Prevalence, Incidence, and Clinical Characteristics of Thyroid Eye Disease in Japan.

Background: Although thyroid eye disease (TED) can impact social and psychological well-being, the epidemiological evidence of TED is lacking in Japan. Methods: Nationwide claims databases provided by JMDC Inc. and Medical Data Vision Co., Ltd. and national population statistics are used. Three TED definitions ranging from a strict definition only including a TED diagnosis to a broad definition including a TED diagnosis and considering ocular symptoms are considered. The proportion of patients by severity and disease activity are estimated based on definitions that would allow identification of those patients within the claims data. Results: The incidence rate per 100 000 person-years ranged from 7.3 to 11.1 for the strict and broad TED definitions, respectively. For fiscal year 2020 (April 2020 to March 2021) the prevalence rate ranged between 24.65 (strict TED) and 37.58 (broad TED) per 100 000 persons. These correspond to 25 383 and 38 697 patients for the strict and broad TED definitions, respectively. Regardless of the definition used, a predominance of female patients was observed, and the highest burden of the disease was seen in the age group of 35 to 59. Mild and inactive forms of TED were predominant (about 85% and 74%, respectively). Conclusion: The incidence and prevalence of TED in Japan were 7.3 to 11.1 per 100 000 person-years and 24.65 to 37.58 per 100 000 persons, respectively. The robust results of this database study add valuable real-world evidence on the incidence and prevalence of TED in Japan.

Incidence and risk factors for Graves' orbitopathy in patients who underwent anti-inflammatory and immunosuppressive treatment during medical treatment for Graves' disease: investigation of 1,553 cases with newly diagnosed Graves' disease and proposal of a predictive score.

Appropriate administration of anti-inflammatory and immunosuppressive treatment (AIIST) is important for patients with Graves' orbitopathy (GO). This study aimed to clarify the incidence and risk factors for GO treated with AIIST and propose a predictive score, among newly diagnosed Graves' disease (GD) patients in Japan. A total of 1,553 GD patients who were newly diagnosed during the year 2011 were investigated. AIIST included local and/or systemic glucocorticoid administration and retrobulbar irradiation. A multivariable Cox proportional hazards model was used to investigate the risk factors for GO underwent AIIST during medical treatment, including at diagnosis, of GD. Then, a GO score was created by summing each point assigned to risk factors based on their coefficient obtained in the Cox model. AIIST was administered to 107 patients (6.9%). The risk factors and hazard ratios for GO underwent AIIST were: age (per 10 years), 1.32 (95% confidence interval: 1.16-1.50), p < 0.0001; TSH binding inhibitory immunoglobulin (TBII) (per 10 IU/L), 1.33 (1.15-1.54), p = 0.0001; and thyroglobulin antibody (TgAb) negativity, 2.98 (1.96-4.59), p < 0.0001. The GO score, ranging from 0 to 8 points, showed moderate performance (area under the curve: 0.71, cut-off value: 5 points, sensitivity: 0.76, specificity: 0.59, positive predictive value: 0.12, negative predictive value: 0.97). AIIST was performed for patients with active manifestations of GO in 6.9% of newly diagnosed GD patients. The risk factors for GO underwent AIIST were higher age, higher TBII, and TgAb negativity. The GO score based on these factors may be useful in managing GO.

Investigation of Meibomian Gland Function and Dry Eye Disease in Patients with Graves' Ophthalmopathy.

