Delayed diagnosis of dilated thyrotoxic cardiomyopathy with coexistent multifocal atrial tachycardia: a case report.

BACKGROUND: Thyroid storm (TS) is a rare but potentially life-threatening sequelae of untreated or undertreated hyperthyroidism. While TS frequently causes high-output heart failure, low-output heart failure related to dilated cardiomyopathy (DCM) is extremely rare. Tachycardia is a common clinical presentation of TS, and ß1-selective blockers are the first-line agents for treating TS-associated tachycardia. However, given that ß-blockers have negative chronotropic and negative inotropic effects, amiodarone may be safe and effective for the treatment of TS-induced tachyarrhythmia in patients with moderate to severe heart failure. While long-term amiodarone administration causes hypothyroidism, or less frequently, hyperthyroidism, little is known about the effects of short-term amiodarone administration on thyroid function. CASE PRESENTATION: A 31-year-old healthy woman presented with worsening dyspnoea. She was tachycardic with multifocal atrial tachycardia (MAT) of 184 beats/min, confirmed by electrocardiogram. Echocardiographic findings were consistent with DCM, with an ejection fraction of 20%. Thus, she was initially diagnosed with acute heart failure due to DCM with coexistent MAT. Tachycardia persisted despite cardioversion attempts and treatment with multiple anti-arrhythmic drugs. Consequently, she rapidly progressed to cardiogenic shock and respiratory decompensation, which required intubation and an intra-aortic balloon pump support. Moreover, the undiagnosed Graves' disease, lack of suspicion, and postponed analysis of thyroid function tests led to a delayed diagnosis of TS. Amiodarone, which was initiated for MAT, unexpectedly ameliorated thyrotoxicosis, resulting in a euthyroid state and the patient's significantly improved condition and cardiac function. She was discharged on day 40. Finally, she underwent total thyroidectomy; thyroid pathology was consisting with Graves' disease. Her postoperative course was uneventful. CONCLUSIONS: Herein, we describe a case of delayed diagnosis of dilated thyrotoxic cardiomyopathy with coexistent MAT. The patient required intensive care due to the catastrophic sequelae and was successfully treated with amiodarone. This is the first case report of TS-associated MAT and highlights the clinical importance of high suspicion of TS in de novo heart failure with any tachyarrhythmia or DCM of unknown etiology and the potential effects of short-term amiodarone administration in the treatment of TS.

Triiodothyronine-predominant Graves' disease in childhood: detection and therapeutic implications.

OBJECTIVE: To assess in a pediatric population, the clinical characteristics and management of triiodothyronine-predominant Graves' disease (T3-P-GD), a rare condition well known in adults, but not previously described in children. DESIGN: We conducted a university hospital-based observational study. METHODS: All patients with GD followed for more than 1 year between 2003 and 2013 (n=60) were included. T3-P-GD (group I) was defined as high free T3 (fT3) concentration (>8.0 pmol/l) associated with a normal free thyroxine (fT4) concentration and undetectable TSH more than 1 month after the initiation of antithyroid drug (ATD) treatment. Group II contained patients with classical GD without T3-P-GD. RESULTS: Eight (13%) of the patients were found to have T3-P-GD, a median of 6.3 (3.0-10.5) months after initial diagnosis (n=4) or 2.8 (2.0-11.9) months after the first relapse after treatment discontinuation (n=4). At GD diagnosis, group I patients were more likely to be younger (6.8 (4.3-11.0) vs 10.7 (7.2-13.7) years) and had more severe disease than group II patients, with higher serum TSH receptor autoantibodies (TRAb) levels: 40 (31-69) vs 17 (8-25) IU/l, P<0.04, and with slightly higher serum fT4 (92 (64-99) vs 63 (44-83) pmol/l) and fT3 (31 (30-46) vs 25 (17-31) pmol/l) concentrations. During the 3 years following T3-P-GD diagnosis, a double dose of ATD was required and median serum fT4:fT3 ratio remained lower in group I than in group II. CONCLUSION: Severe hyperthyroidism, with particularly high TRAb concentrations at diagnosis, may facilitate the identification of patients requiring regular serum fT3 determinations and potentially needing higher doses of ATD dosage during follow-up.

Hepatic dysfunction related to thyrotropin receptor antibody in patients with Graves' disease.

