[Graves' orbitopathy as the cause of diplopia in old age-Differences between young and old]. / Endokrine Orbitopathie als Ursache einer Diplopie im Senium ­ Unterschiede zwischen Jung und Alt.

BACKGROUND: Endocrine orbitopathy (EO) is an autoimmune disease mostly associated with a disease of the thyroid gland, which leads to inflammation, adipogenesis and fibrosis. The severity of EO can vary greatly between individuals, which makes it difficult to exactly predict the natural course of the disease; however, this is important to be able to individually adapt the treatment. The aim of this study was to compare the clinical features, course, treatment and prognosis for patients with EO under 50 years old with older patients. The results of the study with a focus on motility are presented in this special issue. PATIENTS AND METHODS: The hospital records of a randomly selected sample of 1000 patients from the EO databank in Essen (GODE), which includes 4260 patients, were analyzed. The patients were divided into two groups: group 1 ≤50 years and group 2 >50 years. Only patients with complete data sets were included in the statistical analyses. RESULTS: Younger patients (n = 484) presented significantly more frequently with milder EO (53% vs. 33%, p < 0.0001), whereas older patients (n = 448) more frequently suffered from moderate or severe forms (44% vs. 64%, p < 0.0001). Older patients showed more severe strabismus, motility and clinical activity scores (5.9 vs. 2.3 prism diopters, PD/310° vs. 330°, both p < 0.0001, CAS 2.1 vs. 1.7, p = 0.001). Proptosis and the occurrence of optic nerve compression showed no significant differences between the groups (3% each). Multiple logistic regression showed that the necessity for a second eye muscle surgery was most strongly associated with a previous decompression (OR = 0.12, 95 % CI 0.1-0.2, p < 0.0001), followed by orbital irradiation and age. CONCLUSION: In summary, younger patients with EO presented with milder clinical features, such as a lower rate of restrictive motility disorders and weaker expression of signs of inflammation. Therefore, older patients needed steroids, irradiation, eyelid and eye muscle surgery more frequently; however, the risk of dysthyroid optic neuropathy and the necessity of a second eye surgery were not or only slightly associated with age.

Graves' ophthalmopathy: the clinical and psychosocial outcomes of different medical interventions - a systematic review.

BACKGROUND: Graves' ophthalmopathy is a complex autoimmune disorder that can significantly affect quality of life (QoL), vision and physical appearance. Recently, a deeper understanding of the underlying pathogenesis has led to the development of novel treatment options. AIMS: The purpose of this review is to explore the current literature on conventional and novel treatment modalities and to evaluate which interventions provide the most favourable psychological and clinical outcomes in patients with moderate to severe, active Grave's ophthalmopathy. For example, QoL is an important psychosocial outcome of disease management. However, available literature demonstrates that not all clinically effective treatment options improve patients' QoL. METHODS: A systematic literature review was conducted to assess the clinical and psychosocial outcomes of different therapies for Graves' ophthalmopathy. An extensive database search of Ovid Medline, Ovid Embase and Cochrane Central Register of Controlled Trials was conducted. Studies generated were reviewed and the relevant selected data were retrieved and analysed. RESULTS: Results showed intravenous steroids, rituximab (RTX), tocilizumab and teprotumumab were all significantly effective in improving Clinical Activity Scores. Orbital radiotherapy showed a slight improvement in proptosis and diplopia. All interventions were safe with few serious adverse events being reported across all studies. All treatment modalities demonstrated beneficial improvements in both components of the Graves' Ophthalmopathy-QoL (QoL) questionnaire, apart from orbital radiotherapy which only demonstrated improvements in the visual functioning subscale. Teprotumumab was identified to be the most effective intervention for improving both clinical and psychosocial outcomes. However, further research needs to be conducted to evaluate its side effect profile and cost-effectiveness. Nonetheless, with time it has the potential to be a first-line treatment option in the management of active moderate to severe Graves' ophthalmopathy.

