Graves' Ophthalmopathy Research Articles

English

Thyroid-associated orbitopathy (TAO), frequently termed Graves ophthalmopathy, is part of an autoimmune process that can affect the orbital and periorbital tissue, the thyroid gland, and, rarely, the pretibial skin or digits (thyroid acropachy), Although the use of the term thyroid ophthalmopathy is pervasive, the disease process is actually an orbitopathy in which the orbital and periocular soft tissues are primarily affected with secondary effects on the eye. Thyroid orbitopathy (TO) is most prevalent among females in the fourth and fifth decades and is usually associated with thyroid dysfunction. Thyroid-associated orbitopathy may precede, coincide, or follow the systemic complications of dysthyroidism. The ocular manifestations of thyroid-associated orbitopathy include eyelid retraction, proptosis, chemosis, periorbital edema, and altered ocular motility with significant functional, social, and cosmetic consequences. we describe a unique case of unilateral exophthalmos in a young male patient. REPORT OF A CASE: A 30 year old male patient presented with unilateral axial proptosis left eye for 6 months with eye signs of thyroid disease and history of diplopia on up gaze, increased appetite, weight loss, excessive sweating. He also gave complaints of red, gritty, photophobic and watery eyes. His visual acuity was in the right eye 20/40 improving to 20/20 and in the left eye it was 20/40 improving to 20/20. Color vision was normal. There was no RAPD present, Eye signs included Von Graffe's sign (immobility or lagging of the upper eyelid on downward rotation of the eye), Stellwag's sign (infrequent or incomplete blinking), Dalrymple sign (widened palpebral fissure), Gifford sign (Difficulty everting the upper eyelids), Pochin's sign (blinking rate is reduced), Rosenbach's sign (unusual tremor of the eyelids), Snellen's sign (Bruit heard on auscultation over the eye), Mean's sign (increased superior scleral show on upgaze), Kocher's sign (staring and frightened appearance), Mobius' sign (inability to maintain convergence of the eyes), Suker's sign (fixation becomes difficult in extreme lateral gaze). The intraocular pressure in the RE was 17 mm Hg and LE was 19 mm of Hg. There was restriction of movements in the upgaze in the left eye. There was no corneal involvement. The visual fields were normal. Serum T3, T4 were normal with elevated TSH levels, B-scan showed thickened muscle belly of inferior rectus muscle. On CT scan Proptosis of the left eye noted (the distance from the interzygomatic line to anterior aspect of globe is 28 mm), Increase in both intra and extraconal fat is noted in the left eye , Increase in the size and altered signal intensity is noted in the muscle belly of inferior rectus of left eye with sparing of the tendon. On histologic examination Fibrosis with degenerative changes in the eye muscles, Lymphocytic cell infiltration, Accumulation of mucopolysaccharides, interstitial edema with increased collagen production was seen. The patient was treated conservatively with maintenance of euthyroid

Dry Eye in Graves’ Ophthalmopathy: Correlation with Corneal Hypoesthesia

To evaluate dry eye disease and corneal sensitivity in patients with early and active Graves ophthalmopathy (GO). A total of 52 eyes of 26 patients with early GO and 74 eyes of 37 age- and sex-matched controls were included in our study. Dry eye disease was assessed based on the criteria of the International Dry Eye Workshop. Diagnosis of early GO was based on the European Group on Graves' Orbitopathy consensus statement. Clinical Activity Score (CAS) and Werner-NOSPECS Score were determined. Corneal sensitivity was assessed using a Cochet-Bonnet aesthesiometer. A total of 67.8% of patients with early GO and 13.5% of healthy controls had ocular surface dryness (p<0.001). The mean Schirmer test score was significantly lower in patients with early GO (12.88 ± 7.94 mm [right eyes] and 14.04 ± 9.00 mm [left eyes]) than in controls (18.08 ± 7.26 mm [right eyes] and 18.05 ± 7.50 mm [left eyes] [p<0.05]). The tear film break-up time was lower in patients by 5.46 seconds and 5.74 seconds in right and left eyes (p<0.001). We also found a significant reduction in corneal sensitivity in patients with early GO (4.16 ± 0.68 [right eyes] and 4.10 ± 0.89 [left eyes]) than in controls (4.70 ± 0.34 [right eyes] and 4.72 ± 0.34 [left eyes] [p<0.05]). The CAS correlated significantly with the Schirmer test (r = -0.60, p = 0.003). Dry eye is common in early GO even in the absence of apparent exophthalmos and is associated with CAS and reduced corneal sensitivity.

