Orbital radiotherapy for Graves' ophthalmopathy: useful or useless? Safe or dangerous?

Treatment of Graves' ophthalmopathy does not always provide favorable results. After several decades of efforts, glucocorticoids, orbital radiotherapy (OR) and surgery (orbital decompression) remain the milestones in the management of this disease. OR produce favorable results in about 55-60% of patients. Its effectiveness is increased by the association with systemic glucocorticoids. Recent studies have cast some doubts on its real effectiveness and this is discussed by participants in this Forum. Selection of patients is particularly important to assess treatment outcome, because OR is unlikely to provide beneficial effects in patients with longstanding and inactive eye disease. OR is a safe procedure, with very limited side-effects. It should be used in patients older than 35 years of age. It is recommended that a large, multi-center, prospective, randomized and controlled study with well defined inclusion criteria be carried out to draw sound conclusions on the role of OR in the management of Graves' ophthalmopathy.

A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy.

CONTEXT: Although widely used for more than 85 years, the efficacy of radiotherapy for Graves' ophthalmopathy (GO) has not been established convincingly. OBJECTIVE: To evaluate the efficacy of radiotherapy for GO. DESIGN: Prospective, randomized, internally controlled, double-blind clinical trial in a tertiary care academic medical center. PARTICIPANTS: The patients were ethnically diverse males and females over age 30 seen in a referral practice. The patients had moderate, symptomatic Graves' ophthalmopathy (mean clinical activity score, 6.2) but no optic neuropathy, diabetes, recent steroid treatment, previous decompression, or muscle surgery. Forty-two of 53 consecutive patients were enrolled after giving informed consent and fulfilling study entry criteria. Eleven eligible patients declined to participate because of inconvenience, desire for alternative therapy, or concern about radiation. INTERVENTION: One randomly selected orbit was treated with 20 Gy of external beam therapy; sham therapy was given to the other side. Six months later, the therapies were reversed. MAIN OUTCOME MEASURES: Every 3 months for 1 year, we measured the volume of extraocular muscle and fat, proptosis, range of extraocular muscle motion, area of diplopia fields, and lid fissure width. Effective treatment for GO will modify one or more of these parameters. RESULTS: No clinically or statistically significant difference between the treated and untreated orbit was observed in any of the main outcome measures at 6 months. At 12 months, muscle volume and proptosis improved slightly more in the orbit that was treated first. CONCLUSIONS: In this group of patients, representative of those for whom radiotherapy is frequently recommended, we were unable to demonstrate any beneficial therapeutic effect. The slight improvement noted in both orbits at 12 months may be the result of natural remission or of radiotherapy, but the changes are of marginal clinical significance.

The aftermath of childhood hyperthyroidism.

Long-term consequences of juvenile hyperthyroidism can result both from the disease itself and from the treatment used. In most children with thyrotoxicosis, the manifestations of the disease on bone metabolism, cardiac function and neurological and psychiatric findings are related to the hyperthyroid status and disappear with restoration to the euthyroid state. Late late consequences are unknown. Permanent adverse effects are due to the treatments used. Antithyroid drugs are associated with mild adverse consequences in 28% of the patients treated. Serious complications, such as agranulocytosis, aplastic anemia and death, have been reported. Review of surgical complications showed the incidence of permanent hypoparathyroidism 2%, permanent cord paralysis 2% and approximately one death for each 1,000 thyroidectomies. The adverse effects of radioiodine therapy remain largely theoretical, when children were treated with ablative doses of I131. Childhood ophthalmopathy improves after radioiodine therapy.

Are posttherapy radioiodine scans informative and do they influence subsequent therapy of patients with differentiated thyroid cancer?

UNLABELLED: Posttherapy scans (PTS) with a gamma camera are typically used after therapeutic doses of 131I to visualize metastases that may not be seen with lower dose diagnostic scans. During a 16-month period, we studied 81 patients (64 with papillary thyroid cancer and 17 with follicular thyroid cancer), who had both a diagnostic whole-body scan (131I dose 3 mCi) and a PTS. A total of 117 PTS were evaluated. At the time of PTS, clinical or radiologic evidence of metastatic or residual disease was present in 68 patients (84%). The anatomic sites of known disease included, neck (63), mediastinum (23), lung (35), bone (14), trachea (16), esophagus (5), and brain (2). PTS showed focal areas of abnormal uptake not seen in diagnostic scans in 15 scans (13%). Areas with abnormal new uptake included: neck (5), lung (5), mediastinum (4), bone (2), and adrenal (1). In 7 patients (9%) the PTS results impacted future decisions regarding plans for subsequent diagnostic scanning and 131I therapy or changed the patient's risk group category. IN CONCLUSION: (1) 13% of 117 PTS demonstrated abnormal foci of 131I uptake not seen on pretherapy scans and (2) PTS changed management strategy in 9% of the studied patients.

