Inactive Graves' Ophthalmopathy Research Articles

Increased choroidal stromal area in patients with active Graves’ ophthalmopathy based on binarisation method of optical coherence tomographic images

ObjectiveTo investigate the change in choroidal components of patients with Graves’ ophthalmopathy (GO) with different degrees of disease activity and severity by using the image binarisation method of optical coherence...

Performance of T2 mapping in the staging of Graves' ophthalmopathy based on different region of interest selection methods.

Discriminating the stage of Graves' ophthalmopathy (GO) is crucial for clinical decision. Application of conventional T2-weighted imaging in the staging is still limited. To evaluate the performance of T2 mapping based on two different regions of interest (ROIs) for staging GO. In total, 56 GO patients were retrospectively enrolled and divided into two groups according to the clinical activity score (CAS). T2 relaxation time (T2RT) of extraocular muscle (EOM) on T2 mapping based on two different ROIs (T2RTROI-1: ROIs were drawn separately in the four EOMs; T2RTROI-2: ROI was drawn in the most inflamed EOM) was measured and compared between active and inactive groups. Both T2RTROI-1 and T2RTROI-2 values in the active GO were significantly higher than those of inactive GO (P <0.001). T2RTROI-1 and T2RTROI-2 values were positively correlated with CAS (rs=0.73, 0.69; P <0.001). When the T2RTROI-1 value of 83.3 ms and T2RTROI-2 value of 106.3 ms were used as cutoff values for staging GO, respectively, the best results were obtained with areas under the curve (AUCs) of 0.822 and 0.827. There was no significant difference for AUCs between T2RTROI-1 and T2RTROI-2 (P = 0.751). Excellent and good inter-observer agreements were achieved in quantitative measurements for T2RTROI-1 and T2RTROI-2 values, respectively, with intraclass correlation coefficients of 0.954 and 0.882. The T2RT values derived from two different ROIs were useful for assessment of disease activity. Taking reproducibility and diagnostic performance into consideration, T2RTROI-1 would be an ideal image biomarker for staging GO compared to T2RTROI-2.

Triglyceride Glucose Index: A Potential Indicator in the Evaluation of Graves Ophthalmopathy.

To determine the relationship between Graves ophthalmopathy (GO) and triglyceride glucose index (TGI) and to evaluate the predictive importance of this index in terms of GO activity. This retrospective study included 20 inactive GO patients, 20 active GO patients, and 20 healthy controls. TGI was calculated using fasting plasma triglyceride and fasting plasma glucose levels and values were compared between the groups. The receiver operating characteristics curve was used to calculate the optimal TGI cutoff value and the sensitivity and specificity of this value between active and inactive GO groups. No significant difference was detected between the groups in terms of age and gender (p = 0.561 and p = 0.762, respectively). TGI value was 8.49 (8.41, 8.67) in the control group, 8.76 (8.74, 8.87) in the inactive GO group, and 9.06 (8.87, 9.08) in the active GO group (p < 0.001 for control group vs. inactive GO group; p < 0.001 for control group vs. active GO group; p = 0.001 for inactive GO group vs. active GO group). The optimal receiver operating characteristics cutoff value of TGI between active and inactive GO groups was 8.86 with 85% sensitivity and 75% specificity (area under curve: 0.837, p < 0.001, 95% confidence interval: 0.711-0.964). TGI was higher in both inactive and active GO patients compared with controls. It also appears that TGI may be used as a predictive marker indicating GO activity. This cheap and easily accessible parameter may be beneficial in detecting the disease and monitoring its activity in clinical practice.

Quantitative assessment of extraocular muscles in Graves' ophthalmopathy using T1 mapping.