BACKGROUND: Hepatic dysfunction is a common phenomenon in patients with Graves' disease (GD). However, its pathogenesis is not fully understood. We aimed to determine the correlation between the thyrotropin receptor antibody (TRAb) and liver biochemical abnormalities in patients with GD. METHODS: A total of 236 consecutive unrelated inpatients with newly diagnosed and untreated GD were included. Clinical characteristics (age, gender, disease duration) were collected. The liver biochemical values were tested and serum thyroid hormones, anti-thyroid antibodies and thyroid volumes were also evaluated. The patients were divided into hepatic dysfunction (HDF) and normal hepatic function (NHF) groups according to liver biochemical values. RESULTS: We found that 77.9% untreated patients with GD had at least one liver function test abnormality. The levels of TRAb in patients of HDF group were significantly increased compared with those in patients of NHF group, P < 0.001. Linear regression suggested that TRAb has significant correlation with AST, ALP, γ-GTP, TB and DB. Logistic regression concluded that GD patients with high levels of TRAb had a greater possibility of developing liver biochemical abnormalities (OR = 1.069, 95% CI 1.019-1.113). CONCLUSIONS: Hepatic dysfunction is common in patients with GD, and elevation of TRAb may contribute to hepatic dysfunction in patients with GD.

Elevated serum immunoglobulin G4 levels in patients with Graves' disease and their clinical implications.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a new clinical entity that affects various organs with increased IgG4 positive plasmacytes and progressive fibrosis. While IgG4-RDs in association with Hashimoto's thyroiditis or Riedel's thyroiditis have been reported, the relationship between IgG4-RD and Graves' disease (GD) is yet unknown. To elucidate the relation of GD to IgG4-RD, serum IgG4 levels and their clinical implications in patients with GD were investigated. METHODS: In this prospective study, serum IgG4 levels were measured in 109 patients with GD and classified into two groups according to the comprehensive diagnostic criteria of IgG4-RD previously established: (i) GD with elevated-IgG4 levels (≥ 135 mg/dL), and (ii) GD with nonelevated IgG4 (<135 mg/dL). RESULTS: Seven out of 109 patients with GD (6.4%) had elevated serum IgG4 levels [mean ± standard deviation (range): 175.0 ± 44.5 (136-266) mg/dL] and elevated ratios of IgG4/IgG [12.7 ± 4.5% (7.6%-21.2%)]. The remaining patients with GD had serum IgG4 levels and IgG4/IgG ratios of 39.6 ± 27.6 (3-132) mg/dL and 3.2 ± 2.2% (0.3%-11.5%), respectively. Ages in the elevated IgG4 group were significantly higher than those of the nonelevated IgG4 group: 54.7 ± 6.2 versus 43.4 ± 15.4 years, respectively. Ultrasound examinations revealed that the elevated IgG4 group had significantly increased hypoechogenic areas in the thyroid in comparison to the nonelevated IgG4 group (low echo scoring: 1.66 ± 0.81 vs. 0.61 ± 0.89, respectively). In the correlation analysis, TSAb (rs=0.385, n=42) titers were significantly correlated with se rum IgG4 levels, while they were not significantly different between the two groups. In the elevated IgG4 group, symptoms were controllable with a small dose of antithyroidal drug (ATD; n=4), a combination treatment with ATD and L-T4 (n=1), or L-T4 administration only one year after the first visit (n=2). CONCLUSIONS: A small portion of GD patients harbored elevated serum IgG4 levels. They were older, had increased hypoechoic areas in the thyroid, and appeared to be responsive or prone to be hypothyroid after ATD treatment. Thus, the present study suggests the presence of a novel subtype of GD. Measuring serum IgG4 levels may help to distinguish this new entity and provide potential therapeutic options for GD.

Epidemiology of subtypes of hyperthyroidism in Denmark: a population-based study.

OBJECTIVE: Few population-based studies have described the epidemiology of subtypes of hyperthyroidism. DESIGN: A prospective population-based study, monitoring two well-defined Danish cohorts in Aalborg with moderate iodine deficiency (n=311 102) and Copenhagen with only mild iodine deficiency (n=227 632). METHODS: A laboratory monitoring system identified subjects with thyroid function tests suggesting overt hyperthyroidism (low s-TSH combined with high s-thyroxine or s-triiodothyronine). For all subjects, we collected information on medical history, thyroid scintigraphy and thyroid hormone receptor antibody (TRAb) measurement. Information was used to disprove or verify primary overt hyperthyroidism and to subclassify hyperthyroidism into nosological disorders. RESULTS: From 1997 to 2000 (2 027 208 person-years of observation), we verified 1682 new cases of overt hyperthyroidism. The overall standardized incidence rate (SIR) per 100 000 person-years was 81.6, and was higher in Aalborg compared with Copenhagen (96.7 vs 60.0, P<0.001), giving an SIR ratio (SIRR (95% confidence interval (CI))) between moderate versus mild iodine-deficient areas of 1.6 (1.4-1.8). Nosological types of hyperthyroidism (percentage/SIRR (95% CI)): multinodular toxic goitre (MNTG) 44.1%/1.9 (1.6-2.2), Graves' disease (GD) 37.6%/1.2 (0.99-1.4), solitary toxic adenoma (STA) 5.7%/2.4 (1.3-3.5), 'mixed type' hyperthyroidism (TRAb-positive, scintigraphicly multinodular) 5.4%/6.0 (3.0-12), subacute thyroiditis 2.3%/0.9 (0.4-1.4), postpartum thyroid dysfunction 2.2%/1.6 (0.8-3.0), amiodarone-associated hyperthyroidism 0.8%/7.1 (1.1-65), hyperthyroidism after thyroid radiation 0.7%/12.3 (0.8-50), lithium-associated hyperthyroidism 0.7%/0.97 (0.4-4.8) and hyperthyroidism caused by various other factors 0.7%. Lifetime risk for overt hyperthyroidism was 10.5%/6.5%/2.4% (females/all/males). CONCLUSION: Hyperthyroidism was common in Denmark with MNTG and GD as dominating entities. The higher incidence of hyperthyroidism in the most iodine-deficient region was caused by higher frequency of MNTG, 'mixed-type', STA and amiodarone-associated hyperthyroidism.

