Euthyroid graves' ophthalmopathy in a Chinese population: A cross-sectional follow-up study.

OBJECTIVES: A subtype of patients with thyroid eye disease (TED) were found to be euthyroid without prior thyroid dysfunction or treatment, known as Euthyroid Graves' Ophthalmopathy (EGO). We report the prevalence, clinical and serological phenotypes of EGO in a Chinese population. METHODS: A cross-sectional follow-up study. Ethnic Chinese TED patients were managed at the Thyroid Eye Clinic(TEC), Prince of Wales Hospital and TEC, the Chinese University of Hong Kong between September 2007 and July 2021. RESULTS: A total of 66 (5%) patients among the 1266 ethnic Han Chinese TED cohort were diagnosed as EGO, and 6 (9%)of them become dysthyroid over an average of 74-month follow-up. EGO patients were associated with a longer duration between onset of the symptoms to our first consultation (P < 0.0001), a higher male-to-female ratio (P = 0.0045) and a higher age of disease onset (P = 0.0092). Family history of thyroid disease was more common in TED patients (P = 0.0216) than in EGO patients. EGO patients were more likely to present unilaterally (P < 0.0001), and they have a larger difference in MRD1 (P < 0.0001), and extraocular motility (P < 0.0001) between the 2 eyes when compared to the TED patients. Notably, the extraocular motility restriction of the worst eye was more affected in EGO patients (P = 0.0113). The percentages of patients who received IVMP, ORT and emergency or elective surgeries(decompression or squint operation) between EGO and TED were similar. CONCLUSIONS: Understanding the important clinical phenotypes of EGO may help the clinician to make the correct diagnosis. Further study to compare EGO and TED is warranted.

Histopathological features of asymmetric lacrimal gland enlargement in patients with thyroid eye disease.

PURPOSE: Lacrimal gland enlargement can be a feature of thyroid eye disease (TED). Unilateral or asymmetric lacrimal gland enlargement is poorly described and may impede diagnosis. We present the histological and clinical findings of four patients with asymmetric lacrimal gland enlargement. METHODS: A retrospective case note review was performed for patients over two tertiary orbital clinics (Royal Adelaide Hospital, South Australia and the Sussex Eye Hospital, Brighton, United Kingdom) presenting with an asymmetrical lacrimal gland enlargement with a background of TED that underwent biopsy to exclude alternate diagnoses. Baseline data was collected for each patient and histopathological images and reports were reviewed. RESULTS: All four patients were hyperthyroid at time of lacrimal gland biopsy. Biopsy demonstrated nonspecific, lymphoid aggregates, typically of B cell type, with no diagnostic findings to support lymphocyte clonality or IgG4-related disease. One biopsy specimen demonstrated evidence of some fibrosis. CONCLUSION: Asymmetrical lacrimal gland enlargement can occur as part of the TED spectrum but may require biopsy to exclude alternate pathology. Histology demonstrates a non-specific lymphocytic infiltrate.

Post-COVID simultaneous onset of Graves' disease and ocular myasthenia gravis in a patient with a complex ocular motility impairment.

A 74-years-old man experienced severe diplopia one month after recovery from an uncomplicated SARS-CoV-2 infection. Neurological examination was normal whereas ophthalmological examination showed bilateral exophthalmos with a complex ocular motility disorder characterized by a pseudo-internuclear ophthalmoplegia after fatigue associated to impairment of elevation and infraduction. Antibodies against TSH and acetylcholine receptors were positive; subsequent hormonal tests, ultrasonography of thyroid gland, single fiber electromyography and orbit MRI confirmed the diagnosis of concomitant Graves Disease (GD) and Myasthenia Gravis (MG). The coexistence between MG and GD is not rare but simultaneous onset after viral infection is very unsual. The complex ocular disorder simulated a deficit of the oculomotor nerve nuclei, and on clinical examination it posed some problems in the diagnosis. We suggest that recent SARS-COV-2 infection may have triggered a complex autoimmune response.

Müllerotomy with anterior graded Müller muscle disinsertion for Graves upper eyelid retraction: validation of surgical outcomes using Bézier curves.