Advances in artificial intelligence in thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO), also referred to as Graves' ophthalmopathy, is a medical condition wherein ocular complications arise due to autoimmune thyroid illness. The diagnosis of TAO, reliant on imaging, typical ocular symptoms, and abnormalities in thyroid function or thyroid-associated antibodies, is generally graded and staged. In recent years, Artificial intelligence(AI), particularly deep learning(DL) technology, has gained widespread use in the diagnosis and treatment of ophthalmic diseases. This paper presents a discussion on specific studies involving AI, specifically DL, in the context of TAO, highlighting their applications in TAO diagnosis, staging, grading, and treatment decisions. Additionally, it addresses certain limitations in AI research on TAO and potential future directions for the field.

[Four perspectives on Graves' orbitopathy - from the point of view of the patient, general practitioner, endocrinologist, and ophthalmologist]. / Endokrin oftalmopati ur fyra olika perspektiv.

Graves' orbitopathy is a common complication of Graves' disease. The mild form dominates, whereas moderate to severe and sight threatening forms are rarer. They require quick, adequate care, involving cooperation between county hospitals and the regional hospital, and adequate diagnostics and choice of treatments of treatments. A new national guideline for hyperthyroidism has been published in Sweden in January 2023, where these aspects are highlighted. The present guideline requires implementation regionally, as all components are not in place, but reflects the needs of patients. This article highlights important aspects for patients such as information, to be listened to, accessibility and adequate care, but also defines actions necessary in primary care where patients most often seek help at first. Lastly, important medical and practical aspects are reviewed by the endocrinologist and the ophthalmologist.

A Chinese survey of clinical practice on the management of thyroid eye disease.

Objective: The management of thyroid eye disease (TED) has undergone significant changes for decades. The study sought to investigate current clinical practice on the management of TED in China. Methods: An online questionnaire survey was conducted from April to May 2023. The questionnaire involved diagnostic criteria for TED, multidisciplinary treatment (MDT) collaboration, and treatment preference for mild, moderate, and severe TED. Results: A total of 289 questionnaires were collected, with 165 from endocrinologists and 124 from ophthalmologists. Only 36.7% of participants claimed there was an MDT clinical pattern for TED in their institutions. The coverage of biological agents was around 10% or lower. These were distinctly lower than in Western countries. About 62.6% of participants believed the incidence of TED has increased in recent years. Imaging techniques were used widely to assist in the diagnosis of TED. However, there was still controversy regarding the definition of proptosis in the Chinese population. Most doctors managed risk factors and provided orbital supportive treatments of artificial tears and glasses. For mild active TED, endocrinologists (39.4%) were inclined to recommend therapy for hyperthyroidism alone, while ophthalmologists (43.6%) preferred orbital corticosteroid injections. Currently, the most widely used treatment for moderate to severe active TED was high-dose intravenous corticosteroid (94.8%), while orbital radiotherapy combined with immunosuppressive agents was the most recognized second-line therapy (43.6%). Conclusion: The study documented the consistency and differences between current clinical practices in the management of TED in China and the recently updated guidelines. There was a remarkable difference between ophthalmology and endocrinology departments, warranting management optimization.

A comparison of cardiovascular disease, cancer, mortality, and Graves' ophthalmopathy following treatment for hyperthyroidism: A Bayesian network meta-analysis.