Pediatric Graves' disease: controversies in management.

BACKGROUND/AIMS: Graves' disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. Caused by immunologic stimulation of the thyroid-stimulating hormone receptor, lasting remission occurs in only a minority of pediatric patients with GD, including children treated with antithyroid drugs (ATDs) for many years. Thus the majority of pediatric patients with GD will need thyroidectomy or treatment with radioactive iodine (RAI; (131)I). RESULTS: When ATDs are used in children, only methimazole should be used. Propylthiouracil is associated with an unacceptable risk of severe liver injury in children and should never be used as first-line therapy. If remission (defined as normal thyroid function off ATDs) is not achieved after 1 or 2 years of ATD therapy, (131)I or surgery may be considered, with the choice influenced by the age of the individual. When (131)I is used, administered doses should be >150 µCi/g of thyroid tissue. When surgery is performed, near total or total thyroidectomy is recommended. CONCLUSION: Choosing a treatment approach for childhood GD is often a difficult and highly personal decision. Discussion of the advantages and risks of each therapeutic option is essential to help the patient and family select a treatment option.

[In patients with Graves' disease signal-averaged P wave duration positively correlates with the degree of thyrotoxicosis]. / W chorobie Gravesa i Basedowa czas trwania usrednionego zalamka P wykazuje dodatnia korelacje ze stopniem nadczynnosci tarczycy.

Coexistence of the goitre, proptosis and palpitations was observed in XIX century for the first time. Sinus tachyarytmias and atrial fibrillation are typical cardiac symptoms of hyperthyroidism. Atrial fibrillation occurs more often in patients with toxic goiter than in young patients with Grave's disease. These findings suggest that causes of atrial fibrillation might be multifactorial in the elderly. The aims of our study were to evaluate correlations between the parameters of atrial signal averaged ECG (SAECG) and the serum concentration of thyroid free hormones. 25 patient with untreated Grave's disease (G-B) (age 29,6 +/- 9,0 y.o.) and 26 control patients (age 29,3 +/- 6,9 y.o.) were enrolled to our study. None of them had history of atrial fibrillation what was confirmed by 24-hour ECG Holter monitoring. The serum fT3, fT4, TSH were determined in the venous blood by the immunoenzymatic method. Atrial SAECG recording with filtration by zero phase Butterworth filter (45-150 Hz) was done in all subjects. The duration of atrial vector magnitude (hfP) and root meat square of terminal 20ms of atrial vector magnitude (RMS20) were analysed. There were no significant differences in values of SAECG parameters (hfP, RMS20) between investigated groups. The positive correlation between hfP and serum fT3 concentration in group G-B was observed (Spearman's correlation coefficient R = 0.462, p < 0.02). No significant correlations were found between RMS20 and serum fT3 in G-B group and between hfP or RMS 20 and serum fT3 in group K. These findings suggest that occurrence of atrial fibrillation in patients with Grave's disease depends not only on hyperthyroidism but on serum concentration of fT3 also.

[The clinical and laboratory findings in Graves' multinodular type disease].