DEMS - a second generation diabetes electronic management system.

Diabetes electronic management system (DEMS) is a component-based client/server application, written in Visual C++ and Visual Basic, with the database server running Sybase System 11. DEMS is built entirely with a combination of dynamic link libraries (DLLs) and ActiveX components - the only exception is the DEMS.exe. DEMS is a chronic disease management system for patients with diabetes. It is used at the point of care by all members of the diabetes team including physicians, nurses, dieticians, clinical assistants and educators. The system is designed for maximum clinical efficiency and facilitates appropriately supervised delegation of care. Dispersed clinical sites may be supervised from a central location. The system is designed for ease of navigation; immediate provision of many types of automatically generated reports; quality audits; aids to compliance with good care guidelines; and alerts, advisories, prompts, and warnings that guide the care provider. The system now contains data on over 34000 patients and is in daily use at multiple sites.

Towards an optimal model for community-based diabetes care: design and baseline data from the Mayo Health System Diabetes Translation Project.

The objective of the Mayo Health System Diabetes Translation Project is to assess the impact of three different models of care on the overall quality of diabetes care in the community. The unit of study is the primary care practice with a different model of care implemented at each of three sites. The design incorporates a comparison of a diabetes guideline implementation team initiative (Practice model A), a guideline initiative combined with clinical use of a Diabetes Electronic Management System (DEMS) by primary care providers (Practice model B) and a guideline initiative combined with DEMS utilization combined with electronic review of DEMS patient encounters by an endocrinologist (Practice model C). Administrative data sets were used to define the patient population at each practice. Patients were designated as new, attending or non-attending based on their pattern of visits over the preceding 12 months. A random sample of 200 charts from attending patients at each site was audited at baseline for diabetes-related process and outcome measures. This audit will be repeated yearly during the 2 years of the project. Baseline data revealed significant differences across sites in adherence to certain key indicators of the quality of diabetes care including: frequency of documentation of eye examinations (19, 39 and 37% for sites A, B and C, respectively), haemoglobin A1c monitoring (64, 89 and 77%) and microalbumin monitoring (3, 15 and 6%). The interventions being assessed in this study include traditional (diabetes education; guideline implementation) and modern (DEMS; telemedicine specialist review) methods for improving the quality of diabetes care. In spite of variation in baseline quality indicators, the setting and design should lead to broad applicability of the results and help determine an optimal model of diabetes care in the community.

Radioiodine and pregnancy.

The fetal thyroid begins to accumulate radioiodine around the 12th week of pregnancy. Iodide easily crosses the placenta and fetal thyroid uptake can be effectively blocked by administration of radioiodine to the mother. Therapeutic administration of radioiodine to the mother will usually result in fetal hypothyroidism and may be associated with attention deficit disorders and impairment of figurative memory in the offspring. The hazard to a fetus from exposure to a family member, not the mother, who has been treated with radioiodine is very small and can be minimized by adherence to standard post treatment guidelines. Lactating mothers who have received standard diagnostic doses of 131I or who have been treated with 131I should not breast-feed their infant from that point forward. Breast-feeding in future pregnancies is not contraindicated. Pregnancy testing within 48 hours before 131I administration to potentially fertile women is a wise clinical practice. Demonstrated effects of radioiodine on spermatogenesis suggest that it is wise to recommend a 120-day waiting period between radioiodine and fertilization.

The measurement of change in Graves' ophthalmopathy.

Precise measurements of treatment response are a prerequisite for correct interpretation of therapeutic benefit. In the field of Graves' ophthalmopathy we have relied for too long on methods of measurement that are poorly reproducible, subjective, and that often rely on indices derived from aggregated measurements and subjective impressions. In consequence, our conclusions about the benefits of particular therapies are frequently controversial. Until the pathogenic agent of Graves' ophthalmopathy has been identified and is measurable, we are forced to limit our observations to the consequences of the action of that agent. Two critically important consequences are swelling of the retrobulbar muscles and connective tissue and shortening of the extraocular muscle range of contraction. From these primary events all the clinical features of Graves' ophthalmopathy are derived. Effective treatment of Graves' eye disease will affect at least one of five relevant measurements. These are: lid fissure width, range of extraocular motion, diplopia fields, and volume of retrobulbar muscle and connective tissue. These measurements, selected to correspond to the claims of the particular therapy under study, are recommended as the indicators of choice in clinical trials.