Clinical Utility of TSH Receptor Antibodies

TSH receptor antibodies (TRAb) cause Graves' disease (GD) hyperthyroidism. Widely available TRAb measurement methods have been significantly improved recently. However, the role of TRAb measurement in the differential diagnosis of hyperthyroidism, the prediction of remission of GD hyperthyroidism, the prediction of fetal/neonatal thyrotoxicosis, and the clinical assessment of Graves' ophthalmopathy (GO) are controversial. We reviewed and analyzed the literature reporting primary data on the clinical use of TRAb. We focused our analyses on clinical studies analyzing third-generation TRAb assays. The performance of TRAb in the differential diagnosis of overt hyperthyroidism is excellent, with sensitivity and specificity in the upper 90%. TRAb can accurately predict short-term relapses of hyperthyroidism after a course of antithyroid drugs but are less effective in predicting long-term relapses or remissions. Pregnancies in women with GD with negative TRAb are highly unlikely to result in fetal hyperthyroidism, whereas high titers of TRAb in pregnancy require careful fetal monitoring. GD patients with GO frequently have high TRAb levels. However, there are insufficient data to use the test to predict the clinical course of GO and response to treatment. Third-generation TRAb assays are suitable in the differential diagnosis of hyperthyroidism. In GD, TRAb should be tested before deciding whether methimazole can be stopped. TRAb should be used in pregnant women with GD to assess the risk of fetal thyrotoxicosis. The use of TRAb in GO requires further studies.

A Small Molecule Antagonist Inhibits Thyrotropin Receptor Antibody-Induced Orbital Fibroblast Functions Involved in the Pathogenesis of Graves Ophthalmopathy

Graves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction. The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH). Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling. cAMP production, Akt phosphorylation (Ser473pAkt in media and immunoblotting for pAkt/total Akt), and HA production were analyzed. Compound 1 inhibited basal cAMP, pAkt, and HA production and that stimulated by M22 in undifferentiated orbital fibroblasts. Inhibition of HA production was dose-dependent, with a half-maximal inhibitory dose of 830 nM. This compound also inhibited MS-1- and bTSH-stimulated cAMP, pAkt, and HA production. Compound 2 did not inhibit basal HA production but did inhibit M22-stimulated HA production. Because cAMP, pAkt, and HA production are fibroblast functions that are activated via TSHR signaling and are important in the pathogenesis of GO, small molecule TSHR antagonists may prove to be effective in the treatment or prevention of the disease in the future.

The impact of 99mTc-DTPA orbital SPECT in patient selection for external radiation therapy in Graves’ ophthalmopathy

In Graves' ophthalmopathy (GO), there is a demand to differentiate the immunologically active disease state, when immunosuppressive therapy is necessary, from the inactive state, when the patient would not benefit from it. We measured the inflammatory activity in the retrobulbar region using Tc-diethylene triamine pentaacetic acid (DTPA) SPECT before and after external radiation to determine whether this method is suitable for predicting the effectiveness of this therapy. Thirty-two patients with suspected active GO were involved in this retrospective study. The initial image, DTPA uptake value (UV) and its change after therapy were assessed to monitor the effect of the therapy and investigate whether a pretreatment scan is capable of predicting the outcome. Depending on the change in DTPA UV after radiotherapy, three patient groups were formed: decreased, increased or minimally changed (less than 1×10 injected dose (ID)/ml). The initial DTPA UVs of these groups were significantly different (P<0.001). Improvement was observed mainly in patients with higher initial values. When comparing the groups with low (<12×10 ID/ml) versus high (≥12×10 ID/ml) initial uptake, an unexpected increase was observed in the first group after therapy (mean: +2.89±2.66×10 ID/ml), whereas the average change in the DTPA UV was negative in the latter group as anticipated (-2.24±4.47×10 ID/ml, P<0.00001). We found that in GO patients a high DTPA UV may predict the response to orbital radiation therapy. DTPA orbital SPECT may be a suitable technique for the selection of GO patients for radiation therapy.

