Severe Thyroid-associated Orbitopathy Research Articles

Sensitivity of three thyrotropin receptor antibody assays in thyroid-associated orbitopathy.

BackgroundThyrotropin receptor autoantibodies (TSH-RAb) are indispensable biomarkers in the laboratory assessment of thyroid-associated orbitopathy (TAO). Clinical sensitivity of three different assays for TSH-R-Ab determination was evaluated in patients with TAO.Methods87 consecutive TAO patients were enrolled and their serum samples analyzed in parallel with three assays. An ECLIA competitive binding and a chemiluminescent bridge immunoassay were used to measure total and binding TSH-R-Ab concentration, while their functional activity was determined using a stimulatory TSH-R-Ab (TSAb) cellbased bioassay.ResultsCompared to the two binding assays (ECLIA p<0.001, bridge p=0.003), the TSAb bioassay was more sensitive pertaining to the positive detection of TSH-R-Ab in TAO patients. No difference (p=0.057) was noted between the ECLIA and bridge assays regarding sensitivity rate. All patients with active and/or moderate-to-severe TAO tested positive in the TSAb bioassay (100% and 100%, respectively), while the positivity rates for bridge and ECLIA binding assays were 89.7% and 82.1% for active TAO, and 90.2% and 86.3% for severe TAO, respectively. Negative predictive values of the bioassay, bridge, and ECLIA assays were 100%, 75%, and 71%, respectively for active TAO, and 100%, 86%, and 71%, respectively for moderate-to-severe TAO. The superiority of the bioassay was most prominent in euthyroid (ET) TAO. Positivity rates of the TSAb bioassay, bridge and ECLIA binding assays were 89.6%, 75%, and 64.6%, respectively for inactive TAO; 86.1%, 69.4%, and 52.8%, respectively for mild TAO; 87.5%, 62.5%, and 12.5%, respectively for euthyroid TAO. The bridge assay correlated better with the ECLIA binding assay (r=0.893, p<0.001), compared to the bioassay (r=0.669, p<0.001).ConclusionsIn patients with TAO of various activity and severity, the TSAb bioassay demonstrates a superior clinical performance compared to both ECLIA and bridge binding assays.

Evaluation of macular blood flow after intermittent intravenous infusion of high-dose corticosteroids (pulse therapy) in patients with thyroid-associated orbitopathy (TAO) using angio-OCT

PurposeThe aim of this study is to evaluate the changes in macular blood flow index (BFI) in patients with moderate to severe thyroid-associated orbitopathy (TAO) before and after pulse therapy and their relationship with clinical features and disease activity using angio-OCT technology.MethodsWe analyzed twenty-four eyes. Every patient underwent a complete eye examination and angio-OCT analysis (OCT Topcon ImageNet 6; DRI OCT Triton, Topcon Corporation) before (T0) and two months (T2) after pulse therapy. We analyzed macular vascular blood flow in four angiographic levels: superficial plexus (SP), deep plexus (DP), external retina (ER), and choriocapillaris (CC). We used the clinical activity score (CAS) score to define TAO as moderate or severe.ResultsMacular BFI significantly increased at T2 in the DP, ER, and CC (p < 0.01). CAS score (5.8 ± 0.8 vs. 3.9 ± 0.9, p < 0.01) and Hertel exophthalmometry values (22.6 ± 2.3 mm vs. 21.2 ± 2,5 mm, p < 0.01) improved for all patients at T2 compared T0. Mean IOP increased from 13.3 ± 2.8 mmHg to 14.3 ± 2.1 mmHg (p < 0.01). No correlation was found between CAS score and macular BFI in all the analyzed levels.ConclusionsPulse therapy treatment can change macular BFI. In particular, two months alter pulse therapy, all the patients show an increase in macular vascular blood flow in each angiographic level. According to our results, angio-OCT analysis of the macular BFI may be a useful tool in the follow-up of TAO patients after pulse therapy.