To evaluate the performance of T1 mapping in the characterization of extraocular muscles (EOMs) of Graves' ophthalmopathy (GO) patients and investigate its feasibility in assessing the response to glucocorticoid therapy in active GO patients. A total of 133 participants (78 active GO, 23 inactive GO, 18 Graves' disease (GD) patients, and 14 healthy volunteers) were consecutively enrolled from July 2018 to December 2020. Native T1 (nT1) and postcontrast T1 (cT1) values of EOMs were measured and compared. The variations in T1 mapping metrics of EOMs were compared pre/post glucocorticoid treatment in 23 follow-up active GO patients. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed. The nT1 of EOMs in GO patients was higher than that in GD patients and healthy volunteers. The nT1 of superior rectus (SR) in active GO was higher than that in inactive GO patients, and it could be used as a potential marker of GO activity (OR: 1.003; 95% CI: 1.001, 1.004), with a diagnostic sensitivity of 86.3% and specificity of 43.7%. Meanwhile, the cT1 of SR, inferior rectus (IR), and medial rectus (MR) in inactive GO patients were higher than those in active GO patients. The nT1 of EOMs achieved sufficient diagnostic performance in evaluating the response to glucocorticoid therapy for follow-up active GO patients (AUC, 0.797; sensitivity, 71.9%; specificity, 85.7%). T1 mapping could quantitatively assess the activity of GO and the response to glucocorticoid therapy in active GO patients and may even potentially reflect the fibrosis of EOMs. T1 values can reflect the pathological status of the extraocular muscle. T1 mapping could help to quantitatively assess the clinical activity of GO and the response to glucocorticoid therapy in active GO patients. • Graves' ophthalmopathy patients had greater nT1 of extraocular muscles than Graves' disease patients and healthy volunteers, and nT1 of the superior rectus could be a potential marker of Graves' ophthalmopathy activity. • The cT1 of extraocular muscles in inactive Graves' ophthalmopathy patients was higher than that in active Graves' ophthalmopathy patients, and it might be associated with muscle fibrosis. • nT1 of extraocular muscles could offer sufficient diagnostic performance in evaluating the response to glucocorticoid therapy for follow-up active Graves' ophthalmopathy patients.

Evaluation of corneal endothelium and correlation with disease severity in patients with Graves’ ophthalmopathy: A specular microscopy-based study

PurposeTo investigate the possible corneal endothelial damage in Graves’ ophthalmopathy (GO) and its relationship with GO activity. MethodsThis cross-sectional study included 101 eyes of 55 patients with GO. Each eye was assigned a specific clinical activity score (CAS). Accordingly, they were classified as active (CAS ≥ 3) or inactive (CAS< 3). The corneal endothelium was measured using a non-contact specular microscope (Tomey EM-4000; Tomey Corp.). Endothelial cell density (ECD), average cell area (ACA), standard deviation of cell area (SD), coefficient of variation in cell area (CV), hexagonal cell ratio (HEX), and central corneal thickness (CCT) were recorded. ResultsAmong the eyes included in the study, 71 had inactive GO and 30 had active GO. ACA and HEX levels were lower (p<0,001) and CV values were higher (p<0.001) in patients with GO than in healthy subjects. Corneal endothelial cell morphology was altered in active GO compared to inactive GO. The SD (p = 0,009) and CV (p<0,001) were significantly higher in active GO than in inactive GO. When the parameters examined were correlated with CAS, a statistically significant positive correlation was observed between proptosis (p = 0,036, r = 0,385) and CV (p = 0,001, r = 0,595). ConclusionOur study confirmed that morphological changes occur in the corneal endothelium of patients with GO. CV and SD values, in conjunction with CAS, can be used as non-invasive and quantitative indices to examine the activity status of GO. The demonstration of endothelial changes even in GO eyes with low CAS may be considered an incentive to include non-contact specular microscopy in the routine clinical evaluation of all patients with GO.

The combination of T2-mapping value of lacrimal gland and clinical indicators can improve the stage prediction of Graves' ophthalmopathy compared to clinical activity scores.

