT was efficacious in patients with mild TED but did not slow the progression of mild TED to more severe disease.
Five randomized controlled trials compared ORT with corticosteroids in various combinations (98–102). Bartalena et al (98) found that patients randomized to PO corticosteroids and ORT did better than patients randomized to PO corticosteroids alone. Marcocci et al (99) found that PO corticosteroids in combination with ORT was more efficacious than ORT alone. Prummel et al (100) compared ORT with PO corticosteroids and found no difference. Marcocci et al (101) found the addition of IV corticosteroids with ORT was better than PO corticosteroids with ORT. Finally, Ng et al (102) found that ORT in combination with IV corticosteroids was superior to IV corticosteroids alone. The effect of ORT on visual loss due to dysthyroid optic neuropathy has not been studied in a randomized controlled fashion (93). However, there are many reports that have shown dysthyroid optic neuropathy is responsive to either ORT alone or ORT in combination with corticosteroids (34,101,103,104).
The typical ORT protocol for TED is a total of 20 Gy (or 2,000 rads) per orbit fractionated in 10 days (2 Gy/d) over a 2-week period. However, the optimum fractionation, duration, and dosing of ORT remains unsettled, and lower doses seem to perform just as well as higher doses (105). Gerling et al (106) compared 2.4 Gy with 16 Gy of total ORT given over a 16-day period and found no statistical difference between the 2 groups based on 5 predefined outcome measures. In a pilot study, the clinical and radiological effects of low dose (1 Gy/wk) ORT for 10 weeks was explored (107). All 18 patients had improvement in most of the signs or symptoms of TED.
ORT is a relatively safe procedure but should not be recommended in patients with severe uncontrolled hypertension and diabetes mellitus (especially if there is pre-existing diabetic retinopathy) (92). The risk of radiation retinopathy has been estimated to be 1%–2% within the first decade of treatment (93). Cataract formation is also a potential complication of ORT, but in one long-term study, the risk of cataract development was not associated with ORT (108).
Surgical Treatment for Thyroid Eye Disease
In most cases, surgery (orbital decompression, eyelid recession, and strabismus surgery) is indicated for the rehabilitation of patients with stable, nonactive (fibrotic) TED. In active TED, orbital decompression is reserved for patients with severe orbital inflammation, severe proptosis resulting in corneal exposure, uncontrolled glaucoma from orbital congestion, and dysthyroid optic neuropathy (17). Some of the options that need to be considered when performing orbital decompression include (83,109–113):
* Number of orbital walls to be operated upon: 1, 2, or 3.
* Approach: coronal, external, endoscopic, or combined.
* Incision site: extended eyelid crease, transcaruncular, transconjunctival, etc.
* Type of decompression: boney decompression vs fat-only decompression.
* Orbital rim removal with refixation or preservation.
There are multiple retrospective studies that have documented the efficacy of orbital decompression in stabilizing or improving vision in patients with dysthyroid optic neuropathy (103,114–119). Soares-Welch et al (120) reviewed the results of 215 patients (344 eyes) with dysthyroid optic neuropathy that underwent transantral orbital decompression. Of the 205 eyes that had 20/40 or worse vision, 110 eyes (54%) improved by ≥3 Snellen lines and only 8 eyes (2%) lost ≥3 Snellen lines or more.
The timing of when to intervene with orbital decompression, before or after corticosteroid treatment, in patients with dysthyroid optic neuropathy remains unresolved. In the only randomized controlled study that compared IV methylprednisolone (1 g/d for 3 consecutive days, repeated after 1 week followed by a 4-month PO prednisone taper) with orbital decompression (3-wall coronal approach) in patients with dysthyroid optic neuropathy, 5 of 9 patients in the IV methylprednisolone group had improvement in vision compared with only 1 of 6 patients in the orbital decompression group. Interestingly, when the nonresponders in each group (88% of the orbital decompression group and 56% of the IV methylprednisolone group) switched therapy (in addition to receiving ORT in some cases), there was an improvement in vision in all but 2 patients. The authors concluded that IV methylprednisolone should be the first-line treatment for patients with dysthyroid optic neuropathy, and if that fails to improve vision, orbital decompression should be offered (81).
FUTURE TREATMENT OF THYROID EYE DISEASE
A variety of procedures, anti-inflammatory, immunosuppressive, and immunomodulating agents have been investigated in the treatment of TED, but few have been scrutinized in randomized controlled studies (See Supplemental Digital Content, Table E5, http://links.lww.com/WNO/A104) (86,121–176).
Despite our expanding knowledge of the underlying molecular and immunological mechanism of TED, the unpredictable behavior of the disease and confounding results of clinical studies complicate treatment paradigms. In addition, many published studies have provided a vast amount of data that are difficult to synthesize into specific universally accepted treatment recommendations. Organizations such as EUGOGO (http://www.eugogo.eu), International Thyroid Eye Disease Society (http://thyroideyedisease.org), and Neuro-Ophthalmology Research and Development Consortium (http://www.nordicclinicaltrials.com/nordic) are working diligently on both a national and an international level to develop a unifying clinically applicable system to reliably identify disease phase and accurately measure therapeutic outcomes (177). The efforts of these organizations will hopefully culminate in many global, multi-center, randomized controlled trials that will produce evidence-based data that can be uniformly integrated and analyzed to provide the necessary answers to many of the questions that still remain about the optimum management of TED. Until evidence-based guidelines are developed, we offer a treatment algorithm for patients with active TED (Fig. 3).
1. Weetman AP. Graves' disease. N Engl J Med. 2000;343:1236–1248.
2. Kohn LD, Harii N. Thyrotropin receptor autoantibodies (TSHRAbs): epitopes, origins and clinical significance. Autoimmunity. 2003;36:331–337.
3. Bartalena L. Diagnosis and management of Graves disease: a global overview. Nat Rev Endocrinol. 2013;9:724–734.
4. Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves' ophthalmopathy. Thyroid. 2002;12:855–860.
