Ophthalmopathy Index Research Articles

Thiol-disulfide homeostasis as an oxidative stress marker in patients with Graves’ ophthalmopathy

ABSTRACTPurpose: To evaluate thiol-disulfide homeostasis (TDH) and its relationship with clinical findings in patients with Graves’ ophthalmopathy (GO).Methods: This study included 52 patients with GO and 34 healthy controls. Tests of TDH were conducted using the novel automated spectrophotometric method. Clinical activity score (CAS) and ophthalmopathy index were evaluated and relationships with native thiol, disulfide levels and disulfide/native thiol % ratios were analyzed.Results: The mean plasma native thiol levels in GO patients were significantly lower than that of normal controls (p = 0.013) . The mean plasma disulfide levels and disulfide/native thiol % ratio were found to be significantly higher in GO patients than in controls (p = 0.041, p = 0.022; respectively). The mean native thiol levels of active GO patients (n = 24) were significantly lower than that of patients with inactive GO (n = 28) (p = 0.044). The mean disulfide levels and disulfide/native thiol % ratios of active GO patients were significantly higher than that of patients with inactive GO (p = 0.034, p = 0.001; respectively). There was a negative correlation between native thiol and CAS (r = −0.532, p = 0.001) and a positive correlation between disulfide/native thiol % ratio and CAS (r = 0.601, p < 0.001).Conclusions: The impairment of TDH indicates the presence of oxidative stress in moderate-to-severe GO, particularly in active GO and smokers.

Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 × 2 factorial, double-blind, randomised controlled trial

Standard treatment for thyroid eye disease is with systemic corticosteroids. We aimed to establish whether orbital radiotherapy or antiproliferative immunosuppression would confer any additional benefit. CIRTED was a multicentre, double-blind, randomised controlled trial with a 2 × 2 factorial design done at six centres in the UK. Adults with active moderate-to-severe thyroid eye disease associated with proptosis or ocular motility restriction were recruited to the trial. Patients all received a 24 week course of oral prednisolone (80 mg per day, reduced to 20 mg per day by 6 weeks, 10 mg per day by 15 weeks, and 5 mg per day by 21 weeks) and were randomly assigned via remote computerised randomisation to receive either radiotherapy or sham radiotherapy and azathioprine or placebo in a 2 × 2 factorial design. Randomisation included minimisation to reduce baseline disparities in potential confounding variables between trial interventions. Patients and data analysts were masked to assignment, whereas trial coordinators (who monitored blood results), pharmacists, and radiographers were not. The radiotherapy dose was 20 Gy administered to the retrobulbar orbit in ten to 12 fractions over 2 to 3 weeks. Azathioprine treatment was provided for 48 weeks at 100-200 mg per day (dispensed as 50 mg tablets), depending on bodyweight (100 mg for <50 kg, 150 mg 50-79 kg, 200 mg for ≥80 kg). The primary outcomes were a binary composite clinical outcome score and an ophthalmopathy index at 48 weeks, and a clinical activity score at 12 weeks. The primary analysis was based on the intention-to-treat allocation and safety was assessed in all participants. This study is registered with ISRCTN, number 22471573. Between Feb 15, 2006, and Oct 3, 2013, 126 patients were recruited and randomly assigned to groups: 31 patients to radiotherapy plus azathioprine, 31 to sham radiotherapy and azathioprine, 32 to radiotherapy and placebo, and 32 to sham radiotherapy and placebo. Outcome data were available for 103 patients (54 for sham radiotherapy vs 49 for radiotherapy and 53 for placebo vs 50 for azathioprine), of whom 84 completed their allocated treatment of radiotherapy or sham radiotherapy and 57 continued to take azathioprine or placebo up to 48 weeks. There was no interaction betweeen azathioprine and radiotherapy (pinteraction=0·86). The adjusted odds ratio (ORadj) for improvement in the binary clinical composite outcome measure was 2·56 (95% CI 0·98-6·66, p=0·054) for azathioprine and 0·89 (0·36-2·23, p=0·80) for radiotherapy. In a post-hoc analysis of patients who completed their allocated therapy the ORadj for improvement was 6·83 (1·66-28·1, p=0·008) for azathioprine and 1·32 (0·30-4·84, p=0·67) for radiotherapy. The ophthalmopathy index, clinical activity score, and numbers of adverse events (161 with azathioprine and 156 with radiotherapy) did not differ between treatment groups. In both groups, the most common adverse events were mild infections. No patients died during the study. In patients receiving oral prednisolone for 24 weeks, radiotherapy did not have added benefit. We also did not find added benefit for addition of azathioprine in the primary analysis; however, our conclusions are limited by the high number of patients who withdrew from treatment. Results of post-hoc analysis of those who completed the assigned treatment suggest improved clinical outcome at 48 weeks with azathioprine treatment. National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity.

