Graves' Ophthalmopathy Research Articles

Graves' Ophthalmopathy: Epidemiology and Natural History

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.

The alpha chemokine "Interferon gamma-induced protein 10" (IP-10) in Graves' disease

The alpha chemokine Interferon gamma-induced protein 10 (IP-10) and its receptor, CXC receptor 3, appear to contribute to the pathogenesis of Graves' disease (GD) and Graves' ophthalmopathy (GO). Under the influence of Interferon-γ, IP-10 is secreted by thyrocytes (in GD), fibroblasts and preadipocytes (in GO). Determination of high level of IP-10 in peripheral liquids is therefore a marker of a Th1 orientated immune response. Circulating IP-10 is associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients. Methimazole reduces IP-10 secretion by isolated thyrocytes, decreases serum IP-10 levels, and promotes a transition from Th1 to Th2 dominance in patients in GD active phase. In GD patients the decrease of IP-10 after thyroidectomy and radioiodine strongly suggests that this chemokine is mainly produced by the thyroid itself. In GO patients the increased concentrations of IP-10, at least in part, reflect the activity of orbital inflammation. A significant reductions in IP-10 serum concentrations during corticosteroids and or radiotherapy treatments, as compared both to control group and to basal values in GO patients, suggest that this chemokine could serve as a guideline in therapeutic decision-making in patients with GO. Further studies are needed to evaluate whether IP-10 is a novel therapeutic target in GD and GO.

Circulating levels of miR-146a and IL-17 are significantly correlated with the clinical activity of Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is a common autoimmune disease that is difficult to deal with due to limited clinical evaluation methods. Recently miR-146a and Interleukin-17 (IL-17) have been found to be involved in autoimmune disorders and correlated with disease activity. However, it is unclear whether they are involved in Graves' ophthalmopathy (GO). The aim of this study is to investigate the correlation of circulating levels of miR-146a and IL-17 with clinical activity in GO patients. Fifty-seven study subjects were enrolled in four groups according to the corresponding criteria: active-GO, inactive-GO, Graves disease (GD) without ophthalmopathy, and healthy control group. The circulating levels of miR-146a and IL-17 were determined by qRT-PCR and ELISA, respectively. Serum IL-17 levels of GD, inactive-GO, and active-GO groups were all significantly higher than that of control (all P < 0.001). Active-GO group had significantly higher IL-17 level than inactive-GO and GD groups (P = 0.024 and P = 0.001, respectively). Active-GO and inactive-GO group had significantly lower miR-146a expressions than control (P < 0.05). Active-GO group had significantly lower miR-146a than inactive-GO group (P < 0.05). Serum levels of IL-17 and miR-146a were both significantly correlated with clinical activity score (CAS) in GO patients (P < 0.001, P < 0.001, respectively). There was a significant negative correlation of circulating miR-146a expression with serum IL-17 levels (P < 0.01). These findings indicated that circulating levels of miR-146a and IL-17 may be potential biomarkers of active GO, and may play a key role in the progression of GO.

The alpha chemokine "Interferon gamma-induced protein 10" (IP-10) in Graves' disease and Graves'ophthalmopathy

Interferon(IFN)γ-induced protein 10 (IP-10) and its receptor, CXC receptor 3, appear to contribute to the pathogenesis of Graves' disease (GD) and Graves' ophthalmopathy (GO). Under the influence of IFN-γ, IP-10 is secreted by thyrocytes (in GD), fibroblasts and preadipocytes (in GO). Determination of high level of IP-10 in peripheral liquids is therefore a marker of a Th1 orientated immune response. Circulating IP-10 is associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients. Methimazole reduces IP-10 secretion by isolated thyrocytes, decreases serum IP-10 levels, and promotes a transition from Th1 to Th2 dominance in patients with GD active phase. In GD patients the decrease of IP-10 after thyroidectomy and radioiodine strongly suggests that this chemokine is mainly produced by the thyroid itself. In GO patients the increased concentrations of IP-10, at least in part, reflect the activity of orbital inflammation. A significant reductions in IP-10 serum concentrations during corticosteroids and or radiotherapy treatments, as compared both to control group and to basal values in GO patients, suggest that this chemokine could serve as a guideline in therapeutic decision-making in patients with GO. Further studies are needed to evaluate whether IP-10 is a novel therapeutic target in GD and GO.

