Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Efficacy of selenium supplementation for mild-to-moderate Graves' ophthalmopathy in a selenium-sufficient area (SeGOSS trial): study protocol for a phase III, multicenter, open-label, randomized, controlled intervention trial.

BACKGROUND: The therapeutic effect of selenium has been demonstrated in mild Graves' ophthalmopathy (GO) in a European region where selenium status is suboptimal. However, there is a lack of evidence to support selenium use in selenium-sufficient areas. The aim of this study is to evaluate the therapeutic effect of selenium in mild-to-moderate GO in selenium-sufficient South Korea. METHODS: The SeGOSS trial is a multicenter, prospective, randomized, open-label trial in South Korea. Eighty-four patients aged 19 years or older with mild-to-moderate GO will be randomized to receive either vitamin B complex alone or vitamin B complex with selenium for 6 months with three monthly follow-up visits. The primary outcome is comparison of the improvement in quality of life at 6 months from baseline between the control and selenium groups. The secondary outcomes are intergroup differences in changes in quality of life at 3 months, clinical activity of GO at 3 and 6 months, thyroid autoantibody titers at 3 and 6 months, and the response rate at 3 and 6 months from baseline. Quality of life will be measured by questionnaire for patients with GO, and the clinical activity of GO will be evaluated by the clinical activity score (CAS). A positive response is defined as either changes in the CAS < 0 or the changes in the GO-QOL score ≥ 6. DISCUSSION: The SeGOSS study will evaluate the therapeutic potential of selenium for mild-to-moderate GO in a selenium-sufficient area and provide support in tailoring better treatment for GO. TRIAL REGISTRATION: KCT0004040. Retrospectively registered on 5 June 2019. https://cris.nih.go.kr/cris/search/detailSearch.do/14160 .

Management of Graves ophthalmopathy - 2022 update.

Graves ophthalmopathy (GO) occurs in 25-50% cases of Graves disease. Most cases are just mild, only 5% represents eye threatening diseases. About 5-10% of cases could be euthyroid and 10% hypothyroid, respectively. All patients with GO should be assessed for activity (clinical activity score - CAS) and severity of the disease. Essential conditions of the successful treatment are well controlled thyroid dysfunction, smoking cessation and to refer patients with moderate to severe and sight threatening GO to specialized thyroid eye centers as soon as possible. Local therapy to maintain wet eye (lubricants) and supplementation of selenium deficiency is adequate in mild cases of GO. In cases of moderate to severe and sight threatening GO, administration of intravenous glucocorticoids in thyroid eye centers is first line treatment and a combination with mycophenolate or radiotherapy could be considered. When the first-line treatment fails or a contraindication/intolerance to them is present, non-steroid immunosuppressive drugs (mycophenolate, ciclosporin), rituximab, or radiotherapy could be considered. In rare cases of sight threatening GO urge surgical orbital decompression or tarsorrhaphy is warranted.

Current concepts regarding Graves' orbitopathy.

Graves' orbitopathy (GO) is an orbital autoimmune disorder and the main extrathyroidal manifestation of Graves' disease, the most common cause of hyperthyroidism. GO affects about 30% of Graves' patients, although fewer than 10% have severe forms requiring immunosuppressive treatments. Management of GO requires a multidisciplinary approach. Medical therapies for active moderate-to-severe forms of GO (traditionally, high-dose glucocorticoids) often provide unsatisfactory results, and subsequently surgeries are often needed to cure residual manifestations. The aim of this review is to provide an updated overview of current concepts regarding the epidemiology, pathogenesis, assessment, and treatment of GO, and to present emerging targeted therapies and therapeutic perspectives. Original articles, clinical trials, systematic reviews, and meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, Graves' orbitopathy, thyroid eye disease, glucocorticoids, orbital radiotherapy, rituximab, cyclosporine, azathioprine, teprotumumab, TSH-receptor antibody, smoking, hyperthyroidism, hypothyroidism, thyroidectomy, radioactive iodine, and antithyroid drugs. Recent studies suggest a secular trend toward a milder phenotype of GO. Standardized assessment at a thyroid eye clinic allows for a better general management plan. Treatment of active moderate-to-severe forms of GO still relies in most cases on high-dose systemic-mainly intravenous-glucocorticoids as monotherapy or in combination with other therapies-such as mycophenolate, cyclosporine, azathioprine, or orbital radiotherapy-but novel biological agents-including teprotumumab, rituximab, and tocilizumab-have achieved encouraging results.

