The pathogenesis of Graves' ophthalmopathy

The pathology of the orbital changes in Graves' ophthalmopathy (GO) has been discussed in detail. The target tissue is the eye muscle and the damage probably results from autoimmune processes. Cell-mediated immune responses have been demonstrated and an antibody to eye muscle is detectable in 70% of patients. There is no direct evidence for an effect of thyroid hormones or TSH on orbital tissues in GO. The relation between GO and autoimmune thyroid disease is discussed. Present evidence suggests that in GO autoimmune responses are directed to orbital tissue antigens and do not cross-react with thyroid antigens. Clinical studies suggest that all patients with hyperthyroidism have some abnormality of eye muscle, whereas not all patients with ophthalmopathy have evidence of thyroid disease. It is not possible at the present time to be certain whether GO is an integral part of Graves' disease or a separate entity.     

Is sleeping position related to asymmetry in bilateral Graves' ophthalmopathy?

BACKGROUND: In agreement with the systemic nature of Graves' disease, Graves' ophthalmopathy (GO) presents as a symmetric bilateral eye disease in the vast majority of patients. However, asymmetric involvement of both eyes is frequently observed. We hypothesized that sleeping position might be involved in asymmetric GO; when, for example, the preferred sleeping position is on the right side, retrobulbar pressure might be somewhat higher in the right than in the left orbit, resulting in more severe eye changes in the right eye. METHODS: A prospective study in 75 consecutive untreated patients with GO, in whom eye changes and sleeping position were assessed independent of each other. Criteria for asymmetric eye changes were differences between both eyes in the presence of retrobulbar pain or of > or =1 grade in soft tissue involvement, and/or of > or =2 mm in exophthalmos, and/or > or =8 degrees in elevation. Preferred sleeping position was determined by questionnaire. RESULTS: All patients had bilateral GO. Eye changes were symmetrical in 50 patients, and asymmetrical in 25 patients based on differences in proptosis and elevation. Sleeping position did not differ between symmetric and asymmetric GO. Preferred sleeping position was on the left side in 23%; on the right side in 31%; and on the back, on the belly, or unknown in 46%. In patients with asymmetric GO, the most affected ("worst") eye was not related to preferred sleeping position on the right or left side. CONCLUSION: Slight asymmetry of eye changes between both eyes in patients with bilateral GO is not related to preferred sleeping position on either the right or left side.     

Effects of Graves' ophthalmopathy on quality of life

General health-related quality of life is markedly impaired in patients with Graves' ophthalmopathy (GO), and even worse than in patients with other chronic conditions like diabetes, emphysema or heart failure. A disease-specific quality-of-life questionnaire for GO has been developed, the so-called GO-QOL, consisting of two subscales: one for visual functioning (8 questions referring to limitations due to decreased visual acuity and/or diplopia) and one for appearance (8 questions referring to limitations in psychosocial functioning due to changes in appearance). The GO-QOL was found to be a valid and reliable instrument. A minimal clinically important difference (MCID) in the GO-QOL score was derived from data obtained before and after specific eye treatments. Based on the patient's opinions, changes of > or = 6 points (minor surgery) or > or = 10 points (surgical decompression, immunosuppression) are recommended as MCID. It is concluded that the GO-QOL is an useful instrument for measuring changes over time in visual functioning and appearance of GO patients. The GO-QOL is available in six languages, and can be used as a separate outcome measure in clinical studies.     

Psychological implications of Graves' orbitopathy

Patients with thyroid eye disease, Graves' orbitopathy (GO), often appear distressed and it is likely that features of the condition such as disturbances in visual function, orbital discomfort and alterations in facial appearance can impart significant psychological morbidity upon the patient, which in turn can be detrimental to their quality of life. When considering the psychological impact of GO, two elements of the disease are important. The disfiguring changes to the eyes and face can have a direct effect upon psychological health, while physical aspects of the disease such as altered visual acuity, diplopia, orbital pain and lacrimation may influence psychological function as a secondary phenomenon, due to interference with daily living. Evidence appears to confirm the anecdotal impression of many clinicians dealing with GO patients that the prevalence of psychological morbidity in this patient group is high. A 'biopsychosocial' approach to care that addresses biological and psychosocial functioning as major determinants of health is an appropriate strategy when treating patients with GO.     