Associations of CTLA4 Gene Polymorphisms with Graves' Ophthalmopathy: A Meta-Analysis.

Many studies have established that T-lymphocyte antigen-4 (CTLA4) is a susceptible gene for Graves' disease (GD). Also many studies showed the association between the CTLA4 exon-1 49A/G polymorphism and the risk of developing Graves' ophthalmopathy (GO) in GD patients. But those results were inconsistent. In recent years many new studies were published which helped to shed light on the relationship of CTLA4 SNP49 with GO. So we performed the meta-analysis to explore the association between the SNP49 and GO susceptibility in GD patients. Studies up to February 29, 2012, were searched by using PubMed. The odds ratio was used to evaluate the strength of the association. Altogether 12 case-control studies involving 2,505 participants were included in the meta-analysis. Results showed that the G allele was related to the increased risk of GO compared with the A allele under allelic genetic model (OR = 1.14, 95% CI: 1.14–1.72, P = 0.001) in European subgroup. No publication bias was detected. Our results showed that the SNP49 polymorphism of CTLA4 gene was related to increased risk of GO.

CXCR3 and CXCL10 in autoimmune thyroiditis

The chemokine (C-X-C motif) ligand 10 (CXCL10, also called IP-10) was initially identified as a chemokine that is induced by interferon (IFN)-γ. CXCL10 exerts its function through binding to chemokine (C-X-C motif) receptor 3 (CXCR3). CXCL10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, Graves' disease and ophthalmopathy), or systemic (such as systemic lupus erythematosus, mixed cryoglobulinemia, Sjogren syndrome, or systemic sclerosis). The secretion of CXCL10 by CD4+, CD8+, and natural killer is dependent on IFN-γ. Under the influence of IFN-γ, CXCL10 is secreted by thyrocytes. Determination of high level of CXCL10 in peripheral fluids is therefore a marker of a T helper 1 orientated immune response. High levels of circulating CXCL10, have been shown in patients with autoimmune thyroiditis (AT). Among patients with AT, CXCL10 levels were significantly higher in those with a hypoechoic ultrasonographic pattern, that is a sign of a more severe lympho-monocytic infiltration, and in those with hypothyroidism. For these reasons it has been postulated that CXCL10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism. Further studies are needed to investigate whether CXCL10 is a novel therapeutic target in AT.

&lt;sup&gt;60&lt;/sup&gt;Co orbital radiotherapy in Graves' ophthalmopathy

PURPOSE: Graves' ophthalmopathy (GO) is a common cause of morbidity in patients with Graves disease which suboptimal management is widespread. Immunosuppressive drugs and orbital irradiation represent treatment options for patients with moderate to severe and active GO. The aim of this study is to share our initial results from the application of orbital radiotherapy in GO. MATERIAL AND METHODS: Fifteen consecutive patients (12 women and 3 men) at a mean age 52 years (range, 26 to 62 years) with GO underwent radiotherapy of posterior orbit. Research team included a radiotherapist, endocrinologist and ophthalmologist performing the first and the follow-up examinations. Both orbits were examined for soft tissue and cornea involvement, proptosis, eye muscle impairment, visual acuity, visual fields and tonometry. Ophthalmic index was calculated before and after treatment. All the patients had received glucocorticoids before radiotherapy as 46.67% of them required corticosteroids during the period of irradiation and 80% received antithyroid medication. Overall clinical response was evaluated as excellent, good, fair or no response according to Donaldson's criteria. RESULTS: Fifteen patients completed the study with a follow-up of two or more months. All of them received 20 Gy to both orbits. The overall clinical response was excellent in two patients (13.33%), good in seven (46.67%), fair in five (33.33%), and there was no response in one patient (6.67% of the cases). The mean ophthalmopathy index (OI) was 7.2 before treatment and 3 after irradiation. There was a mean OI improvement of 4.2 points (range 2-7) compared to the pretreatment values. Best response was achieved for corneal involvement, soft tissue symptoms, sight loss and eye muscle impairment, while the response for proptosis was limited. No late adverse effects associated with radiotherapy such as cataract and radiation-induced retinopathy were observed at all. CONCLUSION: Our study proved that orbital radiotherapy is an effective and safe treatment option for progressive GO with better results in the early and acute stage of the disease. Scripta Scientifica Medica 2013; 45(4): 41-45.