Serum Selenium Levels in Patients with Graves Disease: Associations with Clinical Activity and Severity in a Retrospective Case-control Study.

PURPOSE: To compare serum selenium levels in Graves patients and non-Graves control participants and to evaluate associations between serum selenium levels and clinical features of Graves orbitopathy (GO). METHODS: We conducted a single-center, retrospective case-control study among 33 patients with Graves disease without GO (GD), 31 patients with diagnosed GO, and 27 unaffected healthy participants enrolled between 2013 and 2020 at Severance Hospital. We compared serum selenium concentrations between the GD, GO, and healthy control groups, and analyzed associations between serum selenium and GO patients' clinical activity scores, severity (assessed through modified NOSPECS scores), and other clinical features using multivariate linear regression analysis. RESULTS: Mean serum selenium levels were 109.30 ± 16.39, 111.39 ± 14.04, and 126.09 ± 21.09 ng/mL in GO patients, GD patients, and healthy control participants, respectively. Mean serum selenium levels in Graves patients with and without orbitopathy were significantly lower than those in the healthy control group (p < 0.05), and mean selenium levels were slightly lower in GO than those in GD patients (p = 0.594). Serum selenium levels were significantly lower in GO patients with eyelid retraction than in patients without retraction (p = 0.038). However, serum selenium levels were not associated with clinical activity scores and modified NOSPECS scores (p = 0.241 and 0.801, respectively). CONCLUSIONS: Serum selenium levels were significantly lower in Graves patients with or without GO, compared to non-Graves control participants. Selenium levels were not associated with clinical activity scores or NOSPECS scores, though we observed an association with eyelid retraction.

The risk factors for Graves' ophthalmopathy.

PURPOSE: This review aimed to provide an overview of current research into the risk factors for Graves' ophthalmopathy (GO). METHODS: To find information about the risk factors for GO, the research database PubMed was searched and relevant articles were obtained to extract information about risk factors. RESULTS: Smoking has been widely accepted as an important risk factor and cigarette smoking cessation has been shown to improve the outcome and decrease the onset of GO. Radioactive iodine on the thyroid may induce hyperthyroidism and increase the occurrence of GO. Selenium deficiency is a risk factor for GO and the supplementation of selenium has been an adjuvant therapy. Decreasing stressful life events (SLE) may help improve GO. Imbalance in intestinal flora is essential to GO, with Yersinia enterocolitica and Escherichia coli both increased in the digestive tract of the individual with GO. In addition, controlling serum cholesterol may help improve GO since adipogenesis is an important pathological change in its pathogenesis. Considering the correlation between Graves' disease and GO, maintaining normal thyroid function hormone level is the first-line therapeutic strategy to prevent progression of GO. An increase in antibodies such as TSHR and IGF-1R is the main predictor of GO. Besides, gender and gene polymorphism are also risk factors towards GO. CONCLUSIONS: Risk factors for GO arise from five sources: physical and chemical environment, social-psychological environment, biological environment, the human organism, and genetic codes. Risk factors within these categories may interact with each other and their mechanisms in promoting the development of GO are complex. Research into risk factors for GO may promote emerging fields related to GO such as control of autoantibodies and intestinal microbiota.

[Graves' orbitopathy]. / Endokrine Orbitopathie.