PURPOSE: To assess with Bézier curves the outcomes of Müllerotomy with anterior graded Müller muscle disinsertion for the treatment of Graves upper eyelid retraction (UER). METHODS: Eighty-six eyelids of 52 inactive GO patients operated from November 2018 to June 2021 were included in this study. All measurements were performed on Bézier curves adjusted to the upper lid contour with a previously validated algorithm. Lid contour was classified regarding grade of superposition (GS) as excellent (GS > 90%), good (GS 85-90%) or poor (< 85%). Surgical success was defined as complete or partial if postoperative grade of asymmetry was < 10% with an excellent or good lid contour, respectively. RESULTS: The mean age was 51 ± 10.4 years with a range from 31 to 78 years and a mean follow-up of 14.4 ± 7.4 months. There was a significant improvement of median GS (p < 0.0001) from preoperative (74.3%; 10.7 IQR) to postoperative values (91.7%; 6.3 IQR). A normalization of postoperative contour peak (- 0.69; 1.27 SD) and MPLD90 (4.2 mm; 0.8 SD) was noticed (p < 0.0001). Postoperative lid contour was excellent in 62 (72%), good in 16 (19%) and poor in 8 eyelids (9%). Surgical success was achieved in 42 patients (81%), from which 34 (81%) were complete. Reintervention was required in 14 eyelids (16%). CONCLUSIONS: Measuring surgical outcomes with Bézier curves allows an automated, complete and objective assessment, giving more consistency to our data compared to previous reports. Müllerotomy with graded Müller muscle disinsertion is a safe and effective procedure for Graves UER, offering predictable results.

Changes in choroidal thickness and choroidal vascularity index in thyroid eye disease: a systematic review.

PURPOSE: To evaluate the evidence for changes in choroidal thickness and choroidal vascularity index (CVI) in people with thyroid eye disease (TED), stratified by severity, as measured by optical coherence tomography (OCT). METHODS: Systematic review, including quality assessment, of published studies investigating choroidal thickness in TED. Outcomes of interest included CVI, subfoveal choroidal thickness, mean choroidal thickness, and peripheral choroidal thickness in four quadrants (superior, inferior, medial, lateral). RESULTS: Nineteen studies were included which contained measurements from 1067 eyes in 798 patients with TED. Most studies found an increased CVI and increased choroidal thickness in patients with TED compared to normal controls, especially in the subfoveal region. In addition, several studies reported an increased thickness in patients with active vs. inactive TED, although the results are equivocal. Finally, many studies reported associations between increased choroidal thickness and worsened clinical measurements of disease activity, such as Clinical Activity Score (CAS). CONCLUSIONS: This systematic review provided evidence for an association between increased CVI/choroidal thickness and TED, suggesting a potential for OCT-measured CVI/choroidal thickness as an objective clinical marker. Given heterogeneity, future studies are needed to assess the role of measuring the choroidal changes in diagnosis and management of TED.

Serum Selenium Levels in Patients With Graves Disease With or Without Thyroid Ophthalmopathy.

BACKGROUND: Graves disease is one of the most common autoimmune thyroid diseases. Thyroid has the highest concentration of selenium (Se) in the body. Se plays a crucial role in the functioning of some thyroid enzymes; however, there are controversial results regarding the administration of serum Se levels in patients with Graves disease. METHODS: In this study, patients with Graves disease with orbitopathy (GO group) or without orbitopathy (GD group) were recruited. Healthy individuals without a history of any disease were enrolled as the control group. Serum Se and thyroid hormone levels, including T3, T4, and thyroid-stimulating hormone (TSH), were measured using atomic absorption and radioimmunoassay techniques, respectively. RESULTS: In this cross-sectional study, 60 and 56 patients and 58 healthy subjects were included in the GO, GD, and control groups. Serum Se levels in the GO, GD, and control groups were 94.53 ± 25.36 µg/dL, 96.82 ± 30.3 µg/dL, and 102.55 ± 16.53 µg/dL, respectively (P = .193). There was a reverse association between the serum Se level and thyroid hormones, including T3, T4, and TSH, in the GO group. However, serum Se levels exhibited a significant reverse association with T4 and TSH hormones but not with T3 in the GD group. CONCLUSION: Our results showed no significant differences in the serum Se levels in the GO and GD groups compared with that in the control group. In addition, we did not detect any significant difference in the serum Se levels between the GO and GD groups.