Spontaneous Improvement of Untreated Mild Graves' Ophthalmopathy: Rundle's Curve Revisited

According to Rundle's curve, Graves' ophthalmopathy (GO) worsens during an initial phase up to a peak of maximum severity, then improves and reaches a static plateau, with the activity curve preceding the severity curve by a few months. To our knowledge, no studies have tried to replicate Rundle's curve, and very few have investigated the natural history of GO. Here, we studied GO natural history retrospectively and tried to identify factors that may affect it. A total of 65 patients with untreated GO underwent an eye assessment after a median of seven months after the appearance of GO and then after a median of 40 months. The primary endpoints were the variation of the single GO features and of the NOSPECS score, as well as the overall outcome of GO. The secondary endpoint was the influence of several variables (age, sex, smoking, GO and thyroid disease duration, thyroid treatment, thyroid status, thyroid volume, anti-TSH receptor autoantibodies) on the outcome of GO. The majority of patients had mild, minimally active GO, and only five had a Clinical Activity Score (CAS) >3. There was a significant reduction of CAS (p<0.0001) and NOSPECS (p=0.01) between the first and last observation, with a timing pattern resembling Rundle's curve. This difference was confirmed even when patients with a CAS >3 at first observation were excluded. At the last observation, 50.8% of patients had improved, 33.8% had remained stable, and 15.4% had worsened moderately or substantially. The overall outcome of GO was not affected by any of the variables under examination. In confirmation of Rundle's observations, untreated GO improves spontaneously with time in the majority of patients, with an activity peak between 13 and 24 months, which may have implications in determining the proper timing of GO treatments.

The different faces of dry eye

This opening lecture will set the scene for the rest of the morning session, when we will discuss different clinical presentations of dry eye syndromes with appropriate illustrations and Teifi will demonstrate how to recognise Sjogrens syndrome and differentiate between evaporative dry eye and lacrimal gland dysfunction, and will discuss the special situations which apply in Graves ophthalmopathy, Parkinsons disease, Acne vulgaris and facial nerve palsy. He will describe the spectrum of dry eye problems, covering the ubiquitous nature of Meibomian Gland Dysfunction but also illustrating some of the less common causes and aspects of dry eye syndromes.

In vivo confocal microscopy of bulbar conjunctiva in patients with Graves' ophthalmopathy

To investigate the bulbar conjunctival changes in patients with Graves' ophthalmopathy (GO) using in vivo confocal microscopy. A total of 15 GO patients and 15 control patients were recruited. Images of the superior site and temporal bulbar conjunctivas were taken by the Heidelberg Retina Tomograph/Rostock Corneal Module. The conjunctival thickness and cell density of superior epithelium, basal epithelium, Langerhans cells, and goblet cells were analyzed. Conjunctival impression cytology was performed to assess the grading of squamous metaplasia of the conjunctival epithelium. The superficial epithelial cell density in the superior bulbar conjunctiva of the GO group was 856.93 ± 461.68 cells/mm(2), which was significantly lower than that in the control group (1581.13 ± 556.34 cells/mm(2); p = 0.002). However, the difference in superficial epithelial cell density in the temporal bulbar conjunctiva between the two groups was not statistically significant. No significant differences in conjunctival thickness and the basal epithelial cell density were noted between the two groups. Increased Langerhans cell density and reduced goblet cell density were noted in the GO group. Impression cytology of the conjunctival epithelium revealed significantly higher degree of squamous metaplasia in the GO group. The superficial epithelial cell density in the upper bulbar conjunctiva showed negative correlation with marginal reflex distance in the GO group. GO patients suffered from more severe bulbar conjunctival damage and inflammation with the superior site than the temporal site. In vivo confocal microscopy can be a rapid and noninvasive tool for the quantitative evaluation of ocular surface changes in patients with GO.