Hyperthyroidism Times 2: Dual Cause of Thyroid Hormone Excess

The most common etiology of Hyperthyroidism is due to circulating antibodies that are directed against the thyroid-stimulating hormone (TSH) receptor, known as Grave’s Disease (GD). Another cause is an autonomously functioning thyroid nodule over-producing hormones or Toxic Adenoma. The mechanism of these two pathologies are very distinct, but the question that arises is, can they coexist?This is a case of 44-year-old female who comes to the clinic referred by her ophthalmologist after been diagnosed with severe thyroid-associated orbitopathy currently on steroid therapy. Thyroid ultrasound has done previously showed enlarged homogenous thyroid gland with a single isoechoic nodule of 2.2x1.6x1.9cm with faint peripheral calcifications and vascularity. The patient was presenting with palpitations, heat intolerance, sweating, and discriminatory features such as double vision and left eye exophthalmos. On physical examination, there was no goiter or palpable thyroid nodules, but it was remarkable for left eyelid lag retraction and mild proptosis. Evaluation showed clinical and biochemical hyperthyroidism with TSH: 0.068 mU/ml (n:0.5-5.0mU/ml), FT4: 1.39ng/dl (n:0.87-1.85ng/dl), TSH receptor antibody: <1.10IU/L and thyroid-stimulating immunoglobulin: 0.54IU/L (borderline high). The patient was placed in antithyroid drugs and B-blockers for disease control. Afterward, the patient underwent a thyroid uptake scan reporting toxic adenoma on the left lobe, however even when the biochemical workup of GD is inconclusive, patient clinical findings are highly suggestive of it. Due to the risk of worsening orbitopathy with radioactive iodine therapy, patient was referred for surgical excision of toxic adenoma and total thyroidectomy was decided since residual thyroid tissue may expose the patient to circulating thyroid-stimulating immunoglobulin leading to hyperthyroidism recurrence and put her at risk of associated thyroid excess detrimental complications. Surgical specimen gross pathology biopsy reported the thyroid gland with hyperplastic changes of Grave’s Disease. Severe thyroid-associated orbitopathy was managed with decompression surgery but did not improve, for which an alternative therapeutic approach is decided with novel immunomodulatory agent and recent approved therapy, Teprotumumab. A monoclonal antibody that works on TSHR/IGF-1R signaling complex involved in Thyroid Eye Disease.Is unusual to see two different superimposing thyroid pathologies, but disease presentations can be atypical and can be present concomitantly. In this scenario, several factors must be taken into consideration when choosing an adequate therapy approach. Our case is an example that we need to individualize management options based on guidelines recommendations, patient’s clinical settings and decreased risks of future complications.

Single-stage Orbital Decompression, Strabismus and Eyelid Surgery in Moderate to Severe Thyroid Associated Orbitopathy

ABSTRACT Purpose To evaluate the outcome of orbital decompression, strabismus and/or eyelid surgery in patients with moderate to severe thyroid-associated orbitopathy, when combined approach is preferred. Methods Retrospective, comparative, non-randomized review of 45 patients operated on from 2015 to 2018. Simultaneous decompression, eyelid and/or strabismus surgery was performed in 34 eyes of 20 subjects (group 1). Patients with multi-step procedures were used as control groups: group 2 included patients with staged decompression and eyelid retraction surgery (15 cases, 19 eyes); group 3 included patients with staged decompression and vertical strabismus surgery (10 cases, 13 eyes). Mean follow-up was 2.9 ± 1.8 years. Mann Whitney two-tailed test was used for paired data, and Fisher’s exact test for categorical data; p <.05 were considered statistically significant. Results Changes in margin reflex distance were not significantly different among patients of subgroup 1A (11 patients, one-step decompression/eyelid surgery) and group 2 (p >.05). Improvement in postoperative diplopia were not significantly different among patients of subgroup 1B (9 cases, one-step decompression/strabismus/eyelid surgery) and group 3 (p >.05). One patient of group 1 had recurrent dysthyroid optic neuropathy that recovered with steroid treatment. No other complications occurred in the one-step surgery group. Conclusions Simultaneous orbital decompression, strabismus and/or eyelid surgery resolved dysthyroid optic neuropathy, decreased proptosis, improved diplopia and eyelid position with a range comparable to that of a multi-step technique. If confirmed in prospective controlled studies, a one-stage approach might be advised to reduce the costs and time needed for rehabilitation in selected patients.

Effect of orbital radiotherapy on the outcome of surgical orbital decompression for thyroid-associated orbitopathy (TAO): a retrospective study in 136 patients.