We prospectively evaluated the relationship between meibomian gland dysfunction (MGD) and Graves' ophthalmopathy (GO) in 19 patients (38 eyes) with subjective dry eye symptoms, compared to 14 age-matched normal participants (14 eyes). Extraocular muscle and lacrimal gland enlargement were evaluated by magnetic resonance imaging (MRI). Ocular surface examinations included fluorescein staining for keratoconjunctival epithelial damage, tear breakup time (TBUT) evaluation, and Schirmer's test. Dry eye symptoms were evaluated with the Dry Eye-related Quality-of-Life Score (DEQS) questionnaire. Lid-margin abnormalities, meibum grade, and meiboscores were assessed using meibography. Clinical activity scores and T2 signal intensity ratios were used to define GO activity. All GO patients had obstructive MGD and 79% exhibited levator muscle enlargement. Ocular surface parameters of TBUT (p = 0.000), meibum score (p = 0.000), eyelid vasculitis (p = 0.000), meiboscore of the upper lid (p = 0.002), total meiboscores (p = 0.001), and DEQS (p = 0.000) significantly differed between GO patients and normal subjects. In addition, GO patients had significantly more abnormalities of the central region of the upper eyelid than normal subjects (p = 0.000). Thus, MGD might be related to eye discomfort and deterioration of the ocular surface in GO patients. Inflammation and morphological meibomian gland changes might be characteristic of GO.

Clinical efficacy of transcutaneous triamcinolone acetonide injection for upper eyelid retraction and swelling in patients with thyroid eye disease.

AIM: To evaluate the efficacy of transcutaneous triamcinolone acetonide (TA) injection for the treatment of upper eyelid retraction and swelling in thyroid eye disease (TED) patients. PATIENTS AND METHODS: This is a case series. Three euthyroid TED patients with features of both upper eyelid retraction and swelling were recruited. TED signs appeared within 6 months prior to treatment. Next, 0.5 mL of TA (40 mg/mL) was transcutaneously injected targeting the orbital fat around the levator palpebrae superioris (LPS) muscle. At each visit, eyelid retraction was evaluated by palpebral fissure height and the presence of scleral show above the superior corneoscleral limbus. Eyelid swelling was judged by the appearance of upper eyelid bulging and the lack of an eyelid sulcus. In addition, the LPS muscle, orbital and retro-orbicularis oculi fat were observed using MRI before and after treatment. RESULTS: Two patients had resolution of their upper lid retraction and swelling within 12 months. In the other patient who had proptosis, eyelid retraction resolved, while eyelid swelling remained mild. In all cases, MRI revealed that treatment resulted in thinner LPS muscle and reduced fat swelling. In addition, both high-intensity signals on T2 images and prolonged T2 relaxation time were normalized. No adverse signs were observed. CONCLUSION: Transcutaneous TA injection was effective as a treatment for upper eyelid retraction and swelling in euthyroid TED patients who had signs within 6 months prior to treatment. Transcutaneous TA injection induced reduction of LPS muscle enlargement and fat tissue swelling. These reductions by transcutaneous TA injection were verified using MRI.

Clinical course of thyroid function and thyroid associated-ophthalmopathy in patients with euthyroid Graves' disease.

BACKGROUND: Euthyroid Graves' disease (EGD) is a rare condition defined as the presence of thyroid-associated ophthalmopathy (TAO) in patients with normal thyroid function. Due to the rarity of this disease, only a limited number of studies and case reports are available for further evaluation of the characteristics of the disease. The aim of this study was to examine the changes in the thyroid function, thyrotropin receptor antibodies (TRAb) and eye symptoms, and then determine whether TRAb is related to TAO in EGD patients. TRAb in this study was defined as including both thyrotropin-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSAb). PATIENTS AND METHODS: Medical records of patients diagnosed with EGD were reviewed. Ophthalmologists specializing in TAO examined the eyes of all subjects. RESULTS: Of the 58 patients diagnosed with EGD, 24.1% developed hyperthyroidism, while 3.4% developed hypothyroidism. A total of 72.4% of the 58 patients remained euthyroid throughout the entire follow-up period. At the initial presentation, TBII and TSAb were positive in 74.5% and 70.5%, respectively. Ophthalmic treatments were administered to 30 (51.7%) out of the 58 patients. A significant spontaneous improvement of the eye symptoms was found in 28 of the EGD patients who did not require eye treatments. EGD patients exhibited positive rates for both TBII and TSAb, with the number of the TRAb-positive patients gradually decreasing while the eye symptoms spontaneously improved over time. There were no correlations found between TRAb at initial presentation and the eye symptoms. CONCLUSION: TBII and TSAb were positive in about 70% of EGD patients at their initial visit. Thyroid functions of EGD patients who have been euthyroid for more than 6.7 years may continue to remain euthyroid in the future.

