The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves' hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.

Grading Severity and Activity in Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) is an autoimmune disorder causing inflammation, expansion, and fibrosis of orbital fat, muscle, and lacrimal gland. This article reviews the different methods of grading severity and activity of TED and focuses on the VISA Classification for disease evaluation and planning management. METHODS: Accurate evaluation of the clinical features of TED is essential for early diagnosis, identification of high-risk disease, planning medical and surgical intervention, and assessing response to therapy. Evaluation of the activity and severity of TED is based on a number of clinical features: appearance and exposure, periorbital tissue inflammation and congestion, restricted ocular motility and strabismus, and dysthyroid optic neuropathy. The authors review these clinical features in relation to disease activity and severity. RESULTS: Several classification systems have been devised to grade severity of these clinical manifestations. These include the NO SPECS Classification, the European Group on Graves Orbitopathy severity scale, the Clinical Activity Score of Mourits, and the VISA Classification as outlined here. The authors compare and contrast these evaluation schemes. CONCLUSIONS: An accurate clinical assessment of TED, including grading of disease severity and activity, is necessary for early diagnosis, recognition of those cases likely to develop more serious complications, and appropriate management planning. The VISA Classification grades both disease severity and activity using subjective and objective inputs. It organizes the clinical features of TED into 4 discrete groupings: V (vision, dysthyroid optic neuropathy); I (inflammation, congestion); S (strabismus, motility restriction); A (appearance, exposure). The layout follows the usual sequence of the eye examination and facilitates comparison of measurements between visits and data collation for research.

Soft Tissue Metrics in Thyroid Eye Disease: An International Thyroid Eye Disease Society Reliability Study.

PURPOSE: To determine the reliability of 3 scales for assessing soft tissue inflammatory and congestive signs associated with thyroid eye disease. METHODS: This was a multicentered prospective observational study, recruiting 55 adults with thyroid eye disease from 9 international centers. Six thyroid eye disease soft tissue features were measured; each sign graded using 3 scales (presence/absence [0-1], 3-point scale [0-2], and percentage [0-100]). Each eye was graded twice by 2 independent raters. Accuracy (fraction of agreement) was calculated between the 2 trials for each rater (intrarater reliability) and between raters for all trials (interrater reliability) to determine the most sensitive scale for each feature that maintained a threshold of agreement greater than 0.70. Trial, intrarater reliability, and interrater reliability were determined by accuracy measurement of agreement for each inflammatory/congestive feature. RESULTS: Fifty-five patients had 218 assessments for 6 thyroid eye disease metrics. The intrarater reliability for each feature was consistently better than the interrater reliabilities. Using an agreement of 0.70 or better, for the interrater tests, conjunctival and eyelid edema could be reliably measured using the 0-1 or 0-2 scale while conjunctival and eyelid redness could only be reliably measured with the binary 0-1 scale. Caruncular edema and superior conjunctival redness could not be measured reliably between 2 raters with any scale. The percentage scale had poor agreement unless slippage intervals of >20% were allowed on either side of the measurements. CONCLUSIONS: Of the specific periocular soft tissue inflammatory features measured between raters in the Clinical Activity Score and Vision, Inflammation, Strabismus, Appearance scales, edema of the eyelids and conjunctiva could reliably be measured by both 0-1 and 0-2 scales, erythema of the eyelid and bulbar conjunctiva could reliably be measured only by the 0-1 scale, and the other parameters of superior bulbar erythema and caruncular edema were not reliably measured by any scale.

¿Qué escala debemos elegir para evaluar actividad y gravedad en la orbitopatía de Graves? / Which scale should we choose to assess activity and severity in Graves orbitopathy?

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Cytokine profiles in clinical subtypes of ophthalmic Graves' disease.