5. Bartalena L, Tanda ML. Clinical practice. Graves' ophthalmopathy. N Engl J Med. 2009;360:994–1001.
6. Naik VM, Naik MN, Goldberg RA, Smith TJ, Douglas RS. Immunopathogenesis of thyroid eye disease: emerging paradigms. Surv Ophthalmol. 2010;55:215–226.
7. Garrity JA, Bahn RS. Pathogenesis of Graves ophthalmopathy: implications for prediction, prevention, and treatment. Am J Ophthalmol. 2006;142:147–153.
8. Douglas RS, Gupta S. The pathophysiology of thyroid eye disease: implications for immunotherapy. Curr Opin Ophthalmol. 2011;22:385–390.
9. Bahn RS. Graves' ophthalmopathy. N Engl J Med. 2010;362:726–738.
10. Kazim M, Goldberg RA, Smith TJ. Insights into the pathogenesis of thyroid-associated orbitopathy: evolving rationale for therapy. Arch Ophthalmol. 2002;120:380–386.
11. Shan SJC, Douglas RS. The pathophysiology of thyroid eye disease. J Neuroophthalmol. 2014;34:177–185.
12. Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SE, Ilstrup DM, Garrity JA, Gorman CA. Chronology of Graves' ophthalmopathy in an incidence cohort. Am J Ophthalmol. 1996;121:426–434.
13. Kendler DL, Lippa J, Rootman J. The initial clinical characteristics of Graves' orbitopathy vary with age and sex. Arch Ophthalmol. 1993;111:197–201.
14. Piantanida E, Tanda ML, Lai A, Sassi L, Bartalena L. Prevalence and natural history of Graves' orbitopathy in the XXI century. J Endocrinol Invest. 2013;36:444–449.
15. Tanda ML, Piantanida E, Liparulo L, Veronesi G, Lai A, Sassi L, Pariani N, Gallo D, Azzolini C, Ferrario M, Bartalena L. Prevalence and natural history of Graves' orbitopathy in a large series of patients with newly diagnosed graves' hyperthyroidism seen at a single center. J Clin Endocrinol Metab. 2013;98:1443–1449.
16. Wiersinga WM, Prummel MF. Graves' ophthalmopathy: a rational approach to treatment. Trends Endocrinol Metab. 2002;13:280–287.
17. Bartalena L, Pinchera A, Marcocci C. Management of Graves' ophthalmopathy: reality and perspectives. Endocr Rev. 2000;21:168–199.
18. Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA. The treatment of Graves' ophthalmopathy in an incidence cohort. Am J Ophthalmol. 1996;121:200–206.
19. Yamamoto K, Okamoto A, Fujio K. Antigen-specific immunotherapy for autoimmune diseases. Expert Opin Biol Ther. 2007;7:359–367.
20. Steinman L. Immune therapy for autoimmune diseases. Science. 2004;305:212–216.
21. Bartalena L, Lai A, Sassi L, Lombardi V, Dalle Mule I, Gandolfo M, Liparulo L, Azzolini C, Piantanida E, Tanda ML. Novel treatment modalities for Graves' orbitopathy. Pediatr Endocrinol Rev. 2010;7(suppl 2):210–216.
22. Bartley GB. Evolution of classification systems for Graves' ophthalmopathy. Ophthal Plast Reconstr Surg. 1995;11:229–237.
23. Dickinson AJ, Perros P. Controversies in the clinical evaluation of active thyroid-associated orbitopathy: use of a detailed protocol with comparative photographs for objective assessment. Clin Endocrinol (Oxf). 2001;55:283–303.
24. Classification of eye changes of Graves' disease. Thyroid. 1992;2:235–236.
25. Douglas RS, Tsirbas A, Gordon M, Khadavi N, Garneau HC, Goldberg RA, Cahill K, Dolman PJ, Elner V, Feldon S, Lucarelli M, Uddin J, Kazim M, Smith TJ, Khanna D; International Thyroid Eye Disease Society. Development of criteria for evaluating clinical response in thyroid eye disease using a modified Delphi technique. Arch Ophthalmol. 2009;127:1155–1160.
26. Terwee CB, Prummel MF, Gerding MN, Kahaly GJ, Dekker FW, Wiersinga WM. Measuring disease activity to predict therapeutic outcome in Graves' ophthalmopathy. Clin Endocrinol (Oxf). 2005;62:145–155.
27. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton P, Mrukowicz J, O'Connell D, Oxman AD, Phillips B, Schünemann HJ, Edejer T, Varonen H, Vist GE, Williams JW Jr, Zaza S; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490.
28. Werner SC. Classification of the eye changes of Graves' disease. Am J Ophthalmol. 1969;68:646–648.
29. Werner SC. Classification of the eye changes of Grave's disease. J Clin Endocrinol Metab. 1969;29:982–984.
30. Werner SC. Modification of the classification of the eye changes of Graves' disease: recommendations of the Ad Hoc Committee of the American Thyroid Association. J Clin Endocrinol Metab. 1977;44:203–204.
31. Donaldson SS, Bagshaw MA, Kriss JP. Supervoltage orbital radiotherapy for Graves' ophthalmopathy. J Clin Endocrinol Metab. 1973;37:276–285.
32. Dolman PJ, Rootman J. VISA Classification for Graves orbitopathy. Ophthal Plast Reconstr Surg. 2006;22:319–324.
33. Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R. Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach. Br J Ophthalmol. 1989;73:639–644.
34. Bartalena L, Baldeschi L, Dickinson AJ, Ecksttein A, Kendall-Taylor P, Marcocci C, Mourits MP, Perros P, Boboridis K, Boschi A, Curro N, Daumerie C, Kahaly GJ, Krossos G, Lane CM, Lazarus JH, Marino O, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM. Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy. Thyroid. 2008;18:333–346.
