Maria Laura Tanda

Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy.

BACKGROUNDnThe chief clinical characteristics of Graves disease are hyperthyroidism and ophthalmopathy. The relation between the two and the effect of treatment for hyperthyroidism on ophthalmopathy are unclear.nnnMETHODSnWe studied 443 patients with Graves hyperthyroidism and slight or no ophthalmopathy who were randomly assigned to receive radioiodine, radioiodine followed by a 3-month course of prednisone, or methimazole for 18 months. The patients were evaluated for changes in the function and appearance of the thyroid and progression of ophthalmopathy at intervals of 1 to 2 months for 12 months. Hypothyroidism and persistent nyperthyroiaism were promptly corrected.nnnRESULTSnAmong the 150 patients treated with radioiodine, ophthalmopathy developed or worsened in 23 (15 percent) two to six months after treatment. The change was transient in 15 patients, but it persisted in 8 (5 percent), who subsequently required treatment for their eye disease. None of the 55 other patients in this group who had ophthalmopathy at base line had improvement in their eye disease. Among the 145 patients treated with radioiodine and prednisone, 50 (67 percent) of the 75 with ophthalmopathy at base line had improvement, and no patient had progression. The effects of radioiodine on thyroid function were similar in these two groups. Among the 148 patients treated with methimazole, 3 (2 percent) who had ophthalmopathy at base line improved, 4 (3 percent) had worsening of eye disease, and the remaining 141 had no change.nnnCONCLUSIONSnRadioiodine therapy for Graves hyperthyroidism is followed by the appearance or worsening of ophthalmopathy more often than is therapy with methimazole. Worsening of ophthalmopathy after radioiodine therapy is often transient and can be prevented by the administration of prednisone.