An update on medical management of Graves' ophthalmopathy

Graves' ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves' disease, is a disorder of autoimmune origin, the pathogenic mechanisms of which are still incompletely understood. Although GO is severe in only 3-5% of affected individuals, quality of life is severely impaired even in patients with mild GO. Management of severe GO can be either medical or surgical (orbital decompression, eye muscle or lid surgery). Medical management relies on the use of high-dose systemic glucocorticoids or orbital radiotherapy, either alone or in combination. Studies carried out in the last 5 yr have shown that glucocorticoids are more effective through the i.v. route than through the oral route. However, particular attention should be paid to possible liver toxicity of i.v. glucocorticoids. Recent randomized clinical trials have, with one exception, confirmed that orbital radiotherapy is an effective and safe therapeutic procedure for GO. At variance with previous encouraging data, recent randomized clinical trials have shown that currently available SS analogs are not very effective in the management of GO. Antioxidants might have a role, at least in mild forms of GO. Particular attention should be paid to correction of risk factors (cigarette smoking, thyroid dysfunction, radioiodine therapy) involved in GO progression.     

Radioiodine therapy of Graves' hyperthyroidism in patients without pre-existing ophthalmopathy: can glucocorticoids prevent the development of new ophthalmopathy?

BACKGROUND: Radioiodine therapy (RIT) combined with glucocorticoids is an effective therapy for Graves' disease, but it is debatable whether glucocorticoids should be applied in patients without Graves' ophthalmopathy (GO). METHODS: The effect of 0.4 - 0.5 mg prednisone every second day over a period of 5 weeks after RIT was monitored over a follow-up period of at least 12 months after RIT. A questionnaire was sent to 186 consecutive patients without GO concerning eye symptoms after RIT. 148 patients (80 %) answered. If eye symptoms had occurred after RIT, additional clinical examination was carried out at our outpatient clinic. The primary endpoint was the absence or onset of GO within the first year after RIT. RESULTS: Within 12 months after RIT the examination confirmed GO in 5 out of 148 patients (3.4 %). In all cases the symptoms were transient. No adverse reaction to the use of prednisone after RIT was noted. CONCLUSIONS: The risk of new GO in the first year after RIT was low and the clinical course of GO was mild when RIT was combined with a low-dose glucocorticoid regimen. Preventive administration of glucocorticoids can therefore be recommended in patients with Graves' disease even without evident GO.     

Usefulness of soluble ICAM-1 measurements for the evaluation of the disease activity and efficiency of therapy in patients with infiltrative Graves' ophthalmopathy

The authors studied serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) in patients with progressive Graves' ophthalmopathy (GO), stable GO, hyperthyroid Graves' disease (GD) without GO and in healthy controls. The highest serum concentrations of sICAM-1 were observed in patients with progressive GO. In patients with stable GO and GD mean serum levels of sICAM-1 were elevated to a lesser degree. Mean serum concentrations of sICAM-1 decreased significantly during treatment of patients with the progressive GO parallel to the improvement of the eye changes. In patients with hyperthyroid GD serum levels of sICAM-1 decreased significantly after they had become euthyroid. Mean sICAM-1 level in the euthyroid GD was markedly decreased in comparison to the group of patients with progressive GO and slightly elevated when compared to stable GO. In conclusion, serum levels of sICAM-1 seems to be a good parameter of disease activity in progressive infiltrative GO. The decrease in sICAM-1 concentrations in patients with the progressive GO closely corresponds to the improvement of the clinical picture of the progressive GO.     