BACKGROUND: Graves' orbitopathy (GO) is an autoimmune orbital disease which is mostly associated with Graves' disease and requires good interdisciplinary cooperation. To minimize irreversible damages a stage-adapted anti-inflammatory therapy is of great importance. MATERIAL AND METHODS: Discussion of the latest results of new findings of the pathogenesis, randomized controlled trials on anti-inflammatory treatments for Graves' orbitopathy and novel therapeutic concepts. RESULTS: In all patients with GO achieving euthyroidism, as well as cessation of smoking is very important to avoid prolongated diseases. Mild cases of GO can be treated with selenium supplementation and artificial tears. The moderate-to-severe, active form of GO requires primarily i. v. steroids in combination with orbital irradiation in case of impaired motility. In patients with insufficient therapeutic response after 6 weeks, treatment should be switched to other immunosuppressive agents. In severe sight-threatening cases even high-dose i. v. steroid treatments are often ineffective and bony orbital decompression is necessary. As latest research data have improved our understanding of the pathophysiology of GO, targeted therapies have been developed for GO. Teprotumumab, an IGF-1 receptor antibody, was shown effective in treating GO patients in a phase III trial and should soon be awarded approval for Europe. Inactive patients, who suffer from disturbing exophthalmos should be also treated with bony decompression before eye muscle or lid surgery. CONCLUSION: The current concept for Graves' orbitopathy is as follows: first anti-inflammatory therapy then surgical correction of the permanent defects. This might be modified in the future, due to the promising effects of targeted therapies.

Clinical efficacy of thyroid-stimulating immunoglobulin detection for diagnosing Graves' disease and predictors of responsiveness to methimazole.

BACKGROUND: As thyroid-stimulating immunoglobulins (TSI) are a sign of Graves' disease (GD), measuring TSI titers is becoming increasingly important for GD diagnosis. This study evaluated the diagnostic accuracy of a new fully automated TSI immunoassay (Immulite™ TSI assay) in GD patients and compared it to the third generation thyroid-stimulating hormone receptor antibody (TRAb) electrochemiluminescence assay (Elecsys Anti-TSHR assay). Additionally, clinical characteristics associated with responsiveness to methimazole in patients with newly diagnosed GD were preliminarily explored. METHODS: This study involved 324 subjects, comprising patients with untreated GD (GD-UT), Graves' ophthalmopathy (GO) patients, GD patients who had been treated for > 12 months (GD-T), autoimmune thyroiditis (AIT) patients, and healthy subjects (HS). The Immulite™ TSI and Elecsys Anti-TSHR assay were performed on all samples. According to their responsiveness to methimazole, the GD-UT patients were divided into rapid and slow responder groups, and their clinical characteristics were compared. RESULTS: A receiver operating characteristic (ROC) curve analysis of GD-UT patients showed that the optimal TSI cut-off value was 0.57 IU/L. Logistic regression revealed that age and initial FT4 and TSI levels in the middle-dose methimazole group were related to a rapid response, while the initial FT4 level, but not TSI, in the high-dose group was also associated with a rapid response. CONCLUSIONS: The clinical diagnostic performance of the Immulite™ TSI assay for diagnosing GD was comparable to that of the Elecsys Anti-TSHR assay. The initial FT4 and TSI levels can be used as predictors of the responsiveness to methimazole in patients with newly diagnosed GD.

A 'Real Life' Service Evaluation Model for Multidisciplinary Thyroid Eye Services.

Background/Aims: There is no universal consensus on the practical implementation and evaluation of the Amsterdam Declaration on Graves Orbitopathy in a Multidisciplinary Thyroid Eye Disease (MDTED) pathway. Recent recommendations from the UK TEAMeD-5 and BOPSS initiative highlight the importance of prevention, screening, and prompt referral of patients with moderate to severe and sight-threatening thyroid eye disease to multidisciplinary (MDTED) clinics and recommends annual auditing. We propose a practical service evaluation model with Key Performance Indicators (KPI) that are achievable and could be implemented across most TED pathways. Material and Methods: We conducted a service evaluation from an integrated TED pathway in London with three MDTED clinics. Data was collected retrospectively from consecutive TED patients included: 1) Patient demographics, 2) Referral to first appointment time, 3) Documented smoking cessation and selenium supplementation advice, 4) Presenting disease activity and severity, 5) Investigations and treatments, including radio-iodine, 6) Time from decision to treatment initiation, 7) Initial and subsequent thyroid status. Results: The median age was 49.0 yrs, 77.5% (183/236) were female and 49.5% (101/204) Afro-Caribbean or Asian. At their first clinic attendance, 47.6% (110/231) were biochemically euthyroid and 76.7% (79/103) at discharge. All 23.1% (52/225) current smokers received smoking cessation advice and 64.8% (153/236) received selenium supplementation advice. Intravenous methylprednisolone was given to 33.9% (80/236) patients and 12.7% (30/236) received second-line immunosuppression. All 7.2% (17/236) patients with sight-threatening disease received treatment within two weeks of diagnosis. Conclusions: This study forms a waymark for other units using TEAMeD-5 and BOPSS audit criteria. Dedicated electronic patient records with ongoing data capture, including quality of life assessments, and diagnostic coding would significantly aid future auditing, improve patient care, and facilitate a national audit of TED management. A future survey when the TED standards have become embedded would be instructive to see whether this has improved TED care.

