Management of patients with Graves' orbitopathy: initial assessment, management outside specialised centres and referral pathways.

Graves' orbitopathy (GO) is uncommon, but responsible for considerable morbidity. A coordinated approach between healthcare professionals is required in order to meet the needs of patients. Early diagnosis can be achieved by a simple clinical assessment. Low-cost effective interventions can be initiated by generalists, which may improve outcomes. Moderate-to-severe GO should be referred to specialised centres. Recommendations for clinical diagnosis, initial management and referral pathways are highlighted.

The effect of B cell depletion therapy on anti-TSH receptor antibodies and clinical outcome in glucocorticoid-refractory Graves' orbitopathy.

OBJECTIVE: This case series documents the response of nine individuals with glucocorticoid-refractory Graves' orbitopathy (GO) to B cell depletion therapy with rituximab (RTX). CONTEXT: Graves' disease (GD) is one of the commonest autoimmune conditions and is frequently associated with inflammatory changes around the eyes (GO). GO frequently results in significant functional visual impairment, and in the most severe cases, it can result in permanent loss of sight. RTX is a therapeutic monoclonal antibody, which targets cell-surface CD-20, resulting in depletion of circulating B lymphocytes. It has been found to be useful for the treatment of a number of autoimmune conditions including, in preliminary studies, GO. DESIGN AND PATIENTS: We have treated nine individuals (1 male, 8 female, age range 37-87 years) with glucocorticoid-resistant GO with RTX since 2008. RTX was administered in divided doses at fortnightly intervals, following 500 mg IV methylprednisolone pretreatment. MEASUREMENTS: Each patient underwent thorough assessment before and after RTX therapy, including thyroid function tests, B cell counts, thyroid autoantibody levels and detailed clinical assessment according to EUGOGO standard protocols. All patients have now been followed up for 16 months or more. RESULTS: There was a significant reduction in thyrotropin receptor binding inhibitory immunoglobulin (TBII) levels in all patients following RTX treatment and a reduction in the clinical activity score (CAS) was seen in all cases. We also report striking improvement in pretibial thyroid dermopathy in one patient following RTX. CONCLUSIONS: This case series adds to the growing literature demonstrating that RTX, administered in our patients with concomitant methylprednisolone, is safe and clinically effective in the treatment of active, moderate to severe and sight-threatening GO. Randomized controlled trials are now needed to confirm the efficacy of RTX for GO.

Inter-observer Variability of Clinical Activity Score: Assessments in Patients With Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) can be difficult to manage. The range of available treatments is expanding rapidly; however, cost is a concern and some patients do not respond. The Clinical Activity Score (CAS) was devised as a measure of disease activity and a potential predictor of response to anti-inflammatory treatment. Despite the widespread use of the CAS, inter-observer variability has not been investigated. The aim of the study was to determine the inter-observer variability of the CAS in patients with TED. DESIGN: Prospective reliability analysis. METHODS: Nine patients with a spectrum of clinical features of TED were assessed by 6 experienced observers on the same day. Agreement among the observers was analyzed using the Krippendorff alpha. RESULTS: The Krippendorff alpha for the total CAS was 0.532 (95% CI = 0.199-0.665), whereas alpha values for the individual components of the CAS varied between 0.171 (CI = 0.000-0.334) for lid redness and 0.671 (CI = 0.294-1.000) for spontaneous pain. Assuming that a CAS value ≥3 implies suitability of the patient for anti-inflammatory treatment, the calculated Krippendorff alpha for agreement among assessors on whether treatment should be given or not given was 0.332 (95% CI = 0.0011-0.5862). CONCLUSIONS: This study has shown unreliable inter-observer variability in total CAS and most individual CAS components, thus highlighting the need for improving the performance of the CAS or seeking other methods to assess activity.

Clinical features of dysthyroid optic neuropathy: a European Group on Graves' Orbitopathy (EUGOGO) survey.