To explore radiological changes of the lacrimal gland (LG) in Graves' ophthalmopathy (GO) and whether a combination of MRI parameters and clinical indicators would be more effective in predicting individual clinical manifestation of GO compared to clinical activity scores (CAS) assessment. A total of 28 patients with GO (56 eyes) and 14 healthy controls (HCs) (28 eyes) were enrolled between July 2020 and July 2021. Patients were classified into the active GO group (CAS ≥ 3) and the inactive GO group (CAS < 3). MRI data and clinical data of LG were collected. The diagnostic performance of MRI parameters and models was assessed by receiver operating characteristic curve analysis. Logistic regression predictive models for staging GO were compared. LG in GO groups had significantly higher Ktrans, Ve, IAUC, ADC, and T2-mapping values (p = 0.006, p < 0.001, p < 0.001, p = 0.048, and p = 0.001, respectively), and significant lower Kep and Vp values (p < 0.001 and p < 0.001 respectively). There were statistically significant differences in T2-mapping value (p < 0.001), the proportion of mild or no obvious redness of conjunctiva (p < 0.001), and the proportion of swelling of caruncle or plica (p < 0.001) between inactive and active groups. In MRI based logistic regression model, the T2-mapping value was an independent risk factor (AUC = 0.832). When combining MRI and clinical indicators, T2-mapping value and age resulted in independent risk factors (AUC = 0.928). Swelling of eyelids, redness of the conjunctiva, swelling of the conjunctiva, swelling of caruncle or plica, and spontaneous retrobulbar pain could be replaced by other objective indicators (AUC = 0.937, 0.852, 0.876, 0.896, and 0.891, respectively). There were significant differences in MRI quantitative parameters of LG between HCs and GO patients. The combination of the T2-mapping value of LG and clinical indicators improved the stage prediction of Graves' ophthalmopathy compared to CAS, thus providing a new idea for enhancing the objectification level of GO data collection.

Choroidal structural evaluation in inactive Graves’ ophthalmopathy

PurposeTo investigate the changes in the choroidal structure in patients with inactive Graves Ophthalmopathy (GO). DesignA prospective, masked, observational cross-sectional study. MethodsChanges in choroidal vascularity index (CVI) were studied in the patients with inactive GO using binarization on enhanced depth imaging optical coherence tomography (EDI-OCT) images. Choroidal area, subfoveal choroidal thickness (SFCT), stromal area, luminal area, CVI and retinal nerve fiber layer (RNFL) thickness was used to compare the eyes of sixty-four age-, gender-matched healthy subjects. All measurements were done separately both subfoveal (1500 µm) and total choroidal area (7500 µm). The relation between CVI or SFCT and age, gender, duration of disease, the severity of disease, TRAb (thyrotropin receptor autoantibody), smoking status, and exophthalmometer readings were evaluated. ResultsThere were 56 patients (30 female, 26 male; mean age: 39.5 ± 11.4 years) in the GO group and 64 patients (34 female, 30 male; mean age: 42.2 ± 5.6 years) in the healthy subject group. There was no statistically significant difference between subjects with GO and healthy controls regarding age (p = 0.24) and gender distribution (p = 0.55). Patients with GO had significantly higher intraocular pressure (p = 0.001) and exophthalmometer readings (p = 0.0001) than the healthy controls. The SFCT, CVI1500 and the stromal area1500 was significantly different between the groups (p = 0.009, p = 0.009, p = 0.011, respectively). Multivariate analysis showed that age (-0.871, p = 0.02) was highly correlated with the decreased SFCT, and duration of disease (0.524, p = 0.001) was significantly positively correlated with SFCT. Luminal area1500 (-0.416, p = 0.0001)and stromal area1500 (-0.657, p = 0.0001) were significantly negatively correlated with CVI1500 in the patients with GO. ConclusionAlthough higher CVI1500 was observed in GO patients than in healthy controls, the degree of increase was not the same in the CVI7500. Age and duration of disease significantly affect the SFCT, and luminal area1500 and stromal area1500 significantly affect the CVI1500.

