The Role of FOXP3 Polymorphisms in Graves' Disease with or without Ophthalmopathy in a Turkish Population.

Objectives: Forkhead box P3 (FOXP3) gene polymorphisms have been evaluated in many autoimmune diseases, including Graves' disease (GD), in different populations. However, those polymorphisms have not been analyzed in GD or Graves' ophthalmopathy (GO) in the Turkish population. In this study, we aimed to evaluate the frequency of FOXP3 polymorphisms in GD with or without ophthalmopathy in a Turkish population. Materials and Methods: The study included 100 patients with GO, 74 patients with GD without ophthalmopathy, and 100 age- and sex-matched healthy controls. In all study participants, rs3761547 (-3499 A/G), rs3761548 (-3279 C/A), and rs3761549 (-2383 C/T) single nucleotide polymorphisms (SNPs) were detected using the polymerase chain reaction-restriction fragment length polymorphism method. The chi-square test was used to evaluate genotype and allele frequencies. Odds ratios and 95% confidence intervals were calculated for genotype and allele risks. Results: In the patient group (including GD with or without ophthalmopathy), the rs3761548 AC and AA genotype and rs3761549 CT genotype were significantly more frequent than in the control group (all p<0.05). No genotypic and allelic differences were observed for rs3761547 between the patient and control groups (all p>0.05). There was no statistically significant difference between the GO and GD without ophthalmopathy groups concerning the allele and genotype frequencies of all three FOXP3 SNPs (all p>0.05). Conclusion: The AC and AA genotypes of rs3761548 (-3279) and CT genotype of rs3761549 (-2383 C/T) were shown to be possible risk factors for GD development in the Turkish population. However, none of the three SNPs was shown to be associated with the development of GO in patients with GD.

T2 Relaxation Time in Extraocular Muscles of Patients with Mild Thyroid- Associated Ophthalmopathy: Comparing T2 Mapping With and Without Fat Suppression Using Different Measurement Methods.

OBJECTIVE: This study aimed to compare the parametric value of T2 with and without fat suppression (FS) on T2 mapping for the evaluation of extraocular muscles (EOMs) in mild thyroid-associated ophthalmopathy (TAO). METHODS: We prospectively recruited 44 consecutive patients with mild TAO seen between May 2020 and October 2022 and 26 healthy controls with no history of eye- or thyroid-related or other autoimmune diseases. Patients with mild TAO were subdivided into active and inactive groups based on their clinical activity scores. The T2 of each EOM was measured over a large and small area of interest on T2-mapping images with and without FS. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficacy of T2 for detecting TAO activity. RESULTS: The T2 was significantly and heterogeneously higher in the active group than in the inactive and control groups (P < 0.05). FS-T2-mapping images had better signal display within and at the edges of the EOMs than those without FS. It was possible to observe high-signal aggregation visible in the periphery of some EOMs, and the central part showed relatively low signals. The maximum T2 measured in small or large areas with and without FS had good diagnostic efficacy for TAO activity, with that of no-FS being better (the area under the ROC curve of the maximum T2 measured in a small area and a large area without FS was 1.0 and 1.0 and P values of < 0.001 and < 0.001, respectively). CONCLUSION: Maximal T2 with or without FS can facilitate the early clinical detection of mild TAO activity. The maximum T2 in a small area can facilitate active staging of patients with mild TAO.

Comparison of macular and optic disc vessel density in thyroid orbitopathy: a comparative octa study.