BACKGROUND: This study was performed to determine clinical features of dysthyroid optic neuropathy (DON) across Europe. METHODS: Forty seven patients with DON presented to seven European centres during one year. Local protocols for thyroid status, ophthalmic examination and further investigation were used. Each eye was classified as having definite, equivocal, or no DON. RESULTS: Graves' hyperthyroidism occurred in the majority; 20% had received radioiodine. Of 94 eyes, 55 had definite and 17 equivocal DON. Median Clinical Activity Score was 4/7 but 25% scored 3 or less, indicating severe inflammation was not essential. Best corrected visual acuity was 6/9 (Snellen) or worse in 75% of DON eyes. Colour vision was reduced in 33 eyes, of which all but one had DON. Half of the DON eyes had normal optic disc appearance. In DON eyes proptosis was > 21 mm (significant) in 66% and visual fields abnormal in 71%. Orbital imaging showed apical muscle crowding in 88% of DON patients. Optic nerve stretch and fat prolapse were infrequently reported. CONCLUSION: Patients with DON may not have severe proptosis and orbital inflammation. Optic disc swelling, impaired colour vision and radiological evidence of apical optic nerve compression are the most useful clinical features in this series.

A modified method for measuring uniocular fields of fixation: reliability in healthy subjects and in patients with Graves orbitopathy.

OBJECTIVE: To assess the intraobserver and interobserver reliability of recording uniocular fields of fixation using a modified perimeter technique in healthy subjects and patients with Graves orbitopathy (GO). Patients with restrictive myopathies, particularly GO, require accurate measurement of monocular excursions. These ductions are recorded in 4 to 12 directions of gaze using a perimeter, producing a plot known as a uniocular field of fixation. While 4 direction plots give limited information on vertical muscles, recording 12 directions is time consuming and uncomfortable. This modified technique uses the 6 directions of gaze corresponding to the primary field of action of each muscle. METHODS: A single observer measured modified uniocular fields of fixation in 35 healthy subjects aged 20 to 60 years to establish normal and age-related ranges for all ductions. Fifteen subjects underwent measurement on 5 separate occasions by the same observer to establish intraobserver reproducibility. A second observer independently performed measurements in 10 of the subjects to determine interobserver reproducibility. Reliability was compared with that measured in 29 patients with GO. RESULTS: The technique was reproducible to within 4 degrees for healthy subjects undergoing assessment by a single observer. When results of 2 observers were compared, the coefficient of repeatability was 7.9 degrees . For subjects with GO, however, maximal variability was 7.8 degrees . For clinical purposes, only a change of 8 degrees or more can be assumed to be significant. CONCLUSIONS: This technique offers advantages for assessing any restrictive myopathy, including GO to within 8 degrees . This level of accuracy is likely to be similar in other centers, and has implications for interpreting GO outcome measures, where 5 degrees was previously taken to represent significant change.

Analysis of peripheral blood T-cell subsets in active thyroid-associated ophthalmopathy: absence of effect of octreotide-LAR on T-cell subsets in patients with thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is thought to be a T-cell-mediated autoimmune disorder. We sought to characterize abnormalities in the peripheral blood T-cell subsets in patients with TAO, and examine whether the long-acting somatostatin analogue, octreotide-LAR, treatment affects these cells. We analyzed peripheral blood T-cell subsets by flow cytometry in 26 euthyroid patients with moderately severe active TAO and 24 controls. Twenty-five of the patients with TAO were enrolled in a randomized trial to receive either 30 mg of octreotide-LAR (n = 11) or placebo (n = 14) every 4 weeks for 16 weeks; all 25 patients subsequently received octreotide-LAR 30 mg every 4 weeks from week 16 to 32. T-cell subsets were analysed at baseline, week 16, and week 32. At baseline, the relative percentage of CD4+ helper T-cells (p = 0.0003) and the CD4+/CD8+ ratio (p = 0.008) were significantly higher in patients with TAO compared to controls. Patients with TAO had higher naïve active T cells (CD45RA+, CD45RA+ CD4+) and lower memory T cells (CD45RO+, CD45RO+ CD4+) than controls. At weeks 16 and 32, there were no significant differences in any T-cell subsets between the octreotide-LAR-treated and placebo groups. These results support a role of T cell in the pathogenesis of TAO, and show that octreotide-LAR has no effect on T-cell subsets during 32-weeks of treatment.