Graves' disease (GD) is an autoimmune thyroid disease characterized among other findings by diffuse goiter. It is possible in GD to find a multinodular goiter (mGD). Are they two different diseases that coexist, or do we have a multinodular type of GD. Questions arise as for the time that this mGD appears in the process of GD and also, as for the clinical and laboratory characteristics of mGD. To answer these questions, we have studied retrospectively and randomly from the archives of the Department of Nuclear Medicine of AHEPA University Hospital, from 2000-2004, 20 female patients with multinodular type of GD (Group A) as first diagnosed by us and 50 female patients with diffuse type of GD (Group B) of about the same age. Patients with mGD had been examined before by us and their GD was documented. No other cause for exophthalmus except GD was found. Patients with any other additional disease were excluded from the study. All patients had 7-10 signs of hyperthyroidism (thyroid index). Many of the patients, after the present study, were given (131)I therapeutically. These groups were divided in subgroups of pre- and menopausal women (A1, B1 and A2, B2 respectively). The mean age of our patients in Groups A and B were 46 and 50 years with a range of 25-65 and 38-69 years respectively. Serum free triodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), thyroid peroxidase antibodies (AbTPO), antithyroglobulin antibodies (AbTG) and anti receptors of thyroid stimulating hormone antibodies (AbTSHR) were tested in all subjects studied by radioimmunoassays (RIA) or radioimmunometric assays (IRMA). All patients were under antithyroid treatment interrupted for about 10 days before the thyroid scan. Thyroid scintiscan was performed 24 h after oral intake of 1.8 MBq of (131)I. Clinical findings were evaluated by a clinical index of hyperthyroidism as modified by us. The time that the mGD appeared since the beginning of GD and the time the GD started were also studied. Our findings were as follows: A mean time of 10.35+/-6.7 years had elapsed from the start of GD till mGD was first diagnosed by us. A mean time of 3.1+/-1.6 years had elapsed after the start of the GD till patients of Group B were examined in this study. No difference in the values of FT3, FT4 and TSH between the two Groups or the Subgroups was found as expected because the clinical status of the patients varied. AbTG, AbTPO and AbTSHR were found in a much higher incidence and in higher values in Group A versus Group B (P=0.007 and 0.001 respectively) and in Subgroups A1, A2 versus B1 and B2 respectively. This increase was significant for AbTG and AbTPO in A2 versus B2 Subgroups and for AbTPO in A1 versus B1 Subgroups (P=0.007, 0.001 and 0.014 respectively). We were unable to find a similar work in the literature. In conclusion, we suggest that mGD as compared to GD: a)develops late in GD and thus patients had more relapses, b) has a higher incidence of abnormal values of AbTPO, AbTG and AbTSHR, c) has significantly higher values of AbTPO and less of AbTG than GD and d) thyroid hormones, clinical index of hyperthyroidism and the incidence of exophthalmos do not differ. Based on the above, we suggest that mGD is a late evolutionary type of GD. The study of patients of both sexes having GD of the same duration as mGD, the study of iodine metabolism and of thyroid gland pathology in these patients, is needed.

[Clinical signs of dysthyroid orbitopathy]. / Signes cliniques de l'orbitopathie dysthyroïdienne.

Dysthyroid ophthalmopathy is an inflammatory disease of the orbit, combined or not with thyroid disorders. However, pure ophthalmologic forms exist, and the diagnosis can be made by the ophthalmologist. The diagnosis is made by examining eyelid malposition, oculomotor disorders, inflammatory signs, proptosis measurement, and by the search for optic nerve pain. We discuss the NOSPECS classification, which can evaluate the severity and progression of the disease.

Thyroid-associated ophthalmopathy: a practical guide to classification, natural history and management.

Thyroid-associated ophthalmopathy (TAO) is an autoimmune disorder that can be divided into three clinical subtypes: congestive, myopathic and mixed ophthalmopathy. It is probably caused by immune cross-reactivity between orbital and thyroid antigens. The best candidate antigens are the thyrotropin receptor and the novel protein, G2s, which is now identified as a fragment of the winged helix transcription factor, FOXP1. The relationship between radioiodine therapy and TAO is controversial, with two randomised controlled trials showing a transient worsening of the eye disease after treatment. The diagnosis of TAO is a clinical one, based on the presence of specific symptoms and signs. Orbital imaging, preferably magnetic resonance imaging, is useful when the diagnosis is in doubt and in patients with suspected optic neuropathy who may benefit from early intervention. Despite their lack of specificity, orbital antibodies may add weight to the diagnosis and may potentially be a useful tool in classifying the different subtypes of TAO and in monitoring disease activity. While antibodies against G2s and the thyrotropin receptor are seen in all subtypes, those against Fp and collagen XIII may be associated with the myopathic and congestive subtypes, respectively, where Fp is the flavoprotein subunit of the mitochondrial enzyme, succinate dehydrogenase. In most patients, TAO is self-limiting and no specific treatment is required. When treatment is indicated, glucocorticoids are the mainstay of therapy. Orbital radiotherapy improves the efficacy of glucocorticoids, but is probably less beneficial as monotherapy. Orbital surgery is best reserved for patients with 'burnt out' inactive disease, but urgent orbital decompression may be required for optic neuropathy. The severity and clinical activity of TAO are important in determining the need for specific treatment and the likelihood of success with medical therapy, respectively.