Circulating IgGs May Modulate IGF-I Receptor Stimulating Activity in a Subset of Patients With Graves' Ophthalmopathy

There is a close association between levels of TSH binding inhibitory immunoglobulins (TBIIs) and Graves' ophthalmopathy (GO). In addition to the TSH receptor, the IGF-I receptor (IGF-IR) has been proposed to be a second autoantigen that plays a role in the pathogenesis of GO. The aim was to study relationships between TBII and serum IGF-IR stimulating activity in relationship to age in patients with GO. We performed a prospective study of 70 patients with GO (26 euthyroid, 39 subclinical hyperthyroid, 5 hyperthyroid; 8 males, 62 females; age, 47.9 ± 1.0 y). Patients were graded according to clinical activity score. IGF-IR stimulating activity was determined by IGF-IR kinase receptor activation assay; TBIIs were measured by immunoassay (Trak). Protein G magnetic beads were used to deplete serum of IgGs. TBII and clinical activity score were positively related (r = 0.30; P = .01). In subjects with TBII above mean +1 SD, IGF-IR stimulating activity was positively related to age (r = 0.43; P = .05), whereas such a relationship was absent for subjects with TBII below the mean +1 SD (r = -0.04; P = .81). Depletion of IgGs from sera of patients with both TBII above the mean +1 SD and IGF-IR stimulating activity above the mean -1 SD decreased IGF-IR stimulating activity, whereas depletion in patients with TBII above the mean +1 SD but IGF-IR stimulating activity below the mean -1 SD did not change IGF-IR stimulating activity. In subjects with TBII above the mean +1 SD, we observed an increase of IGF-IR stimulating activity with age. In a subgroup of these patients, depletion of IgGs significantly decreased IGF-IR stimulating activity, suggesting that, in a subset of patients with GO, IgGs may have IGF-IR stimulating activities.

18-Fluorodeoxyglucose Uptake by Positron Emission Tomography in Extraocular Muscles of Patients with and without Graves' Ophthalmology

Objective. To compare 18-fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) in extraocular muscles (EOMs) of patients with Graves' ophthalmopathy (GO) versus patients without GO. Design. Prospective, observational, comparative, and cross-sectional study. Participants. Thirty-two eyes of patients with GO and seventy eyes of patients without GO. Methods. We prospectively included patients older than 18 years of age with and without GO. FDG-PET imaging study was performed; standardized unit value (SUVmax) was quantified in EOMs. Standard deviation and significant statistical difference (P < 0.05) were calculated. Results. Thirty-two eyes of sixteen patients of the GO group were included, with a mean age of 44.31 (20–71) years. Seventy eyes of thirty-five patients of the group without GO were included, with a mean age of 49.20 (24–77) years. EOMs average uptake of the groups with and without GO were 3.38 ± 1.31 and 1.89 ± 0.51 SUVmax (P < 0.05), respectively. Conclusion. FDG uptake was significantly increased in EOMs of patients with GO. PET gives valuable information and may be a helpful tool in detecting, localizing, and quantifying GO inflammation. Further research is needed to define the role of PET in detecting, grading, and following up GO in order to optimize treatment in the inflammatory stage.

Enalapril Reduces Proliferation and Hyaluronic Acid Release in Orbital Fibroblasts

Orbital fibroblast proliferation and hyaluronic acid (HA) release are responsible for some of the clinical features of Graves' ophthalmopathy (GO). Thus, inhibition of these processes may be a possible therapeutic approach to this syndrome. Enalapril, a widely used antihypertensive drug, was found to have some inhibitory actions on fibroblast proliferation in cheloid scars in vivo, based on which we investigated its effects in primary cultures of orbital fibroblasts from GO patients and control subjects. Primary cultures of GO and control fibroblasts were treated with enalapril or with a control compound (lisinopril). Cell proliferation assays, lactate dehydrogenase release assays (as a measure of cell necrosis), apoptosis assays, and measurement of HA in the cell media were performed. Enalapril significantly reduced cell proliferation in both GO and control fibroblasts. Because enalapril did not affect cell necrosis and apoptosis, we concluded that its effects on proliferation reflected an inhibition of cell growth and/or a delay in cell cycle. Enalapril significantly reduced HA concentrations in the media from both GO and control fibroblasts. Enalapril has antiproliferative and HA suppressing actions in both GO and control fibroblasts. Clinical studies are needed to investigate whether enalapril has any effects in vivo in patients with GO.

Genetic susceptibility to Grave’s disease

The variety of clinical presentations of eye changes in patients with Graves' disease (GD) suggests that complex interactions between genetic, environmental, endogenous and local factors influence the severity of Graves' ophthalmopathy (GO). It is thought that the development of GO might be influenced by genetic factors and environmental factors, such as cigarette smoking. At present, however, the role of genetic factors in the development of GO is not known. On the basis of studies with candidate genes and other genetic approaches, several susceptibility loci in GO have been proposed, including immunological genes, human leukocyte antigen (HLA), cytotoxic T-lymphocyte antigen-4 (CTLA-4), regulatory T-cell genes and thyroid-specific genes. This review gives a brief overview of the current range of major susceptibility genes found for GD.