A prospective study of the effects of radioiodine therapy for hyperthyroidism in patients with minimally active graves' ophthalmopathy

CONTEXT: Radioiodine is an effective and safe treatment for hyperthyroidism but has been implicated as a risk factor for deterioration or new presentation of Graves' ophthalmopathy (GO). Prophylactic glucocorticoids appear to prevent this effect. OBJECTIVE: The objective of this study was to document the course of GO after radioiodine therapy. DESIGN: This was a prospective observational study. Patients were assessed at baseline and 2, 4, 6, and 12 months after radioiodine therapy. SETTING: The study was conducted at a tertiary referral center. PATIENTS: Seventy-two GO patients with minimally active eye disease participated in the study. Intervention: A fixed dose of radioiodine was administered. T(4) was commenced 2 wk later to prevent hypothyroidism. MAIN OUTCOME MEASURES: Change in activity and severity of GO were analyzed. RESULTS: Exophthalmometer readings, the width of the palpebral aperture, diplopia scores, and the clinical activity score improved significantly. By clinically significant criteria, the eye disease improved in four patients (transiently in three of the four cases), most likely attributable to the natural course of the disease. No patient's eyes deteriorated. CONCLUSIONS: Radioiodine is not associated with deterioration of GO in patients with minimally active eye disease when postradioiodine hypothyroidism is prevented.     

Susceptibility genes in Graves’ ophthalmopathy: searching for a needle in a haystack?

The variety of clinical presentations of eye changes in patients with Graves' disease suggests that complex interactions between genetic, environmental, endogenous and local factors influence the development/severity of Graves' ophthalmopathy (GO). At present, the role of genetic factors in the development of GO remains unknown. Based on small case-control association studies with candidate genes, several susceptibility loci in GO have been proposed. These are human leucocyte antigen (HLA, 6p21.3), cytotoxic T-lymphocyte antigen-4 (CTLA-4, 2q33), tumour necrosis factor (TNF, 6p21.3), interferon-gamma (IFN-gamma, 12q14), intercellular adhesion molecule-1 (ICAM-1, 19p13), and thyroid stimulating hormone receptor gene (TSH-R, 14q31). Unfortunately, these results were either not confirmed or require replication in larger studies. There are many reasons for the lack of reproducibility of association studies in GO, including poor characterization of the studied groups and small sample sizes, which may result in both false positive and negative results. Thus, the genetic background of GO remains to be elucidated in future research. However, the possibility that GO may be a genetically heterogeneous disorder, or that the development of GO may be predominantly influenced by environmental factors such as cigarette smoking, can not be disregarded.     

DIFFERENTIATION OF AUTOIMMUNE OPHTHALMOPATHY FROM GRAVES''HYPERTHYROIDISM BY ANALYSIS OF GENETIC MARKERS

Graves' hyperthyroidism and dysthyroid eye disease are closely related autoimmune conditions. Whether the eye disease is an integral part of Graves' disease or a separate entity is controversial. To investigate this we have examined the genetic associations of ophthalmopathy and hyperthyroidism, and compared their phenotype and gene frequencies with a control normal population. HLA-A, B, and DR antigens were typed in 67 patients with dysthyroid eye disease (GO), 60 hyperthyroid patients without significant eye disease (HT) and 500 normal subjects. Patients were also typed for a variety of other genetic markers: blood group systems (10), serum proteins (6) and red cell enzyme systems (10). Increased frequency of B8 and DR3 in Graves' disease was confirmed; B17 occurred less frequently and appears to be protective. HLA antigen frequencies for GO did not differ from HT. The MNS blood group showed a significant association with Graves' disease, the HT patients having a deficit of the s gene compared with controls. The most interesting finding was an increased frequency of blood group P in GO patients compared with either HT or controls. Significant differences were not seen with any of the other HLA antigens, blood groups, protein or enzyme markers considered individually. Multivariate analysis applied first to the HLA and then to the non-HLA systems indicated clear separation of the two patient groups. Although Graves' eye disease shares the same HLA associations as hyperthyroidism, it differs in the increased frequency of P blood group, suggesting that additional genetic factors may determine which patients with Graves' disease develop ophthalmopathy.     

Smoking and autoimmune thyroid disease: the plot thickens

New studies have shown that smoking may protect against the development of thyroid peroxidase antibodies, which may result in a decreased risk of Hashimoto's hypothyroidism (HH), whereas it stimulates the development of Graves' hyperthyroidism (GH). According to the above-mentioned hypothesis, to stop smoking would decrease the risk of GH but increase the risk of HH. Also, smoking has been identified as one of the risk factors for the development or worsening of eye changes after 131I treatment of GH. Additionally, the outcome of medical treatment of Graves' ophthalmopathy (GO) is less favourable in smokers as compared to non-smokers. There is concern also about the effect of passive smoking on autoimmune thyroid disease. In a recent study it has been shown that the latter may have a deleterious effect on childhood GO.     