Reactivation of Graves’ ophthalmopathy post-thyroidectomy for Graves’ disease

Abstract Introduction The impact of thyroidectomy for Graves’ disease (GD) on Graves’ ophthalmopathy (GO) is not well understood. It is generally accepted that thyroidectomy does not exacerbate or precipitate GO in the majority. The aim of this study was to evaluate whether prophylactic glucocorticoid use following total thyroidectomy for GD disease prevents early post-operative reactivation of GO. Methods A retrospective cohort study covering 5 years, studying patients undergoing total thyroidectomy for GD. Patients were divided into 3 groups. Group A (Clinical Activity Score (CAS) unknown): Patients with symptoms such as dry eyes or signs of inactive GO, as assessed by the Endocrine Surgical team; or patients seen by their local ophthalmologist, but with signs of GO not severe enough to warrant referral to the orbital team (tertiary centre). Group B (CAS=0): Patients with burnt out or no GO, as assessed by the orbital team. Group C (CAS &amp;gt;0): Patients with active GO, as assessed by the Orbital team. All were given prophylactic glucocorticoid cover. Results At least one patient in group A (n=14), none in group B (n=10) and five in group C (n=10) had early post-operative reactivation of Graves’ ophthalmopathy. Post-operative worsening of Graves’ ophthalmopathy was associated with CAS &amp;gt;0 (p=0.0325) and thyroid stimulating hormone &amp;lt;0.02 mIU/L (p=0.0136). Conclusion In those receiving prophylactic steroid, six (17.6%) demonstrated worsening GO. This was associated with a CAS &amp;gt;0 and TSH &amp;lt;0.02 mIU/L, suggesting either optimisation of both factors prior to thyroidectomy or considering a more potent steroid regimen.

The Potential Role of Osteopontin in the Pathogenesis of Graves’ Ophthalmopathy

PurposeThe aim of this study is to evaluate the expression of osteopontin (OPN) and its relationship with relative cytokines in patients with Graves’ ophthalmopathy (GO), and to observe the effect of OPN on orbital fibroblasts (OFs) proliferation, migration, and the expression of relative cytokines, as well as the signaling pathways involved in its effect.MethodsThe orbital adipose connective tissue was obtained from 24 patients with GO (12 cases of active GO, and 12 cases of inactive GO) and 12 healthy controls. OFs were isolated from orbital tissues obtained from patients with active GO who were undergoing orbital decompression surgery. Quantitative PCR and Western blot were performed to detect RNA and protein expression. The proliferation and cell migration rates of OFs were measured by methylthiazol tetrazolium (MTT) and the cell scratch test. Signaling pathway inhibitors, such as OPN monoclonal antibody 1A12, ERK1/2 inhibitor PD98059, and PI3K inhibitor LY294002, were applied to determine the involved pathways.ResultsThe mRNA and protein levels of OPN were increased in orbital adipose connective tissue from patients with active GO than those from patients with inactive GO (2.83-fold increase, P < 0.001; 1.91-fold increase, P < 0.05). The OPN mRNA level was positively correlated with CD40 ligand (CD40L) and hyaluronan synthases 2 (HAS2) mRNA in patients with GO. OPN promoted proliferation and migration rate of OFs and induced vascular endothelial growth factor (VEGF) and collagen I mRNA expression, and the effects were inhibited by 1A12 or LY294002.ConclusionsOPN in orbital adipose connective tissues were significantly increase in active GO, and there were significant correlations of OPN with CD40L and HAS2 mRNA levels in patients with GO. OPN promoted proliferation and migration of OFs and induced VEGF and collagen I mRNA expression in OFs through PI3K/Akt signaling pathway. This suggested a role for OPN in the pathogenesis of GO through the activation of OFs.

