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Purpose: Graves' disease (GD) and toxic nodular goiter (TNG) are associated with various comorbidities. However, it is unclarified whether TNG and GD without orbitopathy are associated with glaucoma., Methods: This was a case-control study using record-linkage data from nationwide Danish health registers. 28,461 patients with GD and 17,283 with TNG were included. Each case was age and sex matched with four non-hyperthyroid controls and followed over a mean period of 8 years. Data on glaucoma was obtained by record linkage within the National Danish Patient Register and/or the Danish National Prescription Registry. Logistic and Cox regression models were used to assess the risk of glaucoma before and after the diagnosis of GD and TNG., Results: Compared to controls, there was a significantly increased frequency of glaucoma in patients with GD (4.6 vs. 4.2%, P = 0.006) and in patients with TNG (6.2 vs. 5.7%, P = 0.003). Prior to the diagnosis of hyperthyroidism, the odds ratio (OR) for glaucoma was non-significant in GD (1.09, 95% CI: 1.00-1.18) but slightly increased in TNG (1.13, 95% CI: 1.02-1.24). However, in TNG the OR attenuated completely when only including patients without co-morbidity in the analysis (1.03, 95% CI: 0.93-1.14). After adjustment for pre-existing co-morbidity, the hazard ratio (HR) for glaucoma following GD and TNG was not significantly increased (HR 1.08, 95% CI: 0.98-1.18 and HR 1.10, 95% CI: 0.99-1.21, respectively)., Conclusions: Neither prior to nor following the diagnosis of GD and TNG had any significant association with glaucoma.

The study evaluated clinical efficacy of intensity modulated radiation therapy (IMRT) in treating patients with thyroid-associated ophthalmopathy (TAO) and defined predictive factors that associated with treatment response. A total of 178 TAO patients were treated with retro-orbital IMRT with radiation dose of 20 Gy in 10 fractions. The immediate and long-term treatment response and complications were evaluated. Besides, logistic-regression analysis was conducted to identify possible predictive factors. TAO symptom score significantly fell from the initiation to 6-month post-treatment (P < 0.001). 134 patients (73.2%) had mild to significant response to IMRT, and 172 patients (96.6%) achieved stabilization of TAO without future progression. Current smoker (OR 2.88, 95% CI 1.32-6.29; P = 0.008) and symptom duration longer than 18 months (OR 3.33, 95% CI 1.24-8.93; P = 0.017) were identified as independent predictive factors for non-response of TAO to retro-orbital IMRT. Immediate complications were slight and self-limited, and long-term complications mainly included chronic xerophthalmias in12 patients (6.74%) and cataract formation in 4 patients (2.25%). The study suggested that IMRT was a viable option for treating TAO patients, with a satisfactory symptom control ability and acceptable post-treatment complications.

Purpose: Thyroid-associated orbitopathy (TAO), a clinical manifestation of Graves' disease, is an autoimmune disorder of the orbital and periorbital tissue. Data on the epidemiology and clinical presentation of TAO in Africa are generally scarce and unavailable in Ghana. We investigated the epidemiology and clinical features of TAO among patients with thyroid disorders attending the Korle Bu Teaching Hospital, Accra., Subjects and Methods: This was a descriptive cross-sectional study of patients diagnosed with thyroid disorders which was conducted at the endocrine and orbital clinics of the Korle Bu Teaching Hospital. Diagnosis was based on clinical features and confirmed by a thyroid function test. Data collected and analyzed included demography, systemic and ocular features of thyroid disorder, and thyroid function tests., Results: Of the 194 patients with thyroid disorders recruited, 117 (60.30%) had TAO. The mean age was 45.22 years (standard deviation: 13.90). The male:female ratio was 1:4.45. The most common ocular symptoms were "bulging eyes" (76/65.00%) and "puffy eyelid" (62/53.00%), and the common signs were eyelid retraction (97/82.91%) and proptosis (80/68.38%). Mild TAO was diagnosed in 64.96% of patients with only 6.84% having the severe form. The outcomes of the thyroid function test, thyroid disorder, and severity of TAO did not record any statistically significant differences., Conclusions: The epidemiology is similar to those reported from other parts of the world, but the ocular presentation seems to be milder than in Caucasians., Competing Interests: There are no conflicts of interest.

This article aims to provide baseline data and highlight any major deficiencies in the current level of care provided for adult patients with thyroid eye disease (TED). We undertook a prospective, nonrandomized cross-sectional multicenter observational study. During a 3-month period June-August 2014, consecutive adult patients with TED who presented to nominated specialist eye clinics in the United Kingdom, completed a standardized questionnaire. Main outcome measures were: demographics, time from diagnosis to referral to tertiary centre, time from referral to review in specialist eye clinic, management of thyroid dysfunction, radioiodine and provision of steroid prophylaxis, smoking, and TED classification. 91 patients (mean age 47.88 years) were included. Female-to-male ratio was 6:1. Mean time since first symptoms of TED = 27.92 (73.71) months; from first visit to any doctor with symptoms to diagnosis = 9.37 (26.03) months; from hyperthyroidism diagnosis to euthyroidism 12.45 (16.81) months. First, 13% had received radioiodine. All those with active TED received prophylactic steroids. Seven patients who received radioiodine and did not have TED at the time went on to develop it. Then, 60% patients were current or ex-smokers. 63% current smokers had been offered smoking cessation advice. 65% patients had active TED; 4% had sight-threatening TED. A large proportion of patients (54%) were unaware of their thyroid status. Not enough patients are being provided with smoking cessation advice and information on the impact of smoking on TED and control of thyroid function.

Background: Graves' orbitopathy (GO) is an autoimmune condition, which is associated with poor clinical outcomes including impaired quality of life and socio-economic status. Current evidence suggests that the incidence of GO in Europe may be declining, however data on the prevalence of this disease are sparse. Several clinical variants of GO exist, including euthyroid GO, recently listed as a rare disease in Europe (ORPHA466682). The objective was to estimate the prevalence of GO and its clinical variants in Europe, based on available literature, and to consider whether they may potentially qualify as rare. Recent published data on the incidence of GO and Graves' hyperthyroidism in Europe were used to estimate the prevalence of GO. The position statement was developed by a series of reviews of drafts and electronic discussions by members of the European Group on Graves' Orbitopathy. The prevalence of GO in Europe is about 10/10,000 persons. The prevalence of other clinical variants is also low: hypothyroid GO 0.02-1.10/10,000; GO associated with dermopathy 0.15/10,000; GO associated with acropachy 0.03/10,000; asymmetrical GO 1.00-5.00/10,000; unilateral GO 0.50-1.50/10,000., Conclusion: GO has a prevalence that is clearly above the threshold for rarity in Europe. However, each of its clinical variants have a low prevalence and could potentially qualify for being considered as a rare condition, providing that future research establishes that they have a distinct pathophysiology. EUGOGO considers this area of academic activity a priority.

Background Graves' disease is an autoimmune disorder leading to hyperthyroidism. It is often associated with ophthalmic manifestations. Graves' disease is reported to be rare in the paediatric population. Patients and Methods We performed a retrospective analysis on all patients diagnosed with ophthalmopathy related to Graves' disease at a paediatric age (less than 18 years old) in our institution between 2004 and 2015. Results Eight patients were identified: 6 females and 2 males. The median age at diagnosis was 11.5 years (range 3-16). Ophthalmic signs were: proptosis (6/8), superficial punctate keratitis (5/8), eyelid retraction (4/8), lagophthalmos (2/8), and oculomotor dysfunction (2/8). No patients showed signs of complication such as ocular hypertension or compressive optic neuropathy. Orbital decompression was performed in one patient in a non-emergency setting. Conclusion Ophthalmic involvement in Graves' disease is rarely encountered in paediatric patients. Ophthalmologists should be aware of this entity to ensure that patients with thyroid dysfunction are identified at an early point in time., (Georg Thieme Verlag KG Stuttgart · New York.)