Pathological Findings of the Thyroid Tissue in a Patient with Euthyroid Graves' Disease.

Euthyroid Graves' disease (EGD) is a rare condition marked by the onset of thyroid-associated ophthalmopathy (TAO) in the absence of thyroid dysfunction. The pathogenesis of EGD remains unclear, and a consistent view of the pathological findings of the thyroid tissue has yet to be determined. We herein report a case of EGD in a 34-year-old woman with papillary carcinoma treated with total thyroidectomy. The entire thyroid specimen was investigated, and the thyroid tissue appeared normal. In this report, we discuss the relationship between the pathogenesis of TAO and thyroid dysfunction.

Radioiodine-Associated Exacerbation of Graves' Orbitopathy in the Japanese Population: Randomized Prospective Study.

CONTEXT: Exacerbation of Graves' orbitopathy (GO) after radioiodine (RAI) therapy has been examined in some populations but has not been fully described in Japanese populations. OBJECTIVE: The purpose of this study was to clarify the characteristics of GO exacerbation after RAI therapy and the effectiveness of low-dose prophylactic corticosteroid (PCS). DESIGN AND SETTING: This was a prospective randomized study in Tokyo, Japan. PATIENTS: Between June 2011 and June 2012, 295 patients with Graves' disease with either inactive GO or no GO received RAI therapy. Of these, 147 received no PCS (PCS-Off group), whereas 148 received low-dose PCS (starting dose, 15 mg/day of prednisolone) for 6 weeks (PCS-On group). We used magnetic resonance imaging to thoroughly evaluate GO before and 1 year after RAI therapy. MAIN OUTCOME MEASURES: Outcomes of GO 1 year after RAI therapy were determined. RESULTS: GO exacerbation occurred in 29 patients (9.8%), and only 7 patients (2.4%) required ophthalmic treatment. No significant difference in the frequency of GO exacerbation was seen between the groups (PCS-On group: n = 18 [12.1%]; PCS-Off group: n = 11 [7.5%]; P = .17). Significant prognostic factors were identified as thyroid-stimulating antibody (by 100% linear increase: risk ratio, 1.15; 95% confidence interval, 1.07-1.24; P = .0003) and clinical activity score (≥1 vs 0: risk ratio, 6.40; 95% confidence interval, 2.17-19.7; P = .0009). CONCLUSION: Exacerbation of GO after RAI therapy in the Japanese population appears less common than in other populations. Low-dose PCS did not produce a significant preventive effect and appeared insufficient. Patients presenting with risk factors would thus be recommended to receive higher-dose PCS.

[Dysthyroid optic neuropathy in pregnancy].

BACKGROUND: While development of thyroid eye disease is rarely observed in pregnant women, here we report three cases of pregnant patients with severe dysthyroid optic neuropathy (DON). CASE: Case 1, a 30 year-old woman with thyroid eye disease diagnosed during pregnancy and DON occurring at eight months. Visual acuity was 0.05 in right eye and 0.8 in left. Case 2, a 32 year-old woman with Graves' disease diagnosed during pregnancy and DON occurring at five months. Visual acuity was 0.2 in right eye and 0.09 in left. In cases 1 and 2, since no permission for therapy during pregnancy was obtained from either patient, systemic steroid therapy was performed after delivery. Case 3, a 31 year-old woman with Graves' disease diagnosed during pregnancy. At nine months, DON was diagnosed in both eyes. Visual acuity was 0.07 in right eye and 0.2 in left. An organized systemic steroid therapy following delivery at the end of a normal gestational period was performed. In all three patients, higher levels of thyroid antibodies were observed while thyroid function remained controlled. CONCLUSION: DON developed in pregnant woman with Graves' disease who have higher levels of thyroid antibodies. A close coordination between internists and obstetricians is required for appropriate treatment, including systemic steroid therapy.