Clinical efficacy of intravenous glucocorticoid treatment in Graves’ ophthalmopathy

Abstract Objective To assess the efficacy of intermittent, high-dose treatment with intravenous glucocorticoids (IV GCs) in moderate to severe Graves’ ophthalmopathy (GO). Materials and methods Patients with GO treated with IV GCs from August 2007 to August 2011 at the Endocrinology Department of Reina Sofia Hospital were enrolled into the study. IV pulse prednisolone (7.5 mg/kg/day) was administered twice weekly every two weeks for 6 weeks, and at half the dose for 6 additional weeks. Results Eighteen patients (mean age, 43 ± 11 years) with moderate to severe GO were analyzed (83.3% females). Four were active smokers, five former smokers, and the rest had never smoked. Hyperthyroidism due to Graves’ disease was found in 66.7% of patients, 41.6% of whom had received radioiodine therapy. Response to treatment was satisfactory in 72.2%, partial in 11.1%, and poor in 16.7%. Mild side effects were reported by 5 patients. Before treatment, 83.3% had diplopia, 33.3% eyelid retraction, 72.2% eye pain, and 44.4% exophthalmos. After treatment, only 33.3% had diplopia ( P = .004), 5.6% eyelid retraction ( P = .063), 16.7% eye pain ( P = .002), and 11.1% exophthalmos ( P = .031). Response to treatment was not related to the underlying disease ( P = .866), prior radioiodine treatment ( P = .447), or smoking status ( P = .368). Conclusions Intravenous glucocorticoid therapy decreased activity in patients with moderate to severe active GO, with major improvement occurring in diplopia, eye pain, and exophthalmos. Side effects were mild and uncommon. Treatment response was independent from the underlying disease, prior radioiodine treatment, or smoking status.

The association of carotid cavernous fistula with Graves′ ophthalmopathy

Graves’ ophthalmopathy (GO) is one of the frequent manifestations of the disorder which is an inflammatory process due to fibroblast infiltration, fibroblast proliferation and accumulation of glycosaminoglycans. Eye irritation, dryness, excessive tearing, visual blurring, diplopia, pain, visual loss, retroorbital discomfort are the symptoms and they can mimic carotid cavernous fistulas. Carotid cavernous fistulas are abnormal communications between the carotid arterial system and the cavernous sinus. The clinical manifestations of GO can mimic the signs of carotid cavernous fistulas. Carotid cavernous fistulas should be considered in the differential diagnosis of the GO patients especially who are not responding to the standard treatment and when there is a unilateral or asymmetric eye involvement. Here we report the second case report with concurrent occurrence of GO and carotid cavernous fistula in the literature.

Pulse dexamethasone therapy versus pulse methylprednisolone therapy for treatment of Graves′s ophthalmopathy

Pulse methylprednisolone therapy is the recommended therapy for moderate to severe and active ophthalmopathy, but high dose pulse methylprednisolone therapy is marred by the chances of fulminant hepatic failure and the high cost of therapy. Dexamethasone pulse therapy can be considered as an alternative to pulse methylprednisolone therapy. A prospective randomized control trial was carried out in 21 patients comparing pulse dexamethasone therapy versus pulse methyprednisolone therapy in Graves's ophthalmopathy. This study proved that pulse dexamethasone therapy is a cheaper and equally effective therapy for Graves's ophthalmopathy and the cost of therapy is reduced to at least 1/8th s. Furthermore, dexa had a better effect on reduction of exophthalmos. The dreaded complication of fulminant hepatic failure, associated with high dose of methylprednisolone, is not seen with dexa therapy.