Cigarette Smoking and Treatment Outcomes in Graves Ophthalmopathy

Cigarette smoking is a risk factor for Graves ophthalmopathy [1]. Ophthalmopathy is more frequent and tends to be more severe in smokers than in nonsmokers [2]. Smoking may influence ophthalmopathy through direct irritative effects or by modulating immune reactions that occur in Graves ophthalmopathy [1]. Radioiodine therapy for Graves hyperthyroidism seems to be associated with an increased risk for progression of ophthalmopathy [3-5], but this view is not shared by all investigators [6, 7]. Discrepant results may be related to confounding variables, one of which may be smoking. Severe Graves ophthalmopathy can be treated with medical therapy, usually by glucocorticoids with or without orbital radiation therapy or by orbital decompression [8]. Results of medical treatment are not always satisfactory, and the reasons for nonuniform treatment outcome are not fully understood. We sought to determine whether cigarette smoking influences the untoward effects of radioiodine therapy on ophthalmopathy and the effectiveness of medical therapy for severe ophthalmopathy. Methods Patients Study 1 Study 1 included 300 patients receiving radioiodine treatment for Graves hyperthyroidism with mild or no ophthalmopathy. Mild ophthalmopathy was defined as proptosis less than 22 mm, intermittent or no diplopia, absence of optic neuropathy, and mild conjunctival and periorbital inflammation. Exclusion criteria were severe ophthalmopathy, large goiter requiring thyroidectomy, and contraindications to glucocorticoids. The 300 patients, who previously took part in a study analyzing the effect of radioiodine on ophthalmopathy [5], were assigned by computer-generated random numbers to treatment with radioiodine alone or radioiodine followed by a 3-month course of oral prednisone (initial dosage, 0.4 to 0.5 mg/kg of body weight per day) [3]. Five patients in the radioiodine plus prednisone group were lost to follow-up. Smoking habits did not differ in the two groups. Study 2 This retrospective study included 150 consecutive patients with severe ophthalmopathy (110 women and 40 men; mean age, 41 years [range, 30 to 63 years]) treated from 1989 to 1995 with orbital radiation therapy (20 Gy per eye) and high-dose oral prednisone (initial dose, 80 to 100 mg) [9]. The prednisone dose was gradually tapered, and therapy was discontinued after 6 months. Severe ophthalmopathy was defined as proptosis of 22 mm or more, inconstant or constant diplopia, and marked inflammatory soft-tissue changes with or without optic neuropathy. The study was approved by the institutional review board, and informed consent was obtained from patients. Smoking Habits The number of cigarettes smoked was measured in pack-years, expressed as x = a x b/c, where a = number of cigarettes smoked per day, b = number of years of smoking, and c = 20 cigarettes per pack. Patients who had refrained from smoking for less than 1 year were considered smokers. Smokers were subdivided into light ( 10 pack-years), moderate (11 to 19 pack-years), and heavy smokers ( 20 pack-years). Ocular Evaluation Ocular evaluation, performed by one examiner who was blinded to treatment and smoking groups, included assessment of soft-tissue changes; measurement of proptosis (by Hertel exophthalmometry), ocular tension, and lid width; evaluation of eye muscle function (Hess chart or computerized perimetry); and determination of visual acuity. The activity score was determined according to the method of Mourits and colleagues [10], which includes consideration of seven manifestations (spontaneous retrobulbar pain, pain with eye movements, eyelid erythema, eyelid edema, conjunctival injection, chemosis, and swelling of the caruncle); one point was given to any manifestation, for a score from 0 (no activity) to 7 (very high activity). Each patient provided a self-assessment evaluation sheet. Appearance, progression, and alleviation of ophthalmopathy were defined according to major and minor criteria [5]. Major criteria were variations in exophthalmometer readings and lid width of 2 mm or more, diplopia (intermittent, inconstant, or constant), variations in activity score of 2 points or more, and changes in visual acuity of 1/10 or more. Minor criteria were variations in soft tissues or self-assessment. Appearance, progression, and alleviation of ophthalmopathy were defined by changes in at least two major criteria and one minor criterion [5]. Statistical Analysis Differences in the prevalence of smokers in the two studies were analyzed by using a chi-square test with Yates correction for continuity. Exact binomial 95% CIs were calculated for all proportions. Patients in study 1 were included in an intention-to-treat analysis in which the effects of radioiodine or radioiodine plus prednisone on ophthalmopathy were evaluated according to the predefined criteria outlined above. Role of the Study Sponsor Neither funding source had a role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Study 1 Among patients who received radioiodine alone, 23 (15.3% [95% CI, 10% to 22%]) had progression of ophthalmopathy. Ocular conditions were unchanged in the remaining 127 patients [5]. Among patients who received radioiodine plus prednisone, 0 had progression and 50 of 75 (66.7% [CI, 55% to 77%]) had alleviation of eye disease [5]. In the group that received radioiodine alone, ophthalmopathy progressed in 4 of 68 nonsmokers (5.9% [CI, 3% to 9%]) and 19 of 82 smokers (23.2% [CI, 13% to 33%]) (P = 0.007). In the group that received radioiodine plus prednisone, ophthalmopathy was alleviated in 37 of 58 nonsmokers (63.8% [CI, 51% to 78%]) and 13 of 87 smokers (14.9% [CI, 10% to 22%]) (P < 0.001) (Table 1). Table 1. Smoking Behavior and Outcome of Mild Graves Ophthalmopathy Study 2 Of 150 consecutive patients, 85 (57%) were smokers. Sixty patients (40%) had an excellent or good response to therapy and 59 (39.3%) had a moderate response. Ophthalmopathy remained unchanged in 26 patients (17.3%) and progressed in 5 (4.3%). Duration of ophthalmopathy did not differ among groups. Sixty-one of 65 nonsmokers (93.8% [CI, 90% to 98%]) and 58 of 85 smokers (68.2% [CI, 57% to 78%]) (P < 0.001) responded to therapy (Table 2). Thirty-three of the 58 smokers who responded to therapy (56.9% [CI, 45% to 68%]) and 5 of 27 nonresponders (18.5% [CI, 9% to 29%]) were light smokers (P = 0.01). Table 2. Smoking Behavior and Outcome of Treatment of Severe Graves Ophthalmopathy with Orbital Radiation Therapy and High-Dose Glucocorticoids Discussion The results of our randomized study showed that cigarette smoking was associated with progression of mild ophthalmopathy, seen in 15% of patients after radioiodine therapy. In addition, smoking was associated with reduced efficacy of glucocorticoids given concomitantly with radioiodine. In the retrospective study, smoking and degree of smoking seemed to adversely affect the outcome of orbital radiation therapy and high-dose glucocorticoid treatment in patients with severe ophthalmopathy. Cigarette smoking is a risk factor for Graves ophthalmopathy. The prevalence of smoking is higher in patients with Graves disease who have ophthalmopathy than in those who do not have ophthalmopathy [1], and some [2, 11, 12] but not all [13] studies show a relation between degree and duration of smoking and severity of ophthalmopathy. Tallstedt and associates [4] reported that progression of ophthalmopathy after radioiodine therapy was more frequent in smokers than in nonsmokers, although differences were not statistically significant. Similarly, in a small series of Chinese women, Kung and coworkers [14] found no differences between smokers and nonsmokers in the progression of ophthalmopathy after radioiodine therapy. The differences between our results and those of previous studies may be explained by the larger number of patients and the consequent greater power of our study. Ethnic factors may also be important: Asian patients have a lower risk for ophthalmopathy, and the prevalence of smoking among Asian women is low [11]. Medical management of severe ophthalmopathy mostly relies on orbital radiation therapy or treatment with high-dose steroids, but results are not always favorable [8]. This may be related to several factors, including the long duration or limited activity of ophthalmopathy [8]. Our results suggest that smoking also negatively affects treatment outcome. Of note, several smokers in study 1 had no progression of ophthalmopathy after radioiodine therapy, and the condition improved with concomitant prednisone treatment. Similarly, in study 2, several smokers had excellent or good responses to orbital radiation therapy and high-dose glucocorticoid therapy. This implies that cigarette smoking is only one of many risk factors involved in the progression of ophthalmopathy. Identification of such risk factors should be a goal of future research so that treatment may be improved and disease may be prevented. The mechanisms by which cigarette smoking may affect the course of Graves ophthalmopathy and its response to treatment are largely unknown [1]. Besides having direct irritative effects, smoking may affect immune reactions occurring in the retro-orbital space [15]. Cytokines present in the retro-orbital tissues of patients with Graves ophthalmopathy [16] exert several actions relevant to the pathogenesis of the disease, including induction of expression of MHC class II molecules, heat-shock proteins, and adhesion molecules [16]. Cytokines also stimulate orbital fibroblasts to proliferate and to secrete glycosaminoglycans; the latter are responsible for most manifestations of the disease [15]. Smoking may intervene in cytokine-mediated paracrine and autocrine actions because smoking-induced hypoxia in the retrobulbar space stimulates the release of cytokines [17]. Interleukin-1 may play a pivotal role in this context, and interleuki