Context: Previous association studies suggest the development of Graves' orbitopathy (GO) is variably influenced by environmental risk factors., Objective: To determine the risk factors and predict odds for developing GO in Graves' hyperthyroidism (GH)., Design: Case-control study., Setting: Multi-centre Australian Thyroid-associated Orbitopathy Research group consisting of tertiary endocrinology and ophthalmology outpatients and related private practices., Patients or Other Participants: A total of 1042 participants with GH were designated as cases if they had GO (n = 604) and controls if they did not have GO (n = 438)., Main Outcome Measures: Primary outcome was GO risk factors and secondary outcome was dysthyroid optic neuropathy (DON) with the effects of risk factors measured by odds ratio (OR) using multiple logistic regression, adjusted for known risk factors and exploratory variables., Results: The odds of GO increased by 17% for each decade increase in the age of onset of GH (OR 1.17, confidence interval (CI): 1.06-1.29; P = .002) and by 7% for each year increase in the duration of GH (OR 1.07, CI: 1.05-1.10; P < .001). Smoking increased the odds for GO by 2.22 for current smoker and 2.07 for exsmoker (P < .001), compared with never smoking. The odds of GO are 86% less in Graves' patients using antithyroid medication than those not (OR 0.14, CI: 0.06-0.34; P < .001). Predictors for DON were older age, oculomotility restriction, strabismus, reduced palpebral aperture, and active GO., Conclusions: This study identified increase age of onset, duration of GH, and smoking as risk factors for GO. Usage of antithyroid medication was negatively related to GO. Older patients with restricted ocular motility, strabismus, and active GO are at higher risk of DON and may benefit from early medical intervention.

Purpose: Thyroid-associated orbitopathy (TO) is an autoimmune-mediated orbital inflammation that can lead to disfigurement and blindness. Multiple genetic loci have been associated with Graves' disease, but the genetic basis for TO is largely unknown. This study aimed to identify loci associated with TO in individuals with Graves' disease, using a genome-wide association scan (GWAS) for the first time to our knowledge in TO., Methods: Genome-wide association scan was performed on pooled DNA from an Australian Caucasian discovery cohort of 265 participants with Graves' disease and TO (cases) and 147 patients with Graves' disease without TO (controls). Top-ranked single nucleotide polymorphisms (SNPs) then were genotyped in individual DNA samples from the discovery cohort, and two replication cohorts totaling 584 cases and 367 controls., Results: In the GWAS of pooled DNA samples, several SNPs showed suggestive association with TO at genome-wide P ≤ 10-6; rs953128 located on chr10q21.1, rs2867161 on chr7q11.22, rs13360861 on chr5q12.3, rs7636326 on chr3q26.2, rs10266576 on chr 7q11.22, rs60457622 on chr3q23, and rs6110809 on chr20p12.1. However, the only SNP consistently associated with TO on individual genotyping in the discovery and replication cohorts was rs6110809, located within MACROD2 on chromosome 20p12.1. On combined analysis of discovery and replication cohorts, the minor A allele of rs6110809 was more frequent in TO than in Graves' disease controls without TO (P = 4.35 × 10-5; odds ratio [OR] = 1.77; 95% confidence interval [CI], 1.35-2.32) after adjusting for age, sex, duration of Graves' disease, and smoking., Conclusions: In patients with Graves' disease, a common genetic variant in MACROD2 may increase susceptibility for thyroid-associated orbitopathy. This association now requires confirmation in additional independent cohorts.

Background: Endocrine orbitopathy (Graves' disease) is an autoimmune disease based on a genetic predisposition. Patients with a visible exophthalmos were examined and treated in the department of ophthalmology., Objectives: Is there an association between the formation of exophthalmos and life situations and events?, Material and Methods: A total of 64 patients with exophthalmos due to Graves' disease were asked to complete a questionnaire to evaluate psychosocial morbidity, the quality of life, social background and stressful life events., Results: The results revealed that 60% of the participants had experienced stressful life events (e.g. workplace, parents, children and partner), mainly bereavement in the months before onset of the disease. The psychosocial background revealed that they were predominantly from a low social status and lived in unsatisfactory employment, partner and environmental conditions., Conclusion: Graves' disease is an autoimmune disease and is substantially triggered by psychosocial factors. The necessary interdisciplinary therapy should include medical psychotherapy.

Background/aims: The epidemiology of Graves' orbitopathy (GO) may be changing. The aim of the study was to identify trends in presentation of GO to tertiary centres and initial management over time., Methods: Prospective observational study of European Group On Graves' Orbitopathy (EUGOGO) centres. All new referrals with a diagnosis of GO over a 4-month period in 2012 were included. Clinical and demographic characteristics, referral timelines and initial decisions about management were recorded. The data were compared with a similar EUGOGO survey performed in 2000., Results: The demographic characteristics of 269 patients studied in 2012 were similar to those collected in the year 2000, including smoking rates (40.0% vs 40.2%). Mild (60.5% vs 41.2%, p<0.01) and inactive GO (63.2% vs 39.9%, p<0.01) were more prevalent in 2012. The times from diagnosis of thyroid disease to being seen in EUGOGO centres (6 vs 16 months) and from first symptoms of GO (9 vs 16 months) or from diagnosis of GO (6 vs 12 months) to first consultation in EUGOGO centres were shorter in 2012 (p<0.01). The initial management plans for GO were no different except surgical treatments for patients with mild inactive disease were more frequently offered in the 2012 cohort than in 2000 (27.3% vs 17%, p<0.05), and selenium supplements were offered only in the 2012 cohort (21.2% vs 0%, p<0.01)., Conclusions: These findings suggest that the clinical manifestations of patients with GO may be changing over time in Europe., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Purpose: The natural history of thyroid eye disease follows a biphasic course featuring an initial active stage followed by a durable quiescent stage. Reactivation of thyroid eye disease is defined by recurrence of inflammatory signs and symptoms after a period of stability lasting at least 6 months. It is thought to be rare and is poorly studied. The goal of this study was to define the incidence and characteristics of recurrent thyroid eye disease., Methods: A retrospective chart review of 415 visits of patients with thyroid eye disease was performed between 2006 and 2012. Recurrent cases were identified by subjective historical accounts of disease recurrence, review of prior orbital imaging, and photographic evidence., Results: Among 415 cases of thyroid eye disease, 65 cases of recurrence (15.7%) were identified. Most cases of reactivation occurred within the first 10 years after the initial episode of thyroid eye disease. The mean age of patients at the first event was 42.2 years and 52.6 years at the second event. Eighteen patients had identifiable events that may have triggered disease recurrence. The recurrence rate was higher among patients that had been smokers during their first episode of thyroid eye disease (22%) compared with the nonsmokers (14.6%)., Conclusions: Although uncommon, recurrence of thyroid eye disease does not appear to be as rare as previously believed. A better understanding of the natural history of thyroid eye disease is important as it impacts patient education and management.

Background: At the onset of thyroid-associated orbitopathy (TAO), most patients are hyperthyroid, while scarce data are available on euthyroid/hypothyroid TAO. The aim of this study was to assess the prevalence, phenotype, and psychosocial burden of patients with initially euthyroid/hypothyroid TAO., Methods: The medical records of 461 consecutive and unselected patients with TAO followed at a specialized joint thyroid-eye clinic were analyzed within this retrospective cross-sectional study. Main outcome measures were the prevalence of initially eu- or hypothyroid TAO as well as ophthalmic signs and symptoms, disease-specific quality of life (QoL), work impairment, and rate of psychotherapy in initially eu-/hypothyroid versus hyperthyroid TAO., Results: The prevalences of eu-/hypothyroid and hyperthyroid TAO were 4.3% (n=20; [confidence interval, CI, 2.6-6.3]) and 95.7% (n=441; [9.37-9.74]), respectively. In 12 patients (2.6% [CI 1.3-4.3]), Hashimoto's thyroiditis was present and in 8 (1.7% [CI 0.7-3.0]) no thyroid disease was noted at the time of inclusion. One (0.05%) patient with eu-/hypothyroid TAO and 172 (39%) with hyperthyroid TAO had clinically active TAO (p=0.001). In eu-/hypothyroid versus hyperthyroid patients, 14 (70%) versus 135 (30.6%) had a mild TAO, 6 (30%) versus 183 (64.2%) a moderate-to-severe TAO, and 0 versus 23 (5.4%) had a sight-threatening TAO (p<0.001). TAO was asymmetric in 4 (20%) eu-/hypothyroid and in 27 (6.1%) hyperthyroid patients (p=0.038). Only 5.3% versus 30.2% and 10.5% versus 44.1% of patients with eu-/hypothyroid and hyperthyroid TAO, respectively, were on sick leave (p=0.003) or work disabled (p=0.018). QoL was less impaired in eu-/hypothyroid versus hyperthyroid TAO (median visual functioning and appearance scores: 100 versus 75; p<0.001 and 81.25 versus 75; p=0.315). Of patients with eu-/hypothyroid and hyperthyroid TAO, 15% and 20.2% had psychotherapy respectively (p=0.409). Eu-/hypothyroid TAO was positively (odds ratio 7.05, p=0.060) and negatively (odds ratio: 0.09, p=0.026) associated with a unilateral involvement and thyrotropin-receptor autoantibodies respectively., Conclusions: Compared with hyperthyroid TAO, QoL and working ability are less impaired in eu-/hypothyroid TAO with an often asymmetric and less severe clinical phenotype.