Changes in Graves’ Ophthalmopathy after Radioiodine and Anti-Thyroid Drug Treatment of Graves’ Disease from 2 Prospective, Randomized, Open-Label, Blinded End Point Studies

A significant association between radioiodine therapy (RIT) and the development or the worsening of pre-existing Graves' ophthalmopathy (GO) has been reported. This post-hoc analysis of 2 studies attempted to describe the changes observed in pre-existing or new-onset GO following RIT with the goal of euthyroidism rather than hypothyroidism and to describe the relationship GO changes and the final outcome. In 2 prospective, randomized open-label blinded endpoint trials, patients received radioiodine alone; or, patients received radioiodine or antithyroid drug therapy (ATD). The severity and activity of GO were assessed during a 9-12-year follow-up. The study end points in study 1 were euthyroidism, hyperthyroidism, hypothyroidism, and changes in GO. In study 2, the end points were euthyroidism, hyperthyroidism, hypothyroidism, relapse, and changes in GO. Both RIT and ATD were associated with worsening GO and new-onset GO. Both RIT and ATD led to similar aggravation of pre-existing GO or the development to new-onset GO. After RIT or ATD, the euthyroid patients (without levothyroxine substitution) demonstrated an improvement in GO, with 78-89% patients with preexisting GO exhibiting improvement, whereas hyperthyroid, hypothyroid and relapsed patients had worsening or new-onset GO. Thyroid function is a dominant risk factor. Thyroid function may be the most important determinant in worsening or new-onset GO in both the natural disease course and in treated patients, independent of the kind of treatment. Therefore, we recommend euthyroidism as a goal of treatment.

Duration of intravenous glucocorticoid therapy in patients with Graves ophthalmopathy

Thyroid gland: Duration of intravenous glucocorticoid therapy in patients with Graves ophthalmopathy

Diagnosis and management of Graves disease: a global overview

Graves disease is an autoimmune disorder characterized by goitre, hyperthyroidism and, in 25% of patients, Graves ophthalmopathy. The hyperthyroidism is caused by thyroid hypertrophy and stimulation of function, resulting from interaction of anti-TSH-receptor antibodies (TRAb) with the TSH receptor on thyroid follicular cells. Measurements of serum levels of TRAb and thyroid ultrasonography represent the most important diagnostic tests for Graves disease. Management of the condition currently relies on antithyroid drugs, which mainly inhibit thyroid hormone synthesis, or ablative treatments ((131)I-radiotherapy or thyroidectomy) that remove or decrease thyroid tissue. None of these treatments targets the disease process, and patients with treated Graves disease consequently experience either a high rate of recurrence, if receiving antithyroid drugs, or lifelong hypothyroidism, after ablative therapy. Geographical differences in the use of these therapies exist, partially owing to the availability of skilled thyroid surgeons and suitable nuclear medicine units. Novel agents that might act on the disease process are currently under evaluation in preclinical or clinical studies, but evidence of their efficacy and safety is lacking.

Disease Activity in Graves' Ophthalmopathy: Diagnosis with Orbital MR Imaging and Correlation with Clinical Score

In Graves' ophthalmopathy (GO) it is important to distinguish acute inflammation at an early stage, responsive to immunosuppressive treatment, from inactive fibrotic end stage disease, unresponsive to the same treatment. The purpose of this study was to identify the most relevant signal intensities on orbital MR imaging with contrast administration both to classify patients according to their clinical activity score (defined by a cut-off value of 3) and to make a prediction of patient's CAS. Such threshold was considered as widely used in literature. Sixteen consecutive patients with a diagnosis of GO in different phases of thyroid disease based on clinical and orbital MR imaging signs, and six normal volunteers were examined. Orbital MR imaging was performed on a 1.5 Tesla MR Unit. MR scans were assessed by an experienced neuroradiologist, blinded to the clinical examinations. We found a statistical correlation between CAS and both STIR and contrast enhanced T1-weighted sequences. There was also a statistically significant correlation between STIR and contrast-enhanced T1 images disclosing the possibility of avoiding the injection of contrast medium. Our study proved that signal intensity values on STIR sequence increase in the inflammatory oedematous phase of disease. We confirmed the correlation between signal intensities on this sequence and CAS, showing an increase in signal intensity proportional to the CAS value. So we validated MRI use to establish the activity phase of disease more sensitively than CAS alone.