Orbital radiotherapy for Graves' ophthalmopathy.

Orbital radiotherapy is a well-established method of treatment for severe Graves ophthalmopathy, because of its anti-inflammatory and locally immunosuppressive effects. It has been used for 60 years. Conventional external x-ray and cobalt therapy have been abandoned, and most groups now use supervoltage linear accelerators (4–6 MeV). Cumulative doses may vary, but in most studies a cumulative dose of 20 Gy delivered over 2 weeks was utilized. Successful outcome depends on the selection of patients, because recent onset, active ophthalmopathy is much more favorably affected than longstanding, inactive disease. Inflammatory signs, recent onset eye muscle dysfunction, and optic neuropathy respond well to orbital radiotherapy, while proptosis and longstanding eye muscle restriction respond poorly. Overall, favorable responses have been reported, with few exceptions, in approximately 60% of cases. Combination of irradiation with high-dose systemic glucocorticoids provides better results than either treatment ...

Diagnosis and management of amiodarone‐induced thyrotoxicosis in Europe: results of an international survey among members of the European Thyroid Association

objectiveu2002 To determine how expert European thyroidologists assess and treat amiodarone‐induced thyrotoxicosis (AIT).

The course of Graves' ophthalmopathy is not influenced by near total thyroidectomy : a case-control study

The relationship between the method of treatment of hyperthyroidism due to Graves disease and the course of Graves ophthalmopathy is debated. Antithyroid drug therapy is associated with no change, or even amelioration, of ophthalmopathy. Although controversial, radioiodine may be followed by progression of eye disease, preventable by glucocorticoid administration. Whether thyroidectomy affects the course of ophthalmopathy is uncertain.

Lower Dose Prednisone Prevents Radioiodine-Associated Exacerbation of Initially Mild or Absent Graves’ Orbitopathy: A Retrospective Cohort Study

CONTEXTnRadioiodine (RAI) therapy may cause progression of mild or absent Graves orbitopathy (GO), preventable by oral prednisone. Optimal doses of prednisone are undefined.nnnOBJECTIVEnThe aim of this study was to compare the effectiveness of reported doses [starting dose, >0.3 mg/kg body weight (bw)], and lower (<0.3 mg/kg bw)] doses of prednisone.nnnDESIGN AND SETTINGnWe conducted a retrospective matched cohort study at a University Center.nnnPATIENTSnOf 111 RAI-treated Graves patients with mild or no GO, 35 received no steroid prophylaxis (absence of GO and/or risk factors for RAI-associated GO progression); 28 received low-dose prednisone (starting dose, 0.16-0.27 mg/kg bw; mean +/- sd, 0.22 +/- 0.03 mg/kg bw; group 1); and 48 received higher doses (group 2). Among the latter, 28 (starting dose, 0.32-0.56 mg/kg bw; mean +/- sd, 0.36 +/- 0.05 mg/kg bw) were matched with group 1 according to several relevant variables. Prednisone was started 1 d after RAI and withdrawn after 6 wk.nnnMAIN OUTCOME MEASURESnWe assessed ocular changes (1, 3, and 6 months after RAI) and side effects of prednisone.nnnRESULTSnTwo of 35 patients not receiving steroid prophylaxis (6%) developed mild-to-moderate GO (clinical activity score, 2/7 and 3/7) after RAI. No patients in group 1 or group 2 had GO progression. Side effects were very mild and inconstant, although more frequent in group 2. Both groups showed an increase in bw, an increase that was significantly higher in group 2.nnnCONCLUSIONnLower doses of oral prednisone (about 0.2 mg/kg bw) are as effective as previously reported doses (0.3-0.5 mg/kg bw). A shorter treatment period (6 wk) is probably sufficient. The increase in bw is less using lower doses of prednisone.