Aim: To describe volumes of orbital fat (FV) and extraocular muscles (MV) in Graves' orbitopathy (GO) as a function of the duration of GO., Patients: i) Cross-sectional survey among 95 consecutive patients with untreated GO who had been referred to the combined thyroid-eye clinics of our university hospital. ii) Longitudinal survey among 39 of the 95 patients who did not receive any therapeutic intervention and were followed for 1 year., Methods: A computed tomography (CT)-based and well-validated method for calculating orbital soft tissues. In order to neutralize sex differences, results are expressed as ratios of FV:orbital volume (OV) and MV:OV., Results: i) Patients with GO duration of >1 year had greater FV:OV (0.65 vs 0.55, P=0.004), similar MV:OV (0.22 vs 0.21, not significant (NS)), and more proptosis (22 mm vs 21 mm, P=0.03) as compared to those with shorter duration. ii) As compared to baseline, after 1 year, FV:OV had increased (0.56 vs 0.63, P=0.000), MV:OV had not changed (0.19 vs 0.19, NS), proptosis was higher (20 mm vs 21 mm, P=0.003), and clinical activity scores had become lower (2 vs 1, P=0.02) (median values)., Conclusion: CT images show that a longer duration of GO is associated with a higher orbital FV. Extraocular MV, however, is not associated with GO duration; rather, it is related to the severity of GO., (© 2015 European Society of Endocrinology.)

Background and Aims: Due to the worldwide increasing prevalence of diabetes (DM), patients with both diabetes and Graves' disease (GD) have become more frequent. Sporadic reports indicate that Graves' orbitopathy (GO), a GD complication that affects orbital soft tissues, can be severe in DM patients. The relationship between these diseases is not well understood. This study aims at evaluating the association of GD and GO with autoimmune and non-autoimmune diabetes (DM) and to assess diabetic features that influence GD and GO prevalence and severity., Methods and Results: This retrospective study evaluated GD, GO and DM association in 1211 consecutive GD patients (447 with GO and 77 with DM). A case-control study was carried out to evaluate DM relationship with GO severity by comparing at 1:2 ratio GO patients with or without DM. A strong association was found between GD and T1DM (p = 0.01) but not T2DM. Instead, the presence of GO was strongly associated with T2DM (p = 0.01). Moreover, GO was more frequently severe in GD patients with T2DM (11/30 or 36.6%) than in those without T2DM (1/60 or 1.7%, p = 0.05). T2DM was the strongest risk factor for severe GO (OR = 34.1 vs. 4.4 p < 0.049 in cigarette smokers). DM duration, obesity and vascular complications, but not metabolic control were significant determinants of GO severity., Conclusions: GD is associated with T1DM but not with T2DM, probably because of the common autoimmune background. GO, in contrast, is more frequent and severe in T2DM, significantly associated with obesity, diabetes duration and diabetic vasculopathy but not metabolic control., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Aim: To study the demographics, comorbidities, clinical manifestations and treatment methods of thyroid eye disease (TED) in Singapore., Methods: In this retrospective case series, we analysed the case records of all patients with TED who presented at our multidisciplinary Thyroid Eye Clinic from November 2002 to October 2012., Results: There were a total of 174 patients-111 female patients (63.8%) and 63 male patients (36.2%). The majority of the patients were ethnically Chinese (80.5%), followed by Malay (10.3%) and Indian (6.3%). The mean age was 40.2 years (SD±15.5, range 0.3-87.0). The commonest sign on ophthalmic examination was eyelid retraction (62.1%), followed by proptosis (61.0%) and lid lag (57.5). Acquired epiblepharon and corneal erosions were noted in 11.5% and 29.3% respectively. Eight patients (4.6%) had dysthyroid optic neuropathy. The mean exophthalmometry reading was 18.8 mm (SD±3.32, range 10.0-28.0). Mild, moderate and severe disease was noted in 71.3%, 20.7% and 8.0% respectively. Thyroid dysfunction was managed with anti-thyroid medication only (40.2%), β blockers (19.5%), thyroxine replacement (14.4%), radioactive iodine (14.4%) and block-replace regime (9.8%). Clinically significant active orbitopathy was managed with intravenous corticosteroids (12.1%). Surgical procedures consisted of thyroidectomy (10.3%), eyelid surgery (8.6%), orbital decompression (7.5%), epiblepharon correction (2.3%) and strabismus surgery (0.6%)., Conclusions: Corneal erosion secondary to acquired epiblepharon is a common sign in East Asian patients with TED, thus increased awareness among physicians should be encouraged. Mean exophthalmometry values and frequencies of upper eyelid retraction and oedema are lower in East Asian patients compared with Caucasian patients. Among Singapore's multi-ethnic population, Malay patients with TED had the highest exophthalmometry reading., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Graves' disease (GD) as an immune reconstitution inflammatory syndrome during highly active antiretroviral therapy (HAART) for HIV has previously been reported. However, clinical challenges associated with HIV in the context of thyroid eye disease (TED) are not as well-characterized., Objective: To determine the frequency of coexisting HIV and TED, describe TED presentation and course in the context of HIV, and evaluate management difficulties as well as potential solutions., Methods: Cross-sectional study of all patients with coexisting GD and HIV at University Hospitals Birmingham (2003-2014). Retrospective case note review to identify TED with particular reference to HAART regimen, CD4+ T-cell count, HIV viral load, and TED activity and severity., Results: Of 783 subjects with GD and 1186 with HIV, 11 were identified with both GD and HIV. Of these, three had clinical features of TED; each was of Afro-Caribbean origin, was in their fourth decade, and initially presented with undetectable CD4 T cells and high HIV viral loads. All went on to develop GD >3 years after commencing HAART, with normal CD4 count and undetectable viral load at the time of GD diagnosis. The full spectrum of TED was represented, with two subjects requiring orbital decompression surgery., Discussion: TED in the context of HIV is uncommon. Many challenges exist in such patients, particularly HAART drug interactions with antithyroid and immunosuppressant medications. To better understand TED in HIV and to counsel patients with this copathology most effectively, future multicenter surveillance is required.

Importance: Thyroid-associated ophthalmopathy (TAO) is a common and debilitating manifestation of Graves disease (GD). Presently little is known about factors that may increase the risk of developing TAO among patients with GD., Objective: To identify risk factors associated with the development of TAO among individuals with newly diagnosed GD., Design, Setting, and Participants: In this longitudinal cohort study, all beneficiaries 18 years of age or older with newly diagnosed GD who were continuously enrolled in a large nationwide US managed care network and who visited an eye care professional 1 or more times from 2001 to 2009 were identified. International Classification of Diseases, Ninth Revision, Clinical Modification billing codes were used to identify those who developed manifestations of TAO. Multivariable Cox regression was used to determine the hazard of developing TAO among persons with newly diagnosed GD, with adjustment for sociodemographic factors, systemic medical conditions, thyrotropin levels, and medical and surgical interventions for management of hyperthyroidism., Main Outcomes and Measures: Manifestations of TAO measured by hazard ratios (HRs) with 95% CIs., Results: Of 8404 patients with GD who met the inclusion criteria, 740 (8.8%) developed TAO (mean follow-up, 374 days since initial GD diagnosis). After adjustment for potential confounders, surgical thyroidectomy, alone or in combination with medical therapy, was associated with a 74% decreased hazard for TAO (adjusted HR, 0.26 [95% CI, 0.12-0.51]) compared with radioactive iodine therapy alone. Statin use (for ≥60 days in the past year vs <60 days or nonuse) was associated with a 40% decreased hazard (adjusted HR, 0.60 [CI, 0.37-0.93]). No significant association was found for the use of nonstatin cholesterol-lowering medications or cyclooxygenase 2 inhibitors and the development of TAO., Conclusions and Relevance: If prospective studies can confirm our finding that a thyroidectomy and statin use are associated with substantially reduced hazards for TAO among patients with GD, preventive measures for this burdensome manifestation of GD may become a reality.

