A Review of Pathophysiology and Therapeutic Strategies Targeting TGF-ß in Graves' Ophthalmopathy.

TGF-ß plays a pivotal role in the pathogenesis of GO by promoting orbital tissue remodeling and fibrosis. This process involves the stimulation of orbital fibroblasts, leading to myofibroblast differentiation, increased production of inflammatory mediators, and hyaluronan accumulation. Studies have elucidated TGF-ß's role in driving fibrosis and scarring processes through both canonical and non-canonical pathways, particularly resulting in the activation of orbital myofibroblasts and the excessive accumulation of extracellular matrix. Additionally, recent in vitro and in vivo studies have been summarized, highlighting the therapeutic potential of targeting TGF-ß signaling pathways, which may offer promising treatment interventions for GO. This review aims to consolidate the current understanding of the multifaceted role of TGF-ß in the molecular and cellular pathophysiology in Graves' ophthalmopathy (GO) by exploring its contributions to fibrosis, inflammation, and immune dysregulation. Additionally, the review investigates the therapeutic potential of inhibiting TGF-ß signaling pathways as a strategy for treating GO.

Interaction of MMP-9 in the active phase of Graves' disease with and without ophthalmopathy.

BACKGROUND: Thyroid eye disease (TED) is expressed as orbital inflammation, and serum levels of several proinflammatory cytokines have been studied among Graves' disease (GD) patients with and without TED; however, a more sensitive and specific marker for the different phases of GD and TED is still lacking. METHODS: 17 active TED, 16 inactive TED, 16 GD without TED, and 16 healthy controls were recruited. Serum IL-17A, MMP-2, MMP-3, and MMP-9 were measured by multiplex bead assay. TED hormone and eye parameters were evaluated, and their relationship with cytokine levels was analysed. RESULTS: Serum MMP-9 was higher in active TED than healthy controls, while IL-17A was lower among these patients than in GD without TED and healthy controls. No differences were found in MMP-3 and MMP-2 concentrations. MMP-9 levels were lower in inactive TED patients who underwent radioactive iodine (RAI) therapy and those on levothyroxine replacement, while MMP-9 levels were elevated in patients on methimazole. A negative correlation was found between age at assessment and time of follow-up with MMP-9 levels in inactive TED. Free T3 and ophthalmometry values were positively correlated with MMP-9 in the GD without TED and inactive TED groups, respectively. CONCLUSIONS: Serum MMP-9 was increased in patients with active TED and was related to the RAI treatment, longer follow-up time, and higher ophthalmometry in patients with inactive TED, as well as thyroid function in GD without TED. MMP-9 may be involved in both the active phase of TED and the active phase of inflammation related to GD.

Perioperative Implications in a Hypertrophic Cardiomyopathy Patient Undergoing Endonasal Orbital Decompression: A Case Report.

Thyroid eye disease (TED) is an autoimmune disease of the retro-ocular tissue and occurs in patients with Graves' disease with hyperthyroidism. In severe cases, it can lead to vision loss; hence, timely management is important. Hypertrophic cardiomyopathy (HCM) is one of the systemic manifestations related to hyperthyroidism. We present a case of successful perioperative management of Graves' disease with TED and HCM posted for endonasal decompression surgery. Hyperthyroidism itself has many implications on perioperative anesthetic management, which can become more complicated when associated with co-existing HCM. However, our case proves that detailed preoperative evaluation, vigilant intraoperative monitoring, and adequate analgesia can lead to a smooth perioperative course for HCM patients for non-cardiac surgeries.

Thyroid Eye Disease and Glaucoma: A Cross-Sectional Study Comparing Clinical Characteristics and Disease Severity.

Background and Objectives: This study investigates the relationship between thyroid eye disease (TED) and open-angle glaucoma (OAG), focusing on disease severity and clinical features. Materials and Methods: Conducted at the Timis County Emergency Clinical Hospital, the research included 106 patients, with 53 having both conditions and 53 having only OAG. Key metrics analyzed included intraocular pressure (IOP) using a Goldmann applanation tonometer, the retinal nerve fiber layer (RNFL) thickness, and optic nerve head (ONH) characteristics evaluated using optical coherence tomography (OCT). Results: Results indicated that patients with both TED and OAG experienced a 6.09% reduction in RNFL thickness and showed more rapid disease progression, with 48.35% having active TED. The mean IOP in TED patients was 27.5 ± 4.9 mmHg, which was similar to those with only OAG. Demographic factors, including age and gender, influenced the clinical course and disease severity. Conclusions: These findings underscore the importance of specialized monitoring and treatment strategies for patients with coexisting TED and OAG to prevent vision loss.

A Study on the Effects of Hypothyroidism on the Senses: A Comprehensive Narrative Review.