Peripheral parameters of oxidative stress in patients with infiltrative Graves' ophthalmopathy treated with corticosteroids.

Infiltrative ophthalmopathy, which may develop in patients with Graves' disease, is considered an inflammatory disorder of autoimmune background. There is growing evidence that changed reactive oxygen species (ROS) metabolism plays an important role in pathogenesis of autoimmune diseases. Corticotherapy is a principal method of ophthalmopathy treatment, and its therapeutic effect is partially connected with influence on ROS generation systems. This study was undertaken to investigate corticosteroids treatment influence on blood extracellular indices of ROS metabolism in Graves' ophthalmopathy patients. Plasma indices of free radical generation and scavenging were determined in 22 euthyroid patients with active infiltrative Graves' ophthalmopathy initially, after intensive corticotherapy and after completing of steroid treatment. Age- and sex-matched 24 healthy volunteers and 25 euthyroid Graves' patients without overt ophthalmopathy served as controls. In the ophthalmopathy patients hydrogen peroxide (H(2)O(2)), lipid hydroperoxides (ROOH), thiobarbituric acid-reacting substances (TBARS) and ceruloplasmin (CP) levels and superoxide dismutase (SOD) and catalase (CAT) activities were increased, whereas glutathione peroxidase (GPx) and glutathione reductase (GR) activities were reduced. Intensive corticotherapy resulted in normalization (partial for ROOH) of ROS metabolism peripheral markers. After the withdrawal of corticosteroids a reduction of ophthalmopathy clinical activity was present, yet a marked restoration of increased oxidative stress indices was observed, along with activation of antioxidant defence systems (not significant for CAT activity). These data demonstrate that corticosteroids are effective in reduction of peripheral oxidative stress present in infiltrative Graves' ophthalmopathy, but this effect tends to be transient.

Orbital scintigraphy with the somatostatin receptor tracer 99mTc-P829 in patients with Graves' disease.

UNLABELLED: Receptors for somatostatin (SST) (SSTR) are expressed on various tumor cells as well as on activated lymphocytes. Previous data have shown that (99m)Tc-P829 binds with high affinity to many different types of tumor cells as well as to leukocytes via the human hSSTR2, hSSTR3, and hSSTR5 target receptors. Consequently, (99m)Tc-P829 was successfully introduced as a peptide tracer for tumor imaging. In this study, we evaluated the orbital uptake of (99m)Tc-P829 in patients with active and inactive thyroid-associated orbitopathy (TAO), accompanied by lymphocyte infiltration in the acute stage and by muscle fibrosis in the chronic stage of the disease. METHODS: To evaluate its clinical usefulness in Graves' disease, (99m)Tc-P829 scintigraphy (approximately equal to 740 MBq) was performed in 44 patients with TAO (median duration, 19 mo; range, 1-360 mo). The clinical activity of the orbital disease was graded by the NOSPECS (no signs or symptoms; only signs, no symptoms; signs only; proptosis; eye muscle involvement; corneal involvement; sight visual acuity reduction) classification of the American Thyroid Association, the clinical activity score (CAS), and the superonasal index (SNI). SPECT (360 degrees ) and planar studies were completed within 3 h after injection. Orbital (O) regions of interest (ROIs) were compared with temporoparietal and occipital (OCC) ROIs. Orbital uptake ratios in Graves' disease were compared with data obtained from lung cancer patients with no eye disease (n = 22). RESULTS: Overall, (99m)Tc-P829 biokinetics were the same in Graves' disease patients as in lung cancer patients, showing a rapid blood clearance and visualization of the facial bones within minutes of injection. In all control patients, the orbit appeared as a "cold area," whereas visual orbital accumulation of (99m)Tc-P829 was found in patients with active TAO (O/OCC ratios: 1.26 +/- 0.04 vs. 1.69 +/- 0.04; P < 0.01, respectively). Patients with active eye disease (n = 25) presented with an increased orbital uptake of (99m)Tc-P829 compared with patients with inactive disease (n = 19; O/OCC ratio: 1.12 +/- 0.05; P < 0.01). A statistically significant correlation was found between CAS and the orbital uptake (O/OCC ratio) values (r = 0.90), whereas no correlation could be documented regarding the NOSPECS classification as well as the SNI. CONCLUSION: In TAO, (99m)Tc-P829 yields high orbital binding with good clinical correlation. The better image quality due to the high energy of technetium, the lower radiation dose for patients and personnel, and the short acquisition protocol favor SSTR scintigraphy with (99m)Tc-P829 over (111)In-labeled compounds. The in-house availability of the radiotracer and cost-effectiveness are further advantages.