Background/purpose: To present the results and evaluate the efficacy of endoscopic transnasal orbital decompression for dysthyroid orbitopathy., Methods: Retrospective chart review of patients who underwent endoscopic transnasal orbital decompression from 1996 to 2010 in one institution. We included 42 orbits of 25 patients. Preoperative and postoperative examinations included visual acuity, Hertel exophthalmometry, tonometry, exposure keratitis, and diplopia. The measurements of outcome depend on proptosis reduction, intraocular pressure reduction, and visual acuity improvement of 42 orbits of 25 patients., Results: There were no surgical complications for the 42 orbital decompressions except one patient experienced cerebrospinal fluid leak during the operation. Mean proptosis reduction in all orbits was 1.93 ± 0.25 (mean ± standard deviation, p < 0.01) after 1 month postoperatively and 2.07 ± 0.29 (p < 0.01) after 3 months postoperatively. An average reduction of intraocular pressure was 4.40 ± 0.72 (p < 0.01) and 4.38 ± 0.80 (p < 0.01) respectively after 1 and 3 months postoperatively. Visual acuity increased from a preoperative average of 0.45 ± 0.34 to 0.66 ± 0.36 and 0.70 ± 0.35 after 1 and 3 months postoperatively. In addition, postoperative relief of exposure keratitis is also noted., Conclusion: The transnasal orbital decompression procedure has statistically significant improvements in proptosis, intraocular pressure, and visual acuity. The procedure has obvious benefit in relieving exposure keratitis. Furthermore, there are favorable cosmetic results and rare complications., (Copyright © 2012. Published by Elsevier B.V.)

Introduction: Graves' orbitopathy (GO), thyroid dermopathy (also called pretibial myxedema) and acropachy are the extrathyroidal manifestations of Graves' disease. They occur in 25, 1.5, and 0.3 % of Graves' patients, respectively. Thus, GO is the main and most common extrathyroidal manifestation. Dermopathy is usually present if the patient is also affected with GO. The very rare acropachy occurs only in patients who also have dermopathy. GO and dermopathy have an autoimmune origin and are probably triggered by autoimmunity to the TSH receptor and, likely, the IGF-1 receptor. Both GO and dermopathy may be mild to severe., Management: Mild GO usually does not require any treatment except for local measures and preventive actions (especially refraining from smoking). Currently, moderate-to-severe and active GO is best treated by systemic glucocorticoids, but response to treatment is not optimal in many instances, and retreatments and use of other modalities (glucocorticoids, orbital radiotherapy, cyclosporine) and, in the end, rehabilitative surgery are often needed. Dermopathy is usually managed by local glucocorticoid treatment. No specific treatment is available for acropachy., Perspectives: Novel treatments are presently being investigated for GO, and particular attention is paid to the use of rituximab. It is unknown whether novel treatments for GO might be useful for the other extrathyroidal manifestations. Future novel therapies shown to be beneficial for GO in randomized studies may be empirically used for dermopathy and acropachy.

Purpose: Graves' ophthalmopathy (GO) is an autoimmune condition primarily managed with prolonged courses of glucocorticoids, which can be associated with significant side effects. Orbital radiation therapy (RT) is an alternative treatment that has shown variable efficacy in improving orbital and visual symptoms. In this study, the therapeutic benefit of RT was evaluated in terms of patient's ability to taper their corticosteroid requirements, which may better reflect the proposed mechanism of RT and provide a clinically relevant response endpoint., Methods and Materials: This is a retrospective review of consecutive patients treated with orbital RT for GO between 2000 and 2010 at a single tertiary hospital with a dedicated ocular radiation therapy clinic. The primary measure of treatment response was defined as the ability to taper glucocorticoids following RT without any further exacerbation of orbitopathy symptoms. Additional endpoints including ocular symptoms (diplopia, proptosis, visual acuity, extraocular movement) and need for surgical intervention were reported., Results: Of 86 eligible patients, with a mean follow-up of 9.3 months, 81 (94%) patients responded to RT. Of patients taking corticosteroids at baseline, 91% were able to taper off corticosteroids completely and the remaining patients had decreased their doses by 83%. Diplopia, visual acuity, and extraocular movements improved in 29%, 81%, and 58% of patients, respectively. The median reduction in proptosis was 2.5 mm and 2 mm in the left and right eyes, respectively (range, -18 mm to 23 mm)., Conclusions: Orbital RT is a generally well-tolerated treatment that helps minimize the dose and duration of corticosteroid therapy for patients with GO while improving ocular symptoms, including proptosis and diplopia. Prospective research should consider using corticosteroid requirement as a measure of response to orbital RT for GO., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Previous studies have extensively investigated the pathophysiology, genetics, and lifestyle risk factors of thyroid-associated ophthalmopathy (TAO). The aim of this study was to investigate the independent contribution of ethnic origin, social grade, and level of social deprivation to TAO severity in a large, multiethnic, and urban population., Methods: Retrospective case note review of all TAO patients seen at Birmingham and Midland Eye Centre, United Kingdom over a 14-year period. Ethnicity (White, Asian, or Black) was recorded, and residence postcode was used to determine social grade (National Readership Survey classification) and level of social deprivation (Index of Multiple Deprivation 2007). TAO severity was defined by European Group on Graves' Orbitopathy criteria. Moderate-to-severe: necessity for TAO treatment with oral or intravenous steroid, long-term immunosuppressants, or orbital radiotherapy. Sight-threatening: presence of dysthyroid optic neuropathy (DON) or need for urgent orbital decompression surgery. Multivariable logistic regression was performed to measure the independent influence of ethnicity, social grade, and social deprivation on indicators of severe TAO., Results: Lower social grade was significantly associated with increased odds ratio (OR) of TAO patients having severe TAO, including treatment with oral (OR: 2.3 (95% CI 1.1-5.1) p = 0.03) and intravenous steroid (OR: 2.6 (95% CI 1.0-7.0) p = 0.04) and DON (OR: 4.0 (95% CI 1.2-12.7) p = 0.02), compared with those of highest social grade. Similar results were observed for social deprivation. Ethnicity had no independent association with any measure of TAO severity., Conclusions: In this cohort, lower social grade and higher social deprivation, but not ethnicity, had independent, statistically significant association with more severe TAO.

Purpose: To identify the demographics, risk factors, clinical manifestations and treatment methods of pediatric thyroid eye disease (TED) in a South-East Asian tertiary referral practice., Methods: Retrospective case series of all pediatric patients (aged 18 years and under) who presented to our TED clinic between Jan 2006 and Dec 2012., Results: Thirteen patients (26 eyes) were identified - 8 females (61.5%) and 5 males (38.5%), accounting for 6.2% of all TED patients in our practice. Median age was 10.0 years (range, 0.3-18.0). Positive family history was noted in 9 patients (69.2%) and there were no active/passive smokers. Mean follow-up duration was 1.81 years (range, 0-5.2). Common presenting signs included proptosis (92.3%), eyelid retraction (84.6%), acquired epiblepharon (69.2%), corneal erosion (53.8%), and lagophthalmos (53.8%). None had optic neuropathy or strabismus. Mean exophthalmometry was 17.8 mm (SD ± 3.6 mm, range 13.0-27.0). Ten patients (76.9%) had mild disease, 3 patients (23.1%) had moderate disease and none had severe disease. Clinically significant Active disease as defined in adults (VISA Inflammatory Score >4/10), was not observed in any patient. The majority of the patients were treated conservatively. One patient underwent bilateral orbital decompression for severe proptosis, while two patients underwent bilateral lower epiblepharon correction with good outcomes. None required corticosteroids (oral/pulsed)., Conclusion: Clinical manifestations in pediatric TED are relatively mild and respond well to conservative therapy. Orbital decompression is rarely required but may be considered in children with severe proptosis. Mean exophthalmometry values are lower in East-Asian pediatric TED as compared to Caucasians. Symptomatic acquired epiblepharon, usually associated with keratopathy, is commonly seen in East-Asian pediatric TED; thus, increased awareness among ophthalmologists and pediatricians should be emphasized.

