Selenium and the course of mild Graves' orbitopathy.

BACKGROUND: Oxygen free radicals and cytokines play a pathogenic role in Graves' orbitopathy. METHODS: We carried out a randomized, double-blind, placebo-controlled trial to determine the effect of selenium (an antioxidant agent) or pentoxifylline (an antiinflammatory agent) in 159 patients with mild Graves' orbitopathy. The patients were given selenium (100 µg twice daily), pentoxifylline (600 mg twice daily), or placebo (twice daily) orally for 6 months and were then followed for 6 months after treatment was withdrawn. Primary outcomes at 6 months were evaluated by means of an overall ophthalmic assessment, conducted by an ophthalmologist who was unaware of the treatment assignments, and a Graves' orbitopathy-specific quality-of-life questionnaire, completed by the patient. Secondary outcomes were evaluated with the use of a Clinical Activity Score and a diplopia score. RESULTS: At the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (P<0.001) and less eye involvement (P=0.01) and slowed the progression of Graves' orbitopathy (P=0.01), as compared with placebo. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Exploratory evaluations at 12 months confirmed the results seen at 6 months. Two patients assigned to placebo and one assigned to pentoxifylline required immunosuppressive therapy for deterioration in their condition. No adverse events were evident with selenium, whereas pentoxifylline was associated with frequent gastrointestinal problems. CONCLUSIONS: Selenium administration significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy. (Funded by the University of Pisa and the Italian Ministry for Education, University and Research; EUGOGO Netherlands Trial Register number, NTR524.).

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.

Reactivation of Graves' orbitopathy after rehabilitative orbital decompression.

OBJECTIVE: To present and discuss three cases of apparent reactivation of Graves' orbitopathy (GO) after orbital decompression and to evaluate the incidence of this phenomenon. DESIGN: Observational case series and retrospective follow-up study. PARTICIPANTS: A few weeks after surgery 2 patients with GO (patients 1 and 2), treated at our institution with rehabilitative bony orbital decompression during the static phase of the disease showed clinical and radiologic evidence of reactivated orbitopathy. After this observation, a sample of 249 patients who had consecutively undergone the same treatment for the same reason before the second of the 2 observed patients was selected for this study. METHODS: The records of the selected patients were retrospectively reviewed searching for cases presenting with clinical and radiologic evidence of GO reactivated as a consequence of any type of bony orbital decompression. Patients treated with perioperative systemic glucocorticoids or who had concurrent periorbital diseases, injuries, or surgeries, or who had immunocompromised conditions or a follow-up of < or =2 months, were excluded. MAIN OUTCOME MEASURES: Incidence of reactivation. Clinical history, clinical and radiologic characteristics, treatment modalities, and time course of the reactivation in patients presenting with this phenomenon. RESULTS: Decompression surgery took place between 1994 and 2000. Eleven patients were excluded for having been treated with perioperative glucocorticoids. Only 1 patient (patient 3) presented with reactivation. The incidence of the phenomenon that we regard as reactivation of GO after rehabilitative bony orbital decompression was therefore 1.3% (3/239). In all 3 patients, the reactivation took place a few weeks after surgery, after an early normal convalescence period and could be controlled with systemic immunosuppression or orbital radiotherapy. None of the patients we report developed further episodes of reactivation during the follow-up period (mean, 7.5 years). CONCLUSIONS: Based on its clinical characteristics, we suggest naming our observation delayed decompression-related reactivation and we propose using its acronym DDRR when referring to it. Although DDRR appears to be a rare event, it is important for physicians and patients to be aware of its possible occurrence with rehabilitative decompression surgery.

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.

Thyroid peroxidase autoantibodies in euthyroid subjects.