PURPOSE: To determine the microvascular and structural changes in the peripapillary and macular areas observed in patients with active thyroid orbitopathy(TO) before and after steroid treatment and compare with inactive TO and the control group by optical coherence tomography angiography (OCTA). MATERIAL AND METHOD: This cross-sectional study included 34 eyes of 17 active TO patients, 108 eyes of 54 inactive TO patients, and 60 eyes of 30 healthy controls. Central macular thickness (CMT), ganglion cell layer-inner plexiform layer (GCL-IPL) thickness, central choroidal thickness (CCT), retinal nerve fiber layer (RNFL) thickness, choroidal thickness in the peripapillary region, superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris vessel densities were determined by OCTA in before and after 12-week steroid treatment of active TO cases, inactive TO and control groups. RESULTS: Between the three groups in macula OCTA, a statistically significant difference was observed in the inferior and nasal quadrants in SCP (all p = 0.01) and only in the temporal quadrant choriocapillaris (p = 0.005). In peripapillary OCTA, a statistically significant difference was found only in the central choriocapillaris (p = 0.03). In the comparison of the active group before and after treatment, there was a statistically significant decrease in CMT and CCT; a statistically significant increase was observed in GCL-IPL (all p < 0.01). There was a statistically significant decrease in SCP and DCP only in the central (all p < 0.01). There was a statistically significant increase was found in the lower quadrant macular SCP vessel density and mean macular DCP in post-treatment measurements (p = 0.01 and p = 0.03, respectively). Peripapillary SCP and DCP vessel density was increased after treatment (p < 0.01). CONCLUSION: Active TO group had lower vessel density than inactive group and after treatment, vessel density was increased. Non-invasive quantitative analysis of retinal and optic disc perfusion using OCTA could be useful in early treatment before complications occur and monitoring patients with TO.

Comparison of orbital fibroblasts from Graves' ophthalmopathy and healthy control.

Graves' ophthalmopathy (GO) is an extrathyroidal manifestation of Graves' disease, Orbital fibroblasts (OFs) are recognized as key players in GO pathogenesis, involved in orbital inflammation, tissue remodeling, and fibrosis. This study offers a primary exploration of cell behavior and characteristics on OFs from GO (GO-OFs), and compared to OFs from healthy control (HC-OFs). Results reveal that GO-OFs exhibit delayed migration from tissue fragments, while no significant difference in cell proliferation is observed between GO-OFs and HC-OFs. Aberrant expression pattern of surface proteins Thy-1, TSHR, and IGF-1R suggests shared autoantigens and pathways between GO and GD, contributing to inflammation and fibrosis. Investigations into cytokine responses unveil elevated secretion of hyaluronic acid (HA) and prostaglandin E2 (PGE2) in GO-OFs, emphasizing their role in tissue remodeling. These findings deepen our understanding of OFs in GO pathogenesis, offering potential therapeutic avenues.

EZH2 as a major histone methyltransferase in PDGF-BB-activated orbital fibroblast in the pathogenesis of Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is an extra-thyroidal complication of Graves' disease which can lead to vision loss in severe cases. Currently, treatments of GO are not sufficiently effective, so novel therapeutic strategies are needed. As platelet-derived growth factor (PDGF)-BB induces several effector mechanisms in GO orbital fibroblasts including cytokine production and myofibroblast activation, this study aims to investigate the roles of histone lysine methyltransferases (HKMTs) in PDGF-BB-activated GO orbital fibroblasts by screening with HKMTs inhibitors library. From the total of twelve selective HKMT inhibitors in the library, EZH2, G9a and DOT1L inhibitors, DZNeP, BIX01294 and Pinometostat, respectively, prevented PDGF-BB-induced proliferation and hyaluronan production by GO orbital fibroblasts. However, only EZH2 inhibitor, DZNeP, significantly blocked pro-inflammatory cytokine production. For the HKMTs expression in GO orbital fibroblasts, PDGF-BB significantly and time-dependently induced EZH2, G9a and DOT1L mRNA expression. To confirm the role of EZH2 in PDGF-BB-induced orbital fibroblast activation, EZH2 silencing experiments revealed suppression of PDGF-BB-induced collagen type I and α-SMA expression along with decreasing histone H3 lysine 27 trimethylation (H3K27me3) level. In a more clinically relevant model than orbital fibroblast culture experiments, DZNeP treated GO orbital tissues significantly reduced pro-inflammatory cytokine production while slightly reduced ACTA2 mRNA expression. Our data is the first to demonstrate that among all HKMTs EZH2 dominantly involved in the expression of myofibroblast markers in PDGF-BB-activated orbital fibroblast from GO presumably via H3K27me3. Thus, EZH2 may represent a novel therapeutics target for GO.