OBJECTIVES: This network meta-analysis aimed to evaluate the association of anti-thyroid drugs (ATD), radioactive iodine (RAI), and thyroidectomy with subsequent outcomes in patients with newly-diagnosed hyperthyroidism. METHODS: The Ovid Medline, Ovid Embase, and Cochrane Library databases were searched for observational studies and randomized controlled trials. Included studies were published on or before 1st May 2022 involving at least two of the treatments among ATD, RAI, and thyroidectomy for hyperthyroidism. Pairwise comparisons and Bayesian network meta-analysis were used to estimate hazard ratios (HRs) and their credible interval (CrI) of outcomes, including cardiovascular disease (CVD), cancer, overall mortality, and Graves' ophthalmopathy (GO). RESULTS: A total of 22 cohort studies with 131,297 hyperthyroidism patients were included. Thyroidectomy was associated with lower risks of mortality and GO than ATD (HR = 0.54, 95% CrI: 0.31, 0.96; HR = 0.31, 95% CrI: 0.12, 0.64) and RAI (HR = 0.62, 95% CrI: 0.41, 0.95; HR = 0.18, 95% CrI: 0.07, 0.35). RAI had a higher risk of GO (HR = 1.70, 95% CrI: 1.02, 2.99) than ATD treatment. CONCLUSIONS: This Bayesian network meta-analysis indicated that thyroidectomy was associated with lower risks of mortality and GO in newly-diagnosed hyperthyroid patients compared to ATD and RAI. Relative to ATD, RAI therapy increased the risk of GO.

Redox mechanisms in autoimmune thyroid eye disease.

Thyroid eye disease (TED) is an autoimmune condition affecting the orbit and the eye with its adnexa, often occurring as an extrathyroidal complication of Graves' disease (GD). Orbital inflammatory infiltration and the stimulation of orbital fibroblasts, triggering de novo adipogenesis, an overproduction of hyaluronan, myofibroblast differentiation, and eventual tissue fibrosis are hallmarks of the disease. Notably, several redox signaling pathways have been shown to intensify inflammation and to promote adipogenesis, myofibroblast differentiation, and fibrogenesis by upregulating potent cytokines, such as interleukin (IL)-1ß, IL-6, and transforming growth factor (TGF)-ß. While existing treatment options can manage symptoms and potentially halt disease progression, they come with drawbacks such as relapses, side effects, and chronic adverse effects on the optic nerve. Currently, several studies shed light on the pathogenetic contributions of emerging factors within immunological cascades and chronic oxidative stress. This review article provides an overview on the latest advancements in understanding the pathophysiology of TED, with a special focus of the interplay between oxidative stress, immunological mechanisms and environmental factors. Furthermore, cutting-edge therapeutic approaches targeting redox mechanisms will be presented and discussed.

The changing landscape of thyroid eye disease: current clinical advances and future outlook.

AIMS: This review aims to provide an overview of the current understanding of TED and its pathophysiology. To describe the evidence base for current consensus treatment recommendations and newer biological therapies available as well as to present future therapeutic research. METHODS: We reviewed and assessed the peer-reviewed literature placing particular emphasis on recent studies evaluating the pathophysiology of TED, landmark trials forming the basis of current management and recent clinical trials informing future therapeutics. Searched were made in MEDLINE Ovid, Embase Ovid, US National Institutes of Health Ongoing Trials Register and EU Clinical Trials Register. Keywords included: "Thyroid Eye Disease", "Graves Orbitopathy", "Thyroid Orbitopathy" and "Graves' Ophthalmopathy". RESULTS AND CONCLUSIONS: The pathophysiology of TED involves a complex array of cellular and humoral based autoimmune dysfunction. Previous therapies have been broad-based acting as a blunt instrument on this mechanism with varying efficacy but often accompanied with a significant side effect profile. The recent development of targeted therapy, spearheaded by Teprotumumab has led to an array of treatments focusing on specific components of the molecular pathway optimising their impact whilst possibly minimising their side effect profile. Future challenges involve identifying the most effective target for each patient rather than any single agent being a panacea. Long-term safety profiles will require clarification as unintended immunological consequence downstream may become manifest as seen in other diseases. Finally, future novel therapeutics will entail significant expenditure and may lead to a divergence of available treatment modalities between healthcare systems due to funding disparities.

[Endocrine orbitopathy]. / Endokrine Orbitopathie.