Thyroid-Associated Orbitopathy: Management and Treatment.

Thyroid-associated orbitopathy (TAO) is a leading cause of orbital and strabismus symptoms in adults. Over the last decade, new treatments have greatly changed available options to alleviate symptoms and improve outcomes. This article discusses the pathophysiology and natural disease course of TAO, including when to pursue urgent treatment and when to consider other diagnoses. This article highlights the interventions that may alter the disease course and offers a comprehensive review on evidence-based interventions for both supportive therapy and systemic agents. The surgical strategies and principles for the treatment of TAO are discussed, including indications for combined surgical interventions and varying surgical techniques.

An Interesting Case of Euthyroid Graves' Ophthalmopathy, With Negative Thyroid-Stimulating Hormone Receptor Antibodies.

Thyroid eye disease (TED), also known as Graves' orbitopathy or ophthalmopathy (GO) or Graves' eye disease, is an autoimmune condition of the retroocular tissues associated with Graves' disease. In isolated GO, the patient can present without thyroid hormone dysfunction or systemic symptoms of Graves' disease, in which case it is called euthyroid Graves' ophthalmopathy (EGO). It is very rare for this condition to have negative thyroid-stimulating hormone receptor (TSHR) autoantibodies, and we present such a rare case of a young female, who had progressive bilateral vision loss, intermittent left-sided retroocular headache, and severe bilateral proptosis. The patient was diagnosed with EGO based on multidisciplinary consults, diagnostic orbital magnetic resonance imaging (MRI) results, and a good response to treatment with intravenous steroids. Later, the patient was followed as an outpatient and treated with thyroid orbitopathy-specific immunotherapy with teprotumumab. The patient's response to teprotumumab was excellent and caused significant improvement in visual acuity, proptosis, and chemosis. This adds valuable literature to the medical field and gives insight to clinicians to consider the diagnosis of GO even with seronegative TSHR autoantibodies and euthyroid hormone status. It also adds to the understanding of the complex pathophysiology of this rare condition.

Thyroid eye disease: Redefining its management-A review.

Thyroid eye disease (TED) is a debilitating, vision threatening disease that dramatically alters patients' quality of life. Until recently, the management of TED is a long arduous course with supportive therapy, followed by an extensive surgical treatment plan to reverse the disease endpoints. Teprotumumab offers an early, safe therapeutic intervention to help reverse disease end points such as diplopia and proptosis and improve quality of life.

Ocular Hypertension, Glaucoma or Compressive Neuropathy in Patient with Active TED.

INTRODUCTION: Severe cases of thyroid eye disease with high intraocular pressure and visual field defects are a real diagnostic challenge requiring the exclusion of dysthyroid optic neuropathy and differential diagnosis with glaucoma. AIM: To report а case of a patient with active thyroid eye disease (TED), decreased visual acuity and elevated intraocular pressure. MATERIALS AND METHODS: We present a 52-year-old woman with TED in both eyes, class 2c3c4a6a (NOSPECS), with 6 points (by CAS) activity, who received corticosteroid therapy to a maximum cumulative dose of 5750 mg, with non-insulin-dependent diabetes mellitus and topical antihypertensive treatment with tapticom, brizadopt, and luxfen. The patient received full ophthalmological exam, tonometry, exophthalmometry, computer perimetry, optical coherence tomography (OCT) and computed tomography (CT) scan of orbits. RESULTS: The following results were obtained: BCVA of right eye = 0.6, BCVA of left eye = 0.3; TOD = 26 mm Hg and ТОS = 21 mm Hg; exophthalmometry: 30 mm for the right eye and 31 mm for the left one; diplopia in all directions, edema and hyperemia of the eyelids and conjunctiva, eyelids retraction, sluggish pupil reactions, normal color vision, transparent ocular media, indistinct borders of the optic nerve disc, without glaucomatous excavation, tortuosity and dilation of the venules, retina - without diabetic changes, maculas - with normal reflex; CP datа for a localized inferotemporal visual field defect, CT data for thickening of all extraocular muscles, soft tissue orbital edema, and optic nerves compression. CONCLUSION: Our results confirmed the presence of dysthyroid optic neuropathy based on the decreased visual acuity, ophthalmo-scopic evaluation of the optic nerve head, lack of glaucomatous OCT changes, atypical perimetric changes and the CT data. The optic neuropathy is the most severe complication in patients with TED which develops due to the compression of the optic nerve and/or its blood supply from the enlarged extraocular muscles and soft tissues in the orbital apex and due to the mechanical tension of the optic nerve in cases moderate or severe proptosis is present.