Thyroid peroxidase (TPO) is a key enzyme in the formation of thyroid hormones and a major autoantigen in autoimmune thyroid diseases. Titers of TPO antibodies also correlate with the degree of lymphocytic infiltration in euthyroid subjects, and they are frequently present in euthyroid subjects (prevalence 12-26%). Even within the normal range for thyrotropin (TSH), TPO antibody titers correlate with TSH levels, suggesting that their presence heralds impending thyroid failure. Assays for serum TPO antibodies have become much more sensitive, and very low titers can be found in virtually all subjects. However, titers above an assay-dependent cut-off are a clear risk factor for hypothyroidism; in the Whickham survey the annual risk of developing hypothyroidism in TPO-positive women with normal thyrotropin levels was 2.1%. Measuring TPO antibodies in euthyroid subjects can be used to identify subjects with increased risk for hypothyroidism: e.g. as triage to measure thyrotropin. This could be done in women who wish to become pregnant and those with an increased risk per se who are pregnant (to predict first trimester hypothyroidism, and postpartum thyroid dysfunction), patients with other autoimmune diseases, subjects on amiodarone, lithium, or interferon-alpha, and in relatives of patients with autoimmune thyroid diseases.

The removal of the deep lateral wall in orbital decompression: its contribution to exophthalmos reduction and influence on consecutive diplopia.

PURPOSE: To evaluate the contribution of maximal removal of the deep lateral wall of the orbit to exophthalmos reduction in Graves' orbitopathy and its influence on the onset of consecutive diplopia. DESIGN: Case-control study. METHODS: The medical records of two cohorts of patients affected by Graves' orbitopathy with exophthalmos > or = 23 mm, without preoperative diplopia, were retrieved at random from the pool of patients decompressed for rehabilitative reasons at our institution (01/1990 to 12/2003), and retrospectively reviewed. They had been treated with an extended (cases, group 1, n = 15) or conservative (controls, group 2, n = 15) 3-wall orbital decompression performed through a coronal approach. The deep portion of the lateral wall had been removed in the extended decompression group while preserved in the conservative decompression group. Demographics, preoperative characteristics, and surgical outcome were compared. The difference in mean exophthalmos reduction between groups 1 and 2 was considered to be the contribution of the deep lateral wall to reduction of exophthalmos. RESULTS: Groups 1 and 2 were drawn from a pool of 37 and 335 patients, respectively. Demographics and preoperative characteristics of the two groups were not significantly different. The mean contribution of the deep lateral wall to exophthalmos reduction was 2.3 mm. The onset of consecutive diplopia was not significantly different between the two groups (case n = 2/15, controls n = 5/15; P = .203). Diplopia resolved spontaneously in all the patients of group 1, while all the patients of group 2 required surgery. CONCLUSIONS: Removal of the deep lateral orbital wall as part of a coronal-approach, 3-wall decompression, enhances the degree of exophthalmos reduction without increasing the risk of consecutive diplopia.

Graves' ophthalmopathy: a rational approach to treatment.

The past decade has witnessed great progress in our understanding of Graves' opthalmopathy (GO), although its precise immunopathogenesis remains an enigma. Several clinical studies have provided a more rational basis for treatment of this distressing disease, which significantly lowers the quality of life. A management plan tailored to the patient's needs can be devised according to the severity and activity of the eye disease. In active GO, immunosuppression might be considered. The combination of intravenous pulses of methylprednisolone and retrobulbar irradiation improves eye changes in 88% of patients, and is well tolerated. Once the disease has become inactive, rehabilitative surgery could be performed (orbital decompression, strabismus surgery and eyelid surgery, in that order). The patient should be reassured that functional and cosmetic improvement of eye changes is feasible, but restoration can require one to two years. To a certain extent, refraining from smoking prevents the development or worsening of GO.

Thyrotropin receptor autoantibodies are associated with continued thyrotropin suppression in treated euthyroid Graves' disease patients.