Classification and prediction of the progression of thyroid-associated ophthalmopathy by an artificial neural network.

OBJECTIVE: We have used an artificial neural network in an attempt to classify and predict the progression of thyroid-associated ophthalmopathy (TAO) at the first clinical examination. DESIGN: This retrospective comparative case series included a group of patients examined by the ophthalmologist only once because of the absence of signs of progressive disease (GR1), as subsequently monitored by an endocrinologist, and a group of patients on follow-up because of progressive disease (GR2). PARTICIPANTS AND METHODS: We examined 242 patients, of whom 207 were women and 35 were men. GR1 included 129 patients (257 eyes) who, on ophthalmologic assessment, were further classified as having no TAO (n = 53; GR1a) and only lid signs or inactive, stable TAO (n = 76; GR1b). GR2 included 113 patients (219 eyes). One hundred three normal subjects (205 eyes), 50 women and 53 men, were tested to provide normal ranges for proptosis values. We applied a model of back propagation neural network with 17 input variables, a training matrix of 414 observations, a randomly selected test group of 115 observations, and, as output, the progression of disease. The ophthalmologic assessment included (1) lid fissure measurement, (2) Hertel, (3) color vision, (4) cover test and Hess screen, (5) visual acuity, (6) tonometry, (7) fundus examination, (8) visual field, and (9) orbital computed tomography scan or ultrasonography. Other parameters included in the neural analysis were gender and age of the patients, their cigarette smoking, and the interval between follow-up visits. RESULTS: The prevalence of smokers among patients without TAO was significantly lower than that among those with TAO (P < 0.03). Mean proptosis values (Hertel) were significantly different in GR1, in GR2, and in a group of normal eyes (P < 0.0001), and the changes of values in consecutive measurements were associated with progression of the disease (P < 0.01). Differences of the proptosis values in the two groups of patients were not related to smoking. The neural network correctly classified 78.3% of 115 eyes (87 patients) and predicted TAO progression in 69.2% of 39 eyes (28 patients). CONCLUSIONS: In our opinion, neural network analysis can be successfully applied for classifying TAO and predicting progression at the first clinical examination.

Prediction of the progression of thyroid-associated ophthalmopathy at first ophthalmologic examination: use of a neural network.

In the present work we analyzed patients with thyroid-associated ophthalmopathy (TAO) at various clinical stages of disease progression and implemented a model of neural analysis for disease classification and prediction of progression. We studied 246 patients (group 1), seen only once because they had absent, minimal, or inactive TAO and 152 patients (group 2), seen two or more times because of active and/or progressive TAO. The ophthalmologic assessment included: (1) lid fissure measurement; (2) Hertel; (3) color vision; (4) cover test and Hess screen; (5) visual acuity; (6) tonometry; (7) fundus examination; (8) visual field; (9) orbital computed tomography (CT) scan or ultrasound. A back propagation model of neural network was based on the relative variations of 13 clinical eye signs (input variables) for classification and prediction of disease progression (output variable). Approximately 300 eyes (20%) were randomly selected as a test group. Correlation between expected and calculated patients' classification was highly significant (p < 0.00001). Concordance between clinical assessment and the neural network prediction was obtained in 78 of 117 eyes (67%). We have developed a neural model that allows classification of TAO and preliminary prediction of disease progression at the first clinical examination. The results are validating the classification into the two groups on which our initial assumption was based.

The role of Tc-99m polyclonal human immunoglobulin G scintigraphy in Graves' ophthalmopathy.

OBJECTIVE: The aim of this study was to clarify whether Tc-99m HIG (Polyclonal Human Immunoglobulin G) can image and determine the severity of orbital involvement in patients with Graves' ophthalmopathy. MATERIALS AND METHODS: Twenty-six patients between 19 and 56 years old with Graves' ophthalmopathy were examined. All patients received approximately 370 MBq Tc-99m HIG by i.v. injection. Planar and SPECT examination were performed 4 hours after the injection. Visual and semiquantitative evaluations were performed for both orbits by two independent observers, RESULTS: Clinically active ophthalmopathy patients had noticeably increased orbital accumulation of Tc-99m HIG. In patients with inactive disease, and 14 of 19 had no uptake, whereas 5 patients had orbital radioactivity accumulation. The duration of Graves' ophthalmopathy did not correlate with the presence of active ophthalmopathy and Tc-99m HIG grade. There was no correlation between clinical classification and clinical activity (r = 278). There was a good correlation between clinical activity and the radioactivity grade with r = 0.666 (p = 0.01). The clinical classification closely correlated with Tc-99m HIG grade (r = 0.423, p = 0.05). CONCLUSION: Tc-99m HIG scan can clearly identified clinically active patients, and subclinicial inflammation can be shown by this scintigraphic evaluation. The current preliminary results suggested that Tc-99m HIG SPECT might be useful for the assessment of disease activity in Graves' ophthalmopathy.