Impact of a diabetes electronic management system on the care of patients seen in a subspecialty diabetes clinic.

OBJECTIVE: To compare the compliance with diabetes care performance indicators by diabetes specialists using a diabetes electronic management system (DEMS) and by those using the traditional paper medical record. RESEARCH DESIGN AND METHODS: A DEMS has been gradually introduced into our subspecialty practice for diabetes care. To assess the value of this DEMS as a disease management tool, we completed a retrospective review of the medical records of 82 randomly selected patients attending a subspecialty diabetes clinic (DC) during the first quarter of 1996. Eligible patients were defined by the suggested criteria from the American Diabetes Association Provider Recognition Program. During the first quarter of 1996, approximately one half of the providers began using the DEMS for some but not all of their patient encounters. Neither abstractors nor providers were aware of the intent to examine performance in relationship to use of the DEMS. RESULTS: Several measures were positively influenced when providers used the DEMS. The number of foot examinations, the number of blood pressure readings, and a weighted criterion score were greater (P < 0.01) for providers using the DEMS. There was evidence, although not statistically significant, for lower mean diastolic blood pressures (P = 0.043) in patients and for number of glycated hemoglobins documented (P = 0.018) by users of the DEMS. CONCLUSIONS: Performance and documentation of the process of care for patients with diabetes in a subspecialty clinic are greater with the use of a DEMS than with the traditional paper record.

Euthyroid sick syndrome: an overview.

Abnormalities of thyroid hormone concentrations are seen commonly in a wide variety of nonthyroidal illnesses, resulting in low triiodothyronine, total thyroxine, and thyroid stimulating hormone concentrations. These thyroid hormone changes may be mediated in part by cytokines or other inflammatory mediators, acting at the level of the hypothalamus and pituitary, the thyroid gland, and the hepatic deiodinase system, as well as on binding of thyroxine to thyroid binding globulin. The degree of thyroid function disturbance correlates with disease severity and low levels of thyroid hormones predict a poor prognosis in several illnesses. It remains unresolved whether the hormone responses in the euthyroid sick syndrome represent part of an adaptive response, which lowers tissue energy requirements in the face of systemic illness, or a maladaptive response, which induces damaging tissue hypothyroidism. Consequently, the use of thyroid hormone therapy in the euthyroid sick syndrome is controversial. The small number of controlled trials performed to date have shown conflicting results on the cardiovascular effects of triiodothyronine, and none has had the statistical power to address the question of altered mortality. Future trials of therapy should concentrate on patients with severe nonthyroidal illness and a high mortality rate. Meanwhile, better understanding is needed of the impact of the altered thyroid hormone status on tissue function.

Long-term follow-up of Graves ophthalmopathy in an incidence cohort.

PURPOSE: To provide long-term follow-up data on patients with Graves ophthalmopathy in an incidence cohort of 120 patients. METHODS: Data were obtained from a comprehensive review of each patient's community medical record, a follow-up survey, or both. RESULTS: The median interval between the initial ophthalmic examination and most recent follow-up was 9.8 years (range, 64 days to 17.4 years). Follow-up of more than 5 years was available for 96 patients (80.0 percent), whereas follow-up exceeding 10 years was achieved for 59 patients (49.2 percent). Persistent visual loss from optic neuropathy occurred in two eyes, with final visual acuities of 20/30 and 20/60, respectively. None of the patients reported deterioration of vision attributable to Graves ophthalmopathy in the interval since their last ophthalmic examination at the authors' institution. Two patients (2.2 percent) had constant diplopia, but it was correctable with spectacles (prisms) in each case. Nearly one third of respondents had had ocular discomfort during the preceding 4 weeks; the most frequent cause in 72 percent of patients was dry eyes. Among the respondents to the survey, 60.5 percent believed that the appearance of their eyes had not returned to what it had been before the development of thyroid disease, 51.6 percent thought that their eyes appeared abnormal, and 37.9 percent were dissatisfied with the appearance of their eyes. CONCLUSIONS: Although with treatment few patients have long-term functional impairment from Graves ophthalmopathy, more than one third of patients are dissatisfied with their ultimate appearance. The psychologic, aesthetic, economic, and social sequelae of the disorder require further definition by formal outcomes studies.

