[Four perspectives on Graves' orbitopathy - from the point of view of the patient, general practitioner, endocrinologist, and ophthalmologist]. / Endokrin oftalmopati ur fyra olika perspektiv.

Graves' orbitopathy is a common complication of Graves' disease. The mild form dominates, whereas moderate to severe and sight threatening forms are rarer. They require quick, adequate care, involving cooperation between county hospitals and the regional hospital, and adequate diagnostics and choice of treatments of treatments. A new national guideline for hyperthyroidism has been published in Sweden in January 2023, where these aspects are highlighted. The present guideline requires implementation regionally, as all components are not in place, but reflects the needs of patients. This article highlights important aspects for patients such as information, to be listened to, accessibility and adequate care, but also defines actions necessary in primary care where patients most often seek help at first. Lastly, important medical and practical aspects are reviewed by the endocrinologist and the ophthalmologist.

Smoking enhances proliferation, inflammatory markers, and immunoglobulins in peripheral blood mononuclear cells from Graves' patients.

Graves' disease (GD) and Graves' ophthalmopathy (GO) are complex autoimmune diseases. This study delved into the impact of cigarette smoke extract (CSE), simvastatin, and/or diclofenac on peripheral blood mononuclear cells (PBMCs). Specifically, we explored alterations in IL-1B, IL-6, PTGS2 expression, B- and T-lymphocyte proliferation, and Immunoglobulin G (IgG) production. We also assessed IGF1's influence on B- and T-lymphocyte proliferation. PBMCs from Graves' patients were exposed to CSE with/without simvastatin and/or diclofenac. Gene and protein expression was compared with untreated PBMCs. B- and T-lymphocyte proliferation was assessed following IGF1 treatment. PBMCs exposed to CSE exhibited increased expression of IL-1B (6-fold), IL-6 (10-fold), and PTGS2 (5.6-fold), and protein levels of IL-1B (4-fold), IL-6 (16-fold) and PGE2 (3.7-fold) compared with untreated PBMCs. Simvastatin and/or diclofenac downregulated the expression of PTGS2 (0.5-fold), IL-6 (0.4-fold), and IL-1B (0.6-fold), and the protein levels of IL-1B (0.6-fold), IL-6 (0.6-fold), and PGE2 (0.6-fold) compared with untreated PBMCs. CSE exposure in PBMCs increased the proliferation of B and T lymphocytes by 1.3-fold and 1.4-fold, respectively, compared with untreated. CSE exposure increased IgG (1.5-fold) in supernatant from PBMCs isolated from Graves' patients. IGF1 treatment increased the proliferation of B and T lymphocytes by 1.6-fold. Simvastatin downregulated the proliferation of B and T lymphocytes by 0.7-fold. Our study shows that CSE significantly upregulated the expression and release of the inflammatory markers PTGS2, IL-6 and IL-1B,the IgG levels, and the proliferation of B and T lymphocytes. Additionally, IGF1 increased the proliferation of B and T lymphocytes. Finally, these effects were decreased by diclofenac and/or simvastatin treatment.

Increased risk of Graves´ophthalmopathy in patients with increasing TRAb after radioiodine treatment and the impact of CTLA4 on TRAb titres.

INTRODUCTION: Treatment of Graves´ disease (GD) with radioiodine increases the risk of developing Graves´ ophthalmopathy (GO), and the link between thyroid and orbital tissue may be the presence of TSH-receptors. Radioiodine increases the titers of TRAb and the aim was to investigate the relationship between GO and TRAb titers after treatment with radioiodine and to define the impact of risk genes. METHODS: GD patients without ophthalmopathy or previous treatment with radioiodine were prospectively included at treatment with radioiodine for hyperthyroidism. A follow-up was performed 1 year later for the registration of GO development. The study was performed at a University Hospital Clinic; a referral center of all patients treated with radioiodine in the south of Sweden. The main outcome measures were the development of TRAb, anti-TPO, and anti-TG after 3 months and GO after 12 months and relationship to the genetic background (HLA, CTLA-4, and CYR61). RESULTS: Three months of radioiodine TRAb titers increased in two thirds of patients (p < 0.0005) but not in the other third. Anti-TPO titers were associated with TRAb (R = 0.362, p < 0.0001) but not anti-TG. At follow-up 1 year later (n = 204) 32 patients developed GO with a proportion of 70% in the group increasing in TRAb titers and 30% in the group with unchanged or lower TRAb titers (p-value < 0.0005). Patients with GO had higher titers of TRAb than patients without GO. CTLA-4 (rs231775 SNP) was significantly (p < 0.005) associated with TRAb titers above the median three months after radioiodine. CONCLUSIONS: The increase in TRAb titers after treatment with radioiodine is associated with GO and a genetic variation in CTLA-4 is associated with higher titers of TRAb.