Effect and Prognostic Factors of Systemic Steroid Treatment for Strabismus Associated Thyroid Ophthalmopathy

PURPOSE: To investigate the effect of steroid treatment on strabismus associated with thyroid ophthalmopathy. METHODS: The present retrospective study was conducted on 22 patients diagnosed with strabismus associated with thyroid ophthalmopathy, who were treated with steroids orally or intravenously and followed up for more than one year. Patients were divided into three groups for analysis: an improved group, with no strabismus at the final follow-up visit; a stable group, with no change in the strabismus angle; and a deteriorated group, in which the strabismus angle had worsened. We investigated the characteristics of each group. RESULTS: In the gender/sex distribution of the 22 patients, 11 of the 15 patients in the improved or stable group were female; six of seven patients in the deteriorated group were male (p = 0.012). Two of the 15 patients in the improved or stable group had a smoking history. However, none smoked after the treatment had started. On the other hand, five of seven patients in the deteriorated group had a smoking history and continued to smoke during and after treatment (p = 0.001). No significant between-group differences were observed with respect to age, diplopia period, strabismus angle, or thyroid function level. CONCLUSIONS: Treatment with steroids may improve or stabilize strabismus associated with thyroid ophthalmopathy. However, the effect of treatment may differ, depending on whether the patient continues to smoke after treatment is initiated.

Advances in the management of thyroid eye diseases: An overview.

INTRODUCTION: Thyroid eye disease (TED) remains a notorious ailment for both patients and the treating ophthalmologists. Recent years have witnessed considerable research in the immunopathogenic mechanism of TED that has resulted in an expansion and modification of the available management options. AIM: Purpose of this review is to summarise the advances in the management of thyroid ophthalmopathy. MATERIAL AND METHOD: A thorough literature search and of the past 10 years web search with words Thyroid ophthalmopathy, recent, advances. RESULTS: Recent VISA classification and new serum markers seem to have potential to give diagnostic as well as therapeutic guidance, gauge treatment response and even identify risk of disease progression. Majority of TED patients can be managed conservatively due to its self-limiting nature but if indicated, still steroids are the preferable medical therapy; however, there is an increasing consensus towards the use of parenteral form as compared to the oral one on account of greater efficacy with lesser side effects. Steroid sparing medications, for example, rituximab, infliximab, etanercept, adalimumab, teprotumumab, tocilizumab, tanshinone, are showing encouraging results and form an area of active research. CONCLUSION: Radiation therapy remains as an adjunctive modality in active diseases as a nonmedical treatment for TED with some promising data. Surgical intervention may be required in vision threatening conditions or to counteract the sequel of inflammatory phase. Advances in surgical techniques like stereotactic image-guided balanced orbital decompression with endoscopic approach ensure meticulous dissection with minimal trauma.

Serum CYR61 Is Associated with Disease Activity in Graves' Orbitopathy.