Corneal Endothelium: A Promising Quantitative Index for Graves Ophthalmopathy Activity Evaluation

To investigate the corneal endothelium damage in Graves ophthalmopathy (GO) and its role as a promising quantitative index to evaluate GO activity. Cross-sectional study. This study included 128 eyes of 64 patients with GO. All subjects underwent ophthalmologic examinations, including proptosis, tear break-up time (BUT), corneal fluorescein staining, and Schirmer test. Corneal endothelium was measured by noncontact specular microscope and ocular biometric parameters were measured by IOLMaster 700. Each eye was assigned a specific clinical activity score (CAS), then grouped as active (CAS ≥3 points) or inactive (CAS <3 points). Ocular parameters between the 2 groups were compared using generalized estimating equations accounting for inter-eye correlation, and receiver operating characteristic (ROC) curves were also obtained. Main outcome measures were parameters of corneal endothelium. Among the included eyes, 81 eyes had inactive GO and 47 eyes had active GO. Corneal endothelial cell morphology was altered in active GO compared with inactive GO. The coefficient variation of cell area (CV) was significantly higher in active GO compared with inactive GO (37.0 [34.4-41.2]% vs 33.9 [30.9-36.8]%, P=.001), and positively correlated with CAS (r=0.322, P < .001). Moreover, CV showed a diagnostic capacity to differentiate the active eyes from inactive eyes. The area under the ROC curve was 0.705. Active GO had morphologic changes in corneal endothelium compared with inactive GO. CV is a sensitive indicator to reflect corneal endothelial function, and has the potential to be adopted as a noninvasive, objective, and quantitative index for evaluating the activity status of GO patients.

Smoking effect on peripapillary and macular microvascular structure in inactive Graves' ophthalmopathy.

The aim of this study was to evaluate the smoking effect on peripapillary and macular microvascular structure in patients with inactive Graves' ophthalmopathy (GO) and to compare these structures with those of healthy control subjects. A total of 34 healthy participants (control group), 22 inactive GO patients with smoking (smoker group) and 19 inactive GO patients with non-smoking (non-smoker group) were recruited in this prospective study. After detailed ophthalmological examination, vessel densities (VD) of the superficial capillary plexus (SCP), deep capillary plexus (DCP), retinal peripapillary capillary (RPC) and foveal avascular zone (FAZ) area, and acircularity index (AI) of the FAZ were analysed with optical coherence tomography angiography (OCTA) for each eye. Vessel density in the total peripapillary; superior and inferior sectors of RPC were significantly lower in inactive GO patients with smoking (p < 0.05 for all sectors) compared to control group. Besides, the FAZ AI was significantly higher in smoker and non-smoker inactive GO groups compared to healthy subjects (p = 0.0001, p = 0.0001, respectively). No significant difference was found in the FAZ area, and all SCP, DCP macular measurements between groups (p > 0.05 for all). OCTA findings of lower peripapillary VD in the smoker group show smoking effect on the optic disc head microvasculature in inactive GO patients. These results could reflect early subclinical optic disc vasculature damage in smoker inactive GO subjects.

Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves' Ophthalmopathy through the Regulation of FoxO3a Signaling.

Graves' ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves' disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1β, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue (n = 4) and serum specimens (n = 6) obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO.

Application of Magnetic Resonance Imaging in the Evaluation of Disease Activity in Graves’ Ophthalmopathy

ObjectiveTo evaluate magnetic resonance imaging parameters, T2 signal intensity ratios (SIRs), and normalized apparent diffusion coefficients (n-ADC) of the extraocular muscles (EOMs) in the identification of different stages of Graves’ ophthalmopathy (GO) and to find out the correlation of T2-SIRs and n-ADC values with disease changes after anti-inflammatory treatment. MethodsAltogether, 43 patients (86 orbits) were enrolled and classified into “active” or “inactive” stages by clinical activity score (CAS). Twenty-three (53.5%) patients received anti-inflammatory treatment and underwent a follow-up evaluation. Fifteen age- and gender-matched control participants (30 orbits) were included. T2-SIRs and n-ADC values of EOMs were calculated among GO and healthy controls and were correlated with CAS. Changes in these parameters were also evaluated before and after anti-inflammatory treatment. ResultsMean T2-SIRs and n-ADC values were both significantly higher in GO patients than in controls and higher in active GO than in inactive GO. In the inactive stage, n-ADC values of inferior rectus muscles were still higher than those in healthy controls. Both T2-SIRs and n-ADC values decreased after intravenous steroid pulse therapy. The cutoff value of pretreatment n-ADC was 1.780 to detect stages with specificity of 93.7% and sensitivity of 48.3% (P = .035). ConclusionT2-SIRs and n-ADC values are valuable magnetic resonance imaging indicators of the inflammatory activity in GO by detecting involvement of EOMs. They are also ideal tools to monitor the efficacy of anti-inflammatory treatment in patients with active stage GO. n-ADC values, when combined with CAS, can be promising predictive factors in the detection of stages of diseases.