Graves' Orbitopathy: Current Concepts for Medical Treatment. / Endokrine Orbitopathie: aktueller Stand der medikamentösen Therapie.

BACKGROUND: The therapy of severe manifestations of Graves' orbitopathy (GO) is still a challenge and requires good interdisciplinary cooperation. It is especially important to use stage-adapted anti-inflammatory therapy to avoid irreversible damage. MATERIAL AND METHODS: Discussion of the latest results of multicentre randomised therapy studies on anti-inflammatory treatments for Graves' orbitopathy, as well as new therapeutic concepts. RESULTS: Mild cases of GO can be treated with only selenium supplementation and a watchful waiting strategy. In the moderate-to-severe active form of GO, primary therapy consists of i. v. steroids (cumulative 4 - 5 g) in combination with orbital irradiation in patients with impaired motility. In patients with insufficient therapeutic response after 6 weeks, treatment should be switched to other immunosuppressive agents. In severe sight-threatening disease, bony orbital decompression is usually necessary. As basic research has improved our understanding of the underlying pathophysiology of GO, it has been possible to develop targeted therapies for GO. Teprotumumab, an IGF-1 receptor antibody, was effective in treating GO patients in a phase III trial and should soon be awarded approval for Europe. CONCLUSION: The current therapy concept for Graves' orbitopathy is as follows: first anti-inflammatory therapy then surgical correction of the permanent defects. This may soon be modified, due to the use of targeted therapies.

Change in newly diagnosed Graves' disease phenotype between the twentieth and the twenty-first centuries: meta-analysis and meta-regression.

PURPOSE: According to a few recent studies, the clinical phenotype of Graves' disease (GD) at onset is becoming milder in recent years, in terms of prevalence and severity of hyperthyroidism, goiter and overt eye disease. The aim of this study was to assess the change in GD phenotype across the late twentieth and the early twenty-first centuries. MATERIALS AND METHODS: We carried out a systematic search of studies published between 1/1/1980 and 12/31/2017 describing naïve GD patients at diagnosis. We collected epidemiological, clinical, biochemical and serological data reported in the selected studies, and (1) conducted a single-arm meta-analysis to compare clinical and biochemical characteristics of naïve GD patients before and after year 2000 and (2) performed a meta-regression to identify the trend of the observed clinical presentations. RESULTS: Eighty selected articles were related to the period before the year 2000, 30 to the years 2000-2017. According to demographics, the two defined populations were homogeneous at meta-analysis: overall estimated female prevalence was 81% [95% CI 79-82], mean estimated age of the entire population was 39.8 years [95% CI 38.4-41.1], with no significant differences between pre- and post-2000 groups (p > 0.05). The overall estimated prevalence of smokers was 40% [95% CI 33-46], with no significant difference between the two groups (p > 0.05). Mean estimated free thyroxine (FT4) and free triiodothyronine (FT3) levels at diagnosis were higher in the pre-2000 group: 4.7 ng/dl [95% CI 4.5-4.9] for FT4 and 14.2 pg/ml [95% CI 13.3-15.1] for FT3, as compared to the post-2000 group: 3.9 ng/dl [95% CI 3.6-4.2] for FT4 and 12.1 pg/ml [95% CI 11.0-13.3] for FT3 (all p < 0.01). Goiter estimated prevalence was higher in the pre-2000 group, 87% [95% CI 84-90], than in the post-2000 group, 56% [95% CI 45-67]. Estimated prevalence for Graves' Orbitopathy (GO) was 34% [95% CI 27-41] in the pre-2000 group and 25% [95% CI 19-30] in the post-2000 group (p = 0.03). Accordingly, meta-regression adjusted for covariates showed an average annual reduction of FT4 (- 0.040 ± 0.008 ng/dl, p < 0.0001), FT3 (- 0.316 ± 0.019 pg/ml, p < 0.0001), goiter prevalence (- 0.023 ± 0.008%, p = 0.006), and goiter size (- 0.560 ± 0.031 ml, p < 0.0001). CONCLUSIONS: Our meta-analysis and meta-regression confirmed that GD phenotype at diagnosis is nowadays milder than in the past; we hypothesize that conceivable factors involved in this change are iodoprophylaxis, worldwide decrease in smoking habits, larger use of contraceptive pill and micronutrient supplementation, as well as earlier diagnosis and management.