Thymic stromal lymphopoietin gene promoter polymorphisms and expression levels in Graves’ disease and Graves’ ophthalmopathy

BackgroundGraves disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism, diffuse goiter, autoantibodies against thyroid-specific antigens, and dermopathy. Studies of GD have demonstrated the importance of the Th2 and Th17 immune responses in mediating disease progression. In the present study, we investigated the role of a Th2 cytokine, thymic stromal lymphopoietin (TSLP), in GD and Th17 differentiation.MethodsIn this study, we genotyped 470 patients with GD at 3 single nucleotide polymorphisms (SNPs) in TSLP. In addition, the serum concentrations of TSLP were determined in 432 patients and 272 controls. Ten patients and controls each were further screened using in vitro Th17 differentiation assays. The SNPs were genotyped using ABI TaqMan® SNP genotyping assays. For the Th17 differentiation assays, peripheral blood mononuclear cells (PBMCs) isolated from the patients and controls were placed into Th17 differentiation media, and interleukin 17 expression levels were determined.ResultsHaplotype analysis indicated that patients with the Ht3 (TCC) haplotype have a 3.28-fold higher risk of developing GD (p = 0.007), whereas those with the Ht5 (TCG) haplotype had a 0.03-fold, reduced risk of developing GD (p = 1 × 10−14). SNP rs3806933 (p = 0.007) was associated with female Graves ophthalmopathy (GO). TSLP expression levels were higher in GD patients than in control subjects, and TLSP was also shown to promote the differentiation of Th17 cells in GD patients.ConclusionsThese results suggest that polymorphisms in TSLP may be used as genetic markers for the diagnosis and prognosis of GD. Furthermore, TLSP may be a target for treating GD.

Interleukin-7 expression in tears and orbital tissues of patients with Graves’ ophthalmopathy

The aim of this study was to explore whether IL-7 participates in the pathogenesis of Graves' ophthalmopathy (GO). This was a prospective study. 20 GO patients (40 eyes) and 20 healthy volunteers (40 eyes) were recruited. The tear concentration of IL-7 was measured using ELISA assay. IL-7 expression in orbital tissues was evaluated by immunohistochemistry. Patients with inactive GO had the highest IL-7 concentrations in the tears, followed by healthy controls and patients with active GO per ELISA. Immunohistochemistry analysis showed that IL-7 expression in orbital tissues of the inactive GO samples was higher than that of the volunteers. Changes of IL-7 expression in different phases of GO suggested that IL-7 may play an important role in the pathogenesis of GO.

Evaluación de la efectividad del tratamiento con glucocorticoides intravenosos en la oftalmopatía de Graves

To assess the efficacy of intermittent, high-dose treatment with intravenous glucocorticoids (IV GCs) in moderate to severe Graves' ophthalmopathy (GO).Patients with GO treated with IV GCs from August 2007 to August 2011 at the Endocrinology Department of Reina Sofía Hospital were enrolled into the study. IV pulse prednisolone (7.5 mg/kg/day) was administered twice weekly every two weeks for 6 weeks, and at half the dose for 6 additional weeks.Eighteen patients (mean age, 43 ± 11 years) with moderate to severe GO were analyzed (83.3% females). Four were active smokers, five former smokers, and the rest had never smoked. Hyperthyroidism due to Graves' disease was found in 66.7% of patients, 41.6% of whom had received radioiodine therapy. Response to treatment was satisfactory in 72.2%, partial in 11.1%, and poor in 16.7%. Mild side effects were reported by 5 patients. Before treatment, 83.3% had diplopia, 33.3% eyelid retraction, 72.2% eye pain, and 44.4% exophthalmos. After treatment, only 33.3% had diplopia (P=.004), 5.6% eyelid retraction (P=.063), 16.7% eye pain (P=.002), and 11.1% exophthalmos (P=.031). Response to treatment was not related to the underlying disease (P=.866), prior radioiodine treatment (P=.447), or smoking status (P=.368).Intravenous glucocorticoid therapy decreased activity in patients with moderate to severe active GO, with major improvement occurring in diplopia, eye pain, and exophthalmos. Side effects were mild and uncommon. Treatment response was independent from the underlying disease, prior radioiodine treatment, or smoking status.

Association of IL12B polymorphisms with susceptibility to Graves ophthalmopathy in a Taiwan Chinese population

BackgroundInterleukin 12B (IL12B) gene polymorphisms have been linked to several inflammatory diseases, but their role in the development of Graves ophthalmopathy (GO) in Graves disease (GD) patients is unclear. The purpose of this study was to investigate the disease association of IL12B single nucleotide polymorphisms (SNPs).MethodsA Taiwan Chinese population comprising 200 GD patients with GO and 271 GD patients without GO was genotyped using an allele-specific extension and ligation method. Hardy-Weinberg equilibrium was estimated using the chi-square test. Allele and genotype frequencies were compared between GD patients with and without GO using the chi-square test.ResultsThe genotype and allele frequencies of examined SNPs did not differ between GD patients with and without GO. Although the genotype distribution remained nonsignificant in the sex-stratified analyses, the frequency of the T allele at SNP rs1003199 was significantly higher in patients with GO in the male cohort (P = 6.00 × 10-3). In addition, haplotypes of IL12B may be used to predict the risk of GO (P = 1.70 × 10-2); however, we could not prove the statistical significance of analysis after applying the Bonferroni correction.ConclusionsOur results provide new information that the examined IL12B gene polymorphisms may be associated with susceptibility to GO in the Taiwan Chinese population in a sex-specific manner. This conclusion requires further investigation.