Serum Cystatin C Concentrations in Patients with Graves' Ophthalmopathy.

PurposeTo evaluate the concentration of serum cystatin C (CysC) in patients with Graves’ ophthalmopathy (GO) and the usability of the serum CysC concentrations in the follow-up of the disease.MethodsThirty patients with GO and 30 healthy age-matched volunteers were included in this cross-sectional study. GO was diagnosed based on the European Group on Graves’ Orbitopathy consensus. Serum thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and CysC concentrations were measured in the participants. The serum CysC concentrations were compared between patients with GO and controls. Patients with GO were subdivided into hyperthyroid and euthyroid patients, and their serum CysC concentrations were compared. In addition, the CysC concentrations in hyperthyroid and euthyroid patients with GO were compared separately with those of healthy subjects. Kruskal-Wallis test and Student’s t-test were used for statistical evaluation.ResultsThe mean serum CysC concentrations in GO patients and controls were 1.04 ± 0.36 and 0.74 ± 0.09 mg/L, respectively. There was a statistically significant difference in the serum CysC concentrations between patients with GO and control subjects (p < 0.001). Fifteen patients had hyperthyroid status, and 15 patients had euthyroid status. The mean serum CysC concentrations in hyperthyroid and euthyroid patients with GO were 1.35 ± 0.22 and 0.72 ± 0.13 mg/L, respectively. Serum CysC concentrations were significantly higher in hyperthyroid patients than in euthyroid patients (p = 0.001). In addition, hyperthyroid patients had significantly higher serum CysC concentrations than healthy subjects. Among patients with GO, 21 and nine had mild and moderate-to-severe GO, respectively. Active and inactive GO were observed in eight and 22 patients, respectively.ConclusionsThe serum CysC concentrations in hyperthyroid patients were higher than those in healthy subjects. Moreover, hyperthyroid patients had higher serum CysC concentrations than euthyroid patients. Further studies with a larger sample size are needed to confirm these results.

Analysis of Foveal and Parafoveal Microvascular Density and Retinal Vessel Caliber Alteration in Inactive Graves' Ophthalmopathy.

Purpose We aimed to evaluate foveal and parafoveal density using optical coherence tomography angiography and the alteration on the retinal vessel diameter in patients with inactive Graves' ophthalmopathy compared to age-matched normal population. Materials and Methods. Patients with inactive Graves' ophthalmopathy (study group) and healthy individuals (control group) were enrolled in the cross sectionally designed study. The optical coherence tomography angiography parameters and retinal vessel diameter measurements were assessed between the study and control groups. Foveal and parafoveal microvascular density in the retina was measured using optical coherence tomography angiography. Retinal artery and vein diameter and artery/vein ratio were assessed for retinal vessel caliber changes. Results Patients with inactive Graves' ophthalmopathy had higher values of intraocular pressure, proptosis, and axial length (P=0.001, P=0.001, P=0.001, P=0.001, P=0.001, P=0.001, P=0.001, P=0.001, P=0.001, P=0.001, P=0.001, Conclusion Optical coherence tomography angiography could be a novel and promising noninvasive diagnostic technique in patients with inactive Graves' ophthalmopathy to detect foveal and parafoveal vessel density changes compared to healthy subjects. The decrease of retinal vessel diameter might be observed in patients with inactive graves ophthalmopathy.

Low signal intensities of MRI T1 mapping predict refractory diplopia in Graves' ophthalmopathy.