Expression and clinical significance of connective tissue growth factor (CTGF) in Graves' ophthalmopathy

AimsTo examine the expression of connective tissue growth factor (CTGF) in human cultured orbital fibroblasts from patients with Graves' ophthalmopathy (GO) and investigate whether a correlation exists between the presence...

&lt;sup&gt;60&lt;/sup&gt;Co orbital radiotherapy in Graves' ophthalmopathy

PURPOSE: Graves' ophthalmopathy (GO) is a common cause of morbidity in patients with Graves disease which suboptimal management is widespread. Immunosuppressive drugs and orbital irradiation represent treatment options for patients with moderate to severe and active GO. The aim of this study is to share our initial results from the application of orbital radiotherapy in GO. MATERIAL AND METHODS: Fifteen consecutive patients (12 women and 3 men) at a mean age 52 years (range, 26 to 62 years) with GO underwent radiotherapy of posterior orbit. Research team included a radiotherapist, endocrinologist and ophthalmologist performing the first and the follow-up examinations. Both orbits were examined for soft tissue and cornea involvement, proptosis, eye muscle impairment, visual acuity, visual fields and tonometry. Ophthalmic index was calculated before and after treatment. All the patients had received glucocorticoids before radiotherapy as 46.67% of them required corticosteroids during the period of irradiation and 80% received antithyroid medication. Overall clinical response was evaluated as excellent, good, fair or no response according to Donaldson's criteria. RESULTS: Fifteen patients completed the study with a follow-up of two or more months. All of them received 20 Gy to both orbits. The overall clinical response was excellent in two patients (13.33%), good in seven (46.67%), fair in five (33.33%), and there was no response in one patient (6.67% of the cases). The mean ophthalmopathy index (OI) was 7.2 before treatment and 3 after irradiation. There was a mean OI improvement of 4.2 points (range 2-7) compared to the pretreatment values. Best response was achieved for corneal involvement, soft tissue symptoms, sight loss and eye muscle impairment, while the response for proptosis was limited. No late adverse effects associated with radiotherapy such as cataract and radiation-induced retinopathy were observed at all. CONCLUSION: Our study proved that orbital radiotherapy is an effective and safe treatment option for progressive GO with better results in the early and acute stage of the disease. Scripta Scientifica Medica 2013; 45(4): 41-45.

Clinical outcomes of orbital radiotherapy combined with systemic glucocorticoids for patients with Graves' ophthalmopathy refractory to steroid therapy

PurposeTo investigate the clinical outcomes of combined orbital radiotherapy and systemic glucocorticoids for patients with refractory Graves’ ophthalmopathy (GO). Materials and methodsThe records were retrospectively reviewed of six patients with active moderate-to-severe GO who had been refractory to steroid therapy alone and treated with combined orbital radiotherapy and systemic glucocorticoids. All patients had already received one or more trial of steroid therapy prior to radiotherapy. Two patients had recurrence after steroid cessation, and four were unable to taper corticosteroids partially or completely. Two patients experienced relapse compressive optic neuropathy during tapering of glucocorticoids. The radiation dose was 20 Gy at 2 Gy/fraction. Presenting signs especially for disease activity and severity, treatment outcomes, and side effects were assessed. ResultsAfter combined therapy, complete cessation of corticosteroid therapy and stabilization of disease without recurrence was achieved in all patients. The clinical activity score decreased from 6.0 to 2.5 (p = 0.04). The ophthalmopathy index decreased from 8.2 to 5.7 (p = 0.05), with significant improvement in soft tissue sign (p = 0.03) and extraocular muscle movement (p = 0.03). Both patients with relapse dysthyroid optic neuropathy regained their vision. Side effects of radiotherapy included posterior subcapsular cataract formation in one patient. ConclusionCombined orbital radiotherapy and systemic corticosteroids can help to achieve stable disease and cessation of corticosteroid without recurrence in patients with refractory GO. This technique achieves greater improvement in clinical activity, soft tissue inflammation, and ocular motility.

Oxidative stress in patients with Graves' ophthalmopathy: relationship between oxidative DNA damage and clinical evolution

To evaluate the relationship between oxidative stress and clinical evolution in patients with Graves' ophthalmopathy (GO). Thirty-one euthyroid GO patients and 25 healthy subjects participated in this study. Oxidative DNA damage was assessed by determination of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) level in urine by ELISA. The relationship of oxidative DNA damage to the clinical evolutions of GO, especially the smoking status, clinical activity scores (CAS), and ophthalmopathy index was examined. The mean 8-OHdG was significantly higher in GO patients than that of normal controls (12.6+/-5.7 vs 6.7+/-2.5 ng/mg creatinine, P<0.001). Smokers had significant higher 8-OHdG than did never smokers in GO patients (P=0.029), but not in healthy controls (P=0.374). Among GO patients, only CAS remained significantly correlated with 8-OHdG (P=0.001) after adjusting for age, sex, disease duration, the status of antithyroid drug and smoking, and thyroid-stimulating hormone level. Patients with active GO (CAS>3) had higher 8-OHdG than did the patients with CAS <or=3 (16.3+/-4.9 vs 8.6+/-3.0 ng/mg creatinine). Our findings suggest that urinary 8-OHdG is increased in GO patients and is correlated with the disease activity. Smoking had a higher impact on the increased 8-OHdG among GO patients.