99mTc-Anti-TNF-α Scintigraphy

Different imaging methods applied in the evaluation of a patient with unilateral active Graves ophthalmopathy (GO) are shown in the present paper. 99mTc-Anti-TNF-α scintigraphy is proposed as a promising method, not yet described, for the diagnosis of active ocular disease. It consists of labeling a human monoclonal antibody directed against TNF-α molecule (adalimumab) with technetium (99mTc). The method is based on the demonstration of TNF-α as one of the cytokines enrolled in the initial active phase of GO development. The method may give the perspective to link diagnosis and therapy, including new target-based modalities.

Emerging pharmacotherapy for treatment of Graves’ disease

The clinical triad of Graves’ disease (GD) includes hyperthyroidism, diffuse goiter and the associated ocular condition, Graves’ ophthalmopathy (GO). Hyperthyroidism can cause not only significant ...

Quantitative evaluation of extraocular muscle with high-field magnetic resonance in patients with Graves' ophthalmopathy with upper-lid retraction.

To evaluate the feasibility of high-field magnetic resonance in measuring the thickness and width of extraocular muscles, calculate the ratio of thickness to width, and summarize the characters of the diameters and its ratio in patients with Graves' ophthalmopathy (GO) with upper-lid retraction. Sixteen GO patients with upper-lid retraction (GO group) and 14 healthy control group were enrolled in this study. All the patients underwent enhanced high-field magnetic resonance orbital scan. The thickness and width of extraocular muscles were measured on axial, coronal or oblique sagittal enhanced T1 weighted images. The ratio of thickness to width (R1) and width to thickness (R2) were calculated. The diameters or ratio was evaluated as enlarged when they were 2 standard deviation greater than mean values of extraocular muscle in healthy control. The thickness of levator palpebrae superioris, medial rectus, and inferior rectus muscles in GO group were significantly larger than those in the control group (P=0.000, P=0.017, P=0.032, respectively. The width of superior oblique muscles in GO group was significantly larger than that in control group (P=0.000). The R1 values of levator palpebrae superioris, inferior rectus, medial rectus, and lateral rectus muscles in GO group were significant larger than those in the control group (P=0.000,P=0.037, P=0.019,P=0.032, respectively. The R2 value of superior oblique muscles was significant larger than that in the control group (P=0.027). Aslo in GO group, 32 extraocular muscles showed an increased thickness. 47% of thickened extraocular muscles had an increased R1. Enhanced orbit imaging with high-field magnetic resonance is helpful in the quantitative assessment of the thickness and width of extraocular muscles. In GO patients, in addition to the levator palpebrae superioris muscles, some other extraocular muscles also becomes thicker. Moreover, the increased diameters of superior oblique muscles is mainly due to the increase of its width R1 and R2 values can reflect the thickness and width of extraocular muscles and their relationship.

Pingmu decoction enhances apoptosis of orbital adipocytes derived from patients with Graves’ ophthalmophathy

Graves' ophthalmopathy (GO), an autoimmune disease, has been demonstrated to result from an increased volume of orbital contents, including adipose, connective and extraocular muscle tissues. In our previous study, we showed that Pingmu decoction is capable of alleviating GO progression. In this study, to further investigate the underlying mechanism(s), we examined the effects of Pingmu decoction-containing serum on the proliferation and apoptosis of preadipocytes and adipocytes derived from the orbital adipose tissue of GO patients. Our data demonstrate for the first time that Pingmu decoction-containing serum significantly reduces preadipocyte proliferation and increases adipocyte apoptosis as measured by MTT assay and AnnexinV/FITC staining, respectively. Moreover, Pingmu decoction elevated the levels of cleaved caspase-3, 8 and9 and decreased the levels of cell cycle-related genes compared to those of the control. In addition, cell cycle arrest at the G0/G1 phase was observed following Pingmu decoction treatment. This study shows a mechanism by which Pingmu decoction serves as an effective GO medicine by downregulating preadipocyte proliferation and increasing adipocyte apoptosis.