The Effect of Radioiodine Treatment on TRAb, Anti-TPO, and Anti-TG in Graves' Disease.

BACKGROUND: In Graves' disease (GD), immunocompetent cells infiltrate thyroid tissue with release of TSH-receptor antibodies (TRAb), and radioiodine treatment is known to elicit an immune response with an increase in TRAb. OBJECTIVES: The aim was to study if all patients treated with radioiodine respond with a release of TRAb, anti-thyroperoxidase (anti-TPO), and anti-thyroglobulin (anti-TG). METHODS: This is a prospective observational study. GD patients (n = 131) were admitted for treatment with radioiodine. Thyroid antibodies were measured before and 3 months after iodine-131 treatment. RESULTS: After 3 months, a fold change > 1.1 was found in 66% of the GD patients, while the remaining 34% did not have a change or decrease in in TRAb. Anti-TPO and anti-TG also increased; the former showed an increase in 73% and the latter of 52%, while 27 and 48% decreased/were unchanged. A significant positive correlation was found between TRAb and anti-TPO, but not between TRAb and anti-TG. In the group with an increase in TRAb, the median fold change was 5.1, but there were no additional effects of tobacco smoking. The proportion of females below the median age (51.5 years) was significantly higher in the group that increased in TRAb compared to the one that decreased/was unchanged (66 vs. 34%). CONCLUSIONS: Treatment with radioiodine elicits an increase in thyroid antibodies, but not in all GD patients. The proportion of responders varied and was affected by age, resulting in a stronger immune response at younger age. However, there were no additional effects of smoking.

Study of Deiodinase Type 2 Polymorphisms in Graves' Disease and Ophthalmopathy in a Swedish Population.

BACKGROUND: Deiodinase type 2 (DIO2) is an enzyme that catalyzes the production of the active form of thyroid -hormone triiodothyronine (T3) from thyroxine (T4) and is important for maintaining intracellular T3 levels. Single nucleotide polymorphisms (SNPs) in DIO2 were associated with several diseases. The association of SNPs in DIO2 with Graves' disease (GD) was suggested in 2 Russian studies. OBJECTIVES: The aim of the study was to examine whether SNPs in DIO2 are associated with GD or Graves' ophthalmopathy (GO). METHODS: Seven SNPs in the DIO2 gene - rs225014 (Thr92Ala), rs12885300, rs2267872, rs225011, rs224995, rs225015, and rs2267873 - were studied to assess their association with GD and GO. In total, 712 patients with GD with (n = 311) or without (n = 399) ophthalmopathy and 1,183 sex-matched controls from Malmö, Sweden were analyzed. In GD patients with available data, the SNPs were examined for association with the levels of free T3, free T4, thyroid-stimulating hormone receptor antibodies (TRAb), and thyroid-peroxidase antibodies (TPOAb). RESULTS: Rs225011 was nominally associated with GD (OR 1.18, CI 1.01-1.37, p = 0.036). None of the SNPs were associated with GO. In GD patients, none of the SNPs were associated with the free-T4 (fT4), TRAb, or TPOAb levels. A weak, nonsignificant association was observed between free-T3 (fT3) levels and rs225014 and rs12885300, separately. CONCLUSIONS: Rs225011 in DIO2 was weakly associated with GD. The mechanism behind this association requires further study. None of the investigated common SNPs in DIO2 was significantly associated with GO, fT3, fT4, TRAb, or TPOAb in GD patients.