Hypothyroidism has been found to have long-term effects on each of the senses, but with proper treatment, many of them can be significantly minimized. This paper analyzes the research on the impact of hypothyroidism on the senses of smell, taste, hearing, vision, and thermoregulation. Data were collected from the National Library of Medicine, PubMed, and Google Scholar databases using the keywords "hypothyroidism," "taste," "smell," "vision," "hearing," and "thermoregulation." Approximately 413 articles were found when searching with these parameters, and 30 were used in this paper. Studies were excluded if they were outside this paper's scope or older than 2012. Studies were included if they specifically focused on hypothyroidism and one of the five listed senses. Patients with hypothyroidism had a significantly increased risk of sensorineural hearing loss, decreased perception of the blue-yellow color axis, decreased sense of olfaction and number of olfactory bulbs, and decreased thermogenesis. Hypothyroidism was also found to show increased length of COVID-19-induced anosmia and decreased bitter taste perception. It can be concluded that hypothyroidism has many effects on the senses, particularly an increased risk of sensorineural hearing loss. More studies need to be done on these effects.

The efficacy and safety of selenium supplementation versus placebo in the treatment of Graves' orbitopathy: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Selenium is a trace element crucial for thyroid function, and has potential therapeutic benefits in Graves' orbitopathy (GO). Therefore, we aim to evaluate its efficacy and safety in GO patients to provide valuable insights into its role as a therapeutic option for this condition. DESIGN: Systematic review and meta-analysis. PATIENTS: GO Patients treated with selenium compared to placebo. MEASUREMENTS: Clinical activity score (CAS), Graves' orbitopathy quality of life (GO-QOL), eye symptoms and signs, and adverse events. RESULTS: Out of 1684 records screened, four randomised controlled trials were included. Selenium was superior at 6 months in lowering the CAS (MD = -1.27, 95% confidence interval [CI] [-1.68, -0.85], p < .0001]), improving total GO-QOL (RR = 2.54, 95% CI [1.69-3.81], p < .00001), and improving the visual and the psychological functioning scores (MD = 10.84, 95% CI [4.94-16.73], p = .003), (MD = 12.76, 95% CI [8.51-17.00], p < .00001) respectively. Similarly, it significantly improved these outcomes at 12 months. It also showed a significant decrease in the palpebral aperture at 6 months (MD = -1.49, 95% CI [-2.90, -0.08], p = .04). However, no significant differences were observed in proptosis, soft tissue involvement, ocular motility, and adverse effects. CONCLUSIONS: Selenium is effective in reducing CAS and improving the palpebral aperture and GO-QOL in patients with GO. Additionally, it is safe and has promising therapeutic implications. However, further research is needed to validate its long-term efficacy and safety.

Systematic review of ocular surface treatments in the setting of thyroid eye disease.

Introduction: Approximately 85% of patients with thyroid eye disease experience ocular surface symptoms. Although corneal exposure plays a role in inducing inflammatory changes to the ocular surface, multiple studies reveal more complexity to the abnormal tear film composition and parameters in thyroid eye disease patients including those who do not have proptosis or increased corneal exposure. Currently, a majority of cases of thyroid associated dry eye symptoms are given treatments intended for ocular surface disease arising from different etiologies. Methods: Medline via Ovid, Cochrane CENTRAL, PubMed, and Google Scholar were systematically searched for articles evaluating the efficacy of treatments for dry eye symptoms in patients with thyroid eye disease. Articles were from all geographic regions and dates ranged from inception until October 2023. Results: Seven papers ultimately met inclusion criteria and were included in this review. These papers revealed that multiple topical and non-topical treatment modalities address dry eye symptoms in thyroid eye disease and improve subjective and objective ocular surface parameters. However, due to the few studies that exist and due to disparities in sample size and study design, no overwhelming best practices were identified that could influence clinical practice. Conclusion: This systematic review identifies the current treatments that exist and highlights the clear unmet need for a large population suffering with dry eye symptoms. Ideally, further well-designed investigations into this area would target topical, non-invasive modalities to develop first line options for thyroid eye disease patients.

Psychological aspects of Graves' ophthalmopathy.