Antithyroid treatment effectively restores euthyroidism in patients with Graves' hyperthyroidism. After a few months of treatment, patients are clinically euthyroid with normal levels of thyroid hormones, but in many patients TSH levels remain suppressed. We postulated that TSH receptor autoantibodies could directly suppress TSH secretion, independently from thyroid hormone levels, via binding to the pituitary TSH receptor. To test this hypothesis, we prospectively followed 45 patients with Graves' hyperthyroidism who were treated with antithyroid drugs. Three months after reaching euthyroidism, blood was drawn for the analysis of thyroid hormones, TSH, and TSH binding inhibitory Ig (TBII) levels. After 6.7 +/- 1.5 months since start of antithyroid treatment, 20 patients still had detectable TBII levels, and 25 had become TBII negative. The two groups had similar levels of free T(4) and T(3), but TBII-positive patients had lower TSH values than TBII-negative patients: median 0.09 (range < 0.01-4.30) mU/liter vs. 0.84 (0.01-4.20; P = 0.015). In addition, TSH levels correlated only with TBII titers (r = -0.424; P = 0.004), and not with free T(4) or T(3) values. Our findings suggest that TBII suppress TSH secretion independently of thyroid hormone levels, most likely by binding to the pituitary TSH receptor.

A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy.

Radiotherapy is often used in Graves' ophthalmopathy, but its efficacy has been doubted. We compared its efficacy with sham irradiation in mild ophthalmopathy. In a double-blind randomized trial, 44 patients received orbital irradiation, and 44 were sham-irradiated. The primary outcome was assessed using major and minor criteria. As secondary outcome, we used a disease-specific quality of life questionnaire (the GO-QoL) and compared cost-effectiveness and need for follow-up treatment. The primary outcome was successful in 23 of 44 (52%) irradiated patients vs. 12 of 44 (27%) sham-irradiated patients at 12 months after treatment (relative risk, 1.9; 95% confidence interval, 1.1-3.4; P = 0.02). Radiotherapy was effective in improving eye muscle motility and decreasing the severity of diplopia. However, quality of life improved similarly in both groups. In the radiotherapy group there was less need for follow-up treatment; 66% vs. 84% of the patients needed further treatment (P = 0.049). Retrobulbar irradiation did not prevent worsening of ophthalmopathy, which occurred in 14% of the irradiated and 16% of the sham-irradiated patients. Radiotherapy is an effective treatment in mild ophthalmopathy. However, the improvement upon irradiation may not be associated with an increase in quality of life or a reduction in treatment costs.

Thyroid autoimmunity and miscarriage.

To ascertain the strength of the association between thyroid autoimmunity and miscarriage, we performed a meta-analysis of both case-control and longitudinal studies performed since 1990 when this association was first described. A clear association between the presence of thyroid antibodies and miscarriage was found with an odds ratio (OR) of 2.73 (95 % confidence interval (CI), 2.20-3.40) in eight case-control and ten longitudinal (OR, 2.30; 95 % CI, 1.80-2.95) studies. This association may be explained by a heightened autoimmune state affecting the fetal allograft, of which thyroid antibodies are just a marker. Alternatively, the association can be partly explained by the slightly higher age of women with antibodies compared with those without (mean+/-S.D. age difference, 0.7+/-1.0 years; P<0.001). A third possibility is mild thyroid failure, as thyroid-stimulating hormone (TSH) levels in antibody-positive but euthyroid women are higher than in antibody-negative women: difference 0.81+/-0.58 mU/l (P=0.005). Randomized clinical trials with l-thyroxine (aiming at TSH values between 0.4 and 2.0 mU/l) and with selenium (to decrease antibodies against thyroid peroxidase) are clearly needed to elucidate further the nature of this association.

The environment and autoimmune thyroid diseases.

Genetic factors play an important role in the pathogenesis of autoimmune thyroid disease (AITD) and it has been calculated that 80% of the susceptibility to develop Graves' disease is attributable to genes. The concordance rate for AITD among monozygotic twins is, however, well below 1 and environmental factors thus must play an important role. We have attempted to carry out a comprehensive review of all the environmental and hormonal risk factors thought to bring about AITD in genetically predisposed individuals. Low birth weight, iodine excess and deficiency, selenium deficiency, parity, oral contraceptive use, reproductive span, fetal microchimerism, stress, seasonal variation, allergy, smoking, radiation damage to the thyroid gland, viral and bacterial infections all play a role in the development of autoimmune thyroid disorders. The use of certain drugs (lithium, interferon-alpha, Campath-1H) also increases the risk of the development of autoimmunity against the thyroid gland. Further research is warranted into the importance of fetal microchimerism and of viral infections capable of mounting an endogenous interferon-alpha response.