Adjuvant Treatment of Graves' Disease with Diclofenac: Safety, Effects on Ophthalmopathy and Antibody Concentrations.

BACKGROUND: Orbital morphological changes are often present in patients with Graves' disease (GD) already at diagnosis, and cyclooxygenase type 2 (COX-2) is overexpressed in active Graves' ophthalmopathy (GO). OBJECTIVE: To investigate if adjuvant treatment of GD with the COX inhibitor and peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist diclofenac decreases the development of ophthalmopathy and if laboratory parameters are affected. METHODS: This is a multicenter trial where 61 subjects were randomized to methimazole (block and replace with l-thyroxine) either with or without diclofenac 50 mg 1 × 2 for 12 months. The primary end point development of GO after 24 months was evaluated. Smoking habits were registered and the thyroid parameters TSH, free T4, free T3, TSH receptor antibodies (TRAb) and anti-TPO were followed. Safety parameters (kidney, liver and blood) and adverse events were regularly registered. RESULTS: GO developed in 11% (n = 3) of the patients treated with diclofenac and in 21% (n = 6) of the controls (p = 0.273). The adverse event profile was acceptable without any severe events related to diclofenac. Both TRAb and anti-TPO concentrations decreased during treatment with methimazole, but the anti-TPO concentrations were lower in patients treated with diclofenac after 15 months (p = 0.031). The TRAb concentrations were not significantly changed between groups. Smokers had higher concentrations of TRAb than nonsmokers both at diagnosis of GD (p = 0.048) and after 15 months (p = 0.042). CONCLUSIONS: Treatment with diclofenac had no significant influence on development of GO. Diclofenac reduces anti-TPO concentrations and seems to be safe to use in GD patients.

Presence of Thyroid-Stimulating Hormone Receptor Antibodies in a Patient with Subacute Thyroiditis followed by Hypothyroidism and Later Graves' Disease with Ophthalmopathy: A Case Report.

BACKGROUND: The development of Graves' disease (GD) after subacute thyroiditis (SAT) is very rare and only a limited number of cases have been reported. OBJECTIVES: Here, we report a patient with SAT followed by hypothyroidism and later GD, with ophthalmopathy, occurring 11 years after SAT. CONCLUSION: This case illustrates the appearance of thyroid-stimulating hormone (TSH) receptor antibodies in a female 1 year after SAT, the development of hypothyroidism requiring thyroxine, and later the occurrence of GD with severe ophthalmopathy, 11 years after SAT. The occurrence of SAT and GD may be coincidental but SAT may have induced the appearance of TSH-receptor antibodies, with the bioactivity changing from blocking, leading to hypothyroidism, and later to a stimulating activity that led to GD in a genetically susceptible patient.

Smoking induces overexpression of immediate early genes in active Graves' ophthalmopathy.

BACKGROUND: Cigarette smoking is a risk factor for the development of Graves' ophthalmopathy (GO). In a previous study of gene expression in intraorbital fat, adipocyte-related immediate early genes (IEGs) were overexpressed in patients with GO compared to controls. We investigated whether IEGs are upregulated by smoking, and examined other pathways that may be affected by smoking. METHODS: Gene expression in intraorbital fat was studied in smokers (n=8) and nonsmokers (n=8) with severe active GO, as well as in subcutaneous fat in thyroid-healthy smokers (n=5) and nonsmokers (n=5) using microarray and real-time polymerase chain reaction (PCR). RESULTS: With microarray, eight IEGs were upregulated more than 1.5-fold in smokers compared to nonsmokers with GO. Five were chosen for confirmation and were also overexpressed with real-time PCR. Interleukin-1 beta/IL-1B/(2.3-fold) and interleukin-6/IL-6/(2.4-fold) were upregulated both with microarray and with real-time PCR in smokers with GO compared to nonsmokers. Major histocompatibility complex, class II, DR beta 1/HLA-DRB1/was upregulated with microarray (2.1-fold) and with borderline significance with real-time PCR. None of these genes were upregulated in smokers compared to nonsmokers in subcutaneous fat. CONCLUSIONS: IEGs, IL-1B, and IL-6 were overexpressed in smokers with severe active GO compared to nonsmokers, suggesting that smoking activates pathways associated with adipogenesis and inflammation. This study underlines the importance of IEGs in the pathogenesis of GO, and provides evidence for possible novel therapeutic interventions in GO. The mechanisms activated by smoking may be shared with other conditions such as rheumatoid arthritis.