An Appraisal of the Preventive Effect of Statins on the Development of Graves' Ophthalmopathy: A Hospital-Based Cohort Study.

INTRODUCTION: Graves' ophthalmopathy (GO) is an autoimmune inflammatory disorder observed in a substantial proportion of patients with Graves' disease (GD), with debilitating symptoms of disfiguring, periorbital pain, dry eyes, diplopia, and even visual disturbances. Previous studies involving Western populations have noted discrepancies in risk factors for GO. Therefore, this study aimed to determine the risk factors for GO development and the protective effect of statins in newly diagnosed patients with GD in Taiwan. METHODS: This retrospective case-control study was based on a tertiary center cohort involving patients with GD diagnosed between 2010 and 2019 at the National Taiwan University Hospital (n = 11,035). Patients who were diagnosed or treated elsewhere, had been followed up for less than 6 months or were with a diagnosis of orbital tumor were excluded. Overall, 3578 patients with GD met the inclusion criteria. Univariate and multivariate logistic regression analyses were used to ascertain the odds ratio (OR) of developing GO, with adjustment for sociodemographic factors, interventions for managing GD and thyroid hormone levels, to determine protective and risk factors for GO. RESULTS: In our multivariate model, the use of statins reduced the risk of GO development (OR 0.2; 95% confidence interval [CI] 0.08-0.50; p < 0.001). Thyroid dysfunction including hyperthyroidism (OR 4.2; 95% CI 2.97-5.88; p < 0.001) and hypothyroidism (OR 4.7; 95% CI 3.02-7.19; p < 0.001) was associated with an increased risk of developing GO. Smoking status and lipid profile were not risk factors in our cohort. CONCLUSION: In newly diagnosed patients with GD, the use of statins decreased the risk of developing GO by 80%, whereas serum lipid levels were not considered risk factors. Further nationwide population-based studies may help clarify the differences in risk factors between various ethnic groups. TRAIL REGISTRATION: This trial was approved by the Research Ethics Committee of National Taiwan University Hospital (202202066RINC), retrospectively registered from January 1, 2010 to December 31, 2019.

Causality of blood metabolites and metabolic pathways on Graves' disease and Graves' ophthalmopathy: a two-sample Mendelian randomization study.

OBJECTIVES: There is ample that metabolic dysregulation is involved in Graves' disease (GD) and Graves' ophthalmopathy (GO). Recent studies have identified numerous metabolites associated with GD and GO. However, the causal impact of metabolites on GD and GO remains to be investigated. METHODS: This two-sample Mendelian randomization (MR) analysis investigated the causal relationships between 486 blood metabolites and GD and GO. Sensitivity analysis was also performed to examine heterogeneity and pleiotropy. RESULTS: MR analysis showed that 9 and 13 metabolites were associated with GD and GO, respectively, each meeting the nominal significance criteria (inverse variance weighted, p < 0.05). Additionally, four metabolic pathways were identified for each condition using network-based MetaboAnalyst 5.0. CONCLUSIONS: The metabolites and pathways discovered in this study could serve as circulating metabolic biomarkers for clinical screening and prevention of GD and GO. They can be also used for further studies on the mechanisms and drug targets in GD and GO.

Ocular surface and meibomian gland evaluation in euthyroid Graves' ophthalmopathy.