Endocrine orbitopathy (EO), also known as Graves' orbitopathy or thyroid-associated orbitopathy, is a self-limiting, immunologically induced co-reaction of the retrobulbar tissue of the eye triggered by an autoimmune disease of the thyroid gland. It is particularly associated with Graves' disease and is its most common extrathyroidal manifestation. In addition to typical anamnestic data, characteristic local findings and laboratory changes in immunothyroidism, orbital imaging plays a central role in the diagnosis and management of this disease. This review article provides comprehensive insight into various imaging modalities used to assess morphologic changes associated with EO. A detailed presentation of imaging findings provides a better understanding of orbital physiology.

Thyroid eye disease in Eastern Province of Saudi Arabia: clinical profile and correlation with vitamin D deficiency.

PURPOSE: To obtain clinical data about disease activity and severity of thyroid eye disease (TED) in a tertiary eye hospital in the Eastern Province of Saudi Arabia and to correlate this data with vitamin D levels. METHODS: A clinical observational study was conducted in a specialized eye hospital in Saudi Arabia. It included prospective enrollment of Saudi patients with confirmed TED to evaluate activity and severity according to Clinical Activity Score (CAS) and European Group on Graves' Orbitopathy (EUGOGO), respectively, and also for blood investigation, including thyroid profile and vitamin D levels. In addition, some retrospective data collection included previous medical and surgical treatment and complications. RESULTS: A total of 74 TED patients were included, with a median age of 42 years and a female predominance of 64.9%. Smokers were 18.9%. A family history of thyroid disease was noted in 12.16% of patients. There were 10.8% of patients with active TED. A moderate to severe severity level was observed in 71% of the cases, mild in 15%, and sight-threatening in 6%. Smoking and older age were associated with the active form of TED. There was a 48.4% prevalence of vitamin D deficiency among TED patients and it was not associated with TED severity or activity. CONCLUSIONS: This is the first study demonstrating the clinical profile of TED among Saudi patients. Smoking and older age were associated with TED. Vitamin D deficiency among TED patients was not worse than that of the general Saudi population.

Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Dysthyroid optic neuropathy: a case series at a tertiary ophthalmic referral centre.

BACKGROUND/OBJECTIVES: To determine risk factors and treatment outcomes in dysthyroid optic neuropathy (DON) at a single tertiary ophthalmic centre. METHODS: Retrospective audit of DON patients who have received intravenous methylprednisolone (IVMP) therapy at Royal Victorian Eye and Ear Hospital, Melbourne, Australia from July 2015 to October 2021. RESULTS: Study included 24 patients (58% female) with an average age of 59.8 ± 14.7 years at DON diagnosis. Majority (92%) had Graves' hyperthyroidism and 77% had a smoking history. At diagnosis, average visual acuity (VA) of worse eye was LogMAR 0.46, and 48% had relative afferent pupillary defect. Proptosis (89%) and diplopia (73%) were most commonly present at diagnosis. 78% showed predominantly extra-ocular muscle enlargement, and apical crowding (52%) on radiology. 38% (n = 9/24) responded to IVMP alone, 58% (n = 14/24) progressed to surgical orbital decompression. The average total cumulative dose of IVMP during DON treatment was 6.8 ± 1.9 g. 29% required further treatment after IVMP and surgical decompression, 4 (17%) had additional radiotherapy, and three (13%) required immuno-modulatory therapy. Average final VA was LogMAR 0.207, with all patients having inactive TED at final follow-up (mean 1.7 years). In refractory DON cases, 71% retained VA ≥ 6/9 and 48% had DON reversal. CONCLUSIONS: DON patients typically present in late 50s, with a smoking history and predominant extra-ocular muscle enlargement. High-dose IVMP fully resolved DON in only 38%. A considerable proportion required urgent orbital decompression. Most patients retained good vision at final follow-up.

Understanding the clinical and molecular basis of thyroid orbitopathy: a review of recent evidence.