Ready for OR or not? Human reader supplements Eyesi scoring in cataract surgical skills assessment.

PURPOSE: To compare the internal computer-based scoring with human-based video scoring of cataract modules in the Eyesi virtual reality intraocular surgical simulator, a comparative case series was conducted at the Department of Clinical Sciences - Ophthalmology, Lund University, Skåne University Hospital, Malmö, Sweden. METHODS: Seven cataract surgeons and 17 medical students performed one video-recorded trial with each of the capsulorhexis, hydromaneuvers, and phacoemulsification divide-and-conquer modules. For each module, the simulator calculated an overall score for the performance ranging from 0 to 100. Two experienced masked cataract surgeons analyzed each video using the Objective Structured Assessment of Cataract Surgical Skill (OSACSS) for individual models and modified Objective Structured Assessment of Surgical Skills (OSATS) for all three modules together. The average of the two assessors' scores for each tool was used as the video-based performance score. The ability to discriminate surgeons from naïve individuals using the simulator score and the video score, respectively, was compared using receiver operating characteristic (ROC) curves. RESULTS: The ROC areas for simulator score did not differ from 0.5 (random) for hydromaneuvers and phacoemulsification modules, yielding unacceptably poor discrimination. OSACSS video scores all showed good ROC areas significantly different from 0.5. The OSACSS video score was also superior compared to the simulator score for the phacoemulsification procedure: ROC area 0.945 vs 0.664 for simulator score (P = 0.010). Corresponding values for capsulorhexis were 0.887 vs 0.761 (P = 0.056) and for hydromaneuvers 0.817 vs 0.571 (P = 0.052) for the video scores and simulator scores, respectively. The ROC area for the combined procedure was 0.938 for OSATS video score and 0.799 for simulator score (P=0.072). CONCLUSION: Video-based scoring of the phacoemulsification procedure was superior to the innate simulator scoring system in distinguishing cataract surgical skills. Simulator scoring rendered unacceptably poor discrimination for both the hydromaneuvers and the phacoemulsification divide-and-conquer module. Our results indicate a potential for improvement in Eyesi internal computer-based scoring.

Cataract surgeons outperform medical students in Eyesi virtual reality cataract surgery: evidence for construct validity.

PURPOSE: To investigate construct validity for modules hydromaneuvers and phaco on the Eyesi surgical simulator. METHODS: Seven cataract surgeons and 17 medical students performed capsulorhexis, hydromaneuvers, phaco, navigation, forceps, cracking and chopping modules in a standardized manner. Three trials were performed on each module (two on phaco) in the above order. Performance parameters as calculated by the simulator for each trial were saved. Video recordings of the second trial of the modules capsulorhexis, hydromaneuvers and phaco were evaluated with the modified Objective Structured Assessment of Surgical Skill (OSATS) and Objective Structured Assessment of Cataract Surgical Skill (OSACSS) tools. RESULTS: Cataract surgeons outperformed medical students with regard to overall score on capsulorhexis (p < 0.001, p = 0.035, p = 0.010 for the tree iterations, respectively), navigation (p = 0.024, p = 0.307, p = 0.007), forceps (p = 0.017, p = 0.03, p = 0.028). Less obvious differences in overall score were found for modules cracking and chopping (p = 0.266, p = 0.022, p = 0.324) and phaco (p = 0.011, p = 0.081 for the two iterations, respectively). No differences in overall score were found on hydromaneuvers (p = 0.588, p = 0.503, p = 0.773), but surgeons received better scores from the evaluations of the modified OSATS (p = 0.001) and OSACSS (capsulorhexis, p = 0.003; hydromaneuvers, p = 0.017; phaco, p = 0.001). CONCLUSIONS: Construct validity was found on several modules previously not investigated (phaco, hydromaneuvers, cracking and chopping, navigation), and our results confirm previously demonstrated construct validity for capsulorhexis and forceps modules. Interestingly, validation of the hydromaneuvers module required OSACSS video evaluation tool. A further development of the scoring system in the simulator for the hydromaneuvers module would be advantageous and make training and evaluation of progress more accessible and immediate.