In Graves' ophthalmopathy (GO), fibrosis in extraocular muscles (EOMs) may be related to intravenous glucocorticoid (ivGC)-resistant diplopia. Signal intensity (SI) of magnetic resonance imaging (MRI) T1 mapping can quantify properties of EOM components, including fibrosis. We investigated EOM features of GO patients with diplopia using T1 mapping SI and the predictive value of T1 mapping SI in the response of diplopia to ivGCs. We performed a cross-sectional study that included 13 active GO patients, 34 inactive GO patients with history of diplopia, including 20 with a history of diplopia disappearance, 14 GO patients with refractory diplopia and 35 control subjects. In nine active GO patients, the relationship between T1 mapping SI at pretreatment and at diplopia outcome after ivGC treatment was prospectively investigated. T1 mapping SI of left and right inferior rectus and medial rectus muscles was measured in all participants. T1 mapping SI in inactive GO patients with refractory diplopia was significantly lower than that of other groups in all evaluated EOMs. Diagnostic accuracy for refractory diplopia by T1 mapping SI in GO patients with a history of diplopia disappearance was excellent (AUC 0.89) compared with other assessments. Furthermore, among nine active GO patients, pretreatment T1 mapping SI in four patients with ivGC-resistant diplopia tended to be low compared with the other five patients with improved diplopia. Low intensity T1 mapping in EOMs is likely to be associated with refractory diplopia and may be useful in predicting the response of diplopia to ivGCs.

Altered Retinal Perfusion in Patients with Inactive Graves Ophthalmopathy Using Optical Coherence Tomography Angiography

Objective: The aim of this study was to evaluate retinal and optic nerve head (ONH) perfusion in patients with inactive Graves ophthalmopathy (GO) and compare it to healthy controls using optical coherence tomography angiography (OCTA). Methods: Twenty-nine eyes of 29 patients with inactive GO (study group) and 29 eyes of 29 healthy subjects (control group) were included in this study. The vessel density (VD) data in the superficial and deep retinal OCT angiogram of the macula and the radial peripapillary capillary network (RPC) were extracted and analyzed. OCTA was performed using RTVue XR Avanti with AngioVue (Optovue Inc, Fremont, CA). Clinical activity was evaluated using the clinical activity score, the severity assessment using the NOSPECS classification. Results: The VD in the superficial OCT angiogram and in the OCT angiogram of the ONH was significantly lower in the GO group when compared to the control group (whole en face, P = .016; parafovea, P = .026; RPC peripapillary, P = .027). There was no significant correlation between VD and functional parameters or the NOSPECS classification. Conclusion: Macular VD and ONH capillary density measured using OCTA were significantly lower in the study group compared to healthy controls. Noninvasive quantitative analysis of retinal perfusion using OCTA could be useful in monitoring patients with GO. Abbreviations: CAS = clinical activity score; GO = Graves ophthalmopathy; OCTA = optical coherence tomography angiography; ONH = optic nerve head; RPC = radial peripapillary capillary; rSp = Spearman's correlation coefficient; VD = vessel density.

Lacrimal gland herniation in Graves ophthalmopathy: a simple and useful MRI biomarker of disease activity.

Lacrimal gland (LG) involvement in patients with Graves ophthalmopathy (GO) has been considered as a potential cause of the associated GO symptoms and different studies demonstrated the LG involvement in patients with GO than healthy controls. The aim of this study was to evaluate LG involvement, through measurement of its herniation, using a magnetic resonance imaging (MRI) index, in patients with different GO activities. Thirty-two consecutive Caucasian patients affected by GO were enrolled and grouped in group A (16 with inactive GO, CAS < 3) and B (16 with active GO, CAS ≥ 3) according to their GO activity. All patients underwent clinical-endocrinological assessment, a complete ocular evaluation, and orbital MRI examination. No difference was found between the hormonal parameters, thyroid ultrasound-derived parameters, and thyroid-stimulating hormone (TSH) receptor (TSH-R) antibodies (TRAb) levels in group B and those in group A. The LG herniation (LGH) measurement evaluated by MRI was significantly higher in group B for both right (10.1 (7.3-17) vs. 7 (0-3.4) mm; p = 0.004) and left (8.5 (6.6-13) vs. 5.8 (0-12) mm; p = 0.026) eye than group A. A positive correlation was found between TRAb and LGH herniation (Rho 0.462, p = 0.009). Measurement of LGH seems to be a good marker of the disease and GO activity. • Lacrimal gland herniation is a simple index related to disease activity • Lacrimal gland herniation is correlated to TRAb levels • Lacrimal gland evaluation could be useful to differentiate active from inactive Graves ophthalmopathy in an early stage of disease.