Surgical or medical decompression as a first‐line treatment of optic neuropathy in Graves’ ophthalmopathy? A randomized controlled trial

OBJECTIVE: Only a small percentage of Graves' ophthalmopathy (GO) patients develop optic neuropathy with impending loss of visual acuity. Therapy with methylprednisolone pulses is the treatment of first choice in severe and active GO patients. When the effect is insufficient, patients are usually treated with surgical decompression. We investigated whether surgery could become the first-line treatment, thus preventing treatment with steroids. DESIGN AND SUBJECTS: We performed a randomized trial in 15 patients with very active GO and optic neuropathy. Six patients were treated with surgical decompression, and nine with methylprednisolone i.v. pulses for 2 weeks, followed by oral prednisone for 4 months. The primary outcome was determined by changes in visual acuity. If the eye disease deteriorated despite treatment or did not improve sufficiently, patients were switched to the other treatment arm. RESULTS: The severity and activity of GO in both groups were similar at baseline. The Clinical Activity Score (CAS) was 6.3+/- 0.8 in the surgical group vs. 6.0+/- 0.5 in the steroids group and the Total Eye Score was 24+/- 6 vs. 25+/- 6. In the surgery group, 5/6 patients (82%) did not respond because of insufficient improvement in vision (n=3) or persistent chemosis (n=2), and all needed further immunosuppression. In the steroids group, 4/9 patients (45%) did not improve in visual acuity (P=0.132 vs. surgery group), and these needed decompressive surgery. All patients in whom therapy failed were switched to the other treatment arm and visual acuity improved in almost all patients. Visual acuity improved from 0.36 (0.02--0.40) to 0.90 (0.63--1.0) in the surgery group and from 0.50 (0.32--0.63) to 0.75 (0.32--1.0) in the steroids group at 52 weeks. At long-term follow-up in the surgery group 3/6 patients required squint surgery and 5/9 patients in the steroids group. Eyelid surgery was performed in 5/6 patients in the surgery group and in 4/9 patients in the steroids group. CONCLUSION: Immediate surgery does not result in a better outcome and therefore methylprednisolone pulse therapy appears to be the first-choice therapy.     

Graves' ophthalmopathy: eye muscle involvement in patients with diplopia

BACKGROUND: Diplopia identifies patients with eye muscle involvement in Graves' ophthalmopathy (GO). OBJECTIVE: To identify clinical parameters that could eliminate the need for magnetic resonance imaging (MRI) to assess the activity of inflammation in the eye muscles of GO patients with diplopia. METHODS: In 43 patients with GO with recently developed diplopia, orbital ultrasound and MRI were performed. Muscle diameters and MRI T2 relaxation times were measured, and the amount of orbital connective tissue was calculated from MRI scans and compared with ultrasound readings, diplopia grades, degree of protrusion, ocular pressure, tear production, antibody levels and hormonal parameters of thyroid function. RESULTS: No correlation was found between diameters of 233 extraocular muscles measured by MRI and by ultrasound. For each of the four muscles, there was a diameter above which ultrasound was always unreliable. MRI data were used in further analysis. Of the muscles examined, the inferior rectuses were the most frequently enlarged - at least one, in 93% of cases. Medial, lateral and superior rectuses were enlarged in 59%, 37% and 34% of the orbits respectively. The pattern of muscle involvement of the two orbits tended to be symmetric (r=0.49, P=0.003), particularly for the medial rectuses (r=0.90, P=0.000). Proptosis correlated with the sum of the muscle diameters for a given eye (right eye: r=0.54, P=0.003; left eye: r=0.57, P=0.001), but it failed to correlate with the amount of orbital connective tissue. In 53% of the patients, normal T2 relaxation times were found in all eight muscles. There was only a weak correlation between muscle thickness and T2 relaxation time (r=0.49, P=0.003), indicating that muscle enlargement alone is not a sign of disease activity. The severity of diplopia was independent of T2 relaxation time. The amount of orbital connective tissue showed a negative correlation with the greatest T2 relaxation time for a given eye (r= -0.52, P=0.004); this suggests that disease types exist that have predominant muscle involvement and predominant connective tissue expansion. No correlation between connective tissue expansion and proptosis, diplopia grade, muscle thickness or disease duration was found - that is, connective tissue expansion is not a major factor in diplopia. Both muscle and connective tissue findings were independent of thyroid function. CONCLUSION: Ultrasound and MRI eye muscle diameter readings do not correlate, because of the inherent inaccuracy of orbital ultrasound. Muscle enlargement alone does not mean oedematous swelling and active disease. Neither ultrasound, nor any combination of 11 clinical and laboratory parameters provided the degree of information on muscles and connective tissue that was obtainable by MRI. In unclear cases of recently developed diplopia, before orbital decompression surgery, in the case of treatment failure or if, for any other reason, imaging is needed in GO, MRI is the method of choice.     