PURPOSE: To investigate the clinical implications of cysteine-rich angiogenic inducer 61 (CYR61) in Graves' orbitopathy (GO). METHODS: Sera from 52 GO patients, 23 Graves' disease (GD) patients, and 20 healthy controls, and orbital fat tissue samples from 12 of 52 GO patients and 8 control subjects were included for analysis. Concentrations of CYR61 were measured from sera with an enzyme-linked immunosorbent assay, and CYR61 mRNA expression levels were evaluated from orbital fat tissue with polymerase chain reaction. RESULTS: Serum CYR61 levels were higher in GO patients than in controls (p = 0.001). Patients with active GO showed higher CYR61 levels than those with inactive GO (p < 0.001) or GD (p = 0.004). Expression of CYR61 mRNA was 7.4-fold higher in patients with GO than in healthy controls (p < 0.001). CONCLUSIONS: CYR61 could be an adjuvant biomarker associated with the inflammatory activity of GO.

Neutrophil-to-lymphocyte ratio in thyroid ophthalmopathy.

PURPOSE: To evaluate the neutrophil-to-lymphocyte ratio (NLR) levels to predict the severity of inflammation in thyroid ophthalmopathy (TO). METHODS: Fifty-six patients with TO and 40 healthy subjects were included in this study. TO patients were divided into two groups according to clinical activity score (CAS). Group 1 included 24 active TO patients and Group 2 included 32 inactive TO patients. The thyroid status, white blood cell (WBC), neutrophil, and lymphocyte counts were performed. NLR was calculated by dividing the neutrophil count by the lymphocyte count. RESULTS: The mean age was 53.6 ± 5.4 in active TO group, 54.2 ± 5.6 in inactive TO group, and 52.7 ± 5.2 in the control group. The WBC, neutrophil, lymphocyte and NLR levels were higher in patients with TO than in the control group (p < 0.05). A significant difference in NLR was found between the inactive and active TO groups (p < 0.05). CONCLUSION: NLR values were found to be higher in patients with TO than in controls. NLRvalues were also found higher in active TO patients than in inactive TO patients (Tab. 3, Ref. 26).

MicroRNA-146a contributes to CD4+ T lymphocyte differentiation in patients with thyroid ophthalmopathy.

MicroRNA-146a (miR-146a) is associated with human inflammatory disease, such as thyroid-associated ophthalmopathy (TAO), but its role in human T cells and relevance to TAO remains ambiguous. In this study, T cells of TAO patients showed downregulated expression of miR-146a. We characterized miR-146a in T cells and examined miR-146a as a critical inhibitor of Th1 differentiation processes. MiR-146a inhibited Th1 differentiation processes and cell proliferation of T-lymphocytes. Thus, the results showed that miR-146a was a potent inhibitor of Th1 differentiation and cell proliferation of human T cells and dysregulation of miR-146a contributed to the pathogenesis of TAO.

Thyroid-associated Ophthalmopathy.

Thyroid-associated ophthalmopathy is the most frequent extrathyroidal involvement of Graves' disease but it sometimes occurs in euthyroid or hypothyroid patients. Thyroid-associated ophthalmopathy is an autoimmune disorder, but its pathogenesis is not completely understood. Autoimmunity against putative antigens shared by the thyroid and the orbit plays a role in the pathogenesis of disease. There is an increased volume of extraocular muscles, orbital connective and adipose tissues. Clinical findings of thyroid-associated ophthalmopathy are soft tissue involvement, eyelid retraction, proptosis, compressive optic neuropathy, and restrictive myopathy. To assess the activity of the ophthalmopathy and response to treatment, clinical activity score, which includes manifestations reflecting inflammatory changes, can be used. Supportive approaches can control symptoms and signs in mild cases. In severe active disease, systemic steroid and/or orbital radiotherapy are the main treatments. In inactive disease with proptosis, orbital decompression can be preferred. Miscellaneous treatments such as immunosuppressive drugs, somatostatin analogs, plasmapheresis, intravenous immunoglobulins and anticytokine therapies have been used in patients who are resistant to conventional treatments. Rehabilitative surgeries are often needed after treatment.

Evaluation of retinal nerve fiber layer thickness profile in thyroid ophthalmopathy without optic nerve dysfunction.