PURPOSE: Euthyroid Graves' ophthalmology (EGO) refers to the subgroup of thyroid eye disease patients with distinct clinical presentations. This study evaluated the ocular surface and meibomian gland changes in EGO patients. METHODS: A cross-sectional study was conducted at The Chinese University of Hong Kong including 34 EGO patients and 34 age-and sex- matched healthy controls. Outcome measures include anterior segment examination, keratographic and meibographic imaging. RESULTS: Between 34 EGO patients and 34 age and sex-matched healthy controls, EGO was associated with a higher ocular surface disease index (P < 0.01), higher severity of meibomian gland dropout (upper: P < 0.001, lower: P < 0.00001) and higher percentage of partial blinking (P = 0.0036). The worse affected eyes of the EGO patients were associated with corneal staining (P = 0.0019), eyelid telangiectasia (P = 0.0009), eyelid thickening (P = 0.0013), eyelid irregularity (P = 0.0054), meibomian gland plugging (P < 0.00001), expressibility (P < 0.00001), and meibum quality (P < 0.00001). When the two eyes of the same EGO patient were compared, the degree of meibomian gland dropout was higher among the worse affected eyes (upper: P < 0.00001, and lower: P < 0.00001). Tear meniscus height, lipid layer thickness, and noninvasive break-up time were comparable between the two eyes of EGO patients and also between EGO patients and healthy controls. TMH was positively correlated with the degree of exophthalmos (r = 0.383, P < 0.05). CONCLUSION: EGO patients have more ocular surface complications and meibomian gland dropouts than healthy controls. Almost 60% of them had dry eye symptoms, but aqueous deficiency was not apparent. Further studies are warranted to clarify the mechanism of dry eye in EGO. (249 words).

Superior orbital fissure syndrome after deep lateral orbital wall decompression in Graves' ophthalmopathy.

PURPOSE: The superior orbital fissure contains cranial nerves III, IV, VI, and V1 with their three branches: frontal, lacrimal, and nasociliary. Superior orbital fissure syndrome (SOFS) is rare and can occur as a result of compression of these nerves due to trauma, bleeding, or inflammation in the retrobulbar space, but no cases of SOFS after deep lateral orbital wall decompression (DLOWD) have been reported. The aim of this paper is to describe this pathology, its possible causes, management, and outcome. METHODS: Retrospective study of 575 DLOWD in patients with disfiguring exophthalmos due to Graves' ophthalmopathy performed in our hospital between 2010 and 2023. Three cases of postoperative SOFS were identified based on clinical presentation, history, physical examination, and radiological study. All patients were observed for a minimum of 12 months. RESULTS: SOFS was diagnosed with the presence of ophthalmoplegia, ptosis, fixed and dilated pupils, hypo/anesthesia of the upper eyelid and forehead, loss of corneal reflex, and no loss of vision after DLOWD. Fractures, edema, and hemorrhages were excluded. They were treated with high-dose intravenous steroids and the patients recovered completely. CONCLUSIONS: DLOWD challenges orbital surgeons because it requires removing bones near the globe or neurovascular structures. SOFS may occur due to the proximity and increased pressure on these structures.

Effect of Intraorbital Mechanical Compression on Retinal Microvascular Perfusion in Quiescent Thyroid-Associated Ophthalmopathy Based on Ocular Biomechanics Measured by Corvis ST.

INTRODUCTION: To analyze the correlation between orbital compliance and retinal vessel density (VD) based on dynamic Scheimpflug analyzer (Corvis ST) and optical coherence tomographic angiography (OCT-A). METHODS: In this prospective observational study, 65 eyes of 44 patients with thyroid-associated ophthalmopathy (TAO) in quiescent stage were included (15 males and 29 females). The whole eye movement (WEM) was detected by Corvis ST. The superficial capillary plexus VD (SCP-VD) and deep capillary plexus VD (DCP-VD) were obtained by scanning the 3 × 3 mm area around the fovea using OCT-A, while the peripapillary vessel density (ppVD) was obtained by scanning the 4.5 × 4.5 mm area around the optic disk. Covariances including biomechanically corrected intraocular pressure (bIOP), axial length, age and gender were adjusted during data analysis. RESULTS: The mean WEM of the participants was 0.235 ± 0.066 mm. The mean SCP-VD and DCP-VD in whole image were 46.20% ± 3.77% and 50.51% ± 3.96%; the mean whole pp-VD was 49.75% ± 2.01%. WEM was positively correlated with SCP-VD (r = 0.327, p = 0.01) and the whole pp-VD (r = 0.394, p < 0.01) after adjusting by gender, axial length (AL), age and bIOP, but it was not significantly correlated with DCP-VD (r = 0.072 p = 0.581). CONCLUSION: Increase in orbital pressure might reduce retinal microvascular perfusion. Our data suggest orbital mechanical compression may be an important cause of retinal VD changes in quiescent patients with TAO.