Diagnosis and management of amiodarone-induced thyrotoxicosis : similarities and differences between North American and European thyroidologists

Objectiveu2002 To investigate how North American thyroidologists assess and treat amiodarone‐induced thyrotoxicosis (AIT) and to compare the results with those of the same questionnaire‐based survey previously carried out among European thyroidologists.

Impact of Lithium on Efficacy of Radioactive Iodine Therapy for Graves’ Disease: A Cohort Study on Cure Rate, Time to Cure, and Frequency of Increased Serum Thyroxine After Antithyroid Drug Withdrawal

CONTEXTnRadioactive iodine (RAI) is a common therapy for hyperthyroidism due to Graves disease. A small but significant proportion of patients have recurrence of hyperthyroidism after RAI therapy. Lithium might increase RAI effectiveness by increasing RAI retention in the thyroid. However, whether lithium favorably affects the long-term outcome of RAI therapy is still a matter of argument.nnnOBJECTIVEnThe objective of the study was to compare the efficacy of RAI given with or without concomitant lithium treatment.nnnDESIGNnThis was a retrospective cohort study.nnnSETTINGnThe study was conducted at a tertiary university center.nnnPATIENTSnSix hundred fifty-one patients with newly diagnosed Graves disease participated in the study.nnnINTERVENTIONnTwo hundred ninety-eight patients were treated with RAI plus lithium (900 mg/d for 12 d) and 353 with RAI alone.nnnMAIN OUTCOME MEASURESnProportion of cured patients and time to achieve cure of hyperthyroidism during 1 yr of follow-up was measured.nnnRESULTSnPATIENTS treated with RAI plus lithium had a higher cure rate (91.0%) than those treated with RAI alone (85.0%, P = 0.030). In addition, patients treated with RAI plus lithium were cured more rapidly (median 60 d) than those treated with RAI alone (median 90 d, P = 0.000). Treatment with lithium prevented the serum free T(4) increase after methimazole withdrawal and RAI therapy. Side effects after RAI therapy occurred in a subset of patients and were mild, transient, and without differences in the two groups.nnnCONCLUSIONSnRAI combined with lithium is safe and more effective than RAI alone in the cure of hyperthyroidism due to Graves disease.

Orbital Decompression in Graves' Ophthalmopathy by Medial and Lateral Wall Removal

Objective The objective of this study is to describe a technique for balanced orbital decompression and to analyze the results. Methods and Materials We conducted a retrospective study of 140 patients (276 orbits). Orbital decompression was carried out by removal of the medial orbital wall by ethmoidectomy and complete removal of the lateral wall by bringing out the entire sphenoid wing together with part of the zygomatic bone down to the inferior orbital fissure. Results One hundred thirty-six patients underwent bilateral decompression, 4 patients underwent monolateral decompression. Proptosis was reduced on average by 5.3 mm; 28 (20%) patients showed onset or worsening of diplopia. Conclusions Medial and lateral approach allows a balanced orbital decompression. As some patients may present different degrees of proptosis and visual impairment, we stress the importance of carefully weighing the preoperative conditions of the individual patient when choosing the surgical approach.

Efficacy and Safety of Orbital Radiotherapy for Graves' Orbitopathy

CONTEXTnGraves orbitopathy (GO), when moderate-to-severe and active, requires medical treatment. High-dose glucocorticoids (GCs) represent the first-line treatment. Orbital radiotherapy (OR) has been used for decades, alone or in combination with GCs, but opinions on its efficacy are conflicting.nnnEVIDENCE ACQUISITIONnThe major source of data acquisition included PubMed strategies. Original articles, systemic reviews and metaanalyses, and other relevant citations were screened.nnnEVIDENCE SYNTHESISnRandomized clinical trials evaluating the efficacy of OR are limited. However, available data suggest that OR is a safe treatment, which seems to be effective particularly on ocular motility impairment, especially if it is of recent onset. OR seems to be effective also on soft tissue changes, whereas exophthalmos and long-standing extraocular muscle dysfunction are poorly affected. OR efficacy on dysthyroid optic neuropathy is uncertain. The combination of OR and oral GCs is more effective than either treatment alone, suggesting a synergistic effect of the two treatments. There is no available evidence that the addition of OR to iv GCs provides an advantage over iv GCs alone.nnnCONCLUSIONSnOR can be considered a safe second-line treatment for patients with moderate-to-severe and active GO but less effective than GCs. A possible strategy may include its use in combination with iv GCs in patients whose GO has only partially responded to a first-course of iv GCs alone and is still active. Future studies might address the question of whether the combination of iv GCs and OR might represent the first-line treatment for active GO.