Orbital positron emission tomography/computed tomography (PET/CT) imaging findings in graves ophthalmopathy

BackgroundWe aimed to describe orbital positron emission tomography/computed tomography (PET/CT) imaging findings, both structural and metabolic, in different clinical stages of Graves ophthalmopathy (GO). This prospective, observational, cross-sectional study examined 32 eyes of 16 patients with GO.MethodsPatients were assessed with a complete ophthalmological evaluation and assigned a VISA classification for GO. All patients underwent serum thyroid hormone measurement, antibody profile, and 18-fluorodeoxyglucose positron emission tomography/computed tomography (18-FDG PET/CT) of the orbits. The 18-FDG uptake on PET images was expressed in terms of maximum standard uptake value (SUVmax). CT images were analyzed, and orbital structures were measured in millimeters. Vision, inflammation, strabismus, and overall appearance were assessed according to the VISA classification system, thyroid hormone levels, antibody values, 18-FDG uptake, and thickness of orbital structures.ResultsAltogether, 32 eyes of 16 patients (10 women, 6 men; mean age 44.31 ± 13 years, range 20–71 years) were included. Three patients were hypothyroid, seven were euthyroid, and six were hyperthyroid. CT measurements of extraocular muscle diameter were elevated (P < 0.05), and muscle 18-FDG uptake values were increased. Eyes with a clinical VISA inflammation score of ≤ 4 had an average extraocular muscle SUVmax of 3.09, and those with a score of ≥ 5 had an average SUVmax of 3.92 (P = 0.09), showing no clear correlation between clinically observed inflammation and 18-FDG uptake. 18-FDG uptake values also did not show a correlation with extraocular muscle diameter as measured by CT (R2 = 0.0755, P > 0.05).ConclusionsWe demonstrated a lack of correlation between 18-FDG extraocular muscle uptake and either clinical inflammation score or muscle diameter. Although 18-FDG uptake has been used as an inflammation marker in other pathologies, inflammation in GO may be clinically detected in PET/CT-negative cases, and cases with negative clinical findings may show inflammation on PET/CT. Clinical evaluation is mandatory but may be insufficient and inaccurate for classifying GO. A larger and homogeneous sample size and further research is needed to define the role of PET/CT in detecting, grading, and follow-up of GO to optimize treatment of the inflammatory stage respect clinical methods currently used.

The replication of the association of the rs9355610 within 6p27 with Graves’ disease

The etiology of the autoimmune thyroid diseases (AITDs), Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) is largely unknown. However, genetic susceptibility is believed to play a major role. Recently, Chu et al. conducted a genome-wide association study in a Chinese Han population and identified two novel GD susceptibility loci within 4p14 (rs6832151) and 6q27 (rs9355610). The objective of the study was to replicate these associations in a Japanese population. We analyzed rs6832151 and rs9355610 genotypes in a case-control study based on 457 Japanese AITD patients (286 GD and 171 HT patients) and 222 matched Japanese controls using the high-resolution melting and unlabeled probe methods. Case-control association studies were performed using the c2 and Fisher’s exact tests with Yates correction. We found a significant allelic association between AITD and rs9355610 located in 6q27 (p = 0.023). GD was significantly associated with this SNP (p = 0.0055), while HT showed no significant associations with any SNPs. Moreover, when patients with GD were stratified according to Graves’ ophthalmopathy (GO), there were no allelic associations with GO. These findings suggest the presence of AITD susceptibilty genes, especially in distinct subgroups of GD, in or near 6q27.

A Pilot Study Evaluating 99mTc-anti-TNF-alpha Scintigraphy in Graves' Ophtalmopathy Patients with Different Clinical Activity Score

The present study describes the preliminary results of the use of 99mTc-anti-TNF-α scintigraphy as a new diagnostic approach to evaluate patients presenting with Graves' ophthalmopathy (GO). Patients (n=25) presenting at different inflammatory stages of GO and 10 healthy volunteers underwent 99mTc-anti-TNF-α scintigraphy. Images were obtained 15 min after the intravenous injection of 370 MBq (10 mCi) 99mTc-anti-TNF-α. Planar images were obtained in a 256×256 matrix (each lasting 5 min) and single photon emission computed tomography (SPECT) scan lasting 13 min. Regions of interest (ROI) were drawn on the orbit and cerebral hemispheres. The uptake of 99m Tc-anti-TNF-α in these regions was compared and positive scintigraphy established when the ROI was >2.5. In addition, uptake for each positive exam was scored as either slight (2.6-5.1), moderate (5.2-7.6), or high (>7.6). In this pilot study, 69 orbits were evaluated (1 patient had only 1 eye), and 27 had a positive CAS (≥3/7). Scintigraphies were positive in 38 orbits. Comparing the results of the exams with CAS, a high sensitivity and negative predictive values were determined for scintigraphy (96.3% and 96.7%, respectively). However, the specificity and the positive predictive values were 71.4% and 68.4%, respectively, with an accuracy of 81.2%. The exclusion of examinations that were slightly positive from the analysis resulted in an improvement in test accuracy (95.5%). The preliminary results suggest that 99mTc-anti-TNF-α scintigraphy is a promising procedure for the evaluation of active orbital inflammation in GO.