Serum Vitamin D Deficiency Is an Independent Risk Factor for Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) is an inflammatory orbitopathy with significant impact on visual function and quality of life. Although studies have shown that patients who are deficient in vitamin D are more likely to develop autoimmune conditions, there are no studies demonstrating a definitive correlation between serum 25-hydroxyvitamin D (25(OH)D) deficiency and an increased risk of TED. METHODS: This retrospective case-control study compared serum 25(OH)D levels among 4 groups: 1) Graves disease (GD) patients with TED (n = 89); 2) GD patients without TED (n = 89); and healthy control patients matched to 3) the TED group (n = 356); and 4) the GD group (n = 356). The authors compared 25(OH)D level in the TED group measured within 1 year of TED diagnosis to the most recently measured 25(OH)D level in the GD group using Student t test of the log transformation of serum levels. Linear regression was used to control for other risk factors. Thyroid eye disease patients and GD patients were compared separately to their matched healthy control patients with linear mixed models. RESULTS: Thyroid eye disease patients displayed significantly lower serum 25(OH)D levels than GD patients (24.8 ± 13.2 ng/ml vs. 29.4 ± 13.3 ng/ml; p = 0.006). Controlling for smoking status and previous radioactive iodine treatment did not affect this statistically significant difference. CONCLUSIONS: Low serum vitamin D is associated with TED diagnosis. Assessing and supplementing vitamin D levels may be an important addition to the early management of GD patients. Future research should include longitudinal studies and prospective clinical trials to further explore the mechanism responsible for the observed association.Thyroid eye disease is an inflammatory orbitopathy associated with Graves disease. Vitamin D is a known immune system regulator. The authors show that vitamin D deficiency is associated with the development of thyroid eye disease.

Salzmann's nodular degeneration of cornea associated with thyroid eye disease.

Salzmann's nodular degeneration (SND) typically occurs in patients who are female, 50-60 years old, and have a history of corneal inflammation and irritation. Multiple case reports have documented associations between SND and trachoma, viral infections, trauma, contact lens wear, corneal surgeries and corneal exposure. The authors describe a patient with bilateral SND confirmed by anterior segment optical coherence tomography (OCT) imaging in the context of thyroid eye disease (TED) and history of LASIK. Treatment involved propylthiouracil (PTU), artificial tear use, loteprednol etabonate ophthalmic gel, eyelid taping and selenium supplementation and prospective superficial keratectomy with diamond burr polish.

[Endocrine orbitopathy: the present view of a clinical endocrinologist]. / Endokrinní orbitopatie: aktuální pohled klinického endokrinologa.