Thyroid eye disease (TED) is an autoimmune orbital inflammatory disease which ranges from mild to severe. Tissue remodeling, fibrosis and fat proliferation cause changes in the orbital tissues which can affect esthetics and visual function. In its severe form, it is sight threatening, debilitating, and disfiguring and may lead to social stigma, the embarrassment about which has an impact on the quality of life of those affected and the family members. The pathogenesis of TED, which is influenced by genetic, immunological, and environmental factors, is complex and not fully elucidated. However, it remains unknown what factors determine the severity of the disease. Recent research has revealed a number of diagnostic and prognostic biomarkers of this disease. In this overview of TED, we focus on new insights and perspectives regarding biological agents that may provide a basis for new treatment modalities.

Computed tomography and magnetic resonance imaging of the orbit in the diagnosis and treatment of thyroid-associated orbitopathy - experience from practice. A Review.

The purpose is to acquaint readers with the contribution of imaging methods (IMs) of the orbit, specifically computed tomography (CT) and magnetic resonance imaging (MRI), in the diagnosis of thyroid-associated orbitopathy (TAO). Methods: IMs of the orbit are an indispensable accessory in the clinical and laboratory examination of TAO patients. The most frequently used and probably most accessible method is an ultrasound examination of the orbit (US), which, however, has a number of limitations. Other methods are CT and MRI. Based on the published knowledge implemented in our practice and several years of experience with the diagnosis and treatment of TAO patients, we would like to point out the benefits of CT and MRI in the given indications: visualisation of the extraocular muscles, assessment of disease activity, diagnosis of dysthyroid optic neuropathy and differential diagnosis of other pathologies in the orbit. Our recommendation for an ideal MRI protocol for disease activity evaluation is also included.  Conclusion: IMs play an irreplaceable role not only in the early diagnosis of TAO, but also in the monitoring of the disease and the response to the applied treatment. When choosing a suitable IM for this diagnosis, a number of factors must always be taken into account; not only availability, cost and burden for the patient, but especially the sensitivity and specificity of the given method for the diagnosis of TAO.

Dysthyroid Optic Neuropathy.

PURPOSE: Dysthyroid optic neuropathy (DON) is a sight-threatening complication of thyroid eye disease (TED). This review provides an overview of the epidemiology, pathogenesis, diagnosis, and current therapeutic options for DON. METHODS: A literature review. RESULTS: DON occurs in about 5% to 8% of TED patients. Compression of the optic nerve at the apex is the most widely accepted pathogenic mechanism. Excessive stretching of the nerve might play a role in a minority of cases. Increasing age, male gender, smoking, and diabetes mellitus have been identified as risk factors. Diagnosis of DON is based on a combination of ≥2 clinical findings, including decreased visual acuity, decreased color vision, relative afferent pupillary defect, visual field defects, or optic disc edema. Orbital imaging supports the diagnosis by confirming apical crowding or optic nerve stretching. DON should be promptly treated with high-dose intravenous glucocorticoids. Decompression surgery should be performed, but the response is incomplete. Radiotherapy might play a role in the prevention of DON development and may delay or avoid the need for surgery. The advent of new biologic-targeted agents provides an exciting new array of therapeutic options, though more research is needed to clarify the role of these medications in the management of DON. CONCLUSIONS: Even with appropriate management, DON can result in irreversible loss of visual function. Prompt diagnosis and management are pivotal and require a multidisciplinary approach. Methylprednisolone infusions still represent first-line therapy, and surgical decompression is performed in cases of treatment failure. Biologics may play a role in the future.