TNFSF15 Polymorphisms are Associated with Graves’ Disease and Graves’ Ophthalmopathy in a Han Chinese Population

ABSTRACT Purpose Previous studies revealed an association of tumor necrosis factor super family-15 (TNFSF15) gene polymorphisms with several autoimmune diseases, but their roles in the development of Graves’ disease (GD) and Graves’ ophthalmopathy (GO) remain unclear. The aim of this study was to explore the correlation between TNFSF15 single nucleotide polymorphisms (SNPs) and susceptibility to GD and GO in a Han Chinese population. Materials and Methods This case-control study enrolled 813 healthy controls and 315 GD patients including 229 patients with GO. Eight SNPs of TNFSF15 (rs3810936, rs6478108, rs6478106, rs4979462, rs10817669, rs4246905, rs10733612, and rs10759734) were detected by TaqMan real-time PCR assay or PCR-restriction fragment length polymorphism (PCR-RFLP) and the possible association of these eight SNPs with the risk of GD and GO was analyzed. Allele frequencies and genotype distributions were compared using χ2 test. A stratified analysis was also performed according to clinical activity score (CAS) and sex. Results In comparison with the controls, the CT genotype of rs3810936 and the T allele of rs4979462 were decreased in GD patients. GD patients with GO also showed a lower frequency of the rs3810936 CT genotype and the rs4979462 T allele than the controls. Inactive GO patients showed a lower frequency of the rs3810936 CT genotype than controls, while GD females demonstrated a lower incidence of the T allele in rs4979462 and rs6478106 than the controls. Furthermore, GO females exhibited a lower rate of the rs4979462 T allele than the controls. Conclusions Our results suggest that TNFSF15 rs3810936 and rs4979462 polymorphisms are associated with the susceptibility of GD and GO in a Han Chinese population. Additionally, rs3810936 may affect the activity of GO, and rs4979462 may correlate with the sexual dimorphism observed in GD and GO.

99mTc-DTPA SPECT/CT provided guide on triamcinolone therapy in Graves' ophthalmopathy patients.

Distinguishing between the active and inactive stages of Graves' ophthalmopathy (GO) is essential for making treatment decisions. 99mTc-DTPA SPECT/CT is sensitive in identifying inflammation in extraocular muscles of GO patients, which we designate 99mTc-DTPA-active. This study aimed to evaluate the response of 99mTc-DTPA-active GO patients to local immunosuppressive therapy. Sixty-four 99mTc-DTPA-active GO patients (89 eyes) were retrospectively analyzed. Forty-five patients (64 eyes) received repeated peribulbar triamcinolone injection, and 19 patients (25 eyes) received no immunosuppressive treatment. Ophthalmological assessment, including clinical activity score, eyelid retraction, eyelid aperture, proptosis, diplopia, and ocular mobility, was recorded before and after treatment. Compared with untreated patients, the clinical activity score decreased significantly (P < 0.001) while eye symptoms (soft-tissue swelling and eyelid retraction and aperture) improved significantly (P = 0.02, P < 0.001, P < 0.001, respectively) in treated patients after six months. The inferior and medial recti were significantly smaller (P < 0.001, P < 0.001, respectively), and 99mTc-DTPA uptake in the two recti was significantly less (P = 0.001, P = 0.01, respectively) in treated patients than in untreated patients after 3 months. Clinical activity score of < 3 does not indicate inactive GO, as revealed with 99mTc-DTPA SPECT/CT. Patients with 99mTc-DTPA-active GO can improve the symptoms with peribulbar triamcinolone injection.