Monocyte-to-high-density lipoprotein ratio and systemic immune-inflammation index: Potential parameters for the evaluation of disease activity and severity in Graves' ophthalmopathy?

PURPOSE: To assess changes in monocyte-to-high-density lipoprotein (HDL) ratio (MHR), neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) with Graves' ophthalmopathy (GO) and their possible relation with GO disease activity and severity. METHODS: A total of 20 patients with GO and 24 healthy controls were involved in the study. The thyroid status, MHR (monocyte count/HDL cholesterol level), NLR (neutrophil count/lymphocyte count) and SII [(neutrophil count × platelet count)/lymphocyte count] were compared between the groups. The relation of systemic inflammation parameters with disease activity and severity was evaluated. RESULTS: The mean Clinical Activity Score (CAS) was 0.75 ± 0.78 in the GO group. None of the patients were active. The severity was mild for 14 (70.0%) patients and moderate-to-severe for 6 (30.0%) patients. MHR (17.28 ± 5.56 vs. 13.28 ± 5.08), NLR (2.51 ± 1.09 vs. 1.69 ± 0.53) and SII [600.42 (391.79-837.16) vs. 413.69 (344.26-603.82)] values were significantly increased in GO patients than in the controls (p = 0.017, p = 0.005 and p = 0.036, respectively). CAS was significantly correlated with MHR (r = 0.815, p < 0.001), NLR (r = 0.768, p = 0.017) and SII (r = 0.837, p < 0.001). The severity of GO was associated with increased MHR, NLR and SII (p = 0.019, p = 0.036 and p = 0.008, respectively). ROC analysis demonstrated that MHR, NLR and SII have a good ability to differentiate GO patients from healthy individuals. CONCLUSION: GO patients have higher MHR and SII levels than healthy controls. Higher MHR, NLR and SII values were associated with increasing disease severity and activity, supporting the efficacy of these non-invasive, low-cost markers in determining the course of GO. Future prospective controlled trials are needed to elucidate the relation between inflammatory markers and GO.

The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves' Ophthalmopathy.

Graves' ophthalmopathy (GO), or thyroid eye disease (TED), is the most frequent extrathyroidal manifestation of Graves' disease (GD). Inflammation and subsequent aberrant tissue remodeling with fibrosis are important pathogenesis. There are many proposed mechanisms and molecular pathways contributing to tissue remodeling and fibrosis in GO, including adipogenesis, fibroblast proliferation and myofibroblasts differentiation, oxidative stress, endoplasmic reticulum (ER) stress, hyaluronan (HA) and glycosaminoglycans (GAGs) accumulation in the extracellular matrix (ECM) and new concepts of epigenetics modification, such as histone modification, DNA methylation, non-coding RNAs, and gut microbiome. This review summarizes the current understanding of ECM proteins and associated tissue remodeling in the pathogenesis and potential mediators for the treatment of GO.

Selenium supplementation in inactive moderate to severe Graves' orbitopathy patients: a randomized controlled trial.