Long-term effects of Graves' ophthalmopathy on health-related quality of life.

OBJECTIVE: Little is known about the long-term effects of Graves' ophthalmopathy (GO) on health-related quality of life (HRQL) after the eye treatment is considered to be finished. The aim of this study was to quantify these effects using validated HRQL questionnaires. DESIGN: A cross-sectional follow-up study was carried out in GO patients who had started radiotherapy and/or prednisone treatment between 1982 and 1992. METHODS: Between 1998 and 2000 these patients received an HRQL questionnaire containing the SF-36, EuroQol and GO-QOL questionnaires. All patients were invited for a follow-up ophthalmological examination. HRQL scores of the respondents were compared with those of two reference populations of 'healthy' persons and to scores of several other GO populations. RESULTS: One hundred and sixty-eight patients were included; 163 completed the HRQL questionnaire and 154 visited the outpatient clinic. The median follow-up was 11.7 years. A considerable number of symptoms related to GO were found. More than half of the patients had diplopia and 28% had a low visual acuity. Sixty per cent had a proptosis of at least 20 mm. The HRQL scores were considerably better than those of newly diagnosed GO patients (untreated) and GO patients who completed the questionnaire during treatment, but worse than those of 'healthy' persons. Although we did not perform a longitudinal study, we included a selected group of patients who had been treated with radiotherapy and/or prednisone in the Academic Medical Centre of the University of Amsterdam, and though we could not assess HRQL at comparable times after receiving treatment, this is the first study that presents any data on the long-term effects of GO on HRQL. CONCLUSION: GO has a marked negative effect on HRQL, even many years after treatment. These findings suggest that GO should be considered a chronic disease. Aftercare is needed for these patients after their immunosuppressive and surgical treatments.

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.

Interferon-alpha and autoimmune thyroid disease.

Interferon-alpha (IFN alpha) is the main therapeutic agent in patients infected with the hepatitis C virus (HCV). It is rather safe, but is known to induce the production of autoantibodies and can lead to the occurrence of autoimmune disease. This minireview focuses on the induction of autoimmune thyroid disease (AITD) in HCV-infected patients treated with IFN alpha. Females carry a higher risk to develop AITD upon IFN alpha treatment, with a relative risk of 4.4 (95% confidence interval 3.2-5.9). The presence of thyroid peroxidase antibodies before therapy has a relative risk for AITD of 3.9 (95% confidence interval 1.9-8.1). IFN alpha-associated AITD can consist of autoimmune primary hypothyroidism, Graves' hyperthyroidism, and destructive thyroiditis, with hypothyroidism being the most common side effect. The clear association between AITD and IFN alpha use suggests that high endogenous IFN alpha levels may also be associated with naturally occurring AITD. High endogenous IFN alpha levels are seen in patients infected with certain viruses. It is concluded that IFN alpha is one of the environmental factors capable of triggering the onset of AITD in genetically susceptible individuals.

Ultra short-loop feedback control of thyrotropin secretion.

Evidence is accumulating that pituitary hormone secretion is not only regulated by feedback from hormones produced in the target organs (long feedback) on the pituitary and the hypothalamus (feedforward), but also by a feedback of the hypophyseal hormones at the hypothalamic (short feedback) and the pituitary (ultra-short feedback) level. Inhibition of thyrotropin (TSH) and MSH secretion by pituitary preparations by adding exogenous TSH or MSH to the medium was already observed in the 1960s, as was the phenomenon that adrenocorticotropic hormone (ACTH) injected in the hypothalamus lowered plasma corticosterone levels. These early observations have now been corroborated by the demonstration of the receptors for various pituitary hormones in the hypothalamus and the adenohypophysis. The thyrotropin receptor (TSHR) is found on folliculo-stellate cells in the pituitary, which are known to influence the neighboring endocrine cells. This pituitary TSR-receptor is also recognized by TSHR receptor autoantibodies, which can downregulate TSH secretion independently from thyroid hormone levels, and are therefore thought to be responsible for the frequently observed suppressed TSH levels in patients with Graves' disease who are otherwise euthyroid.