PURPOSE: To examine the association of cytokines in the two clinical subtypes of ophthalmic Graves' disease by comparing cytokine expression in the fat and ethmoid tissue of type I and type II patients. METHODS: Patients needing orbital decompression or eyelid surgery were identified and enrolled into a prospective study. Patients were assigned to the type I or type II subclassification, based on the presence of diplopia. Orbital fat, sinus tissue or muscle removed during surgery was evaluated. The mRNA expression profiles of Th1 cytokines (TNF-alpha/beta, IFN-gamma, IL-2) and Th2 cytokines (IL-4, IL-5, IL-6, IL-10) were analyzed using real time PCR. RESULTS: 30 patients were enrolled in the study: 5 type I (80% female), 14 type II (71% female) and 11 controls (73% female). There were 14 decompressions (3 type I and 11 type II), 17 lid procedures (2 type I, 4 type II and 11 controls) and 10 ethmoidectomies (3 type I and 7 type II). The average ages were 45, 56 and 66 in the type I, type II and control groups, respectively. There was more TNF-alpha (p value 0.009) and IL-6 (p value 0.04) in ethmoid sinus cells of type II patients compared to ethmoid sinus cells of type I patients and a trend of higher expression of all cytokines in type II patients. CONCLUSIONS: There is a trend towards greater mRNA expression of both Th1 and Th2 cytokines in both orbital fat and ethmoidal sinus tissue of type II patients compared to type I patients.

Surgical effects of various orbital decompression methods in thyroid-associated orbitopathy: computed tomography-based comparative analysis.

OBJECTIVES: To evaluate the surgical effects of orbital fat decompression and bony decompression in each orbital wall using computed tomography (CT) in thyroid-associated orbitopathy (TAO). METHODS: In 27 TAO patients (48 orbits) with exophthalmos who underwent orbital wall decompression combined with fatty decompression, we recorded the resected orbital fat volume intraoperatively and estimated the decompression volume of the orbital wall in the deep lateral, medial and inferior walls using postoperative orbit CT images. Then, the correlation between exophthalmos reduction by Hertel reading and decompression volume in each area was analyzed to validate the surgical predictability, surgical efficiency and contribution level to total exophthalmos reduction. RESULTS: The decompression volume in orbital fat and the deep lateral wall showed relatively high correlation with exophthalmos reduction (surgical predictability) compared to medial and inferior wall. The surgical efficiency was highest at deep lateral wall (2.704 ± 0.835 mm/cm(3)), followed by medial wall (0.892 ± 0.527 mm/cm(3)), orbital fat (0.638 ± 0.178 mm/cm(3)) and inferior wall (0.405 ± 0.996 mm/cm(3)). The actual contribution level to total exophthalmos reduction was highest in fatty decompression, followed by deep lateral decompression. CONCLUSION: In TAO patients with exophthalmos, orbital fat and deep lateral orbital wall are more predictable and contributory surgical targets for postsurgical exophthalmos reduction.

Do subtypes of graves' orbitopathy exist?

PURPOSE: To describe the prevalence of fat and muscle volume (MV) increase in Graves' orbitopathy (GO) patients, calculated from computed tomography scans, and the associated ophthalmic and endocrine characteristics. DESIGN: Consecutive, observational case series. PARTICIPANTS: Ninety-five consecutive Caucasian GO patients attending the thyroid eye clinic. METHODS: Volumetry using age-specific reference values in untreated GO patients who had been rendered euthyroid. MAIN OUTCOME MEASURES: Subgroups in GO and main characteristics. RESULTS: Four subgroups could be distinguished: Group 1, no fat volume (FV) or MV increase (n = 24); group 2, only FV increase (n = 5); group 3, only MV increase (n = 58); and group 4, both FV and MV increase (n = 8). Patients with an increase of MV were older and had higher thyroid-stimulating hormone-binding inhibitory immunoglobulin TBII, more proptosis, and more impaired ductions than those without MV increase. Patients with an increase of FV differed from those without FV increase only in having more proptosis. The clinical activity score did not differ between the 4 groups. CONCLUSIONS: Of these GO patients, 25% have orbital fat and MVs within an age-specific reference range. An increase of the FV is seen in only 14% of GO patients and characterized by proptosis. Muscle enlargement occurs in 70% of patients and is associated with older age, higher TBII values, more proptosis, and impaired motility.