AIM: To evaluate retinal nerve fiber layer (RNFL) thickness profile in patients of thyroid ophthalmopathy with no clinical signs of optic nerve dysfunction. METHODS: A prospective, case-control, observational study conducted at a tertiary care centre. Inclusion criteria consisted of patients with eyelid retraction in association with any one of: biochemical thyroid dysfunction, exophthalmos, or extraocular muscle involvement; or thyroid dysfunction in association with either exophthalmos or extra-ocular muscle involvement; or a clinical activity score (CAS)>3/7. Two measurements of RNFL thickness were done for each eye, by Cirrus HD-optical coherence tomography 6mo apart. RESULTS: Mean age of the sample was 38.75y (range 13-70y) with 18 males and 22 females. Average RNFL thickness at first visit was 92.06±12.44 µm, significantly lower than control group (101.28±6.64 µm) (P=0.0001). Thickness of inferior quadrant decreased from 118.2±21.27 µm to 115.0±22.27 µm after 6mo (P=0.02). There was no correlation between the change in CAS and RNFL thickness. CONCLUSION: Decreased RNFL thickness is an important feature of thyroid orbitopathy, which is an inherent outcome of compressive optic neuropathy of any etiology. Subclinical RNFL damage continues in the absence of clinical activity of the disease. RNFL evaluation is essential in Grave's disease and active intervention may be warranted in the presence of significant damage.

Current Trends in the Management of Thyroid Ophthalmopathy / 한양의대학술지

Thyroid ophthalmopathy (TO) is an autoimmune inflammatory disorder involving the orbit characterized by inflammation and swelling of the extraocular muscles and an increase in orbital fat and connective tissue. Despite extensive research, TO continues to be a difficult condition for the patient to cope with and for the clinician to treat. Current treatments consist of systemic immunosuppression, orbital irradiation, and surgery. It is promising for patient refractory to conventional therapy that pathogenesis of TO at molecular level which advance development of new therapies targeting cellular immunity are now better understood. Future therapies targeting immune system or specific molecules are under investigation and show promise for the future. This review will describe current trends in the management of TO, from well-established therapies such as glucocorticoids, orbital irradiation and orbital decompression to more innovative therapies targeting immune system or specific molecules involved in TO pathogenesis.

Characterization and outcomes of repeat orbital decompression for thyroid-associated orbitopathy.

Orbital decompression for thyroid-associated orbitopathy (TAO) is commonly performed for disfiguring proptosis, congestion, and optic neuropathy. Although one decompression typically achieves goals, a small percentage requires repeat decompression. We performed a 10-year retrospective chart review of all orbital decompressions for TAO at a single tertiary referral institution. Four-hundred and ninety-five orbits (330 patients) were decompressed for TAO, with 45 orbits (37 patients) requiring repeat decompression. We reviewed the repeat cases for indications, clinical activity scores, approach, walls decompressed, and outcomes. Nine percent of orbits required repeat decompression for proptosis (70%), optic neuropathy (25%) or congestion (45%). Sixty-four percent were for recurrence of disease, 36% were for suboptimal decompression. Three incisional approaches were used: lateral upper eyelid crease, inferior transconjunctival, and transcaruncular, with inferior transconjunctival being most common. Of the three walls removed, deep lateral, inferior, and medial, the deep lateral wall was most common (51%). A repeat lateral decompression was the most frequent pattern. Of 37 patients requiring repeat decompression, 40% had diplopia prior to repeat, and an additional 24% developed diplopia after the repeat. Whereas previous studies published by our group cited only 2.6% of deep lateral wall orbital decompressions leading to new-onset primary gaze diplopia, repeat orbital decompressions have a much higher rate of post-operative diplopia. The new onset primary gaze diplopia after repeat decompression group had a higher average preoperative CAS (3.3 vs. 2.4, p < 0.01), higher mean blood loss (56 vs. 19 mL, p = 0.04), more frequent medial wall decompressions (47% vs. 29%, p = 0.33), and greater proptosis reduction (2.4 vs. 1.7 mm, p = 0.24).

A case of protruding eyeballs and diminishing vision.

This case report discusses issues related to a 56-year-old man from Bangalore who presented with complaints of a gradual protrusion of his eyeballs along with diminishing vision for the previous month. The approach to diagnosis and management issues around this unusual presentation is dicussed.