Chronology of Graves' ophthalmopathy in an incidence cohort.

PURPOSE: To determine the chronologic characteristics of Graves' ophthalmopathy in an incidence cohort of 120 patients. METHODS: We reviewed the community medical records of 120 patients residing in Olmsted County, Minnesota, in whom Graves' ophthalmopathy had been diagnosed between 1976 and 1990. RESULTS: Median age at the time of diagnosis of Graves' ophthalmopathy was 43 years; the minimum and maximum ages were 8 and 88 years, respectively. Among 108 patients with hyperthyroidism, ophthalmopathy was diagnosed in the six-month interval preceding the diagnosis of thyroid dysfunction in 20 patients (18.5%); ophthalmopathy was concurrent with the diagnosis of hyperthyroidism in 22 patients (20.3%); and ophthalmopathy developed in the six-month interval after thyroid diagnosis in 24 patients (22.2%). Ophthalmopathy was diagnosed more than six months before the diagnosis of hyperthyroidism in only four additional patients (3.7%), whereas ocular changes developed six months or more after thyroid disease in the remaining 38 patients (35.2%). There was no significant seasonal variation in the diagnosis of either thyroid dysfunction or ophthalmopathy. Treatment of hyperthyroidism with iodine-131 did not appear to influence the course of Graves' ophthalmopathy. CONCLUSIONS: There is a strong temporal relationship between the thyroid and eye manifestations of Graves' disease. The diagnosis of Graves' ophthalmopathy tends to follow the diagnosis of hyperthyroidism. Treatment with iodine-131 does not appear to influence the course of Graves' ophthalmopathy. Although both childhood Graves' disease and Graves' ophthalmopathy are uncommon, ophthalmopathy occurs at all ages.

Clinical features of Graves' ophthalmopathy in an incidence cohort.

PURPOSE: To determine the clinical characteristics of an incidence cohort of patients with Graves' ophthalmopathy. METHODS: We reviewed the community medical records of 120 patients residing in Olmsted County, Minnesota, in whom Graves' ophthalmopathy was diagnosed between 1976 and 1990. RESULTS: Among 120 patients with Graves' ophthalmopathy, 108 (90%) patients had Graves' hyperthyroidism, one (1%) had primary hypothyroidism, four (3%) had Hashimoto's thyroiditis, and seven (6%) were euthyroid. At some point in their clinical course, eyelid retraction was present in 108 patients, whereas the approximate frequency of exophthalmos was 62% (73 patients); restrictive extraocular myopathy, 43% (51 patients); and optic nerve dysfunction, 6% (seven patients). Only six (5%) patients had eyelid retraction, exophthalmos, optic nerve dysfunction, extraocular muscle involvement, and hyperthyroidism. At the time of diagnosis of ophthalmopathy, upper eyelid retraction and eyelid lag were documented in 85 and 52 patients, respectively, and the most frequent ocular symptom was pain (36 patients, 30%). Diplopia was noted at the initial examination by 20 patients, lacrimation was present in 25 patients, 19 patients had photophobia, and nine patients had blurred vision. Decreased vision from optic neuropathy was present in less than 2% of eyes at the time of diagnosis. Thyroid dermopathy and acropachy accompanied Graves' ophthalmopathy in five patients (4%) and one (1%) patient, respectively. Myasthenia gravis occurred in only one patient. CONCLUSIONS: Eyelid retraction is the most common clinical sign of Graves' ophthalmopathy. The complete constellation of typical features (hyperthyroidism, eyelid retraction, exophthalmos, restrictive extraocular myopathy, and optic nerve dysfunction) occurs relatively infrequently.

The treatment of Graves' ophthalmopathy in an incidence cohort.