Virtual reality cataract surgery training: learning curves and concurrent validity.

PURPOSE: To investigate initial learning curves on a virtual reality (VR) eye surgery simulator and whether achieved skills are transferable between tasks. METHODS: Thirty-five medical students were randomized to complete ten iterations on either the VR Caspulorhexis module (group A) or the Cataract navigation training module (group B) and then two iterations on the other module. Learning curves were compared between groups. The second Capsulorhexis video was saved and evaluated with the performance rating tool Objective Structured Assessment of Cataract Surgical Skill (OSACSS). The students' stereoacuity was examined. RESULTS: Both groups demonstrated significant improvements in performance over the 10 iterations: group A for all parameters analysed including score (p < 0.0001), time (p < 0.0001) and corneal damage (p = 0.0003), group B for time (p < 0.0001), corneal damage (p < 0.0001) but not for score (p = 0.752). Training on one module did not improve performance on the other. Capsulorhexis score correlated significantly with evaluation of the videos using the OSACSS performance rating tool. For stereoacuity < and ≥120 seconds of arc, sum of both modules' second iteration score was 73.5 and 41.0, respectively (p = 0.062). CONCLUSION: An initial rapid improvement in performance on a simulator with repeated practice was shown. For capsulorhexis, 10 iterations with only simulator feedback are not enough to reach a plateau for overall score. Skills transfer between modules was not found suggesting benefits from training on both modules. Stereoacuity may be of importance in the recruitment and training of new cataract surgeons. Additional studies are needed to investigate this further. Concurrent validity was found for Capsulorhexis module.

Stereoacuity and intraocular surgical skill: effect of stereoacuity level on virtual reality intraocular surgical performance.

PURPOSE: To evaluate the effect of stereoacuity on various intraocular surgical skills in inexperienced medical students using a virtual reality intraocular surgical simulator. SETTING: Department of Clinical Sciences, Malmö: Ophthalmology, Skåne University Hospital, Malmö, Sweden. DESIGN: Comparative case series. METHODS: Ninth-semester medical students performed 1 iteration on each of the following 3 cataract training modules: navigation, forceps, and capsulorhexis. Before the simulator training, the trainees received standardized instructions and were allowed to perform 1 training round on the cataract navigation training module. After completion of the training, the level of stereoacuity was measured using TNO charts. Surgical performance for each task was measured, and performance parameter scores were recorded. RESULTS: The study included 70 students. The simulator performance score correlated with the level of stereoacuity for the navigation training module (Spearman r = 0.377, P=.001) and forceps training module (Spearman r = 0.306, P=.01), showing a gradual increase in surgical performance with increasing stereoacuity. No such relationship was found for the capsulorhexis module (Spearman r = 0.18, P=.136). CONCLUSIONS: A gradual detrimental effect on initial intraocular surgical skill with decreasing stereoacuity was shown. This calls for studies of the impact of deficient stereopsis on long-term training effects.

Gene expression in Graves' ophthalmopathy and arm lymphedema: similarities and differences.