Graves orbitopathy (GO) occurs in 25-50 % cases of Graves disease. Only in 5 % of patients the eye threatening GO is present. About 5-10 % and 10 % cases are present in euthyroid and hypothyroid patients respectively. All patients with GO should be assessed for activity (clinical activity score - CAS) and severity of the disease. Basic preconditions of the treatment are maintenance of euthyroidism, an effort to stop smoking, and referring of patients with moderate to severe and sight threatening GO to specialized thyroid eye centers. The first line treatment includes maintenance of wet eye (lubricants), supplementation of selenium deficiency, intravenous glucocorticoids, radiotherapy and surgery. Cases with moderate to severe GO should be treated with intravenous glucocorticoids in thyroid eye centers, however, the risk/benefit ratio in all cases should be considered. Cases with sight threatening GO should be immediately referred to thyroid eye centers, high-dose intravenous glucocorticoids are administered, and when the clinical response is absent within 2 weeks, surgical orbital decompression is recommended. Other immunosuppressive drugs (cyclosporine, mycophenolate mofetil) or biological therapy (teprotumumab) are not routinely recommended because of lack of evidence obtained by randomized controlled trials.Key words: clinical activity score - dysthyroid optic neuropathy - Graves orbitopathy - intravenous glucocorticoids - mycophenolate mofetil.

Conjuntivitis recurrente de causa no aclarada. ¿Hipertiroidismo? / Recurrent conjunctivitis of unknown origin. Hyperthyroidism?

El hipertiroidismo en la infancia es muy infrecuente; en la mayoría de los casos es de origen autoinmune (enfermedad de Graves). La tríada clásica se compone de bocio, oftalmopatía y dermatopatía. Su presentación clínica en la edad pediátrica es muy variable y de comienzo habitualmente insidioso, lo que en muchas ocasiones conlleva una demora en el diagnóstico y tratamiento. Presentamos el caso de una paciente de 12 años que consulta por una conjuntivitis crónica bilateral refractaria a tratamientos tópicos habituales, que finalmente fue derivada al Servicio de Endocrinología Pediátrica ante la sospecha de oftalmopatía de Graves (AU)

Hyperthyroidism in childhood is a very rare condition, and in most cases of autoimmune etiology (Graves’ disease). The classic triad consists of goiter, ophthalmopathy and dermopathy. Clinical presentation in children is highly variable and often with an insidious onset, which on many occasions may cause a delay on its diagnosis and treatment. A case is reported here where a 12-year-old patient, who showed a refractory bilateral chronic conjunctivitis refractary to topical usual treatments, was finally referred to the Pediatric Endocrinology Department due to the likelihood of her suffering from Graves' ophthalmopathy (AU)

VARIABLES AFFECTING THE LONG-TERM OUTCOME OF GRAVES ORBITOPATHY FOLLOWING HIGH-DOSE INTRAVENOUS GLUCOCORTICOID PULSE THERAPY IN PATIENTS NOT TREATED WITH ORBITAL RADIOTHERAPY.

OBJECTIVE: Intravenous (iv) glucocorticoids (GC) (ivGC) are used for active Graves orbitopathy (GO), but factors affecting GO outcome are poorly understood. We performed a retrospective study to investigate the variables affecting GO after ivGC. METHODS: We evaluated 83 consecutive GO patients treated with ivGC but not orbital radiotherapy (ORT) and re-examined them after a median of 47 months. The endpoints were the relationships between GO outcome or additional treatments with age, sex, smoking habits, thyroid volume, thyroid treatment, time since thyroid treatment, antithyroid-stimulating hormone receptor antibodies (TRAb), GO duration, GO features, and follow-up time. RESULTS: GO features improved after treatment, resulting in moderate and marked amelioration in ~75% and ~41% of patients respectively. By multivariate analysis, a moderate GO improvement correlated with diplopia at first observation, which was more severe in responders. A marked GO improvement correlated with time between first and last observation and time after thyroid treatment, which were longer in responders. This likely reflected the combination of an early effect of GC and a late, spontaneous improvement of GO, as shown by analyses of GO outcome at various time points. Additional treatments after ivGC correlated by multivariate analysis with eyelid aperture, diplopia and NOSPECS score (NOSPECS stands for no GO signs [N], only eyelid sign [O], soft tissue involvement [S], proptosis [P], extraocular motility restriction [E], corneal involvement [C], and sight loss [S]) at first observation, which were more severe in responders. CONCLUSION: Our study shows that response to ivGC increases with time, likely reflecting the known tendency of GO to improve spontaneously, and is more pronounced when GO is more severe to begin with, which is associated with more additional treatments. ABBREVIATIONS: ANOVA = analysis of variance CAS = clinical activity score GC = glucocorticoids GO = Graves orbitopathy 131I = radioactive iodine iv = intravenous ivGC = high-dose intravenous glucocorticoid pulse therapy MMI = methimazole OD = orbital decompression ORT = orbital radiotherapy TRAb = antithyroid-stimulating hormone receptor antibodies.