Comparison of practical methods for urinary glycosaminoglycans and serum hyaluronan with clinical activity scores in patients with Graves' ophthalmopathy

OBJECTIVE: Immunosuppressive treatment of Graves' opthalmopathy (GO) should be restricted to patients with active eye disease, but assessing disease activity is difficult. Several methods to evaluate GO activity have been introduced, but none of them is satisfactory. Glycosaminoglycans (GAGs) are complex polysaccharides that participate on the pathogenesis of GO and attempts to correlate its local increase to urinary GAGs (uGAGs) or serum hyaluronan (sHA) have been made, but the available techniques are labourious, time-consuming and difficult for routine use. The aim of the present study is to develop practical and simple methods for uGAGs and sHA and compare them to the activity and severity of thyroid-associated ophthalmopathy. DESIGN, PATIENTS AND MEASUREMENTS: We developed a microelectrophoresis technique for uGAGs and a fluoroassay for sHA and assessed each in 152 patients with Graves' disease, 25 without GO and 127 with GO, classified according to the Clinical Activity Score (CAS). All patients had been euthyroid for > 2 months. RESULTS: Patients with inactive disease (CAS = 2, n = 100) had uGAGs (4.2 +/- 1.3 micro g/mg/creatinine) and sHA (11.1 +/- 7.2 micro g/l) that did not differ from normal subjects (3.1 +/- 1.1 micro g/mg/creatinine, n = 138 and 13.9 +/- 9.6 micro g/l, n = 395). In contrast, patients with active eye disease (CAS = 3, n = 27) had uGAGs (8.4 +/- 2.7 micro g/mg/creatinine) and sHA (32.3 +/- 17.8 micro g/l) 2-3 times higher than those patients with inactive eye disease. Using a cut-off of 6.1 micro g/mg creatinine for uGAGs and 20.7 micro g/l for sHA we found, respectively, 85% and 81% sensitivity and 93% and 91% specificity for each test. The positive and negative predictive values were 77% and 96% for uGAGs and 71% and 95% for sHA. CONCLUSION: Employing these two new methods we have established a significant relationship between the levels of uGAGs and/or sHA and the clinical activity of GO. Therefore, together with CAS, uGAGs determination, and, to a lesser degree, sHA, would be very useful in the discrimination from active and inactive ocular disease and aid in deciding on the best therapy for GO patients.     

Assessment of disease activity in Graves' ophthalmopathy by orbital ultrasonography and clinical parameters