PURPOSE: To determine the frequencies of medical and surgical treatments in an incidence cohort of 120 patients with Graves' ophthalmopathy. METHODS: We reviewed the community medical records and administered a follow-up questionnaire. RESULTS: Of the 120 patients, 89 (74.2%) required either no therapy or only supportive measures. Six patients (5.0%) were treated with systemic corticosteroids. One patient had orbital radiotherapy. Twenty-four patients (20.0%) underwent one or more surgical procedures. The cumulative probabilities of undergoing ophthalmic surgery of any type were 5.0% by one year after the diagnosis of ophthalmopathy, 9.3% after two years, 15.9% after five years, and 21.8% after ten years. The need for surgery was significantly related to age (P < .01; Cox proportional hazards model) but was not significantly dependent on gender (P = .5) or the interaction of age and gender (P = .15). The overall risk of the need for surgery was 2.6 times greater in patients older than 50 years (95% confidence interval, 1.2 to 5.8) than in younger patients. There were no significant differences between tobacco smokers and nonsmokers in the cumulative probabilities of undergoing surgery. CONCLUSION: In 24 (20%) patients, one or more surgical procedures were used to treat Graves' ophthalmopathy. The probability of surgical intervention was significantly related to patient age (older than 50 years), but it was not related to gender or smoking.

The incidence of Graves' ophthalmopathy in Olmsted County, Minnesota.

PURPOSE: To determine the incidence of Graves' ophthalmopathy. METHODS: A population-based cohort of all Olmsted County, Minnesota, residents who had ophthalmopathy associated with autoimmune thyroid disease between Jan. 1, 1976, and Dec. 31, 1990, was identified through the medical diagnostic index of the Mayo Clinic and the Rochester Epidemiology Project. RESULTS: One hundred twenty incident patients were identified, of whom 103 (85.8%) were women (P = .00001; normal relative deviate test). The overall age-adjusted incidence rate for women was 16.0 cases per 100,000 population per year, whereas the rate for men was 2.9 cases per 100,000 population per year (standardized rate ratio, 5.5; 95% confidence interval, 3.3 to 9.3). The distribution of incidence rates by five-year age groups included peak incidence rates in the age groups 40 to 44 years and 60 to 64 years in women, and 45 to 49 years and 65 to 69 years in men. CONCLUSIONS: Incidence rates for Graves' ophthalmopathy exhibited an apparent bimodal peak for both men and women, although the peaks for men occurred approximately five years after those for women. No explanation for these trends was apparent from the data collected.

Distant metastases in papillary thyroid carcinoma: 100 cases observed at one institution during 5 decades.

The present study was designed to define the factors that predict survival in patients with distant metastases (DM) from papillary thyroid carcinoma. We performed a retrospective review of the records of 100 consecutive patients (45 females and 55 males; age range, 8-91 yr) who developed DM after primary treatment at our institution from, 1940-1989. Median follow-up for the 20 survivors was 21 yr (range, 3-38). Cause-specific survival rates at 5, 10, and 15 yr were 40%, 27%, and 24%, respectively, and were not significantly different between the eras 1940-1954, 1955-1969, and 1970-1989 (P = 0.74). By univariate analysis, age at diagnosis of DM was the most important predictor of survival (P < 0.0001), with improved survival occurring in younger patients. Tumor-related factors associated with improved survival included complete resection of the primary tumor (P < 0.005), histological grade 1 (P = 0.006), diploid nuclear DNA (P = 0.03), and lung as first site of DM (P = 0.018). By univariate analysis, use of radioiodine therapy was associated with improved survival (vs. other forms of therapy, P < 0.001). However, by multivariate analysis only age, site of DM, and degree of extrathyroidal invasion of the primary tumor were identified as significant predictors of survival. None of the four treatment variables (external radiation, surgery, chemotherapy, or radioiodine) was a significant predictor of survival in the Cox model. Our retrospective data indicate that 1) outcome has changed little over 5 decades for patients with DM from papillary thyroid carcinoma; and 2) current forms of therapy do not appear to impact on survival.

Diagnostic criteria for Graves' ophthalmopathy.

PURPOSE: To propose criteria for the diagnosis of Graves' ophthalmopathy. METHODS: We reviewed the evolution of nomenclature describing Graves' ophthalmopathy. and the diagnostic schema used in key published reports. RESULTS: A laboratory test or clinical finding pathognomonic for Graves' ophthalmopathy currently is not available or recognized. Extant diagnostic criteria may exclude appropriate cases. CONCLUSIONS: Graves' ophthalmopathy is considered to be present if eyelid retraction occurs in association with objective evidence of thyroid dysfunction or abnormal regulation, exophthalmos, optic nerve dysfunction, or extraocular muscle involvement. The ophthalmic signs may be unilateral or bilateral, and confounding causes must be excluded. If eyelid retraction is absent, then Graves' ophthalmopathy may be diagnosed only if exophthalmos, optic nerve involvement, or restrictive extraocular myopathy is associated with thyroid dysfunction or abnormal regulation and if no other cause for the ophthalmic feature is apparent.