35. Bartalena L, Baldeschi L, Dickinson AJ, Ecksttein A, Kendall-Taylor P, Marcocci C, Mourits MP, Perros P, Boboridis K, Boschi A, Curro N, Daumerie C, Kahaly GJ, Krossos G, Lane CM, Lazarus JH, Marino O, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM. Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol. 2008;158:273–285.
36. Stan MN, Bahn RS. Risk factors for development or deterioration of Graves' ophthalmopathy. Thyroid. 2010;20:777–783.
37. Gerding MN, van der Meer JW, Broenink M, Bakker O, Wiersinga WM, Prummel MF. Association of thyrotrophin receptor antibodies with the clinical features of Graves' ophthalmopathy. Clin Endocrinol (Oxf). 2000;52:267–271.
38. Bartalena L. Prevention of Graves' ophthalmopathy. Best Pract Res Clin Endocrinol Metab. 2012;26:371–379.
39. Bartalena L, Marcocci C, Pinchera A. Cigarette smoking and thyroid eye disease. In: Dutton JJ, Haik BG, eds. Thyroid Eye Disease: Diagnosis and Treatment. New York, NY: Marcel Dekker Inc, 2002:251–259.
40. Prummel MF, Wiersinga WM. Smoking and risk of Graves' disease. JAMA. 1993;269:479–482.
41. Bartalena L, Marcocci C, Tanda ML, Manetti L, Dell'Unto E, Bartolomei MP, Nardi M, Martino E, Pinchera A. Cigarette smoking and treatment outcomes in Graves ophthalmopathy. Ann Intern Med. 1998;129:632–635.
42. Eckstein A, Quadbeck B, Mueller G, Rettenmeier AW, Hoermann R, Mann K, Steuhl P, Esser J. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br J Ophthalmol. 2003;87:773–776.
43. Prummel MF, Wiersinga WM, Mourits MP, Koornneef L, Berghout A, van der Gaag R. Effect of abnormal thyroid function on the severity of Graves' ophthalmopathy. Arch Intern Med. 1990;150:1098–1101.
44. Prummel MF, Wiersinga W, Mourits MP, Koorneef L, Berghout A, Van der Gaag R. Amelioration of eye changes of Graves' ophthalmolopathy by achieving euthyroidism. Acta Endocrinol (Copenh). 1989;121(suppl 2):185–189.
45. Brent GA. Clinical practice. Graves' disease. N Engl J Med. 2008;358:2594–2605.
46. Cooper DS. Antithyroid drugs. N Engl J Med. 2005;352:905–917.
47. Hegedus L, Bonnema SJ, Smith TJ, Brix TH. Treating the thyroid in the presence of Graves' ophthalmopathy. Best Pract Res Clin Endocrinol Metab. 2012;26:313–324.
48. Bartalena L. The dilemma of how to manage Graves' hyperthyroidism in patients with associated orbitopathy. J Clin Endocrinol Metab. 2011;96:592–599.
49. Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell'Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E, Pinchera A. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med. 1998;338:73–78.
50. Marcocci C, Bruno-Bossio G, Manetti L, Tanda ML, Miccoli P, Iacconi P, Bartolomei MP, Nardi M, Pinchera A, Bartalena L. The course of Graves' ophthalmopathy is not influenced by near total thyroidectomy: a case-control study. Clin Endocrinol (Oxf). 1999;51:503–508.
51. Guo Z, Yu P, Liu Z, Si Y, Jin M. Total thyroidectomy vs bilateral subtotal thyroidectomy in patients with Graves' diseases: a meta-analysis of randomized clinical trials. Clin Endocrinol (Oxf). 2013;79:739–746.
52. Witte J, Goretzki PE, Dotzenrath C, Simon D, Felis P, Neubauer M, Röher HD. Surgery for Graves' disease: total versus subtotal thyroidectomy—results of a prospective randomized trial. World J Surg. 2000;24:1303–1311.
53. Barczynski M, Konturek A, Hubalewska-Dydejczyk A, Golkowski F, Nowak W. Randomized clinical trial of bilateral subtotal thyroidectomy versus total thyroidectomy for Graves' disease with a 5-year follow-up. Br J Surg. 2012;99:515–522.
54. Jarhult J, Rudberg C, Larsson E, Selvander H, Sjövall K, Winsa B, Rastad J, Karlsson FA; TEO Study Group. Graves' disease with moderate-severe endocrine ophthalmopathy-long term results of a prospective, randomized study of total or subtotal thyroid resection. Thyroid. 2005;15:1157–1164.
55. Kriss JP, Pleshakov V, Rosenblum AL, Holderness M, Sharp G, Utiger R. Studies on the pathogenesis of the ophthalmopathy of Graves' disease. J Clin Endocrinol Metab. 1967;27:582–593.
56. Ponto KA, Zang S, Kahaly GJ. The tale of radioiodine and Graves' orbitopathy. Thyroid. 2010;20:785–793.
57. Rasmussen AK, Nygaard B, Feldt-Rasmussen U. (131)I and thyroid-associated ophthalmopathy. Eur J Endocrinol. 2000;143:155–160.
58. Acharya SH, Avenell A, Philip S, Burr J, Bevan JS, Abraham P. Radioiodine therapy (RAI) for Graves' disease (GD) and the effect on ophthalmopathy: a systematic review. Clin Endocrinol (Oxf). 2008;69:943–950.
59. Bartalena L, Marcocci C, Bogazzi F, Panicucci M, Lepri A, Pinchera A. Use of corticosteroids to prevent progression of Graves' ophthalmopathy after radioiodine therapy for hyperthyroidism. N Engl J Med. 1989;321:1349–1352.
60. Tallstedt L, Lundell G, Torring O, Wallin G, Ljunggren JG, Blomgren H, Taube A. Occurrence of ophthalmopathy after treatment for Graves' hyperthyroidism. The Thyroid Study Group. N Engl J Med. 1992;326:1733–1738.