OBJECTIVE: To study if A-mode ultrasonography (US) in combination with the Clinical Activity Score (CAS) and duration of Graves' ophthalmopathy (GO) could predict the response to immunosuppression in Graves' ophthalmopathy. DESIGN: A prospective clinical study. PATIENTS AND METHODS: Fifty-six consecutive patients with moderately severe GO were treated with retrobulbar irradiation (10 fractions of 2 Gy). Before treatment the internal reflectivity in the extraocular eye muscles, the CAS, and the duration of Graves' ophthalmopathy were assessed and related to the therapeutic outcome 26 weeks after irradiation. RESULTS: Twenty-eight (50%) of the patients responded favourably to radiotherapy (four patients became worse, and 24 did not change), and the eye muscle echogenecity indeed tended to be lower in the responders than in the non-responders (P = 0.09). From a receiver operator characteristics curve, a cut-off value of 30% yielded a good positive predictive value of 85%, but the negative predictive value was only 60%. The CAS (>/= 4/10) had a positive predictive value of 65%, and a negative predictive value of 56%. When combining the ultrasound with the CAS, the positive predictive value increased to 74% and the negative predictive value to 72%. Adding the duration of eye symptoms (cut-off 18 months), the prediction of response further improved: positive predictive value 79%, and negative predictive value 89%. CONCLUSIONS: A-mode ultrasonography has a rather good positive predictive value, but its poor negative predictive value precludes its use as sole activity parameter. By adding the Clinical Activity Score and duration of Graves' ophthalmopathy, the negative predictive value increased considerably. By using this combination, inactive disease can be identified more precise, permitting rehabilitative surgery at an earlier stage in these patients.     

解读欧洲Graves眼病专家组管理共识

Graves眼病(GO)的管理存在一些分歧,主要是循证医学的证据太少.为了规范GO的管理,欧洲GO专家组(EUGOGO)组织了相关多学科的专家讨论.最后形成了 EUGOGO共识.该共识的主要内容包括:(1)强调建立多学科组成的甲状腺眼病专科团队,且不主张非专科医生诊治GO.(2)提出了实用的GO病情评估指标.(3)活动性中、重度GO患者可行甲基强的松龙(甲强龙)冲击治疗,且最好与眼眶放射治疗合用.必要时可行减压手术.(4)康复或矫形手术应在GO稳定6个月以上才能进行.     

Recombinant thyrotropin-induced orbital uptake of [111In-diethylenetriamine-pentacetic acid-D-Phe1]octreotide in a patient with inactive Graves' ophthalmopathy

Here we describe the case of a 60-yr-old nonsmoking woman with a history of Graves' disease associated with papillary thyroid carcinoma. After tumor removal, during the diagnostic follow-up for thyroid cancer, there was evidence of severe Graves' ophthalmopathy (GO) successfully treated with iv glucocorticoids. After this treatment, GO entered inactive status. The patient was then reevaluated for thyroid cancer with human recombinant TSH (rTSH). Orbital [111In-diethylenetriamine-pentacetic acid (DTPA)-D-phe1]octreotide scan was also performed, and results were negative. Shortly after rTSH administration, a moderate and transient pain behind the eye globes at rest and during eye movement was reported, with an increase in the activity score but without further GO progression. Twenty-four hours after rTSH administration, the patient was submitted to a second [111In-DTPA-D-phe1]octreotide scan, revealing significant orbital uptake, likely related to rapid accumulation of activated lymphocytes with inflammatory cytokines or fibroblasts expressing somatostatin receptors in the orbital tissue or interstitial edema due to the inflammation process. At last follow-up performed after 1 yr, there was no evidence of active thyroid cancer or changes in GO severity and/or activity, and orbital [111In-DTPA-D-phe1]octreotide uptake was negative. This case further supports the involvement of TSH receptor in the pathogenesis of GO. It also confirms the usefulness of orbital [111In-DTPA-D-phe1]octreotide scan to evaluate GO activity.     

Human retroocular fibroblasts in vitro: a model for the study of Graves' ophthalmopathy

Orbital connective tissue and extraocular muscles are histologically abnormal in patients with Graves' ophthalmopathy (GO). Although extraocular muscles have been extensively studied as a target for autoimmune attack in the disease, no system has been available to study retroocular fibroblasts in GO. We developed a technique to isolate fibroblasts from minced explants of connective tissue removed in the course of transantral orbital decompression surgery for GO. Postmortem specimens from individuals without evidence of thyroid disease were obtained from the same anatomical site. Confluent cells could be passaged at least 10 times with stable morphology and frozen with greater than 75% viability. An enzyme-linked immunosorbent assay was used to study the in vitro binding of serum immunoglobulin G (IgG) to these cells. We found no difference in the degree of specific binding between GO cells and cells from normal individuals. However, there was significantly greater binding of IgG from GO sera than of that from normal serum to retroocular GO fibroblasts. These results suggest that serum IgG autoantibodies against normal retroocular fibroblasts are present in some GO patients.