Orbitopatía tiroidea. Puntos clave para el diagnóstico y tratamiento / Thyroid orbitopathy. Tricks for diagnosis and treatment

La orbitopatía tiroidea (OT) es una patología autoinmune de etiología desconocida. Se trata de una enfermedad edematosa e inflamatoria crónica y a veces subaguda o aguda, cuyas características principales son edema palpebral, úlceras corneales, hipertensión ocular, exoftalmos generalmente bilateral, estrabismo restrictivo, diplopía y neuropatía óptica. El objetivo principal es realizar una revisión y actualización acerca del enfoque diagnóstico y terapéutico de la OT. Realizar una revisión y actualización acerca del enfoque diagnóstico, terapéuticos de la OT. Métodos: Revisión de la literatura publicada referente a la OT y manera actual de enfocar esta patología. Resultados: La OT es una enfermedad inflamatoria orbitaria con un posible origen autoinmune y que suele asociarse a trastornos metabólicos de la glándula tiroidea. Fisiopatológicamente su mecanismo no está claro. Afecta mayormente a mujeres y está negativamente influenciada por factores como el tabaquismo, la edad, el sexo y la raza. Es imprescindible clasificarla en cuanto a su severidad y su actividad para un correcto manejo. Conclusiones: El conocimiento clínico de OT es esencial para el diagnóstico precoz de la enfermedad. El tratamiento médico, en caso de OT activa, debe ser precoz, agresivo y acorde a la fase en que se presente el paciente con el fin de evitar las graves consecuencias de la OT. El tratamiento quirúrgico deberá ser lógico y ordenado, pero a su vez rápido, con el fin de devolver al paciente al entorno laboral, social y familiar. (AU)

Purpose: Thyroid orbitopathy (TO) is an autoimmune disease of unknown etiology. It is a chronic and sometimes subacute or acute edematous and inflammatory disease, the main characteristics of which are eyelid edema, corneal ulcers, ocular hypertension, generally bilateral exophthalmos, restrictive strabismus, diplopia and optic neuropathy. The main purpose of this work is to review and update the current diagnostic and therapeutic approaches. To propose a practical, basic and precocious approach based in the knowledge of the TO. Methods: Literature review and exposition of our experience in the management of TO. Results: TO is an inflammatory orbital disease that probably has an autoimmune origin and most of the time is related to systemic disorders of the thyroid gland. Pathogenesis of the disease is not yet fully understood. Women are more likely to develop TO, and the disease is clearly affected by several factors such as smoking, age, sex and race. It is crucial to determine TO severity and activity for a correct management. Conclusions: Clinical knowledge is essential for the early diagnosis of this disorder, and it is the most important factor for the proper management of the disease. The medical treatment must be initiated promptly and should be aggressive and based in the current phase of the disease, in order to avoid the severe damage that follows TO. The surgical approach must be logical and sequential, but, on the other hand, must be rapid and aggressive in order to return the patient to his/her labour, social and familiar environment. (AU)

Graves' Orbitopathy Models: Valuable Tools for Exploring Pathogenesis and Treatment.

Graves' orbitopathy (GO) is the most common extrathyroidal complication of Graves' disease (GD) and severely affects quality of life. However, its pathogenesis is still poorly understood, and therapeutic options are limited. Animal models are important tools for preclinical research. The animals in some previous models only exhibited symptoms of hyperthyroidism without ocular lesions. With the improvements achieved in modeling methods, some progressive animal models have been established. Immunization of mice with A subunit of the human thyroid stimulating hormone receptor (TSHR) by either adenovirus or plasmid (with electroporation) is widely used and convincing. These models are successful to identify that the gut microbiota influences the occurrence and severity of GD and GO, and sex-related risk factors may be key contributors to the female bias in the occurrence of GO rather than sex itself. Some data provide insight that macrophages and CD8+ T cells may play an important pathogenic role in the early stage of GO. Our team also replicated the time window from GD onset to GO onset and identified a group of CD4+ cytotoxic T cells. In therapeutic exploration, TSHR derived peptides, fingolimod, and rapamycin offer new potential options. Further clinical trials are needed to investigate these drugs. With the increasing use of these animal models and more in-depth studies of the new findings, scientists will gain a clearer understanding of the pathogenesis of GO and identify more treatments for patients.