BACKGROUND: Graves' ophthalmopathy (GO) and lymphedema share some pathogenetic mechanisms, such as edema, inflammation, and adipogenesis. The aim of this study was to examine similarities and differences between chronic GO and chronic lymphedema. METHODS: Intraorbital adipose tissue was collected from patients with active (n = 10) or chronic GO (n = 10) and thyroid-healthy controls (n = 10). Arm subcutaneous adipose tissue was obtained from patients with chronic arm lymphedema (n = 10), where the unaffected arm served as a control. Gene expression was studied using microarray and real-time polymerase chain reaction. RESULTS: The following genes were significantly upregulated (p < 0.05) in lymphedema but not in GO and have functions in wound healing, fibrosis, fat metabolism, inflammation, differentiation, development, adhesion, and the cytoskeleton: ATP-binding cassette, sub-family G (WHITE), member 1 (ABCG1), actin, alpha 2, smooth muscle, aorta (ACTA2), secreted frizzled-related protein 2 (SFRP2), tenascin C (TNC), pentraxin-related gene, rapidly induced by IL-1 beta (PTX3), and carboxypeptidase X (M14 family), member 1 (CPMX1). In chronic GO, but not in lymphedema, adipocyte-related immediate early genes known to be overexpressed in patients with active GO were upregulated but at a lower level than previously shown for the active phase. Genes of the Wnt pathway, such as secreted frizzled-related protein 1, 2, and 3, were up- and downregulated in both chronic GO and lymphedema. Parathyroid hormone-like hormone (PTHLH) was downregulated (p = 0.01) and apolipoprotein L domain containing 1 (APOLD1) was upregulated (p = 0.05) in both active and chronic GO. CONCLUSIONS: There are more differences than similarities between chronic ophthalmopathy and chronic lymphedema, but both conditions exhibit less inflammation and adipogenesis compared to the active phases. In lymphedema, fibrosis dominates. PTHLH, which can inhibit adipogenesis, is downregulated both in active and chronic ophthalmopathy, indicating the possibility of an increased risk of adipogenesis.

Thyroid-associated ophthalmopathy; quality of life follow-up of patients randomized to treatment with antithyroid drugs or radioiodine.

OBJECTIVE: The objective of this study was to investigate quality of life (QoL) in patients with Graves' disease treated with radioiodine or antithyroid drugs. DESIGN AND METHODS: The design of the study consists of an open, prospective, randomized multicenter trial between radioiodine and medical treatment. A total of 308 patients were included in the study group: 145 patients in the medical group and 163 patients in the radioiodine group. QoL was measured with a 36-item Short Form Health Status Survey questionnaire (SF-36) at six time points during the 48-month study period. RESULTS: Patient who developed or got worse of thyroid-associated ophthalmopathy (TAO) at any time point during the 4-year study period (TAO group) had lower QoL when no respect was paid to the mode of treatment. TAO occurred in 75 patients who had radioiodine treatment at some time point during the study period as compared with TAO in 40 medically treated patients (P<0.0009). Comparisons between the group of patients who have had TAO versus the group without TAO, in relation to treatments and time, showed significantly decreased QoL scores for the TAO groups at several time points during the study. In patients without TAO, there were no differences in QoL related to mode of treatment. CONCLUSIONS: The QoL in patients with Graves' ophthalmopathy was similar in radioiodine and medically treated patients, but patients who developed or had worsening of TAO had decreased QoL independent of mode of treatment. Furthermore, patients with TAO recovered physically within 1 year but it took twice as long for them to recover mentally.

Internet-based assessment of medical students' ophthalmoscopy skills.

PURPOSE: Ophthalmoscopy is an important skill in undergraduate medical education. The use and outcome of a novel Internet-based method for assessing motor skills-related aspects of ophthalmoscopy skills in medical students are described. METHODS: A total of 139 students in Malmö and 255 students in Umeå were assessed during four consecutive semesters. An optic disc photograph was obtained in each student. At assessment each student was asked to examine the eye of a fellow student. Fifteen disc photographs were displayed on a computer screen. One of the photographs was from the fellow student. The remaining images had been randomly selected. The student was asked to identify the optic disc of the fellow student from the 15 photographs on the screen. In one semester, the time spent on this by each student was recorded. RESULTS: All students completed the task. The average pass ratio was 96.4% (ranging from 94.0% to 98.0%). Median student times were 5.53 mins in Malmö and 6.36 mins in Umeå. CONCLUSIONS: This is the first automated, Internet-based assessment of an ophthalmic motor skill performed in co-operation between universities. The method used bears more similarities to real-life ophthalmoscopy than methods that use model eyes. Time investments and infrastructure demands were comparatively low. The method was designed for stand-alone assessment of ophthalmoscopy or as an objective structured clinical examination station, but it may also be used during the learning process. The collaboration between universities was easily transformed into routine practice and similar projects should be encouraged to increase the standardization of assessment.

Thyroid-associated ophthalmopathy after treatment for Graves' hyperthyroidism with antithyroid drugs or iodine-131.