In patients with moderate to severe thyroid-associated orbitopathy (TAO), orbital radiation therapy (ORT) can prevent disease progression. In the sequelae stage, orbital decompression surgery can be useful in case of functional discomfort. The aim of this study was to evaluate the effect of orbital ORT on the outcomes of decompression surgery. In this retrospective study, we included 136 patients who had had bilateral orbital decompression between 1995 and 2016. Before surgery, 38 patients received Radiation Therapy (RT+) while 98 did not (RT-). All RT+ patients and 20 RT- patients had systemic corticosteroid treatment. In both groups surgical outcome was evaluated by exophthalmos reduction (mm), palpebral fissure (mm), distance between the lid margin and the corneo-scleral limbus (mm), existence of conjunctival hyperemia and diplopia. In both RT+ and RT- groups, surgery improved the proptosis, significantly greater in RT+(3.66 ± 1.79 mm) than in RT- group (2.85 ± 1.80 mm) (p < 0.019). No significant differences were noted in the palpebral fissure, the distance from the lid margin to the corneo-scleral limbus. After surgery, only one patient (5%) in the RT+ group presented with new-onset diplopia, whereas in the RT- group there were 14 (36%) patients (p < 0.007). After orbital decompression, the number of conjunctival hyperemia decreased by 6 (21%) in the RT+ group versus 21 (60%) in the RT- group (p < 0.006). Orbital radiotherapy during the inflammatory phase enhances the outcomes after orbital decompression in TAO. After surgery we observed a greater improvement in proptosis and in diplopia for RT+ versus RT- patients.

Objectively Measuring Observer Attention in Severe Thyroid-Associated Orbitopathy: A 3D Study.

Measure the attentional distraction of facial deformity related to severe thyroid-associated orbitopathy using three-dimensional (3D) images and eye-tracking technology. Observers recruited at an academic tertiary referral center viewed 3D facial images of patients with severe thyroid-associated orbitopathy (TAO) and controls without TAO. An infrared eye-tracking monitor recorded their eye movements and fixations in real time. Multivariate Hotelling's analysis, followed by planned posthypothesis testing, was used to compare fixation durations for predefined regions of interest, including the eyes, nose, mouth, central triangle, and remaining face without the central triangle between severe TAO patients and controls. One hundred sixteen observers (mean age 26.4 years, 51% female) successfully completed the eye-tracking experiment. The majority of their attention was directed toward the central triangle (eyes, nose, mouth). On multivariate analysis, there were significant differences in the distribution of attention between control and severe TAO faces (T2 = 49.37; F(5,922) = 9.8314, P < 0.0001). On planned posthypothesis testing, observers attended significantly more to the eyes (0.77 seconds, P < 0.0001, 95% confidence interval [CI], 0.51, 1.03 seconds) and less to the nose (-0.42 seconds, P < 0.0001, 95% CI, -0.23, -0.62 seconds) in severe TAO patients. There was no significant difference in time spent on the mouth, the total time spent on the central triangle, or time spent in the remaining face between the two groups. Severe TAO distracted observer attention toward the eyes compared to control patients. These data lend insight into how TAO may alter observers' perceptions of these patients. Future studies should investigate how these changes in observer gaze patterns may reflect the social perception of TAO patients. NA Laryngoscope, 129:1250-1254, 2019.

Severe thyroid-associated orbitopathy manifesting two years post total thyroidectomy for follicular carcinoma variant of the thyroid

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Thyroid Stimulating Antibodies Are Highly Prevalent in Hashimoto's Thyroiditis and Associated Orbitopathy.