Planning health care for patients with Graves' orbitopathy.

BACKGROUND: To describe disease parameters of patients with Graves' orbitopathy in a tertiary referral center in order to plan health care resource allocations. To investigate whether the clinical activity and/or the severity of the disease can be used as a predictor of the duration of treatment. METHODS: Retrospective, observational, non-comparative case series. One hundred and seventeen charts of GO-patients, randomly chosen out of a pool of 1600, referred to the Orbital Unit of the University Medical Centre Utrecht between 1 January 1992 and 1 January 2002, were analysed. Relevant parameters, such as age, gender, race, disease duration, smoking habits, concomitant diseases, previous treatment, symptoms and signs, number and sort of investigations, severity and activity scores, number and sort of treatments, treatment duration and outcome of treatment were retrieved and analysed. Disease activity and severity at entry were tested as possible predictors of disease duration and extent of treatment. RESULTS: Clinical profile at presentation; duration of the disease; extent of treatment; predictors of disease duration and of number of treatment interventions were the main outcome measures. Three percent of patients had Only Signs, but No Symptoms (OSNS), 61% had mild, 27% had moderately severe and 9% had severe GO. Fifteen percent had inactive disease at presentation, 65% had borderline activity and only 20% had active orbitopathy. Sixty percent complained about eyelid swelling and/or proptosis. The average period of eye treatment was 2.5 years (range: 0-110 months), during which patients were seen at an average of 8 times. Twenty percent needed no treatment at all. Fifteen percent were treated with nothing but lubricants and/or prisms. Twenty-five percent were treated with immunosuppressive modalities. Fifty-six percent underwent one or more surgical corrections. The Clinical Activity Score (CAS) was found to be significantly related to the duration of the treatment (p < 0.001), to the number of visits (p < 0.001), and to the number of surgical interventions (p < 0.001). CONCLUSIONS: The majority of GO patients referred to a tertiary referral centre has no or borderline disease activity and 'mild' orbitopathy, disfiguring eyelids and proptosis being the most frequent complaints. The disease activity as assessed with the CAS can be used to predict the duration and extent of the treatment.

Oxidative stress and antioxidant activity in orbital fibroadipose tissue in Graves' ophthalmopathy.

PURPOSE: To investigate the oxidative stress and antioxidant activity in the orbit in Graves' ophthalmopathy (GO). MATERIALS AND METHODS: Orbital fibroadipose tissue samples were obtained from 13 cases during orbital fat decompression surgery. All cases demonstrated features of moderate or severe GO according to the European Group on Graves' Orbitopathy classification. The disease activity was evaluated with the Clinical Activity Score, and the clinical features of GO were evaluated with the Ophthalmopathy Index. Orbital fibroadipose tissue samples of 8 patients without any thyroid or autoimmune disease were studied as controls. In the tissue samples, lipid hydroperoxide level was examined to determine the level of oxidative stress; glutathione level to determine antioxidant level; superoxide dismutase, glutathione reductase, and glutathione peroxidase activities to determine antioxidant activity. RESULTS: Lipid hydroperoxide level and all three antioxidant enzyme activities were found to be significantly elevated, while glutathione level significantly diminished in tissue samples from GO cases compared to controls (p < 0.05). Glutathione levels in tissue samples of GO cases showed negative correlation with Ophthalmopathy Index (r = -0.59, p < 0.05). CONCLUSIONS: The antioxidant activity in the orbit is enhanced in GO. However, the oxidative stress appears to be severe enough to deplete the tissue antioxidants and leads to oxidative tissue damage. This study may support the possible value of antioxidant treatment in GO.