Aims: The aims of this study were to examine trends over time and geographical variation in the annual incidence of surgical orbital decompression for thyroid-associated ophthalmopathy (TAO) in England., Methods: Data on hospital admissions for orbital decompression surgery in patients with thyroid disease were analysed using English national Hospital Episode Statistics for admissions from 1991-2011., Results: Annual rates of orbital decompression surgery performed for patients with thyroid disease increased from 0.06 (95% confidence interval, 0.04--0.09) per 100,000 population in 1991, to 0.62 (0.54--0.67) in 2008, and then fell to 0.56 (0.48--0.60) in 2011. The surgical rate was highest in women aged 45--64 years. Geographical analysis showed significant variation across strategic health authority areas in surgical rates, from 0.22 (0.14-0.35) to 1.04 (0.79-1.34) people per 100,000 population per year in 2007-2011., Conclusion: The incidence of orbital decompression surgery performed annually in England has increased substantially over the past two decades, but peaked in 2008 and decreased since then. Significant geographical variation exists in surgical rates. Potential reasons for the decline include improved management of thyroid disease itself, but altered threshold in medical versus surgical management of TAO may also have played a role. The Amsterdam Declaration and EUGOGO treatment guidelines may also have influenced decisions about whether to operate on these patients.

Graves' disease (GD) is a common autoimmune condition. At its core, stimulatory autoantibodies are directed at the thyroid-stimulating hormone receptor (TSHR), resulting in dysregulated thyroid gland activity and growth. Closely associated with GD is the ocular condition known as thyroid-associated ophthalmopathy (TAO). The pathogenesis of TAO remains enigmatic as do the connections between the thyroid and orbit. This review highlights the putative molecular mechanisms involved in TAO and suggests how these insights provide future directions for identifying therapeutic targets. Genetic, epigenetic, and environmental factors have been suggested as contributory to the development of GD and TAO. Thyroid-stimulating hormone receptor and insulin-like growth factor receptor (IGF-1R) are expressed at higher levels in the orbital connective tissue from individuals with TAO than in healthy tissues. Together, they form a functional complex and appear to promote signaling relevant to GD and TAO. Orbital fibroblasts display an array of cell surface receptors and generate a host of inflammatory molecules that may participate in T and B cell infiltration. Recently, a population of orbital fibroblasts has been putatively traced to bone marrow-derived progenitor cells, known as fibrocytes, as they express CD45, CD34, CXCR4, collagen I, functional TSHR, and thyroglobulin (Tg). Fibrocytes become more numerous in GD and we believe traffic to the orbit in TAO. Numerous attempts at developing complete animal models of GD have been largely unsuccessful, because they lack fidelity with the ocular manifestations seen in TAO. Better understanding of the pathogenesis of TAO and development of improved animal models should greatly accelerate the identification of medical therapy for this vexing medical problem.

Patients with low thyroid peroxidase antibodies (anti-TPO) and increased TSH-receptor antibodies (TRAb) at diagnosis of Graves' disease (GD) have been suggested to have an increased risk to develop Graves' ophthalmopathy (GO). The aim was to evaluate if GO development can be predicted.This is an observational study with registration of possible GD and GO risk factors.399 patients with GD were registered 2003-2008 in Malmö, Sweden and out of these 310 were retrospectively followed up to 6 years. The main outcome measures were anti-TPO titer, TRAb titer, smoking habits, radioiodine treatment and GO development.TRAb was assessed with a third generation assay at GD diagnosis in 231 patients. The proportion of patients with GO increased above the median 6.3 IU/L both at diagnosis of GD (p=0.001) and at follow-up (p=0.0001).The distribution of GO patients anti-TPO above or below 20 kIU/L at diagnosis of GD was similar between groups (p=0.239). However at follow-up anti-TPO<20 kIU/L was associated with an increased proportion of newly developed GO as compared to the cohort with anti-TPO>20 kIU/L (p=0.018).87% of patients who developed GO after GD diagnosis had TRAb above 6.3 IU/L and/or anti-TPO below 20 kIU/L. The proportion of GO was doubled in GD patients treated with radioiodine but could not explain the described findingsAnti-TPO<20 kIU/L and/or TRAb>6.3 IE/L at the time of GD diagnosis were associated with an increased risk to develop GO after diagnosis of GD., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

Background & Objectives: The prevalence of Graves' ophthalmopathy (GO) varies widely in different ethnic groups. Indians have been reported to have a lower prevalence of Graves' ophthalmopathy as compared to Caucasians of European origin, but data are sparse and inconclusive. We studied the prevalence, clinical features and association of GO in Indian patients with Graves' disease attending a referral centre in north India., Methods: A prospective study was conducted on 235 consecutive newly referred north Indian patients with Graves' disease presenting to a tertiary care centre in north India. All patients underwent a comprehensive ophthalmological examination as per the European Group on Graves' Orbitopathy (EUGOGO) recommendations., Results: GO was diagnosed in 65 patients (prevalence 28%; 95% confidence interval 22-33%). The prevalence was similar in males (28%) and females (27%). It was mild in 83 per cent, moderate-severe in 15 per cent and sight-threatening in only 2 per cent of cases. Ophthalmopathy was clinically active in only two (3%) cases. Upper eyelid retraction was the most common manifestation (83%), followed by exophthalmos (75%). Extra-ocular muscle involvement (5%) and optic nerve dysfunction (2%) were uncommon. The risk of GO was 3.9- fold (95% confidence interval 1.1-13.6) higher in smokers compared to non-smokers. However, severity of disease in smokers was similar to non-smokers. On multivariate logistic regression analysis, GO was associated only with high thyrotropin receptor antibody titres and current smoking., Interpretation & Conclusions: Among north Indian patients with GD studied at a referral center, the prevalence of GO was similar to Caucasians of European descent, but clinically active and severe ophthalmopathy was uncommon. More studies are needed to confirm these findings.

Introduction: Radioactive iodine (RAI) therapy may induce or worsen orbitopathy (GO) in Graves' disease (GD). The aim of this study was a prospective assessment of the risk of GO exacerbation in a GD patients cohort submitted to RAI therapy for hyperthyroidism., Material and Methods: 208 consecutive GD patients treated with 131I in 2007 were enrolled. The analysis was performed on 156 patients strictly monitored for one year. Glucocorticosteroid (GCS) prophylaxis was administered if GO symptoms or GO history were present, and in cases of tobacco smokers even without GO symptoms. Clinical and biochemical evaluation at one, three, six, and 12 months after therapy was performed in the whole group, then at 24 months in 138 patients., Results: There was no severe GO progression in patients without GO symptoms at the time of RAI treatment. The risk of severe GO worsening for preexisting GO patients (demanding systemic GCS administration) during the 12-month follow-up after RAI therapy was 10%. 12 and 24 months after 131I administration, stable improvement compared to the initial GO status had been achieved in most (98-96%) patients., Conclusions: 1. In patients with mild GO, the risk of severe GO worsening after RAI therapy is acceptable, as long as RAI therapy is applied with GCS cover. 2. In patients without GO symptoms at the time of RAI therapy but with a history of GO and with subclinical GO diagnosed by MRI only, the risk of severe progression is minimal. 3. Distant outcomes of RAI treatment confirmed its safety in GO patients.

Graves' ophthalmopathy (GO) is an autoimmune disorder of the orbit that is clinically relevant in 25-50% of patients with Graves' disease and 2% of patients with chronic thyroiditis. The age-adjusted annual incidence of clinically relevant GO is 16 per 100,000 population in women and 2.9 in men. At the onset of ophthalmopathy, 80-90% of patients have hyperthyroidism, with the rest having euthyroidism or hypothyroidism. The natural history of GO consists of two phases: an active inflammatory phase and a static phase. Anti-inflammatory therapy is indicated for the first phase of GO. Approximately 5% of patients experience late reactivation of GO. Asians appear to have less severe manifestations, with milder orbital edema, proptosis and muscle restriction. Genetic, anatomic and environmental factors influence the development of GO. Aging, thyroid dysfunction, thyroid stimulating hormone (TSH) receptor antibodies, smoking and radioiodine treatment for hyperthyroidism also influence the development and course of GO.

Unlabelled: Graves' disease (GD) is an autoimmune thyroid disease with complex and not fully established etiology. It occurs when environmental factors influence people genetically prone to this illness. The aim of this study was to determine the impact of selected factors (endogenous and environmental) on the course and complications of disease in patients with recurrent GD., Materials and Methods: Two hundred and four patients with relapsed GD, treated in the Clinical Department of Endocrinology in University Hospital in Cracow in years 2004-2006 and then in 2011 were retrospectively analyzed. Patients who agreed to participate in the study were sent questionnaire to complete. Demographic and clinical data were collected and entered into a database. Patient data included: gender, place of living, lifestyle (smoking), family history of autoimmune diseases, the course of the disease, its symptoms and the treatment strategy. Furthermore the medical documentation was analyzed. Descriptive statistical analyses were made., Results: The study showed a significant difference in the frequency of appearance of ophthalmopathy between men and women (80% and 37.14%, respectively, p = 0.041), between smokers and nonsmokers (61.9% and 21.05%, respectively, p = 0.022) and between the age of patients with positive and negative family history of autoimmune diseases (37.6 years and 50.5 years respectively, p = 0.002)., Conclusions: 1. Male gender is a risk factor for ophthalmopathy in GD. 2. Cigarette smoking affects the risk of Graves' ophthalmopathy. 3. A positive family history of thyroid diseases and/or autoimmune diseases promotes the development of GD at a younger age.

