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.

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.

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.

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.

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.