[Treatment results in 25 patients with Graves' ophthalmopathy between 1998 and 2001]. / Behandlungsergebnisse an 25 Patienten mit endokriner Orbitopathie im Zeitraum zwischen 1998 und 2001.

In our outpatient clinic 25 patients with Graves' ophthalmopathy were treated, 21 women, mean age 58.8 years (range 19-74 years) and 4 men, mean age 47.5 years (range 38-56 years). In the female group two showed euthyroid Graves' ophthalmopathy and one Hashimoto's disease; in the male group one showed euthyroid ophthalmopathy. Treatment was done depending on the findings of the NOSPECS-classification in identical way for each group. Final results were obtained three and six months after therapy, at that time all patients were euthyroid. In five patients (two men and three women) sicca-treatment was sufficient because the ophthalmopathy improved by therapy of the thyroid disease only. Three women were treated by oral steroids over three months and had a complete remission. Nine women were treated by oral steroids and external radiation, six of them showed major improvement but in one case orbital decompression had to be done. Somatostatin therapy was done over six months in six women who showed no change after oral steroids plus radiation. Out of them five showed major improvement but in spite of a positive octreoscan in one case orbital surgery had to be performed. Two men were treated by oral steroids and external radiation without change of disease, somatostatin therapy was not done because of a negative octreoscan. With the exception of one nonsmoking woman in whom orbital surgery had to be done, the treatment results were worse in smokers.

[Endocrine orbitopathy--diagnosis]. / Endokrine Orbitopathie--Diagnostik.

Various modifications of classic Werner classification for endocrine orbitopathy are used. The application of this NOSPECS-scheme on the ocular and periocular changes in Graves' disease is discussed.

Graves' ophthalmopathy: natural history and treatment outcomes.

BACKGROUND: The pathogenesis of Graves' ophthalmopathy has not been yet clarified, and from a therapeutic standpoint Graves' ophthalmopathy remains an enigma. The natural course and effects of different treatment regimens are poorly documented. RESULTS: The mean observation period was 3.23 years (1-8.9 years) for all 196 patients, and 2.85 years (1-8.9 years) for the 81 patients with Graves' ophthalmopathy. The gender distribution was 77% female and 23% male in patients with Graves' disease and ophthalmopathy, and 81% female and 19% male in those patients without ophthalmopathy (p = 0.57). Seventy per cent of the patients developed Graves' ophthalmopathy within 12 months before or after the onset of the hyperthyroidism. Among the 81 patients with ophthalmopathy 53 (65%) received no therapy or only local protective agents. Twenty-five of these patients improved substantially, 26 did not change, and 2 deteriorated progressively. These results were independent of the severity of the EO (p = 0.42). Among the 11 patients initially treated with systemic corticosteroids 7 improved, 3 did not change, and 1 worsened. Five patients received initially orbital irradiation. Three improved and 2 did not change after radiotherapy. Orbital decompression was performed in 3 patients. Nine patients received a combination treatment. CONCLUSION: In conclusion, our study of a relatively large patient sample revealed the known epidemiological facts regarding Graves' disease and endocrine ophthalmopathy. The majority of patients needed no therapy or only local protective agents, and 47% improved spontaneously. Systemic corticosteroids and orbital irradiation appear to be equally effective as initial treatment in patients with more severe forms of Graves' ophthalmopathy.

Clinical significance of classification of Graves' disease according to the characteristics of TSH receptor antibodies.