PURPOSE: This study was designed to evaluate the effect of selenium supplementation in inactive moderate-severe Graves' orbitopathy (GO) patients. METHODS: This study was a single-center, placebo-controlled, double-masked, randomized trial. Inactive moderate-severe GO participants were randomized to receive six months of 200 micrograms/day of selenium supplementation or placebo. Thorough eye exams, clinical activity score (CAS), Graves' Ophthalmopathy quality of life questionnaire (GO-QOL), and serum selenium level were evaluated at baseline and 6 months after the interventions. The chi-squared or Fisher's exact test was used to compare categorical variables. The t-test and the paired t-test were used to compare continuous variables between two independent samples and two dependent samples, respectively. RESULTS: A total of 25 participants were enrolled, 13 in the selenium group and 12 in the placebo group. Both groups had adequate baseline serum selenium levels at 98.96 ± 15.63 mcg/L and 102.55 ± 17.71 mcg/L, respectively. After 6 months of intervention, the selenium group showed a greater improvement in palpebral aperture (mean difference: -1.4 ± 1.7 mm, p = .04) compared to the placebo group (-0.3 ± 2.7 mm). Notably, 5(41.67%) people in the placebo group developed larger palpebral apertures. Proptosis, ocular motility, and soft tissue signs did not change significantly. GO-QOL and CAS score improvement showed no statistically significant difference between both groups. Minor adverse effects were observed. CONCLUSIONS: Selenium supplementation has a positive effect on eyelid aperture even in inactive moderate-to-severe GO patients with a sufficient baseline selenium level.

Optical coherence tomography and shear wave elastography findings in Graves ophthalmopathy.

PURPOSE: The main feature of Graves ophthalmopathy (GO) is revealed by determining the activity and severity of the disease. We aimed to evaluate the use of imaging methods can also provide additional information about the severity of this disease. METHODS: Optical coherence tomography (OCT) and shear wave elastography (SWE) findings were compared in 32 patients with mild GO group and in the healthy control group. Measuring for TSH receptor antibody (TRAb) serum level is used third-generation assay. RESULTS: In Graves group, optic nerve sheath diameter (ONSD) values were increased in both eyes (p < 0.001, p < 0.001). SWE measurements showed a significant increase both eye optic nerve (ON) and right eye soft tissue elasticity values in GO group (p < 0.001, p < 0.001, p < 0.001, respectively). There was a significant thinning in left temporal retinal nerve fiber layer (RNFL) thickness and left RNFL peripapillary thickness in GO group (p < 0.001, p < 0.025, respectively). There was a correlation between left eye OCT and SWE findings. Also, there was a significant difference between the median left eye ON and soft tissue elasticity results in the TRAb-positive GO group (p = 0.049, p = 0.048, respectively). CONCLUSION: SWE measurements showed a significant increase both eyes ONSD, ON and right eye soft tissue elasticity values in GO group. GO group was significant thinning in some left eye regions in OCT measurements. There was a correlation between left eye OCT and SWE findings. In addition to clinical activity score and TRAb, SWE and OCT can be used to monitor in patients with GO.

Assessment of Schlemm's canal with swept-source optical coherence tomography in Graves' ophthalmopathy.

PURPOSE: To evaluate the Schlemm's canal (SC) parameters obtained by swept-source optical coherence tomography (OCT) different in Graves' ophthalmopathy (GO) eyes compared to healthy eyes. METHODS: This cross-sectional observational study evaluated 64 eyes of 32 GO cases and 56 eyes of 28 healthy controls. The study was conducted between October 2020 and June 2021. SC images were obtained from the temporal limbus of individuals using swept-source OCT. SC length (SCL) and SC area (SCA) were measured. The relationship between SC parameters in the patient group and intraocular pressure (IOP), retinal nerve fiber layer (RNFL) thickness, Graves' disease (GD) duration, and clinical activity score (CAS) was evaluated. RESULTS: In the GO group, 64 eyes of 32 patients were evaluated, and in the age and gender-matched healthy control group, 56 eyes of 28 individuals were assessed. SC images from 4 eyes of 4 patients in the patient group and 1 eye of 1 patient in the control group were not clear, preventing SCL and SCA measurements for these eyes. SCL and SCA measurements were found to be lower, and IOP and Hertel values were higher in the GO group compared to the healthy controls. However, no significant correlation was observed between SCL and SCA with IOP, RNFL thickness, GD duration, GO duration, or CAS in the GO group. In the GO group, the mean value of SCA was found to be higher in eyes with glaucoma or OHT compared to those without. CONCLUSION: These findings indicate that SC in GO-affected eyes is shorter and has a smaller area than in healthy individuals. Additionally, higher IOP and Hertel values were observed in the GO group compared to healthy controls. This study suggests that assessing SC using anterior segment OCT could provide valuable insights into the regulation of IOP and the development of glaucoma in GO-affected eyes.