Thyroid-associated orbitopathy (TAO) rarely occurs in patients with Hashimoto's thyroiditis (HT). There is evidence that TSH receptor stimulating antibodies (TSAb) play a role in the pathogenesis of TAO. In this report, the prevalence of TSAb in HT patients with and without TAO was studied. This is a longitudinal observational study. The study took place in an academic joint thyroid-eye clinic. A total of 1055 subjects were included. TSAb was measured with a Food and Drug Administration-cleared bioassay that uses Chinese hamster ovary cells expressing a chimeric TSH receptor and a cAMP response element-dependent luciferase. Results of TSAb activity were reported as percentage of specimen-to-reference ratio (SRR%, cutoff >140%). We measured the association of TSAb with the risk of TAO in patients with HT. Of 700 consecutive and unselected patients with HT, 44 (6%) had overt TAO. Patients with HT+TAO were older (P < .001), heavier smokers (P = .032), and clustered less with autoimmune diseases (P = .005). All healthy controls were TSAb negative. In contrast, serum was TSAb positive in 30/44 (68.2%) and 36/656 (5.5%, P < .001) patients with HT+TAO and HT, respectively. Compared to patients with HT only, serum TSAb levels were higher in HT+TAO (median SRR%, 25th and 75th percentiles): 45, 35-65 vs 192.5, 115-455.3, P < .001. Highest TSAb values were noted in patients with active and severe TAO vs those with mild and inactive TAO: 486, 392-592 vs 142, 73-192.5; P < .001. The odds ratio of TSAb positivity for the risk of TAO adjusted for gender and age was 55.9 (95% confidence interval [CI], 24.6-127, P < .0001), whereas the odds ratio per 10-fold change in TSAb SRR% (quantitative TSAb) was 133 (95% CI, 45-390, P < .0001). The area under the receiver operating characteristic curve for qualitative and quantitative TSAb was 87.2% (95% CI, 80.6-93.8) and 89.4% (95% CI, 84.1-94.7), respectively. TSAb is strongly associated with TAO in HT and TSAb may contribute to the pathophysiology of TAO.

Thyroid Stimulating but Not Blocking Autoantibodies Are Highly Prevalent in Severe and Active Thyroid-Associated Orbitopathy: A Prospective Study.

The clinical utility of the functional TSH receptor autoantibodies was prospectively evaluated in patients with thyroid-associated orbitopathy (TAO). Ophthalmic, endocrine, and serological investigations were performed in 101 consecutive patients with severe and active TAO. Serum thyroid stimulating (TSAb) and blocking (TBAb) antibody levels were measured with two bioassays using cells that express a chimeric TSH receptor and CRE-dependent luciferase. TSAb results are expressed as percentage of specimen-to-reference ratio (SRR %). Blocking activity is defined as percent inhibition of luciferase expression relative to induction with bovine TSH alone. All 101 consecutively followed-up patients with severe and active TAO were TBAb negative. In contrast, 91 (90%) were TSAb positive of whom 90 had Graves' disease. Serum TSAb levels correlated with the diplopia score (P = 0.016), total severity eye score (P = 0.009), proptosis (P = 0.007), lid aperture (P = 0.003), upper lid retraction (P = 0.006), keratopathy (P = 0.04), and thyroid binding inhibiting immunoglobulins (TBII, P < 0.001) and negatively with the duration of TAO (P = 0.002). Median serum values of TSAb were SRR% 418 (range 28% to 795%). TSAb, not TBAb, are highly prevalent in severe/active TAO and serum TSAb levels correlate with clinical disease severity.

Severe thyroid-associated orbitopathy in Hashimoto's thyroiditis. Report of 2 cases

Thyroid-associated orbitopathy (TAO) is characterized by immune-mediated inflammation of the extraocular muscles surrounding orbital connective tissue and adipose tissue. Severe orbitopathy related to autoimmune thyroid disease often occurs in patients with Grave's disease, but it is rare in patients with Hashimoto's thyroiditis. The pathogenesis of TAO is unclear. Several studies have noted a strong correlation between the levels of antibodies to thyrotropin receptor antibody (TRAb) and TAO in Graves' disease. Mild upper eyelid retraction has been reported to be common in Hashimoto's thyroiditis patients, however severe orbitopathy is rare. We report two cases of severe TAO in patients with Hashimoto's thyroiditis who required systemic glucocorticoid therapy and orbital irradiation to treat the TAO. The activity of the TAO was high in both patients, because their clinical activity scores (CAS) for the orbitopathy were high, and magnetic resonance imaging (MRI) showed enlargement of the extraocular muscles and an increase in T2 signal intensity and prolonged T2 relaxation time which indicate an active stage of inflammation. We tested the presence of TRAb by three different assays and were negative in both patients. Since the eye muscle damage cannot be due to TSH receptor antibodies, other pathogenetic mechanisms may be responsible for the orbitopathy in patients with Hashimoto's thyroiditis.