CONTEXT: Previous randomized trials have suggested an association between radioiodine treatment for Graves' hyperthyroidism and thyroid-associated ophthalmopathy (TAO). OBJECTIVES: The aim of the study was to compare the occurrence of worsening or development of TAO in patients who were treated with radioiodine or antithyroid drugs. DESIGN: We conducted a randomized trial (TT 96) with a follow-up of 4 yr. PATIENTS, SETTING, AND INTERVENTION: Patients with a recent diagnosis of Graves' hyperthyroidism were randomized to treatment with iodine-131 (163 patients) or 18 months of medical treatment (150 patients). Early substitution with T(4) was given in both groups. MAIN OUTCOME MEASURE: Worsening or development of TAO was significantly more common in the iodine-131 treatment group (63 patients; 38.7%) compared with the medical treatment group (32 patients; 21.3%) (P < 0.001). RESULTS: The risk for de novo development of TAO was greater in patients treated with iodine-131 (53 patients) than with medical treatment (23 patients). However, worsening of TAO in the 41 patients who had ophthalmopathy already before the start of treatment was not more common in the radioiodine group (10 patients) than in the medical group (nine patients). Smoking was shown to influence the risk of worsening or development of TAO, and smokers treated with radioiodine had the overall highest risk for TAO. However, in the group of smokers, worsening or development of TAO was not significantly associated with the choice of treatment for hyperthyroidism. CONCLUSIONS: Radioiodine treatment is a significant risk factor for development of TAO in Graves' hyperthyroidism. Smokers run the highest risk for worsening or development of TAO irrespective of treatment modality.

COX-2 and SCD, markers of inflammation and adipogenesis, are related to disease activity in Graves' ophthalmopathy.

CONTEXT: Inflammation and adipogenesis are two parallel processes with increased activity in severe Graves' ophthalmopathy. OBJECTIVE: The aim of this work was to define target genes for therapeutic intervention in adipogenesis and inflammation in Graves' ophthalmopathy. DESIGN: Orbital tissue was obtained from patients with ophthalmopathy in acute or chronic phase undergoing orbital surgery to study gene expression followed by the study of potential intervention mechanisms in preadipocytes. SETTING: Clinic of Endocrinology, University Hospital, Malmö, Sweden. PARTICIPANTS: Patients in acute severe or in chronic phase of ophthalmopathy. INTERVENTIONS: Lateral orbital decompression in acute phase and restorative surgery in chronic phase. In vitro treatment of preadipocytes with rosiglitazone and diclofenac. MAIN OUTCOME MEASURE: Gene expression in intraorbital tissue or preadipocytes and differentiation of preadipocytes. RESULTS: A marker of adipose tissue, stearoyl-coenzyme A desaturase (SCD), and the proinflammatory gene, cyclooxygenase-2 (COX-2), were overexpressed in patients in active phase compared to the chronic phase of ophthalmopathy. In growth-arrested preadipocytes stimulated with rosiglitazone, COX-2 expression increased temporarily within 1 hour and decreased to undetectable levels after 48 hours. In contrast, SCD and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression increased continuously from day 2 to day 7 during adipogenesis. Diclofenac, an inhibitor of cyclooxygenases with antagonistic effects on PPAR-gamma, reduced the number of mature adipocytes by approximately 50%. CONCLUSION: We conclude that inflammation and adipogenesis decrease with a decrease in activity of ophthalmopathy and that the nonsteroidal antiinflammatory drug diclofenac inhibits adipogenesis. This may represent a putative future treatment of endocrine ophthalmopathy.

Thyrostimulin (a TSH-like Hormone) expression in orbital and thyroid tissue.