Stereotactic radiotherapy of radiation-induced meningioma previously irradiated retrobulbar for Graves' ophthalmopathy: A case report.

A 69-year-old woman was diagnosed with an asymptomatic intracranial tumor nine years ago and has been followed with annual MR imaging studies. Two years ago, the tumor had grown in size, requiring treatment. She experienced ophthalmopathy due to hyperthyroidism 27 years ago and was treated with 20 Gy in 10 fractions using parallel opposed beams to her bilateral posterior eyeballs, supplemented with steroid pulse therapy. The tumor originated in the medial aspect of the right sphenoid border and compressed the temporal lobe, while bone infiltration was observed, partially extending to the soft tissue outside the maxillary sinus. The tumor was removed by craniotomy. The pathological diagnosis was atypical meningioma (WHO grade II). Four months postsurgery, the resection cavity's tumor exhibited growth inclination, necessitating Gamma Knife radiosurgery. Radiation planning was executed at a marginal tumor dose of 30 Gy in 5 fractions. Since the optic nerve had been previously exposed to radiation, a plan was devised to minimize radiation exposure. The dose on the optic nerve was limited to 6.9 Gy in 5 fractions. She did not experience any visual or visual field disruptions postradiation. This is a case of radiation-induced meningioma resulting from radiation therapy for Graves' ophthalmopathy and is the first reported case of a grade II meningioma. The patient's condition calls for adjuvant radiation therapy following surgical removal. Accordingly, a radiation treatment plan that safeguards the optic nerve, which was previously exposed to radiation, was deemed indispensable.

Statins and thyroid eye disease (TED): a systematic review.

PURPOSE: Thyroid eye disease (TED) is the foremost extrathyroidal manifestation of Graves' disease (GD). Currently, available treatments do not entirely prevent the long-term consequences of TED and have distinct disadvantages. Therefore, this systematic review explored available evidence regarding the efficacy of statins in preventing and treating TED. METHODS: Relevant studies investigating statin usage in patients with GD or TED were identified by searching Medline (Pubmed and Ovid), Scopus, Web of Science, ProQuest, and Cochrane Library databases (from the database inception to September 2023). The review was done according to the PRISMA statement. Web searching was done independently by two investigators. Two researchers independently extracted the data, and any disagreement was adjudicated by consensus. Based on the study design, the studies' quality appraisal was done using the Newcastle-Ottawa Scale (NOS) and Version 2 of the Cochrane risk-of-bias tool (RoB2). RESULTS: The literature search identified 145 publications, of which four met the inclusion criteria (Three retrospective cohort studies and one randomized clinical trial) and were reviewed in full text. The two retrospective cohort studies demonstrated the beneficial effects of statins on TED in newly diagnosed GD Stein et al. showed that statins, regardless of the type, prevent or delay TED (HR: 0.74 (0.65-0.84)), especially in men or treatment duration of more than one year. Nilsson et al. fascinatingly revealed that at least 60 days of statin usage in the preceding year could decrease the risk of TED development by around 40%. One RCT showed a higher treatment response for active moderate-to-severe TED in patients with hypercholesterolemia who took atorvastatin 20 mg in addition to ivGC for 24 weeks without any increase in serious side effects. The retrospective study revealed that the need for reconstructive surgery was reduced in patients with severe TED who received statin therapy. CONCLUSION: Statin therapy could be a potential adjunctive modality for preventing and treating TED. TRIAL REGISTRATION: PROSPERO registration number: CRD42022315522.