Stress is not associated with thyroid peroxidase autoantibodies in euthyroid women.

OBJECTIVE: Multiple genes and environmental factors play a role in the etiology of autoimmune thyroid disease (AITD). In Graves' hyperthyroidism, stress is such an environmental factor, but whether it plays a role in Hashimoto's hypothyroidism is unknown. We used validated questionnaires to evaluate an association between TPO antibodies, an early marker for AITD, and self-reported stress. SUBJECTS AND METHODS: Recently Experienced Stressful Life Events, Daily Hassles, and mood (tendency to report positive and negative affects) were assessed in 759 euthyroid subjects. RESULTS: TPO antibodies were found in 183/759 (24%) of subjects. The TPO-Ab positive subjects were older (39.7+/-12 vs. 34.2+/-12 years; p<.001) than the TPO-Ab negative subjects, but the number of daily hassles (24+/-14 vs. 25+/-14; p=.24), the number of stressful life events (10+/-6 vs. 11+/-6; p=.09), and the scores on the affect scales (22.1+/-7.4 vs. 22.2+/-7.3; p=.89 for negative affect and 38.2+/-5.1 vs. 38.3+/-5.3; p=.91 for positive affect) were similar in TPO-Ab positive and TPO- Ab negative subjects. CONCLUSIONS: We found no association between recently experienced stressful life events, daily hassles or mood and the presence of TPO antibodies in these euthyroid women.

Risk factors for and prevalence of thyroid disorders in a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease.

OBJECTIVE: Autoimmune thyroid disease (AITD) is a common disorder especially in women, and both genetic and environmental factors are involved in its pathogenesis. We wanted to gain more insight into the contribution of various environmental factors. Therefore, we started a large prospective cohort study in subjects at risk of developing AITD, for example healthy female relatives of AITD patients. Here we report on their baseline characteristics. SUBJECTS: Only first- or second-degree female relatives of patients with documented AITD were included. MEASUREMENTS: Smoking habits, oestrogen use, pregnancy history and iodine exposure were assessed by questionnaires, and correlated to the thyroid function and antibody status. RESULTS: Of 803 subjects, 440 came from families with more than one patient with documented AITD. Of these families, 33% had documented cases of both Graves' disease and Hashimoto's thyroiditis. Although the subjects were in self-proclaimed good health, 3.6% were found to have hypothyroidism (overt disease in 1.3%) and 1.9% had hyperthyroidism (overt disease in 0.4%). These patients were older than the euthyroid subjects and were mostly positive for thyroid peroxidase (TPO) antibodies. Oestrogen use was associated with a lower rate of hyperthyroidism [relative risk (RR) 0.169; 95% confidence interval (CI) 0.06-0.52], whereas having been pregnant was associated with a higher relative risk for hyperthyroidism (RR 6.88; 95% CI 1.50-30.96). Of the 759 euthyroid subjects, 24% had TPO antibodies. Smoking and oestrogen use were negatively correlated with the presence of TPO antibodies. In the euthyroid subjects, TPO antibody titre correlated positively with TSH levels (r = 0.386; P < 0.001). CONCLUSIONS: The high prevalence of evidence for autoimmune thyroiditis at baseline supports the importance of genetic factors in its pathogenesis. The co-occurrence of Hashimoto's thyroiditis and Graves' disease within one family suggests a common genetic basis for these diseases. Oestrogen use is associated with a lower risk, and pregnancy with a higher risk for developing hyperthyroidism. The positive correlation between TPO antibody titres and TSH levels in euthyroid subjects suggests that TPO antibodies are indeed a marker of future thyroid failure.