Diagnosis of Graves' orbitopathy (DiaGO): results of a pilot study to assess the utility of an office tool for practicing endocrinologists.

CONTEXT: In active Graves' orbitopathy (GO), treatment can improve the final cosmetic and visual outcome. Diagnostic delay results in significant morbidity and increases patient dissatisfaction. However, it can be challenging for endocrinologists to recognize GO and decide who should be referred for ophthalmic care. OBJECTIVE: DiaGO, a clinical assessment tool, was developed for use in patients with Graves' disease (GD). The tool is designed to alert clinicians to the possibility of GO and prompt early ophthalmic assessment. DESIGN AND SETTING: A 20-point assessment tool was devised and tested on 104 GD patients: 27 "positive controls" with GO and 77 people with GD attending endocrine clinics over 17 months. Those scoring positively in endocrine clinics were referred for ophthalmic assessment. Both the appropriateness of the referral and subsequent treatment were assessed. RESULTS: Eighty-eight of the 104 patients (85%) were female (mean age, 48.5 y; range, 18-76 y). All 27 "controls" scored positively. Of the 77 people evaluated with GD, 27 (35%) scored above the threshold for referral and GO was confirmed in 24/26 (92%) who attended for specialist ophthalmic assessment. Twelve of these 24 (50%) were offered specific treatment following ophthalmology review. CONCLUSIONS: The timely diagnosis of GO is important because early intervention in active disease can improve prognosis. DiaGO alerts clinicians to the possibility of GO and prompts referral to specialist ophthalmic care. It is quick and easy to use and does not require specialist ophthalmic skills. Overall, half of those referred after use of DiaGO were offered specific treatment, suggesting its use might significantly improve the management of patients.

Double-blind, placebo-controlled trial of octreotide long-acting repeatable (LAR) in thyroid-associated ophthalmopathy.

Several uncontrolled studies suggest octreotide is beneficial in thyroid-associated ophthalmopathy (TAO); however, the natural tendency of TAO to improve mandates randomized, controlled trials. We report results of a double-blind, placebo-controlled trial of octreotide long-acting repeatable (LAR). Fifty euthyroid patients (11 males, 39 females; age 22-74 yr, median 50 yr) with active TAO [clinical activity score (CAS) > or =3, NOSPECS (no signs or symptoms; only signs, no symptoms; signs only; proptosis; eye muscle involvement; corneal involvement; sight visual acuity reduction) 2a-5a] of median duration 0.9 yr received either 30 mg LAR or placebo every 4 wk for 16 wk; both groups then received 30 mg LAR for wk 16-32 and were followed up without treatment for a further 24 wk. Objective assessments included all individual parameters of TAO, CAS, and derived scores for soft tissue inflammation (STI) and ophthalmopathy index (OI). During wk 0-16 there was significant reduction in STI, subjective diplopia, and CAS in LAR-treated patients; STI and CAS were also reduced with placebo. The OI reduced by -1.12 in LAR (P = 0.0017) vs. -0.23 in placebo (P = 0.33), giving a barely significant treatment effect by Wilcoxon (P = 0.043), but analysis of covariance failed to confirm this (P = 0.16). During wk 16-32 there was no significant change in OI in either group. The overall results (wk 0-32) showed reduction in STI and CAS in both groups. In this double-blind, placebo-controlled trial, no significant therapeutic effect of octreotide LAR was seen in patients with moderately severe TAO. The improvements in both treated and placebo groups emphasize that the results of open studies must be viewed with caution.

Multi-center study on the characteristics and treatment strategies of patients with Graves' orbitopathy: the first European Group on Graves' Orbitopathy experience.