Purpose: To determine the prevalence of thyroid eye disease among dysthyroid Korean patients and to analyze the relationship between demographic data, lifestyle risk factors, and status of thyroid disease and thyroid eye disease., Methods: All dysthyroid patients who visited endocrinology clinics in 24 general hospitals in Korea during a chosen one-week period were enrolled in this cross-sectional study. Data were collected during an interviewer-administered questionnaire and chart review. Demographic data, lifestyle risk factors, and status of thyroid disease variables were analyzed as risk factors using multivariable regression models to identify independent associations with thyroid eye disease., Results: A total of 1,632 dysthyroid patients were included (1,301 females [79.7%] and 331 males [20.3%]). Two hundred eighty-three of these patients (17.3%) had thyroid eye disease. Multiple logistic regression analyses revealed that female gender, young age, Graves' disease, dermopathy, anti-thyroid medication treatment, and radioiodine treatment were independent risk factors for thyroid eye disease., Conclusions: The lower prevalence of thyroid eye disease in dysthyroid Korean patients and the influence of gender on risk factors in this study are novel findings compared to studies performed involving Europeans. Although the risk factors for thyroid eye disease are understood in part, a more in-depth comparative study of gender and ethnic groups is needed to fully understand the biological significance of the demographic factors.

Graves' disease is a common autoimmune disorder that can be complicated, especially in smokers, by an orbitopathy which can sometimes jeopardize vision and result in functional sequelae affecting quality of life of these patients. Although the diagnosis of dysthyroid orbitopathy is usually obvious, clinical evaluation must specify the stage of progression (clinical activity score) and severity according to the European Group EUGOGO classification. At first, rapid restoration of the euthyroid state, smoking cessation and simple symptomatic ophthalmic treatment are suggested. In the case of severe or active orbitopathy, oral or intravenous corticosteroid therapy with or without orbital radiation therapy (and even emergency orbital surgery in the case of compressive optic neuropathy) should be implemented. Ultimately, orbital surgery (orbital decompression in cases of exophthalmos), oculomotor surgery (diplopia) or eyelid surgery (retraction) may be required depending on the severity of sequelae. A multidisciplinary approach involving ophthalmologist, endocrinologist and orbital surgeon should facilitate an overall diagnosis and treatment plan for these patients., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Orbital fibroblast differentiation to adipocytes is a peroxisome proliferator-activated receptor g (PPARg)-dependent process essential for pathogenic tissue remodeling in Graves' orbitopathy (GO). PPARg2 Pro¹²Ala polymorphism modulates expression and/or function of the molecule encoded by this gene and is a promising locus of GO. Here, we analyzed associations of PPARg2 Pro¹²Ala with clinical manifestation of GO in 742 Polish Caucasians including 276 Graves' disease (GD) patients. In our study, the Ala¹² allele and Ala¹² variant (Ala¹²Ala and/or Pro¹²Ala genotype) decreased the risk of GO (p = 0.000012 and p = 0.00013). Moreover, Ala¹²Ala genotype was observed only in patients without GO (p = 0.002). GD patients with Ala¹² variant had less active and less severe eye symptoms. Female carriers of the Ala¹² allele rarely developed GO, but the marker was not related to symptoms of GO. The opposite finding was recorded in males, in whom the studied polymorphism was related to activity, but not to the development, of GO. In Ala¹² variant carriers without familial history of thyroid disease, risk of GO was lower than in persons with a familial background. The Ala¹² allele seemed to protect smokers from GO, but in nonsmokers, such a relation was not obvious. A multivariate analysis indicated the Pro¹²Ala marker as an independent risk factor of eye symptoms (p = 0.0001) and lack of Ala increases the risk of GO 3.24-fold. In conclusion, the gain-of-function Ala¹² variant protects against GO and modulates the course of the disease.

Graves' orbitopathy (GO) is an autoimmune disorder and the main extrathyroidal expression of Graves' disease. There is a spectrum of ocular involvement in Graves' disease, from complete absence of symptoms and signs to sight-threatening conditions. The prevalence of GO varies in different published series of Graves' patients, due to confounding factors (new diagnosis vs long-lasting disease, way of defining and assessing ocular involvement, treatment of hyperthyroidism with potentially GO-modifying treatments, such as radioiodine). Recent studies, however, suggest that most Graves' patients have mild or no GO at presentation, while moderate-to-severe GO is rare, and sight-threatening GO (mostly due to dysthyroid optic neuropathy) is exceptional in non-tertiary referral centers. The natural course of GO is incompletely defined, particularly in patients with moderate- to-severe GO, because these patients require prompt and disease-modifying therapies for orbital disease. In patients with mild GO at presentation, progression to severe forms is rare, while partial or complete remission is frequent. Progression of pre-existing GO or de novo occurrence of GO is more likely in smokers. There seems to be a trend towards a decline in progression of GO, possibly due to a better control of risk factors (cigarette smoking, thyroid dysfunction, etc.) and a closer interaction between endocrinologists and ophthalmologists allowing an improved integrated management of thyroid and orbital disease.

Background: Graves' ophthalmopathy (GO) develops or worsens in up to one-third of patients treated with radioactive iodine (RAI) for Graves' hyperthyroidism. We sought to identify the prevalence of development or worsening of GO in patients treated with RAI for Graves' hyperthyroidism and to identify the risk factors associated with that outcome., Methods: We identified a retrospective cohort of consecutive patients treated with RAI at Mayo Clinic (Rochester, MN) between 2005 and 2006. We assessed their medical records for evidence of hypothyroidism and development or worsening of GO in the year after therapy. Hypothyroidism was defined as thyrotropin >3.0 mIU/L or free thyroxine <0.8 ng/dL., Results: We identified 291 consecutive patients who received RAI therapy during the study period, with 195 out of 291 having complete follow-up data for a one-year period. GO was present in 46 out of 195 patients (23.6%) at baseline. After RAI treatment, GO developed or worsened in 25 out of 195 patients (12.8%) and it was associated with hypothyroidism at first follow-up (p=0.011) with an odds ratio (OR) of 3.3 [95% confidence interval (CI) 1.3-8.7]. More smokers than nonsmokers developed new or worse GO (17.7% vs. 11.8%), but that difference did not reach statistical significance (p=0.35). Preexisting GO (24% of patients) was associated with a higher risk for negative GO outcome compared with patients who had no GO at baseline (11%; p=0.021). Both development of hypothyroidism by the first visit after RAI therapy (OR 3.6) and preexistent GO (OR 2.8) remained significant in a multivariate analysis. Development of hypothyroidism was more likely in patients with longer duration to first follow-up (p<0.001). By 6-8 weeks after RAI treatment, the prevalence of hypothyroidism was ∼40%, while that of hyperthyroidism was only 20%., Conclusions: The presence of hypothyroidism at the first assessment of thyroid function after RAI administration is a strong predictor for adverse GO outcome. This risk is highest in patients with preexisting GO. We suggest that in order to prevent clinical hypothyroidism and the associated risk for GO, the optimal time for first measurement of fT4 is before 6 weeks after RAI therapy.

Background: The prevalence and natural history of Graves' orbitopathy (GO) are poorly documented., Methods: A large series of 346 patients with newly diagnosed and recent onset Graves' hyperthyroidism seen at a single (nontertiary referral) center over an 8-year period were enrolled in an observational prospective study and evaluated for GO activity and severity according to the EUGOGO (European Group on Graves' Orbitopathy) criteria. After excluding patients immediately treated for moderate-to-severe GO, patients undergoing total thyroidectomy or radioactive iodine treatment, and patients lost to follow-up, 237 patients were submitted to antithyroid drug (ATD) treatment, with ocular evaluation at 6, 12, and 18 months., Results: Among the whole cohort, at presentation 255 (73.7%) had no ocular involvement, 70 (20.2%) had mild and inactive GO, 20 (5.8%) had moderate-to-severe and active GO, and 1 (0.3%) had sight-threatening GO with dysthyroid optic neuropathy. Of the 237 patients who completed the 18-month follow-up during or after ATD treatment, 194 (81.9%) had no GO at baseline. Progression to moderate-to-severe GO occurred in 5 (2.6%) of these patients. Of the 43 (18.1%) patients with mild and inactive GO at baseline, 1 (2.4%) progressed to moderate-to-severe GO, and 25 (58.1%) experienced complete remission., Conclusions: Most patients with newly diagnosed Graves' disease have no ocular involvement. Moderate-to-severe and active GO or sight-threatening GO are rare at presentation and rarely develop during ATD treatment. Most patients (>80%) with no GO at baseline do not develop GO after an 18-month follow-up period. Remission of mild GO occurs in the majority of cases.