Risk Factors Associated with the Severity of Thyroid-Associated Orbitopathy in Korean Patients

PurposeThe purpose of this study is to identify risk factors for severe thyroid-associated orbitopathy (TAO) and compressive optic neuropathy in Korean patients.MethodsThis study was a retrospective comparative case series. All TAO patients who were first seen at our institution between 2005 and 2009 and who had follow-up periods of at least 6 months were included. Patients were divided into mild or moderate and severe TAO groups. Cases were also segregated based on the presence or absence of optic neuropathy. Demographics, smoking status, comorbidities, thyroid hormonal status, thyroid autoantibody levels, and clinical presentations were assessed.ResultsA total of 99 patients (83 with mild to moderate courses and 16 with severe courses; 90 without optic neuropathy and 9 with optic neuropathy) were included in this study. On multiple logistic regression analysis, smoking status was a predictive risk factor for a severe course of TAO and the development of optic neuropathy (odds ratios = 6.57 and 10.00, respectively). Other factors such as age, gender, free T4 level, thyroid binding-inhibiting immunoglobulin, and a history of diabetes were not predictive of severe TAO or optic neuropathy.ConclusionsAlthough various factors may influence the severity of TAO and the development of optic neuropathy, this study showed that smoking was a risk factor for severe TAO and the development of optic neuropathy. Therefore, it is important for patients with Graves' disease to refrain from smoking. Frequent and careful observation should also be performed in current smokers, as TAO patients who smoke are susceptible to a severe course and/or optic neuropathy.

Long-term multidisciplinary follow-up of unilateral thyroid-associated orbitopathy

Background Thyroid-Associated Orbitopathy (TAO) is an autoimmune disease characterized by orbital inflammation involving both adipose tissue and extra-ocular muscles (EOM). Whereas bilateral and possibly asymmetric orbital involvement is commonly found at radiological work-up, mono-orbital involvement is poorly documented, and ascribed to an initial and/or transient stage of subsequent bilateral TAO. Methods From a cohort of two hundred TAO patients, we selected retrospectively fourteen patients with initial clinical unilateral TAO. Five of them were excluded because of clinical bilateralization. Results The sex ratio was 0.8 (4M, 5F), and mean age 44.6 years (range: 18–63). All patients were euthyroid when the initial magnetic resonance imaging (MRI) was performed. One patient was treated with Levothyroxine, because of subclinical hypothyroidism. Eight patients (six smokers) suffered from Graves' disease, of 1–4 years duration, for which they were treated with antithyroid drugs. A thyroidectomy was performed in two patients. None of the patients ever received radioiodine. Six patients remained euthyroid after stopping of the antithyroid regimen, and two became hypothyroid. Seven patients had active, and two severe TAO. Four of nine patients exhibited bilateralization of TAO on initial MRI. Clinical status ultimately improved or normalized in all. In two patients, MRI performed after 9 years demonstrated partial shrinkage of previously enlarged EOMs, together with fatty involution of involved muscles. Conclusions Unilateral TAO is not different and just as severe as bilateral TAO. At initial work-up MRI shows signs of bi-laterality in 45% (4/9), with mild involvement of 1 or 2 extra-ocular muscles. The radiological status of affected muscles does not normalize, even in the very long term.

Thyroid-Associated Orbitopathy

Thyroid-associated orbitopathy (TAO) is usually diagnosed clinically. Early presentation of TAO such as ocular irritation, lid puffiness, and mild retraction may be overlooked and misdiagnosed. Careful clinical evaluation, laboratory investigations, and orbital imaging studies are needed for diagnosing early TAO. Knowing the pathogenesis will open the door for obtaining directed and effective treatment for the inflammatory process in TAO. Most patients with mild to moderate active TAO are treated with observation alone as the available treatment modalities effective in controlling the disease have many potential side effects. Severe active TAO, compressive optic neuropathy, and severe exposure keratopathy are the main indications for treatment with immunosuppressant agents, orbital radiotherapy, or orbital decompression. Surgery remains the final rehabilitation in TAO, which should be done during cicatricial (inactive) TAO when reliable and stable results can be obtained.