UNLABELLED: To improve management of patients with Graves' orbitopathy, a multi-center collaborative approach is necessary in order to have large enough sample sizes for meaningful randomized clinical trials. This is hampered by a lack of consensus on how to investigate the eye condition. The European Group on Graves' Orbitopathy aims to overcome this and has designed a preliminary case record form (CRF) to assess Graves' orbitopathy patients. This form was used in this first multi-center study. AIM: To investigate patient characteristics and treatment strategies in 152 new consecutively referred patients with thyroid eye disease seen in nine large European referral centers. METHODS: Newly referred patients with Graves' orbitopathy were included who were seen between September and December 2000. Demographic data and a complete ophthalmological assessment were recorded. RESULTS: One-hundred and fifty-two patients (77% females) were included. Diabetes was present in 9%, and glaucoma or cataract in 14% of patients. Forty percent were current smokers, 9% also had dermopathy, and only 33% reported a positive family history of thyroid disease. Mild eye disease was seen in 40%, moderately severe eye disease was seen in 33% and severe eye disease was seen in 28% of patients. Soft tissue involvement was the most frequent abnormality (seen in 75%), proptosis > or =21 mm was found in 63%, eye motility dysfunction in 49%, keratopathy in 16% and optic nerve involvement was found in 21% of patients. According to the clinical impression, 60% had active eye disease. Immunosuppressive treatment was planned more frequently in active patients (57/86; 66%) than in inactive patients (5/57, 9%; Chi-square 46.16; P<0.02). There were no important differences among the eight centers regarding the severity and the activity of their patients. CONCLUSIONS: In view of the large number of patients recruited in only 4 months, multi-center studies in the eight EUGOGO centers appear to be feasible.

Parameters predicting outcomes of strabismus surgery in the management of Graves' ophthalmopathy.

BACKGROUND: Ocular dysmotility is a common feature of Graves' ophthalmopathy and frequently requires strabismus surgery. We reviewed the short-term results of strabismus surgery for Graves' ophthalmopathy to determine pre- and perioperative parameters predictive of postoperative outcome. METHODS: A retrospective review of Graves' ophthalmopathy patients who underwent strabismus surgery. Outcomes were correlated with preoperative and operative characteristics. The main outcome measure was field of binocular single vision score. Residual postoperative strabismus was considered a secondary outcome. Preoperative characteristics examined included age and laterality at onset, sex, disease activity, smoking status, and treatment for Graves' ophthalmopathy. Good outcome was defined as field of binocular single vision >50% and heterophoria in the primary position. Moderate outcome was defined as a field of binocular single vision 1% to 50% with heterotropia but with correctable diplopia in the primary position using prisms or head tilt. Poor outcome was defined as no measurable field of binocular single vision and intractable diplopia. RESULTS: Fifty patients were identified: 28 women, 22 men; mean age, 54 years (SD +/- 12.8). Thirty-seven (74%) had good and 13 (26%) had moderate or poor outcomes. Preoperative characteristics that were associated with good outcomes were symmetry of orbitopathy at Graves' ophthalmopathy onset (chi(2) = 7.5, p = 0.001) and earlier timing of surgery (t = -2.9, p = 0.003). CONCLUSION: Relative symmetry of orbitopathy at onset and a shorter time interval between onset of orbitopathy and surgery, while allowing for disease stability, are predictive of a good outcome following strabismus surgery for Graves' ophthalmopathy.

Secondary orbital implants after evisceration: a new conjunctiva-sparing technique.

PURPOSE: To describe a new conjunctiva-sparing technique for secondary orbital implantation after evisceration. METHODS: Two patients with conjunctival cicatrization and a volume-deficient anophthalmic socket had implantation of an intraconal biointegratable implant. This was placed through a lateral canthal approach, after temporary disinsertion of the lateral rectus, thereby avoiding further injury to the conjunctiva. RESULTS: A good surgical outcome was achieved in both patients. There were no intraoperative or postoperative complications, and both have remained stable for nearly 2 years. CONCLUSIONS: Secondary intraconal implantation through the lateral canthal approach is safe and effective and suitable for patients in whom it is desirable to avoid a conjunctival incision.