Objective: To examine the usefulness of the Hospital Anxiety and Depression Scale (HADS) for screening psychiatric morbidity in Chinese patients with Graves' ophthalmopathy., Methods: A cross-sectional study was conducted from 1 January 2010 to 31 December 2010 at the specialist eye outpatient clinic at Pamela Youde Nethersole Eastern Hospital. All euthyroid patients diagnosed with Graves' ophthalmopathy were recruited. They were interviewed with the Chinese version of the HADS and the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I. Demographic data and clinical background information were collected from the patients and their hospital records were reviewed., Results: In all, 124 patients were recruited into the study. Current prevalence of psychiatric disorders was 32%, of which 19% were current depressive disorders and 19% were current anxiety disorders. The HADS provided the best discriminating power for screening for psychiatric morbidity at a cut-off threshold of 10/11. For screening of depressive and anxiety disorders, the cut-off thresholds were 4/5 and 6/7 respectively., Conclusion: Depression and anxiety disorders were common in the local population of patients with Graves' ophthalmopathy. Recognising the predictors for psychiatric morbidity could assist clinicians to identify those patients with a predisposition to developing psychiatric complications, and refer them for appropriate treatment. The HADS can be considered as a screening tool for psychiatric morbidity in patients with Graves' ophthalmopathy.

Objective: To evaluate early strabismus treatment in patients suffering from diplopia after orbital decompression for dysthyroid orbitopathy., Patients and Methods: We conducted a chart review of 51 patients (87 orbits) who underwent orbital decompression from July 1998 to June 2007. Ocular deviations, incidence of diplopia according to the type of decompression performed and the type and results of strabismus surgery were evaluated., Results: Diplopia was induced by decompression in 34.2% of patients, with no statistically significant difference with respect to the type of decompression performed. Forty-nine percent of patients had postoperative diplopia. Strabismus surgery was performed on average 10.9weeks after decompression. Diplopia persisted in two patients (8%)., Conclusion: Early strabismus surgery and the intraoperative relaxed muscle positioning technique appear to provide favorable results. It allows for a more rapid rehabilitation. Better adapted choice of decompression technique may improve final outcomes., (Copyright © 2012. Published by Elsevier Masson SAS.)

Mild to moderate forms of orbitopathy are common in auto-immune thyroid diseases, whereas severe forms are rare. Euthyroidism restoration, no smoking, and ocular local lubricants are necessary for all the patients. In case of mild orbitopathy, treatment by selenium is now indicated. Active forms of thyroid orbitopathy are better treated by IV steroids. Surgery is indicated in optic neuropathy resistant to steroids and in sequellar forms of the disease.

Context: Disfiguring proptosis and functional impairment in patients with Graves' orbitopathy (GO) may lead to impaired earning capacity and to considerable indirect/direct costs., Objective: The aim of the study was to investigate the public health relevance of GO., Design and Setting: This cross-sectional study was performed between 2005 and 2009 at a multidisciplinary university orbital center., Patients: A total of 310 unselected patients with GO of various degrees of severity and activity participated in the study., Interventions: We conducted an observational study., Main Outcome Measures: We measured work disability and sick leave as well as the resulting indirect/direct costs of GO-specific therapies., Results: Of 215 employed patients, 47 (21.9%) were temporarily work disabled, and 12 (5.6%) were permanently work disabled. Five (2.3%) had lost their jobs, and nine (4.2%) had retired early. The mean duration of sick leave was 22.3 d/yr. Compared with the German average of 11.6 d/yr, 32 (15%) patients had taken longer sick leaves. The duration of sick leave correlated with the disease severity (P = 0.015), and work disability correlated with diplopia (P < 0.001). Multivariable analysis identified diplopia as the principal predictor for work disability (odds ratio, 1.7; P < 0.001). The average costs due to sick leave and work disability ranged between 3,301€ (4,153$) and 6,683€ (8,407$) per patient per year. Direct costs were 388 ± 56€ (488 ± 70$) per patient per year and per year were higher in sight-threatening GO (1,185 ± 2,569€; 1,491 ± 3,232$) than in moderate-to-severe (373 ± 896€; 469 ± 1,127$; P = 0.013) or in mild GO (332 ± 857€; 418 ± 1,078$; P = 0.016). Total indirect costs ranged between 3,318€ (4,174$) (friction cost method) and 6,738€ (8,476$) (human capital approach). Work impairment as well as direct and indirect costs of GO significantly correlated with the scores of the internationally standardized and specific GO quality-of-life questionnaire., Conclusions: Productivity loss and a prolonged therapy for GO incur great indirect and direct costs.

Background: Optimal doses of i.v. glucocorticoids for Graves' orbitopathy (GO) are undefined., Methods: We carried out a multicenter, randomized, double-blind trial to determine efficacy and safety of three doses of i.v. methylprednisolone in 159 patients with moderate to severe and active GO. Patients were randomized to receive a cumulative dose of 2.25, 4.98, or 7.47 g in 12 weekly infusions. Efficacy was evaluated objectively at 12 wk by blinded ophthalmologists and subjectively by blinded patients (using a GO specific quality of life questionnaire). Adverse events were recorded at each visit., Results: Overall ophthalmic improvement was more common using 7.47 g (52%) than 4.98 g (35%; P = 0.03) or 2.25 g (28%; P = 0.01). Compared with lower doses, the high-dose regimen led to the most improvement in objective measurement of ocular motility and in the Clinical Activity Score. The Clinical Activity Score decreased in all groups and to the least extent with 2.25 g. Quality of life improved most in the 7.47-g group, although not reaching statistical significance. No significant differences occurred in exophthalmos, palpebral aperture, soft tissue changes, and subjective diplopia score. Dysthyroid optic neuropathy developed in several patients in all groups. Because of this, differences among the three groups were no longer apparent at the exploratory 24-wk visit. Major adverse events were slightly more frequent using the highest dose but occurred also using the lowest dose. Among patients whose GO improved at 12 wk, 33% in the 7.47-group, 21% in the 4.98-group, and 40% in the 2.25-group had relapsing orbitopathy after glucocorticoid withdrawal at the exploratory 24-wk visit., Conclusions: The 7.47-g dose provides short-term advantages over lower doses. However, this benefit is transient and associated with slightly greater toxicity. The use of a cumulative dose of 7.47 g of methylprednisolone provides short-term advantage over lower doses. This may suggest that an intermediate-dose regimen be used in most cases and the high-dose regimen be reserved to most severe cases of GO.

Context: Population-based data on the incidence and clinical presentation of moderate to severe Graves' orbitopathy (GO) are scarce, and virtually nothing is known on the effect of an iodization program on the incidence and presentation of GO., Objective: The objective of the study was to characterize incident moderate to severe GO in North Jutland County, Denmark, during the period 1992-2009, before and after the Danish salt iodization program., Design and Patients: The design of the study was a prospective register of patients with incident moderate to severe GO in a population during 8.9 million persons × years of observation., Setting: The study was conducted at a thyroid-eye clinic of university hospital., Main Outcome Measures: Clinical presentation and incidence before and after the year 2000 initiation of the mandatory Danish iodization of salt were measured. The incidence of GO was related to the incidence of Graves' hyperthyroidism (GH) in the same population., Results: The incidence rate of moderate to severe GO was 16.1/million per year (women: 26.7; men: 5.4), with no change associated with iodization of salt. The moderate to severe GO incidence was 4.9% of the incidence of GH. The incidence rate ratio between women and men with GO (4.9) was not different from the ratio in GH. Compared with GH, only a few patients (<2%) suffered from moderate and severe GO below the age of 40 yr, whereas GO was relatively common in age groups 40-60 yr (∼8%)., Conclusions: Approximately 5% of the patients with Graves' disease develop moderate to severe GO, with a similar risk in women and men with Graves' disease. The risk of GO is much higher in patients aged 40-60 yr than in young patients with Graves' disease. Salt iodization was not associated with a change in the incidence of GO.