Combined glucocorticoids and cyclophosphamide in the treatment of Graves' ophthalmopathy: a systematic review and meta-analysis.

PURPOSE: To evaluate the efficacy and safety of combined glucocorticoids (GCs) and cyclophosphamide (CYC) treatment in Graves' ophthalmopathy (GO). METHODS: We searched PubMed, Embase, Cochrane Library, and four Chinese databases (Chinese National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), WanFang, and SinoMed) for any published randomized controlled trials (RCTs) produced from inception to December 1, 2023. Articles obtained using appropriate keywords were selected independently by two reviewers according to the established inclusion and exclusion criteria. FINDINGS: We retrieved 1120 records which were eventually reduced to 13 RCTs which were then included in this evaluation. Pooled results indicated that the experimental group (CYC/GCs) showed a higher response rate than control group (GCs or negative control) (RR 1.27; 95% confidence interval 1.19 to 1.37). The subgroup analysis showed that the difference in response rates among treatment protocols (CYC/P, CYC/MPS, CYC/DEX) was not statistically significant (p = 0.23). IMPLICATIONS: The combination of GCs and CYC could be recommended as a therapeutic option for GO, especially in patients who experience recurrence after a withdrawal GCs, have a poor response to GCs, or cannot obtain monoclonal antibody agents for various reasons.

Orbital apex syndrome in pediatric thyroid eye disease: A case report and literature review.

Thyroid eye disease is an autoimmune disorder with clinical manifestations including lid retraction, proptosis, decreased visual acuity, and strabismus, and an incidence rate of 0.79 to 6.5 cases per 100,000 children. While reports are rare, the symptoms of thyroid eye disease in children have been found to be similar to those in adults, although typically milder. A 17-year-old girl presented with diplopia and hypoesthesia of the left forehead. Other clinical symptoms included mildly reduced visual acuity, restricted ocular movement, ptosis, and lid edema of the left eye. On the basis of blood tests, including a thyroid function test, Graves' disease was diagnosed, and a complication of Graves' disease was conjectured to have caused orbital apex syndrome due to thyroid eye disease, characterized by the involvement of cranial nerves II, III, IV, and VI, and the ophthalmic division of cranial nerve V. Following steroid pulse therapy, ophthalmic symptoms improved, and the patient is currently taking the antithyroid agent methimazole. To the best of our knowledge, this is the first report to describe orbital apex syndrome in pediatric thyroid eye disease, and the presented data will contribute to the future analysis of the clinical features of atypical pediatric thyroid eye disease.

The Top 100 Most-Cited Articles on Thyroid Eye Disease: A Bibliometric Study.

PURPOSE: This review analyzed the top 100 most-cited thyroid eye disease (TED) papers. METHODS: In November 2022, Scopus was searched for the most highly cited TED works since inception. For each paper, journal of origin and impact factor, corresponding author country and specialty affiliation, citation count, publication year, database-affirmed study funding, and open-access status were extracted. RESULTS: A total of 76 primary and 24 secondary articles were published between 1969 and 2021 across 29 journals, with a median (range) of 186.5 (133-930) citations. The most cited journal was Journal of Clinical Endocrinology and Metabolism (25 articles; 5126 citations). The most cited article was 'Graves' ophthalmopathy' (Bahn 2010; New England Journal of Medicine; 930 citations). Articles hailed from 10 countries, with most from the United States (38 articles; 9194 citations). Endocrinology (n = 59) and ophthalmology (n = 26) were the most common corresponding authors. Nineteen first authors contributed multiple articles. Only journal impact factor was significantly associated with citation count (p = .0002; ρ = 0.45). CONCLUSION: A variety of medical disciplines, Western countries, and study personnel contributed to highly cited thyroid eye disease research. Thus, this research area is not exceedingly informed by any singular perspective. Further, it can be interpreted with increased confidence for their generalizability of results to patients globally.