61. Kung AW, Yau CC, Cheng A. The incidence of ophthalmopathy after radioiodine therapy for Graves' disease: prognostic factors and the role of methimazole. J Clin Endocrinol Metab. 1994;79:542–546.
62. Traisk F, Tallstedt L, Abraham-Nordling M, Andersson T, Berg G, Calissendorff J, Hallengren B, Hedner P, Lantz M, Nyström E, Ponjavic V, Taube A, Törring O, Wallin G, Asman P, Lundell G; Thyroid Study Group of TT 96. Thyroid-associated ophthalmopathy after treatment for Graves' hyperthyroidism with antithyroid drugs or iodine-131. J Clin Endocrinol Metab. 2009;94:3700–3707.
63. Lai A, Sassi L, Compri E, Marino F, Sivelli P, Piantanida E, Tanda ML, Bartalena L. Lower dose prednisone prevents radioiodine-associated exacerbation of initially mild or absent graves' orbitopathy: a retrospective cohort study. J Clin Endocrinol Metab. 2010;95:1333–1337.
64. Vannucchi G, Campi I, Covelli D, Dazzi D, Currò N, Simonetta S, Ratiglia R, Beck-Peccoz P, Salvi M. Graves' orbitopathy activation after radioactive iodine therapy with and without steroid prophylaxis. J Clin Endocrinol Metab. 2009;94:3381–3386.
65. Salvi M, Currò N. Management of mild Graves' orbitopathy. In: Wiersinga WM, Kahaly GJ, eds. Graves' Orbitopathy: A Multidisciplinary Approach—Questions and Answers. Basel, Switzerland: Krager, 2010:111–119.
66. Marcocci C, Marino M. Treatment of mild, moderate-to-severe and very severe Graves' orbitopathy. Best Pract Res Clin Endocrinol Metab. 2012;26:325–337.
67. Costa PG, Saraiva FP, Pereira IC, Monteiro ML, Matayoshi S. Comparative study of Botox injection treatment for upper eyelid retraction with 6-month follow-up in patients with thyroid eye disease in the congestive or fibrotic stage. Eye (Lond). 2009;23:767–773.
68. Morgenstern KE, Evanchan J, Foster JA, Cahill KV, Burns JA, Holck DE, Perry JD, Wulc AE. Botulinum toxin type a for dysthyroid upper eyelid retraction. Ophthal Plast Reconstr Surg. 2004;20:181–185.
69. Verity DH, Rose GE. Acute thyroid eye disease (TED): principles of medical and surgical management. Eye (Lond). 2013;27:308–319.
70. Zang S, Ponto KA, Pitz S, Kahaly GJ. Dose of intravenous steroids and therapy outcome in Graves' orbitopathy. J Endocrinol Invest. 2011;34:876–880.
71. Bartalena L. Graves' orbitopathy: imperfect treatments for a rare disease. Eur Thyroid J. 2013;2:259–269.
72. Zoumalan CI, Cockerham KP, Turbin RE, Volpe NJ, Kazim M, Douglas RS, Feldon SE. Efficacy of corticosteroids and external beam radiation in the management of moderate to severe thyroid eye disease. J Neuroophthalmol. 2007;27:205–214.
73. Stiebel-Kalish H, Robenshtok E, Hasanreisoglu M, Ezrachi D, Shimon I, Leibovici L. Treatment modalities for Graves' ophthalmopathy: systematic review and metaanalysis. J Clin Endocrinol Metab. 2009;94:2708–2716.
74. Macchia PE, Bagattini M, Lupoli G, Vitale M, Vitale G, Fenzi G. High-dose intravenous corticosteroid therapy for Graves' ophthalmopathy. J Endocrinol Invest. 2001;24:152–158.
75. Kauppinen-Makelin R, Karma A, Leinonen E, Löyttyniemi E, Salonen O, Sane T, Setälä K, Viikari J, Heufelder A, Välimäki M. High dose intravenous methylprednisolone pulse therapy versus oral prednisone for thyroid-associated ophthalmopathy. Acta Ophthalmol Scand. 2002;80:316–321.
76. Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves' orbitopathy. J Clin Endocrinol Metab. 2005;90:5234–5240.
77. Aktaran S, Akarsu E, Erbagci I, Araz M, Okumus S, Kartal M. Comparison of intravenous methylprednisolone therapy vs. oral methylprednisolone therapy in patients with Graves' ophthalmopathy. Int J Clin Pract. 2007;61:45–51.
78. Zang S, Ponto KA, Kahaly GJ. Clinical review: intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab. 2011;96:320–332.
79. Bartalena L, Krassas GE, Wiersinga W, Marcocci C, Salvi M, Daumerie C, Bournaud C, Stahl M, Sassi L, Veronesi G, Azzolini C, Boboridis KG, Mourits MP, Soeters MR, Baldeschi L, Nardi M, Currò N, Boschi A, Bernard M, von Arx G; European Group on Graves' Orbitopathy. Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves' orbitopathy. J Clin Endocrinol Metab. 2012;97:4454–4463.
80. Marcocci C, Watt T, Altea MA, Rasmussen AK, Feldt-Rasmussen U, Orgiazzi J, Bartalena L; European Group of Graves' Orbitopathy. Fatal and non-fatal adverse events of glucocorticoid therapy for Graves' orbitopathy: a questionnaire survey among members of the European Thyroid Association. Eur J Endocrinol. 2012;166:247–253.
81. Wakelkamp IM, Baldeschi L, Saeed P, Mourits MP, Prummel MF, Wiersinga WM. Surgical or medical decompression as a first-line treatment of optic neuropathy in Graves' ophthalmopathy? A randomized controlled trial. Clin Endocrinol (Oxf). 2005;63:323–328.