Facial disfigurement: is it in the eye of the beholder? A study in patients with Graves' ophthalmopathy.

OBJECTIVES: The importance of facial disfigurement in many diseases necessitates a reliable and valid measure of disfigurement severity for clinical studies. The hypothesis is that a universal concept of disfigurement exists and can be measured in a reliable way. The objectives of this study were to investigate if persons, in particular patients and physicians, can agree on facial disfigurement severity; and to determine the relative contribution of predefined clinical characteristics of patients with Graves' ophthalmopathy (GO) to the overall rating of facial disfigurement severity. DESIGN: A panel study was carried out in four different panels, each consisting of four members. PATIENTS: We randomly selected 100 slide pairs of GO patients from four available study populations, involving mild, moderate and severe GO patients (mean age 49 years, 76% female) who were treated with either radiotherapy, sham-irradiation, prednisone or orbital decompression. MEASUREMENTS: All panel members individually scored the disfigurement severity of 100 GO patients shown on standardized slides on a Visual Analog Scale. In total, 1600 ratings were collected. We calculated within- and between-panel agreement of disfigurement severity and identified determinants of disfigurement. RESULTS: Agreement within a panel varied from 0.65 to 0.79 and was highest within the panel of ophthalmologists. Between-panel agreement was 0.67 and was highest between ophthalmologists and laypersons. Compared with the global average, patients overrated and endocrinologists underrated disfigurement severity. Female panellists rated the patients, on average, more disfigured than male panellists. Important determinants of disfigurement were eyelid retraction, severe eyelid swelling and proptosis. Their relative importance was consistent across panels and in contrast to current measures of GO severity. CONCLUSION: Facial disfigurement severity can be measured in a reliable way using panels of panellists. Except for some systematic differences between panellists, facial disfigurement does not seem to be in the eye of the beholder.

Orbital irradiation for Graves' ophthalmopathy: Is it safe? A long-term follow-up study.

PURPOSE: We evaluated the frequency of long-term complications of orbital irradiation (radiation-induced tumors, cataract, and retinopathy) in comparison with glucocorticoids. DESIGN: We conducted a follow-up study in a cohort of 245 Graves' ophthalmopathy patients who had been treated with retrobulbar irradiation (20 Gy in 2 weeks) and/or oral glucocorticoids between 1982 and 1993 in our institution. Irradiated patients were compared with nonirradiated patients. METHODS: Data on mortality and cause of death were obtained. Living patients were invited to participate in a follow-up study. Possible retinopathy was assessed in a masked fashion and defined as the presence of > or =1 hemorrhages and/or microaneurysms on red-free retina photographs. If >5 lesions were present, patients were categorized as suffering from definite retinopathy. Cataract was assessed using the Lens Opacity Classification System II score. MAIN OUTCOME MEASURES: Mortality, prevalence of retinopathy, prevalence of cataract, and type of cataract. RESULTS: Thirty-seven of the 245 patients had died, none of them from an intracranial tumor. Mortality was similar in the irradiated (27/159 [17%]) and nonirradiated patients (10/86 [12%]; P = 0.264). One hundred fifty-seven of the 208 living patients (75%) consented to participate in a follow-up ophthalmologic investigation; the mean follow-up time (+/- standard deviation) was 11+/-3 years. Possible retinopathy was present in 15% of patients, 22 of the irradiated and 1 of the nonirradiated patients (P = 0.002). In 5 patients (all had been irradiated), definite retinopathy (i.e., >5 retinal lesions) was present. Of these, 3 had diabetes mellitus, and 1 had hypertension. Diabetes was associated with both possible (P = 0.029) and definite (P = 0.005) retinopathy, with a relative risk of 21 (95% confidence interval, 3-179). The prevalence and severity of cataract were similar in the radiotherapy group (29%) and the glucocorticoid group (34%); it should be noted that 88 of 104 of the irradiated patients were also treated with oral glucocorticoids. CONCLUSION: The data suggest that orbital irradiation for Graves' ophthalmopathy is a safe treatment modality, except possibly for diabetic patients.