Clinical outcomes of orbital radiotherapy combined with systemic glucocorticoids for patients with Graves' ophthalmopathy refractory to steroid therapy

PurposeTo investigate the clinical outcomes of combined orbital radiotherapy and systemic glucocorticoids for patients with refractory Graves’ ophthalmopathy (GO). Materials and methodsThe records were retrospectively reviewed of six patients with active moderate-to-severe GO who had been refractory to steroid therapy alone and treated with combined orbital radiotherapy and systemic glucocorticoids. All patients had already received one or more trial of steroid therapy prior to radiotherapy. Two patients had recurrence after steroid cessation, and four were unable to taper corticosteroids partially or completely. Two patients experienced relapse compressive optic neuropathy during tapering of glucocorticoids. The radiation dose was 20 Gy at 2 Gy/fraction. Presenting signs especially for disease activity and severity, treatment outcomes, and side effects were assessed. ResultsAfter combined therapy, complete cessation of corticosteroid therapy and stabilization of disease without recurrence was achieved in all patients. The clinical activity score decreased from 6.0 to 2.5 (p = 0.04). The ophthalmopathy index decreased from 8.2 to 5.7 (p = 0.05), with significant improvement in soft tissue sign (p = 0.03) and extraocular muscle movement (p = 0.03). Both patients with relapse dysthyroid optic neuropathy regained their vision. Side effects of radiotherapy included posterior subcapsular cataract formation in one patient. ConclusionCombined orbital radiotherapy and systemic corticosteroids can help to achieve stable disease and cessation of corticosteroid without recurrence in patients with refractory GO. This technique achieves greater improvement in clinical activity, soft tissue inflammation, and ocular motility.

Correction of Lower Lid Retraction Using TarSys Bioengineered Grafts for Graves Ophthalmopathy

To investigate the efficacy of decellularized porcine-derived membrane (tarSys; IOP Inc), a bioengineered eyelid spacer graft, for lower lid retraction correction in patients with Graves ophthalmopathy. Retrospective observational case series study. This was a retrospective review of patients with Graves ophthalmopathy undergoing lower eyelid retraction surgery using decellularized porcine-derived membrane bioengineered eyelid spacer grafts from 2008 through 2011. Outcome measures included lower eyelid height (measured from the corneal light reflex to the lower eyelid margin, or marginal reflex distance-2 [MRD2]), reduction of lagophthalmos, cosmetic appearance, complications, and need for further surgery. Presurgery and postreconstruction photographs were reviewed for functional and cosmetic outcome. A total of 32 Graves patients and 37 eyelids underwent lower eyelid retraction surgery using decellularized porcine-derived membrane. There were 10 male and 22 female patients with mean age of 41.8 ± 8.6 years. Mean improvement in MRD2 was 1.4 ± 0.4 mm. Mean reduction of lagophthalmos was 1.3 ± 0.4 mm. There are statistically significant differences between preoperative and postoperative MRD2 and lagophthalmos (paired t test, both P < .0001). No evidence of infection and corneal erosion was noted and none of the patients needed further surgeries. Prolonged lower lid swelling and slight puffy appearance were noted for 6 patients. The swelling and puffy appearance resolved completely 3 months after surgery. Conjunctival granuloma formation was found in 1 patient. The cosmetic result was satisfactory in all cases. Decellularized porcine-derived membrane, a bioengineered graft, is effective for the management of lower lid retraction in patients with Graves ophthalmopathy. It can offer an alternate graft for eyelid reconstruction.

Cohort Study on Radioactive Iodine–Induced Hypothyroidism: Implications for Graves' Ophthalmopathy and Optimal Timing for Thyroid Hormone Assessment

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. 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. 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%. 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.