82. Guy JR, Fagien S, Donovan JP, Rubin ML. Methylprednisolone pulse therapy in severe dysthyroid optic neuropathy. Ophthalmology. 1989;96:1048–1052.
83. Rootman J, Dolman PJ. Thyroid orbitopathy. In: Rootman J, ed. Diseases of the Orbit. A Multidisciplinary Approach, 2nd edition. Philadelphia, PA: Lippincott Williams & Wilkins, 2003:169–212.
84. Mehdi Y, Hornick JL, Istasse L, Dufrasne I. Selenium in the environment, metabolism and involvement in body functions. Molecules. 2013;18:3292–3311.
85. Huang Z, Rose AH, Hoffmann PR. The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2012;16:705–743.
86. Marcocci C, Kahaly GJ, Krassas GE, Bartelena L, Prummel M, Stahl M, Altea MA, Nardi M, Pitz S, Bobordis K, Sivelli P, von Arx G, Moorits MP, Baldeschi L, Bencivelli W, Wiersinga W. Selenium and the course of mild Graves' orbitopathy. N Engl J Med. 2011;364:1920–1931.
87. Steinbrenner H. Interference of selenium and selenoproteins with the insulin-regulated carbohydrate and lipid metabolism. Free Radic Biol Med. 2013;65:1538–1547.
88. King AJ. Should we be considering selenium in glaucoma? Br J Ophthalmol. 2009;93:1132–1133.
89. Vinceti M, Mandrioli J, Borella P, Michalke B, Tsatsakis A, Finkelstein Y. Selenium neurotoxicity in humans: bridging laboratory and epidemiologic studies. Toxicol Lett. 2013 (epub ahead of print).
90. Belerwaltes WH. X-ray treatment of malignant exophthalmos: a report on 28 patients. J Clin Endocrinol. 1953;13:1090–1100.
91. Kazim M, Garrity JA. Orbital radiation therapy for thyroid eye disease. J Neuroophthalmol. 2012;32:172–176.
92. Tanda ML, Bartalena L. Efficacy and safety of orbital radiotherapy for Graves' orbitopathy. J Clin Endocrinol Metab. 2012;97:3857–3865.
93. Bradley EA, Gower EW, Bradley DJ, Meyer DR, Cahill KV, Holck DE, Woog JJ. Orbital radiation for Graves ophthalmopathy: a report by the American Academy of Ophthalmology. Ophthalmology. 2008;115:398–409.
94. Prummel MF, Terwee CB, Gerding MN, Baldeschi L, Mourits MP, Blank L, Dekker FW, Wiersinga WM. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy. J Clin Endocrinol Metab. 2004;89:15–20.
95. Viani GA, Boin AC, De Fendi LI, Fonseca EC, Stefano EJ, Paula JS. Radiation therapy for Graves' ophthalmopathy: a systematic review and meta-analysis of randomized controlled trials. Arq Bras Oftalmol. 2012;75:324–332.
96. Mourits MP, van Kempen-Harteveld ML, Garcia MB, Koppeschaar HP, Tick L, Terwee CB. Radiotherapy for Graves' orbitopathy: randomised placebo-controlled study. Lancet. 2000;355:1505–1509.
97. Gorman CA, Garrity JA, Fatourechi V, Bahn RS, Petersen IA, Stafford SL, Earle JD, Forbes GS, Kline RW, Bergstralh EJ, Offord KP, Rademacher DM, Stanley NM, Bartley GB. A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy. Ophthalmology. 2001;108:1523–1534.
98. Bartalena L, Marcocci C, Chiovato L, Laddaga M, Lepri G, Andreani D, Cavallacci G, Baschieri L, Pinchera A. Orbital cobalt irradiation combined with systemic corticosteroids for Graves' ophthalmopathy: comparison with systemic corticosteroids alone. J Clin Endocrinol Metab. 1983;56:1139–1144.
99. Marcocci C, Bartalena L, Bogazzi F, Bruno-Bossio G, Lepri A, Pinchera A. 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. 1991;14:853–860.
100. Prummel MF, Mourits MP, Blank L, Berghout A, Koornneef L, Wiersinga WM. Randomized double-blind trial of prednisone versus radiotherapy in Graves' ophthalmopathy. Lancet. 1993;342:949–954.
101. Marcocci C, Bartalena L, Tanda ML, Manetti L, Dell'Unto E, Rocchi R, Barbesino G, Mazzi B, Bartolomei MP, Lepri P, Cartei F, Nardi M, Pinchera A. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves' ophthalmopathy: results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab. 2001;86:3562–3567.
102. Ng CM, Yuen HK, Choi KL, Chan MK, Yuen KT, Ng YW, Tiu SC. Combined orbital irradiation and systemic steroids compared with systemic steroids alone in the management of moderate-to-severe Graves' ophthalmopathy: a preliminary study. Hong Kong Med J. 2005;11:322–330.
103. Trobe JD, Glaser JS, Laflamme P. Dysthyroid optic neuropathy. Clinical profile and rationale for management. Arch Ophthalmol. 1978;96:1199–1209.
104. Jeon C, Shin JH, Woo KI, Kim YD. Clinical profile and visual outcomes after treatment in patients with dysthyroid optic neuropathy. Korean J Ophthalmol. 2012;26:737–739.
105. Kahaly GJ, Rosler HP, Pitz S, Hommel G. Low- versus high-dose radiotherapy for Graves' ophthalmopathy: a randomized, single blind trial. J Clin Endocrinol Metab. 2000;85:102–108.
106. Gerling J, Kommerell G, Henne K, Laubenberger J, Schulte-Monting J, Fells P. Retrobulbar irradiation for thyroid-associated orbitopathy: double-blind comparison between 2.4 and 16 Gy. Int J Radiat Oncol Biol Phys. 2003;55:182–189.