The incidence of Graves' orbitopathy (GO) is 16/100,000 in females and 2.9/100,000 in males as studied in Olmsted county. It can be calculated that the approximate prevalence is 0.25%. There is a gender bimodal distribution. Go usually occurs at the time of onset of the hyperthyroidism but may present up to a year before that time or as long as 5 years afterwards. Around 10-15% of patients have never been hyperthyroid and some are hypothyroid at GO presentation. Although the incidence of GO has probably been decreasing during the last 2 decades definite figures for this assertion are not available. Risk factors that may influence the incidence of GO include cigarette smoking and radioiodine treatment of hyperthyroidism. There are also complex genetic factors with multiple susceptibility alleles that contribute to the expression of the disease. The probability is that a reduction of the incidence of GO will be achieved by influencing the environmental factors., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: The aim of our study was to report the incidence of complications requiring early or late reoperation after bone and fat orbital decompression for Graves's ophthalmopathy., Patients and Method: We conducted a retrospective bicentric study in the Maxillofacial Surgery Departments of Marseille and Lyon. Ninety patients were selected from 2006 to 2010, accounting for 168 orbital decompressions. The surgical indication was morphological and functional for all patients. Several surgical techniques were used: bone and fat orbital decompression by trans-palpebral resection, two or three wall orbital decompression, malar valgization., Results: Ten patients were reoperated for 12 revisions, two patients needed two revisions. There were four early revisions for two retro-orbital hematoma, one inadequate orbital decompression with persistent posterior compressive optic neuropathy, and one recurrent maxillary sinusitis with proptosis. The other eight revisions were carried out later for three cases of insufficient correction, four cases of proptosis relapse, and one for excessive correction with enophthalmos. All patients had satisfactory morphological and functional results despite revision surgery., Discussion: Most reoperations are difficult to anticipate and their prevention is based on more or less specific recommendations. Patients should be informed of the risks and benefits and accept the possibility of reoperation. A systematic multidisciplinary consultation would standardize and improve the management of these patients, by detecting patients at risk of complications and thus reoperation., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Objective: The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO)., Design: A questionnaire-based survey among members of the European Thyroid Association (ETA) who treat GO., Results: A response was obtained from 128 ETA members of which 115 used GC therapy for GO. The majority of respondents (83/115, 72%) used intravenous (i.v.) GC, with a relatively wide variety of therapeutic regimens. The cumulative dose of methylprednisolone ranged between 0.5 and 12 g (median 4.5 g) for i.v.GC and between 1.0 and 4.9 g (median 2.4 g) for oral GC. Adverse events were often reported during oral GCs (26/32, 81%); most side effects were non-severe, but ten respondents reported severe adverse events (hepatic, cardiovascular, and cerebrovascular complications), including two fatal cases, both receiving a total of 2.3 g prednisone. Adverse events were less common in i.v.GC (32/83 respondents, 39%), but mostly consisted of severe events, including seven fatal cases. All but one fatal event occurred in cumulative i.v.GC doses (>8 g) higher than those currently recommended., Conclusions: GCs are preferentially administered i.v. for the treatment of GO in Europe. Both oral and i.v.GC may be associated with severe adverse effects, including fatal cases, which are more frequently reported in daily or alternate day i.v.GC. IvGC therapy should be undertaken in centers with appropriate expertise. Patients should be carefully examined for risk factors before treatment and monitored for side effects, which may be asymptomatic, both during and after treatment.

Thyroid ophthalmopathy is one of the features of auto-immune thyroid diseases. Exophtalmos is not the only sign of this affection and may even be absent in severe sight-threatening cases. All subjects with this ophtalmopathy should benefit from euthyroidism restoration, smoking withdrawal and local measures. Objective and repeated assessment should identify the mild and stable disease carrying a fair prognosis and therefore recognize without delay the other patients for whom an optimal management will be supported by a multidisciplinary and expert team. The treatment of choice for moderate-to-severe and active ophthalmopathy is intravenous glucocorticoids. Sight-threatening cases not rapidly alleviated by intravenous glucocorticoids warrant surgical decompression. Later on, surgery (orbital decompression, squint surgery, eyelid surgery, in this order) will eventually be needed for inactive disease., (Copyright © 2011. Published by Elsevier Masson SAS.)

Background and Aim: Several trials have proved the efficacy of intravenous (IV) steroids in Graves' orbitopathy (GO). However, the impact of administered dose and therapy schedule has not been assessed yet., Subjects and Methods: Nine randomized and 14 non-randomized controlled trials of IV steroids in GO were evaluated according to the applied single and cumulative doses with respect to outcome, efficacy on clinically relevant issues and adverse events., Results: High single (1 g per day) and cumulative (>6 g) doses of IV steroids are superior to lower single (0.5 g/d) and cumulative (<5 g) doses with respect to therapy response (84 vs 75%; p=0.034 and 83 vs 77%; ns, respectively), improvement of eye symptoms (87 vs 75%, p=0.052 and 85 vs 71%; ns, respectively) and disappearance of diplopia (32 vs 27%; ns and 48 vs 27%; p=0.08, respectively). Decrease of both clinical activity score (3 vs 2.5 points and 2.5 vs 3, ns) as well as proptosis (-1.4 vs -1.2 mm, ns and 1.5 vs 1.2, ns) are similar in both groups. However, high single and/or cumulative doses are accompanied with a 2-fold higher rate of adverse events (56 vs 28%; p<0.001 and 52 vs 33%; p=0.034, respectively)., Conclusions: Tailoring the IV steroid dose to severity of GO can be concluded and implies that a prospective randomized trial comparing different doses of IV steroids in active/severe GO is keenly warranted.

Aims: The aim of this study was to compare demographics, clinical manifestations, associated systemic and ocular factors, severity and activity of patients with unilateral thyroid eye disease (U-TED) versus bilateral thyroid eye disease (B-TED)., Materials and Methods: In a cross-sectional study, all patients with Graves' hyperthyroidism and primary hypothyroidism seen in an endocrinology clinic were included from September 2003 to July 2006. Demographics, complete eye examination, severity score (NOSPECS, total eye score), and clinical activity score were recorded and compared in the B-TED and U-TED groups of patients., Results: From 851 patients with thyroid disorders, 303 (35.6%) had TED. Thirty-two patients (32/ 303, 10.56%) were found to have U-TED. Patients with U-TED (mean age 31.6 ± 11.6 years) were significantly younger than patients with B-TED (mean age 37.7 ± 14.7 years). Monovariate analysis (Chi-square and independent sample t-test) showed a significantly higher severity score in B-TED (U-TED 4.09±4.05, B-TED: 6.7±6.3; P= 0.002) and more activity score in B-TED (U-TED= 1.03±0.96, B-TED: 1.74±1.6, P= 0.001). However, multivariate analysis did not show any significant difference between the two groups in terms of age, gender, type of thyroid disease, duration of thyroid disease and TED, severity and activity of TED, smoking habit, and presentation of TED before or after the presentation of thyroid disease (0.1

Purpose: The purpose of this study is to identify risk factors for severe thyroid-associated orbitopathy (TAO) and compressive optic neuropathy in Korean patients., Methods: This study was a retrospective comparative case series. All TAO patients who were first seen at our institution between 2005 and 2009 and who had follow-up periods of at least 6 months were included. Patients were divided into mild or moderate and severe TAO groups. Cases were also segregated based on the presence or absence of optic neuropathy. Demographics, smoking status, comorbidities, thyroid hormonal status, thyroid autoantibody levels, and clinical presentations were assessed., Results: A total of 99 patients (83 with mild to moderate courses and 16 with severe courses; 90 without optic neuropathy and 9 with optic neuropathy) were included in this study. On multiple logistic regression analysis, smoking status was a predictive risk factor for a severe course of TAO and the development of optic neuropathy (odds ratios = 6.57 and 10.00, respectively). Other factors such as age, gender, free T4 level, thyroid binding-inhibiting immunoglobulin, and a history of diabetes were not predictive of severe TAO or optic neuropathy., Conclusions: Although various factors may influence the severity of TAO and the development of optic neuropathy, this study showed that smoking was a risk factor for severe TAO and the development of optic neuropathy. Therefore, it is important for patients with Graves' disease to refrain from smoking. Frequent and careful observation should also be performed in current smokers, as TAO patients who smoke are susceptible to a severe course and/or optic neuropathy.