Pure eye muscle involvement in endocrine orbitopathy.

We present a long-term follow-up examination concerning patients with isolated extra-ocular muscle involvement in thyroid-related orbitopathy. Within the previous 13 years we observed 7 patients with endocrine orbitopathy and marked myopathy of the extra-ocular muscles. Five of these patients had no detectable proptosis, 2 of them showed a minimal unilateral proptosis. Five patients showed elevated thyroid-stimulating hormone (TSH) receptor auto-antibodies and 6 patients a marked swelling of the extra-ocular eye muscles on CT or MRI scans. One patient had elevated antibodies against thyroid peroxidase and against thyroglobulin and normal TSH receptor auto-antibodies. Four of 7 patients underwent clinical and radiological follow-up examination 1-9 years later. In 3 of these 4 patients, the clinical syndrome had completely resolved. None of the patients had developed any proptosis. The swelling of the eye muscles on radiological imaging had at least partially resolved. We conclude from our results that apart from the frequent subtype of endocrine orbitopathy with predominant proptosis there is a separate subtype in which proptosis neither exists initially nor develops in the further course. Probably these subtypes have a specific immunological antibody profile although they do not differ concerning the thyroid-stimulating antibodies.

[The problems of endocrine ophthalmopathy].

Based on her own rich and many years' experience in following-up and treating patients with endocrine ophthalmopathy (EOP) and on the data available in the Russian and foreign literature, the author states the problems of EOP. These include the terminology and classification of a pathological process, a uniform treatment protocol by taking into account its form, compensation and development stages, the development of clear indications for decompressive operations on the orbit.

Clinical evaluation of Graves ophthalmopathy in north-east Islamic Republic of Iran.

This study evaluated the prevalence and severity of ophthalmic manifestations in all Graves disease patients (n = 68) presenting to endocrine clinics at Mashad University of Medical Sciences between December 2002 and September 2005. The mean age of patients was 38.0 (SD 14.0) years, range 15 to 71 years. The most common complaints were foreign body sensation (54.0%) and puffy eyelids (48.4%). The most common apparent abnormality was lid retraction in 64.2% of patients (bilateral in 95.3% of cases). The patients had a mean modified Werner's NO SPECS classification score of 3.00 (SD 1.46). The score was significantly higher in males than females [3.58 (SD 1.44) versus 2.63 (SD 1.35)] and was positively correlated with age.

Magnetic resonance imaging and ultrasound measurements of extraocular muscles in thyroid-associated ophthalmopathy at different stages of the disease.

PURPOSE: To assess extraocular muscle (EOM) involvement in thyroid-associated orbitopathy (TAO) of different stages with magnetic resonance imaging (MRI) and ultrasound techniques. METHODS: A total of 32 patients with TAO were divided into three groups according to whether they had mild active, pronounced active or longstanding inactive disease. Six patients with Graves' disease but no clinical signs of TAO and 10 healthy control subjects were also studied. Muscle volume and cross-sectional area were measured with MRI. A-scan ultrasound was used to measure muscle thickness. RESULTS: The average MRI volume and maximal cross-sectional area of the EOM were significantly larger in patients with pronounced active and longstanding inactive TAO than in control subjects. Increased average muscle thickness measured by ultrasound was found mainly in patients with longstanding disease. Muscle enlargement was seen with MRI and ultrasound in individual patients in all patient groups, including those with Graves' disease but no TAO. Bilateral muscle enlargement was revealed by MRI in about two-thirds of patients with mild active TAO and in all patients with pronounced active and longstanding inactive TAO. Bilateral involvement estimated with ultrasound was less common in all patient groups. The MRI and ultrasound findings were not well correlated in any patient group. CONCLUSIONS: Extraocular muscle enlargement was seen in all patient groups with TAO of differing levels of severity. Measurements with MRI of muscle volume or maximal cross-sectional area are considered good indicators of muscle enlargement in TAO.