107. Cardoso CC, Giordani AJ, Wolosker AM, Souhami L, Manso PG, Dias RS, Segreto HR, Segreto RA. Protracted hypofractionated radiotherapy for Graves' ophthalmopathy: a pilot study of clinical and radiologic response. Int J Radiat Oncol Biol Phys. 2012;82:1285–1291.
108. Wakelkamp IM, Tan H, Saeed P, Schlingemann RO, Verbraak FD, Blank LE, Prummel MF, Wiersinga WM. Orbital irradiation for Graves' ophthalmopathy: is it safe? A long-term follow-up study. Ophthalmology. 2004;111:1557–1562.
109. Goldberg RA. The evolving paradigm of orbital decompression surgery. Arch Ophthalmol. 1998;116:95–96.
110. Goldberg RA, Kim AJ, Kerivan KM. The lacrimal keyhole, orbital door jamb, and basin of the inferior orbital fissure. Three areas of deep bone in the lateral orbit. Arch Ophthalmol. 1998;116:1618–1624.
111. Ben Simon GJ, Schwarcz RM, Mansury AM, Wang L, McCann JD, Goldberg RA. Minimally invasive orbital decompression: local anesthesia and hand-carved bone. Arch Ophthalmol. 2005;123:1671–1675.
112. Garrity JA. Orbital lipectomy (fat decompression) for thyroid eye disease: an operation for everyone? Am J Ophthalmol. 2011;151:399–400.
113. Mourits MP, Bijl H, Altea MA, Baldeschi L, Boborides K, Curro N, Dickinson AJ, Eckstein A, Freidel M, Guastella C, Kahaly GJ, Kalmann R, Krossos GE, Lane CM, Lareida J, Marcocci C, Marino M, Nardi M, Mohr CH, Neoh C, Pinchera A, Orgiazzi J, Pitz S, Saeed P, Sellari-Franceschini S, Stahl M, von Arx G, Wiersinga WM. Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures. Br J Ophthalmol. 2009;93:1518–1523.
114. Chu EA, Miller NR, Grant MP, Merbs S, Tufano RP, Lane AP. Surgical treatment of dysthyroid orbitopathy. Otolaryngol Head Neck Surg. 2009;141:39–45.
115. Kazim M, Trokel SL, Acaroglu G, Elliott A. Reversal of dysthyroid optic neuropathy following orbital fat decompression. Br J Ophthalmol. 2000;84:600–605.
116. Hallin ES, Feldon SE, Luttrell J. Graves' ophthalmopathy: III. Effect of transantral orbital decompression on optic neuropathy. Br J Ophthalmol. 1988;72:683–687.
117. Warren JD, Spector JG, Burde R. Long-term follow-up and recent observations on 305 cases of orbital decompression for dysthyroid orbitopathy. Laryngoscope. 1989;99:35–40.
118. Hutchison BM, Kyle PM. Long-term visual outcome following orbital decompression for dysthyroid eye disease. Eye (Lond). 1995;9(pt 5):578–581.
119. Goh MS, McNab AA. Orbital decompression in Graves' orbitopathy: efficacy and safety. Intern Med J. 2005;35:586–591.
120. Soares-Welch CV, Fatourechi V, Bartley GB, Beatty CW, Gorman CA, Bahn RS, Bergstralh EJ, Schleck CD, Garrity JA. Optic neuropathy of Graves disease: results of transantral orbital decompression and long-term follow-up in 215 patients. Am J Ophthalmol. 2003;136:433–441.
121. Savino G, Balia L, Colucci D, Battendieri R, Gari M, Corsello SM, Pontecorvi A, Dickmann A. Intraorbital injection of rituximab: a new approach for active thyroid-associated orbitopathy, a prospective case series. Minerva Endocrinol. 2013;38:173–179.
122. Mitchell AL, Gan EH, Morris M, Johnson K, Neoh C, Dickinson AJ, Perros P, Pearce SH. The effect of B cell depletion therapy on anti-TSH receptor antibodies and clinical outcome in glucocorticoid-refractory Graves' orbitopathy. Clin Endocrinol (Oxf). 2013;79:437–442.
123. Shen S, Chan A, Sfikakis PP, Hsiu Ling AL, Detorakis ET, Boboridis KG, Maurikakis I. B-cell targeted therapy with rituximab for thyroid eye disease: closer to the clinic. Surv Ophthalmol. 2013;58:252–265.
124. Madaschi S, Rossini A, Formenti I, Lampasona V, Marzoli SB, Cammarata G, Politi LS, Martinelli V, Bazzigaluppi E, Scavini M, Bosi E, Lanzi R. Treatment of thyroid-associated orbitopathy with rituximab—a novel therapy for an old disease: case report and literature review. Endocr Pract. 2010;16:677–685.
125. Katoh N, Matsuda M, Ishii W, Morita H, Ikeda S. Successful treatment with rituximab in a patient with stiff-person syndrome complicated by dysthyroid ophthalmopathy. Intern Med. 2010;49:237–241.
126. Krassas GE, Stafilidou A, Boboridis KG. Failure of rituximab treatment in a case of severe thyroid ophthalmopathy unresponsive to steroids. Clin Endocrinol (Oxf). 2010;72:853–855.
127. Salvi M, Vannucchi G, Campi I, Currò N, Simonetta S, Covelli D, Pignataro L, Guastella C, Rossi S, Bonara P, Dazzi D, Ratiglia R, Beck-Peccoz P. Rituximab treatment in a patient with severe thyroid-associated ophthalmopathy: effects on orbital lymphocytic infiltrates. Clin Immunol. 2009;131:360–365.
128. El Fassi D, Nielsen CH, Hasselbalch HC, Hegedus L. Treatment-resistant severe, active Graves' ophthalmopathy successfully treated with B lymphocyte depletion. Thyroid. 2006;16:709–710.