Bilateral optic nerve edema presenting as initial manifestation of thyroid eye disease.

A 48-year-old smoker with a history of hyperthyroidism treated 10 years prior to presentation with radioactive iodine ablation of the thyroid gland presented to his ophthalmologist with a 2-week history of transient loss of vision in the right eye occurring for 1 to 2 hours each morning. He denied ocular pain, diplopia or change in the prominence of one or both eyes. Examination revealed 2 mm of relative proptosis on the right, bilateral temporal flare and lower lid retraction. There was minimal upper lid retraction and no evidence of lid lag. Ocular motility was full. Dilated fundoscopic examination revealed bilateral optic nerve edema, right more than left. CT of the orbit demonstrated enlargement of the extraocular muscles bilaterally with marked enlargement of the right medial rectus and left inferior rectus muscles resulting in crowding at the orbital apex bilaterally. Laboratory testing revealed the patient to be hyperthyroid. The patient was treated with high dose oral steroids followed by orbital radiation. Hyperthyroidism was managed by the patient's primary care physician. Visual symptoms rapidly improved with oral steroids and orbital radiation. Optic nerve edema completely resolved. Repeat CT imaging demonstrated a reduction in the enlargement of the extraocular muscles with relief of bilateral optic nerve compression.

[Graves' ophthalmopathy]. / Endokrine Orbitopathie.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease and the full clinical picture can impair the quality of life of the patients considerably. Active inflammation can often be effectively treated by intravenous steroids/immunosuppression, however does not lead to full remission, since inflammation rather quickly results in irreversible fibrosis and increase of orbital fat. Very important is the control of risk factors (smoking cessation, good control of thyroid function, selenium supplementation) to prevent progression to severe stages. Treatment should rely on a thorough assessment of activity and severity of GO. Rehabilitative surgery (orbital decompression, squint surgery, eyelid surgery) is needed in many patients to restore function and appearance. Anti-thyroid-stimulating hormone (TSH) receptor antibodies do specifically occur in these patients and correlate to the course of thyroid and eye disease. The levels of these antibodies can be used for treatment decisions at certain time points of the disease.

Graves' ophthalmopathy treated with protracted hypofractionated low-dose adaptive radiotherapy: case report and review of the literature.

Graves' ophthalmopathy (GO) is the most common extra-thyroidal manifestation of Graves' disease. The treatment options for GO are high-dose glucocorticoids, selenium, rituximab, cyclosporine, orbital radiotherapy (RT), and surgery. A 43-year-old male patient was referred to our clinic with complaints of severe bilateral proptosis, diplopia, and orbital pain at both globes for 1 year. Pretreatment magnetic resonance imaging revealed bilateral proptosis, the expansion of bilateral optic nerves sheath, the increase of right medial muscle thickness, and a mass at the right eyehole. Patient was treated with 1 Gy per fraction per week with a total dose of 10 Gy over 10 weeks with adoptive intensity-modulated radiotherapy technique. During RT at 3rd and 6th weeks, a moderate shrinkage of the lesions was observed. The patient has been disease free, has had no complaints for 36 months, and has not required any surgical intervention. No late side effects such as retinopathy or cataract were observed. Orbital RT with innovative techniques may be considered as an initial local treatment for GO. With adoptive protracted low dose RT, a good clinical and radiological response could be seen without increasing early and late reactions.