A characteristic optic disc appearance associated with myopia in subjects with Graves' ophthalmopathy and in subjects with primary open-angle glaucoma.

PURPOSE: To determine if qualitatively defining the appearance of optic disc change was a valid characteristic of myopia in subjects with Graves' ophthalmopathy (GO) or primary open-angle glaucoma (POAG). METHODS: WE DEFINED TYPICAL TILT APPEARANCE AS THE SIMULTANEOUS PRESENCE OF THE FOLLOWING: an elliptical optic disc, a crescent, unequal sharpness of the cupping margin (horizontally), and nasally displaced vessels in the optic cup. Ninety-two eyes from 92 subjects each with GO or with POAG and no severe complications were included in the study after matching for spherical refractive errors. Using our definition of tilt appearance, two independent observers subjectively judged optic disc photographs. One observer repeated judgments in 70 randomly selected eyes and judgment reproducibility was assessed using kappa statistics. Tilt ratio was used as a quantitative parameter. RESULTS: The numbers of eyes judged as having a typical tilt appearance in the GO group and in the POAG group were 25 (27.2%) and 39 (42.4%), respectively, by one observer (P = 0.0297), and 12 (13%) and 44 (47.8%), respectively, by another observer (P < 0.0001). Intra- and interobserver reproducibility of tilt judgment were very good (kappa = 0.93) and good (kappa = 0.65), respectively. Tilt ratio did not significantly differ between the two groups. Analytical results including background factors were essentially the same for the two observers: multivariate logistic regression for one observer's judgment showed that the presence of the typical tilt appearance was associated with belonging to the glaucoma group (odds ratio [OR], 6.25; P = 0.0054), tilt ratio (OR per 0.01, 0.77; P < 0.0001), and spherical refractive error (OR per diopter, 0.80; P < 0.003). CONCLUSION: The optic disc feature we designated as typical tilt was associated with myopia, and its frequency was higher in subjects with POAG compared to those with GO.

Proptosis in dysthyroid ophthalmopathy: a case series of 10,931 Japanese cases.

PURPOSE: This observational case series investigated the occurrence and distribution of proptosis in Japanese patients with dysthyroid ophthalmopathy (DO). The relationship among lid retraction, lid swelling, and enlargement of extraocular muscles was also analyzed. METHODS: From 1993 to 2002, 10 931 patients (2240 men and 8691 women, average age; 39.9 ± 14.0 years) with abnormal thyroid function were examined for proptosis. Proptosis was measured using a Hertel exophthalmometer, and lid swelling and retraction were classified. Orbital magnetic resonance imaging or computed tomography was used to quantify enlargement of the extraocular muscles. RESULTS: Clinically significant proptosis (≥15 mm) was present in 74.2% patients and was classified as mild (15-17 mm, 39.1%), moderate (18-20 mm, 25.9%), or severe (>20 mm, 9.2%). The average exophthalmometer reading was 17.2 ± 3.2 mm, with proptosis less pronounced with age (p < 0.001) and more pronounced in men than women (18.2 ± 3.4 mm vs. 17.0 ± 3.1 mm; p < 0.001). Lid retraction was present in 57.7% of patients, lid swelling in 46.9%, and muscle enlargement in 40.8% of patients. Multiple regression analysis revealed proptosis was strongly correlated with a young age and the male gender, followed by extraocular muscle enlargement and lid retraction and swelling (p < 0.001). CONCLUSIONS: This study assessed the measurable features of proptosis in Japanese patients with DO and contributes to the understanding by correlating symptoms and signs of DO.