129. Salvi M, Vannucchi G, Campi I, Rossi S, Bonara P, Sbrozzi F, Guastella C, Avignone S, Pirola G, Ratiglia R, Beck-Peccoz P. Efficacy of rituximab treatment for thyroid-associated ophthalmopathy as a result of intraorbital B-cell depletion in one patient unresponsive to steroid immunosuppression. Eur J Endocrinol. 2006;154:511–517.
130. Salvi M, Vannucchi G, Curro N, Introna M, Rossi S, Bonara P, Covelli D, Dazzi D, Guastella C, Pignataro L, Ratiglia R, Golay J, Beck-Peccoz P. Small dose of rituximab for graves orbitopathy: new insights into the mechanism of action. Arch Ophthalmol. 2012;130:122–124.
131. Khanna D, Chong KK, Afifiyan NF, Hwang CJ, Lee DK, Garneau HC, Goldberg RA, Darwin CH, Smith TJ, Douglas RS. Rituximab treatment of patients with severe, corticosteroid-resistant thyroid-associated ophthalmopathy. Ophthalmology. 2010;117:133–139 e2.
132. Salvi M, Vannucchi G, Campi I, Currò N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P. Treatment of Graves' disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol. 2007;156:33–40.
133. Silkiss RZ, Reier A, Coleman M, Lauer SA. Rituximab for thyroid eye disease. Ophthal Plast Reconstr Surg. 2010;26:310–314.
134. Brabant G, Peter H, Becker H, Schwarzrock R, Wonigeit K, Hesch RD. Cyclosporin in infiltrative eye disease. Lancet. 1984;1:515–516.
135. Howlett TA, Lawton NF, Fells P, Besser GM. Deterioration of severe Graves' ophthalmopathy during cyclosporin treatment. Lancet. 1984;2:1101.
136. Weetman AP, McGregor AM, Ludgate M, Beck L, Mills PV, Lazarus JH, Hall R. Cyclosporin improves Graves' ophthalmopathy. Lancet. 1983;2:486–489.
137. Kahaly G, Schrezenmeir J, Krause U, Schweikert B, Meuer S, Muller W, Dennebaum R, Beyer J. Ciclosporin and prednisone v. prednisone in treatment of Graves' ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest. 1986;16:415–422.
138. Prummel MF, Mourits MP, Berghout A, Krenning EP, van der Gaag R, Koornneef L, Wiersinga WM. Prednisone and cyclosporine in the treatment of severe Graves' ophthalmopathy. N Engl J Med. 1989;321:1353–1359.
139. Chang TC, Kao SC, Huang KM. Octreotide and Graves' ophthalmopathy and pretibial myxoedema. BMJ. 1992;304:158.
140. Durak I, Durak H, Ergin M, Yurekli Y, Kaynak S. Somatostatin receptors in the orbits. Clin Nucl Med. 1995;20:237–242.
141. Krassas GE, Dumas A, Pontikides N, Kaltsas T. Somatostatin receptor scintigraphy and octreotide treatment in patients with thyroid eye disease. Clin Endocrinol (Oxf). 1995;42:571–580.
142. Krassas GE, Kaltsas T, Dumas A, Pontikides N, Tolis G. Lanreotide in the treatment of patients with thyroid eye disease. Eur J Endocrinol. 1997;136:416–422.
143. Ozata M, Bolu E, Sengul A, Tasar M, Beyhan Z, Corakci A, Gundogan MA. Effects of octreotide treatment on Graves' ophthalmopathy and circulating sICAM-1 levels. Thyroid. 1996;6:283–288.
144. Uysal AR, Corapcioglu D, Tonyukuk VC, Güllü S, Sav H, Kamel N, Erdoğan G. Effect of octreotide treatment on Graves' ophthalmopathy. Endocr J. 1999;46:573–577.
145. Kung AW, Michon J, Tai KS, Chan FL. The effect of somatostatin versus corticosteroid in the treatment of Graves' ophthalmopathy. Thyroid. 1996;6:381–384.
146. Dickinson AJ, Vaidya B, Miller M, Coulthard A, Perros P, Baister E, Andrews CD, Hesse L, Heverhagen JT, Heufelder AE, Kendall-Taylor P. Double-blind, placebo-controlled trial of octreotide long-acting repeatable (LAR) in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2004;89:5910–5915.
147. Wemeau JL, Caron P, Beckers A, Rohmer V, Orgiazzi J, Borson-Chazot F, Nocaudie M, Perimenis P, Bisot-Locard S, Bourdeix I, Dejager S. Octreotide (long-acting release formulation) treatment in patients with graves' orbitopathy: clinical results of a four-month, randomized, placebo- controlled, double-blind study. J Clin Endocrinol Metab. 2005;90:841–848.
148. Stan MN, Garrity JA, Bradley EA, Woog JJ, Bahn MM, Brennan MD, Bryant SC, Achenbach SJ, Bahn RS. Randomized, double-blind, placebo-controlled trial of long-acting release octreotide for treatment of Graves' ophthalmopathy. J Clin Endocrinol Metab. 2006;91:4817–4824.
149. Bloise W, Mimura LY, Moura J, Nicolau W. Treatment of mild to moderate Graves' ophthalmopathy with sodium diclofenac: a pilot study. Arq Bras Endocrinol Metabol. 2011;55:692–695.
150. Kuriyan AE, Phipps RP, O'Loughlin CW, Feldon SE. Improvement of thyroid eye disease following treatment with the cyclooxygenase-2 selective inhibitor celecoxib. Thyroid. 2008;18:911–914.
151. Butnaru D, Perez-Moreiras JV, Sanchez-Ramon S. Anti-IL-6R therapy on Graves' ophthalmopathy. Clin Immunol. 2013;147:120–121.
152. Durrani OM, Reuser TQ, Murray PI. Infliximab: a novel treatment for sight-threatening thyroid associated ophthalmopathy. Orbit. 2005;24:117–119.
153. Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM. The effect of etanercept on Graves' ophthalmopathy: a pilot study. Eye (Lond). 2005;19:1286–1289.