OBJECTIVE: To investigate gene expression of thyrostimulin in orbital and thyroid tissue from patients with and without Graves' disease. DESIGN: Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was used for detection of thyrostimulin gene expression in intraorbital adipose tissue from patients with severe ophthalmopathy and thyroid healthy controls in addition to thyrostimulin expression in normal thyroid tissue, multinodular goiter tissue, and Graves' thyroid tissue. MAIN OUTCOME: In intraorbital tissue, thyrostimulin expression was identified in both patients and controls with fluorescence intensities varying between 0.23 and 0.88 in patients and 0.29 and 8.9 in controls before treatment with DNase. The signal of thyrostimulin was weak or absent in intraorbital adipose tissue from patients with ophthalmopathy and thyroid healthy controls after treatment of samples with DNase. This was in contrast to the expression of the thyroid-stimulating hormone (TSH) receptor and the housekeeping gene cyclophilin A that were detected both before and after DNase treatment. Similar results were found when analyzing human and rat thyroid tissue. CONCLUSIONS: Neither did we demonstrate gene expression of thyrostimulin in intraorbital adipose tissue or in thyroid tissue, nor could we confirm earlier findings in rat thyroid tissue. Whether thyrostimulin is a regulator of thyroid function has to be further investigated in future studies.

Overexpression of immediate early genes in active Graves' ophthalmopathy.

CONTEXT: In Graves' ophthalmopathy a major problem is an increase in the intraorbital adipose tissue volume. OBJECTIVE: The aim of this work was to define mechanisms of orbital adipogenesis. DESIGN: This was an open-label prospective study. SETTING: The study was conducted at the Clinic of Endocrinology, University Hospital. PARTICIPANTS: The study consisted of patients (n = 5) with severe ophthalmopathy with affection of the optic nerve and thyroid healthy controls (n = 5). INTERVENTIONS: We performed lateral decompression of orbital tissue in patients unresponsive to corticosteroids and restorative surgery of the upper eyelid in thyroid healthy controls. MAIN OUTCOME MEASURE: We made large-scale measurements of gene expression, with microarray technique based on determination of fluorescence intensities in cases and controls. RESULTS: A marker of adipose tissue, stearoyl-coenzyme A desaturase, was overexpressed in ophthalmopathy, and selection criteria were set to favor identification of genes known to be expressed in normal adipogenesis. The immediate early gene, cysteine-rich, angiogenic inducer, 61 (CYR61), was overexpressed in addition to 15 other immediate early genes (IEGs), and the expression of selected IEGs was confirmed with RT-PCR: CYR61, cyclooxygenase-2, dual-specificity phosphatase 1, B cell translocation gene 2, and early growth response 1. CYR61-responsive genes, known to participate in inflammation, IL-1beta, matrix metalloproteinase-3, and vascular endothelial growth factor were also overexpressed. Patients showed greater expression of CYR61 in the active than the chronic phase of ophthalmopathy, indicating that CYR61 is a marker of disease activity. Cyclooxygenase-2, the target gene of IL-1beta, was also overexpressed, although all patients had been treated with corticosteroids. CONCLUSION: Adipocyte-related IEGs are overexpressed in active ophthalmopathy, and CYR61 may have a role in both orbital inflammation and adipogenesis and serve as a marker of disease activity.

Appearance of the pattern deviation map as a function of change in area of localized field loss.

PURPOSE: To determine the influence of the spatial extent and the depth of localized field loss on the computation of the General Height (GH) method for estimating the diffuse component of visual field loss and, therefore, on the subsequent appearance of the Pattern Deviation (PD) map. METHODS: Varying shapes and depths of localized glaucomatous field loss were modeled in each of 82 Humphrey Field Analyzer Program 30-2 fields (82 normal eyes) by superimposing, on the fields from the normal eyes, the PD defect depth (P < 0.05) of one visual field from each of 123 patients with glaucoma. The difference in GH between each of the 10,086 modeled fields and the GH in the corresponding measured normal field was derived and the relationship to possible differences in the location-by-location significance levels of each pair of PD maps determined. RESULTS: For the group mean overestimation in the GH of -0.79 dB, the 50th, 90th, and 95th percentiles of the modeled fields described 23.4%, 37.9%, and 42.6% locations, respectively, exhibiting an underestimation in PD statistical significance. As the size of the superimposed field loss increased, the overestimation of the GH increased, and the underestimation of PD statistical significance became more apparent. This error was independent of defect depth. CONCLUSIONS: The localized component of field loss in glaucoma produced an overestimation of diffuse loss and a consequent underestimation of the severity of focal loss by PD analysis. This effect increased as the spatial extent of the loss became more extensive and will lead to an underestimation of progressive localized field loss.