Purpose: This review aims to discuss the psychological aspects of Graves' ophthalmopathy (GO), estimate the prevalence of depression and anxiety disorders in GO, examine whether these psychiatric disorders are more prevalent in GO than in Graves' disease (GD) without eye disease, and evaluate the main contributors for depression and anxiety in GO. Methods: A review of the literature. Results: Both depression and anxiety are associated with GO. The prevalence of depression and anxiety disorders specifically in GO patients was estimated at 18-33% and 26-41%, respectively. The reported prevalence in GD patients ranged from 9% to 70% for depression and from 18% to 88% for anxiety disorders. Significantly higher levels of depression and anxiety were found in GD patients compared with patients with non-autoimmune hyperthyroidism. Conflicting results have been reported regarding the association of antithyroid autoantibodies with depression and anxiety disorders. Serum thyroid hormone levels do not correlate with the severity of depression and anxiety. An improvement of psychiatric symptoms is observed in hyperthyroid patients after treatment of thyrotoxicosis. Moreover, depression and anxiety are significantly related to impaired quality of life (QoL) in GO. Exophthalmos and diplopia were not associated with depression nor anxiety, but orbital decompression and strabismus surgery do seem to improve QoL in GO patients. Conclusions: The results of this review suggest that altered thyroid hormone levels and autoimmunity are prognostic factors for depression and anxiety in GO. With regard to the visual and disfiguring aspects of GO as contributing factors for depression and anxiety, no decisive conclusions can be made.

Deep learning methods for diagnosis of graves' ophthalmopathy using magnetic resonance imaging.

Background: The effect of diagnosing Graves' ophthalmopathy (GO) through traditional measurement and observation in medical imaging is not ideal. This study aimed to develop and validate deep learning (DL) models that could be applied to the diagnosis of GO based on magnetic resonance imaging (MRI) and compare them to traditional measurement and judgment of radiologists. Methods: A total of 199 clinically verified consecutive GO patients and 145 normal controls undergoing MRI were retrospectively recruited, of whom 240 were randomly assigned to the training group and 104 to the validation group. Areas of superior, inferior, medial, and lateral rectus muscles and all rectus muscles on coronal planes were calculated respectively. Logistic regression models based on areas of extraocular muscles were built to diagnose GO. The DL models named ResNet101 and Swin Transformer with T1-weighted MRI without contrast as input were used to diagnose GO and the results were compared to the radiologist's diagnosis only relying on MRI T1-weighted scans. Results: Areas on the coronal plane of each muscle in the GO group were significantly greater than those in the normal group. In the validation group, the areas under the curve (AUCs) of logistic regression models by superior, inferior, medial, and lateral rectus muscles and all muscles were 0.897 [95% confidence interval (CI): 0.833-0.949], 0.705 (95% CI: 0.598-0.804), 0.799 (95% CI: 0.712-0.876), 0.681 (95% CI: 0.567-0.776), and 0.905 (95% CI: 0.843-0.955). ResNet101 and Swin Transformer achieved AUCs of 0.986 (95% CI: 0.977-0.994) and 0.936 (95% CI: 0.912-0.957), respectively. The accuracy, sensitivity, and specificity of ResNet101 were 0.933, 0.979, and 0.869, respectively. The accuracy, sensitivity, and specificity of Swin Transformer were 0.851, 0.817, and 0.898, respectively. The ResNet101 model yielded higher AUC than models of all muscles and radiologists (0.986 vs. 0.905, 0.818; P<0.001). Conclusions: The DL models based on MRI T1-weighted scans could accurately diagnose GO, and the application of DL systems in MRI may improve radiologists' performance in diagnosing GO and early detection.

Assessment of surgical strategies for management of complicated strabismus reoperation in Graves' ophthalmopathy.

PURPOSE: Strabismus reoperation in Graves' ophthalmopathy (GO) is complicated and challenging. The purpose of this study was to evaluate the various surgical strategies of strabismus reoperation and their outcomes in patients with GO. METHODS: A retrospective study was conducted on strabismus reoperations performed at the Zhongshan Ophthalmic Center of Sun Yat-sen University, Guangzhou, China from 2008 to 2018. Data collected included sex, age at surgery, duration of deviation, ocular alignment, ocular motility, various surgical procedures performed and surgical outcomes. Surgical methods included rectus recession for newly developed strabismus, rectus resection for undercorrection and anterior advancement of a previously recessed rectus for overcorrection. Surgical success was defined as an absence of diplopia, a horizontal deviation of ≤ 10 prism diopters (PD) and a vertical deviation of ≤ 5 PD at distance in primary and reading positions. RESULTS: Of the 153 GO patients receiving strabismus surgery, 27 cases (20 males, 7 females) underwent reoperation for strabismus, with a reoperation rate of 17.6%. Success rates of reoperation in patients with a previous undercorrection and overcorrection were 45% and 71.4%, respectively. Success rates of rectus recession, rectus resection and anterior advancement were 47.1%, 66.7% and 50%, respectively. Two patients underwent the third surgery. The overall success rate was 51.9%. CONCLUSIONS: Rectus recession is an effective method for GO patients with newly-developed strabismus. Rectus resection may benefit some patients with undercorrection who underwent a maximal degree of rectus recession. Anterior advancement of a previously recessed rectus is effective for cases with overcorrection.