154. Dandona P, Marshall NJ, Bidey SP, Nathan A, Havard CW. Successful treatment of exophthalmos and pretibial myxoedema with plasmapheresis. Br Med J. 1979;1:374–376.
155. Lewis RA, Slater N, Croft DN. Exophthalmos and pretibial myxoedema not responding to plasmapheresis. Br Med J. 1979;2:390–391.
156. Glinoer D, Etienne-Decerf J, Schrooyen M, Sand G, Hoyoux P, Mahieu P, Winand R. Beneficial effects of intensive plasma exchange followed by immunosuppressive therapy in severe Graves' ophthalmopathy. Acta Endocrinol (Copenh). 1986;111:30–38.
157. Dandona P, Marshall N, Bidey S, Nathan AW, Havard CW. Exophthalmos and pretibial myxoedema not responding to plasmapheresis. Br Med J. 1979;2:667–668.
158. Glinoer D, Schrooyen M. Plasma exchange therapy for severe Graves' ophthalmopathy. Horm Res. 1987;26:184–189.
159. Glinoer D, Etienne-Decerf J, Schrooyen M, Sand G, Hoyoux P, Mahieu P, Winand R. Beneficial effects of intensive plasma exchange followed by immunosuppressive therapy in severe Graves' ophthalmopathy. Metab Pediatr Syst Ophthalmol. 1988;11:133–140.
160. Berlin G, Hjelm H, Lieden G, Tegler L. Plasma exchange in endocrine ophthalmopathy. J Clin Apher. 1990;5:192–196.
161. Sawers JS, Irvine WJ, Toft AD, Urbaniak SJ, Donaldson AA. Plasma exchange in conjunction with immunosuppressive drug therapy in the treatment of endocrine exophthalmos. J Clin Lab Immunol. 1981;6:245–250.
162. Kelly W, Longson D, Smithard D, Fawcitt R, Wensley R, Noble J, Keeley J. An evaluation of plasma exchange for Graves' ophthalmopathy. Clin Endocrinol (Oxf). 1983;18:485–493.
163. Cap J, Ceeova V, Skacha M, Rezek P, Vlcek P, Blaha M. Plasma filtration in the treatment of Graves' ophthalmopathy: a randomized study. J Clin Apher. 2010;25:209–215.
164. Seppel T, Schlaghecke R, Becker A, Engelbrecht V, Feldkamp J, Kornely E. High-dose intravenous therapy with 7S immunoglobulins in autoimmune endocrine ophthalmopathy. Clin Exp Rheumatol. 1996;14(suppl 15):S109–S114.
165. Baschieri L, Antonelli A, Nardi S, Alberti B, Lepri A, Canapicchi R, Fallahi P. Intravenous immunoglobulin versus corticosteroid in treatment of Graves' ophthalmopathy. Thyroid. 1997;7:579–585.
166. Antonelli A, Saracino A, Alberti B, Canapicchi R, Cartei F, Lepri A, Laddaga M, Baschieri L. High-dose intravenous immunoglobulin treatment in Graves' ophthalmopathy. Acta Endocrinol (Copenh). 1992;126:13–23.
167. Kahaly G, Pitz S, Muller-Forell W, Hommel G. Randomized trial of intravenous immunoglobulins versus prednisolone in Graves' ophthalmopathy. Clin Exp Immunol. 1996;106:197–202.
168. Kolodziej-Maciejewska H, Reterski Z. Positive effect of bromocriptine treatment in Graves disease orbitopathy. Exp Clin Endocrinol. 1985;86:241–242.
169. Lopatynsky MO, Krohel GB. Bromocriptine therapy for thyroid ophthalmopathy. Am J Ophthalmol. 1989;107:680–681.
170. Harden RM, Chisolm CJS, Cant JS. The effect of metrodinazole on thyroid function and exophthalmos in man. Metabolism. 1967;16:890–898.
171. Jones DI. The effect of metronidazole on exophthalmos in man. J Endocrinol. 1968;41:609–610.
172. Rogvi-Hansen B, Perrild H, Christensen T, Detmar SE, Siersbaek-Nielsen K, Hansen JE. Acupuncture in the treatment of Graves' ophthalmopathy. A blinded randomized study. Acta Endocrinol (Copenh). 1991;124:143–145.
173. Finamor FE, Martins JR, Nakanami D, Paiva ER, Manso PG, Furlanetto RP. Pentoxifylline (PTX)—an alternative treatment in Graves' ophthalmopathy (inactive phase): assessment by a disease specific quality of life questionnaire and by exophthalmometry in a prospective randomized trial. Eur J Endocrinol. 2004;14:277–283.
174. Balazs C, Kiss E, Vamos A, Molnar I, Farid NR. Beneficial effect of pentoxifylline on thyroid associated ophthalmopathy (TAO)*: a pilot study. J Clin Endocrinol Metab. 1997;82:1999–2002.
175. Bouzas EA, Karadimas P, Mastorakos G, Koutras DA. Antioxidant agents in the treatment of Graves' ophthalmopathy. Am J Ophthalmol. 2000;129:618–622.
176. Kahaly G, Lieb W, Muller-Forell W, Mainberger M, Beyer J, Vollmar J, Staiger C. Ciamexone in endocrine orbitopathy. A randomized double-blind, placebo-controlled study. Acta Endocrinol (Copenh). 1990;122:13–21.
177. Prummel MF, Bakker A, Wiersinga WM, Baldeschi L, Mourits MP, Kendall-Taylor P, Perros P, Neoh C, Dickinson AJ, Lazarus JH, Lane CM, Heufelder AE, Kahaly GJ, Pitz S, Orgiazzi J, Hullo A, Pinchera A, Marcocci C, Sartini MS, Rocchi R, Nardi M, Krassas GE, Halkias A. 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. 2003;148:491–495.