BACKGROUND: It has been widely accepted that the epitope(s) and/or functional characteristics of thyrotropin receptor antibodies (TSHRAb) from Graves' patients are heterogenous among patients. However, the clinical significance of such heterogeneity has not been systematically evaluated yet. We were to elucidate and find the clinical significance of heterogeneity for TSH receptor antibodies in Graves' disease. METHODS: We measured stimulating TSHRAb (TSAb) activities using CHO-hTSHR cells, FRTL-5 cells and chimeric receptor expressing cells (Mc1 + 2 and Mc2), specific blocking TSHRAb (TSBAb) activities using Mc2 cells and TBII activities using porcine thyroid membrane in 136 patients with untreated hyperthyroid Graves' disease. RESULTS: Based on various TSHRAb activities from each patient, the patients could be categorized into 7 subgroups by cluster analysis; 1) Group 1 (n = 41) was characterized by moderate TSAb activities both in CHO-hTSHR cells and in FRTL-5 cells, typical TSAb epitope, rare blocking antibodies and high TBII activities. 2) Group 2 (n = 16) was characterized by the presence of blocking TSHRAb in most patients, albeit the other characteristics were the same as those in Group 1. 3) Group 3 (n = 19) patients had low TSAb activities both in CHO-hTSHR cells and in FRTL-5 cells, seldom had blocking TSHRAb, but they had high TBII activities. 4) Group 4 (n = 30) could be categorized as 'mild disease' group, as they had low activities in all kinds of TSHRAb assay and had low antimicrosomal antibody activities. 5) Group 5 (n = 14) was characterized by moderate TSAb activities with atypical epitope(s), rare blocking TSHRAb and moderate TBII activities. 6) Group 6 (n = 10) patients had very high TSAb activities with typical epitopes, seldom blocking TSHRAb and low TBII activities. 7) Group 7 (n = 6) was characterized by very high TSAb activities with atypical epitopes and high TBII activities. Pretreatment serum thyroid hormone level was low only in group 4 patients compared to the other 6 groups (p < 0.05). The size of goiter was significantly larger in those in group 1 and group 3 (p < 0.05) compared to the other 5 groups. The prevalence of clinically significant ophthalmopathy was higher in group 2 patients than the other 6 groups (50% vs. 27.5%, p = 0.06). Among 6 kinds of TSHRAb activities, only the blocking TSHRAb activity was significantly associated with the presence of ophthalmopathy in multivariate analysis. CONCLUSION: These results suggest that the differences in epitopes for TSAb or the presence of blocking TSHRAb is not a major factor in determining the degree of thyrotoxicosis in Graves' disease. Although the pathogenic mechanism is not clear yet, we suggest that patients with ophthalmopathy have different TSHRAb repertoire from those without ophthalmopathy in Graves' disease.

Clinical significance of classification of Graves' disease according to the characteristics of TSH receptor antibodies

BACKGROUND: It has been widely accepted that the epitope(s) and/or functional characteristics of thyrotropin receptor antibodies (TSHRAb) from Graves' patients are heterogenous among patients. However, the clinical significance of such heterogeneity has not been systematically evaluated yet. We were to elucidate and find the clinical significance of heterogeneity for TSH receptor antibodies in Graves' disease. METHODS: We measured stimulating TSHRAb (TSAb) activities using CHO-hTSHR cells, FRTL-5 cells and chimeric receptor expressing cells (Mc1 + 2 and Mc2), specific blocking TSHRAb (TSBAb) activities using Mc2 cells and TBII activities using porcine thyroid membrane in 136 patients with untreated hyperthyroid Graves' disease. RESULTS: Based on various TSHRAb activities from each patient, the patients could be categorized into 7 subgroups by cluster analysis; 1) Group 1 (n = 41) was characterized by moderate TSAb activities both in CHO-hTSHR cells and in FRTL-5 cells, typical TSAb epitope, rare blocking antibodies and high TBII activities. 2) Group 2 (n = 16) was characterized by the presence of blocking TSHRAb in most patients, albeit the other characteristics were the same as those in Group 1. 3) Group 3 (n = 19) patients had low TSAb activities both in CHO-hTSHR cells and in FRTL-5 cells, seldom had blocking TSHRAb, but they had high TBII activities. 4) Group 4 (n = 30) could be categorized as 'mild disease' group, as they had low activities in all kinds of TSHRAb assay and had low antimicrosomal antibody activities. 5) Group 5 (n = 14) was characterized by moderate TSAb activities with atypical epitope(s), rare blocking TSHRAb and moderate TBII activities. 6) Group 6 (n = 10) patients had very high TSAb activities with typical epitopes, seldom blocking TSHRAb and low TBII activities. 7) Group 7 (n = 6) was characterized by very high TSAb activities with atypical epitopes and high TBII activities. Pretreatment serum thyroid hormone level was low only in group 4 patients compared to the other 6 groups (p < 0.05). The size of goiter was significantly larger in those in group 1 and group 3 (p < 0.05) compared to the other 5 groups. The prevalence of clinically significant ophthalmopathy was higher in group 2 patients than the other 6 groups (50% vs. 27.5%, p = 0.06). Among 6 kinds of TSHRAb activities, only the blocking TSHRAb activity was significantly associated with the presence of ophthalmopathy in multivariate analysis. CONCLUSION: These results suggest that the differences in epitopes for TSAb or the presence of blocking TSHRAb is not a major factor in determining the degree of thyrotoxicosis in Graves' disease. Although the pathogenic mechanism is not clear yet, we suggest that patients with ophthalmopathy have different TSHRAb repertoire from those without ophthalmopathy in Graves' disease.