Total Thyroidectomy in Treatment of Graves' Ophthalmopathy

The aim of the study. The present report is an attempt at answering the question regarding the ocular status in the course of thyroid ophthalmopathy following surgical treatment. A retrospective analysis included a group of patients presenting with various ophthalmologic symptoms in the course of Gravesi disease. The analysis focused on the clinical ophthalmologic status determined based on eye examinations and determinations of the level of thyroid stimulating hormone receptor antibody (TRAb), as well as on changes in the above parameters in pre and postoperative examinations. Material and methods. Between January 2005 and December 2006, 61 patients were managed surgically for Gravesi disease. The group consisted of 53 (86.9%) females and eight (13.1%) males. Their mean age was 45.5‐12 years, with the range of 18 to 71 years. Prior to surgery, the mean duration of pharmacotherapy was 27.3 months, with the range of 3-120 months. The severity of the disease was determined using the NOSPECS classification and the resultant ophthalmopathy index according to Donaldson. Ocular symptoms were assessed prior to treatment and subsequently at 3, 6 and 12 months after thyroidectomy. Determinations of TSH, fT4 and antithyroid antibodies TRAb were done in all the patients before and 12 months after surgical treatment. In the present investigations, determinations of the thyroid stimulating hormone receptor antibody (TRAb) levels were done by radioimmunoassay. Results. All the 61 patients were treated surgically. The following procedures were performed: total thyroidectomies in 35 (57.4%) patients, the so-called Dunhill operations (total lobectomy plus subtotal resection of the contralateral side) in 14 (23%), and subtotal bilateral lobectomies in 12 (19.6%) subjects. Determinations of thyroid stimulating hormone receptor antibody TRAb levels were done preoperatively in 61 (100%) patients and postoperatively in 54 (88.5%) individuals. In the present series, preoperative TRAb values were significantly elevated (>2 IU/L) in as many as 56 (91.8%) patients. After the surgery, TRAb normalized in 35 (57.4%) patients (<1 IU/L n absent) from 9.14‐10.7 to 0.95‐0.45 IU/L (p<0.001, test t). The differences are statistically significant. Borderline antibody values (between 1 and 2 IU/l) were noted in 5 (8.1%) patients before and in 18 (29.5%) after the procedure. The ophthalmologic assessment based on the Donaldson ophthalmopathy index, which combines scores awarded while evaluating five classes (soft tissues, degree of exophthalmus, oculomotor muscle status, corneal status, visual acuity) included 54 (88.5%) of 61 patients. The value of the index changed in the entire investigated group, what was manifested in a statistically significant decrease in the ophthalmopathy index from 6.1‐2.32 prior to treatment to 3.31‐2.09 after the surgery (p<0.001, test t). Deterioration of the general ocular status as confirmed by the initial ophthalmopathy index was confirmed by ophthalmology in five patients. Subjective complaints of deteriorated vision were reported by three patients Conclusions. The use of ultrasonic scalpel in thyroid surgery a reduction of mean operating time, achieving good hemostasis and improved cosmetic results without increased risk of morbidity

Oxidative Stress and Antioxidant Activity in Orbital Fibroadipose Tissue in Graves' Ophthalmopathy

Purpose: To investigate the oxidative stress and antioxidant activity in the orbit in Graves' ophthalmopathy (GO). Materials and Methods: Orbital fibroadipose tissue samples were obtained from 13 cases during orbital fat decompression surgery. All cases demonstrated features of moderate or severe GO according to the European Group on Graves' Orbitopathy classification. The disease activity was evaluated with the Clinical Activity Score, and the clinical features of GO were evaluated with the Ophthalmopathy Index. Orbital fibroadipose tissue samples of 8 patients without any thyroid or autoimmune disease were studied as controls. In the tissue samples, lipid hydroperoxide level was examined to determine the level of oxidative stress; glutathione level to determine antioxidant level; superoxide dismutase, glutathione reductase, and glutathione peroxidase activities to determine antioxidant activity. Results: Lipid hydroperoxide level and all three antioxidant enzyme activities were found to be significantly elevated, while glutathione level significantly diminished in tissue samples from GO cases compared to controls (p < 0.05). Glutathione levels in tissue samples of GO cases showed negative correlation with Ophthalmopathy Index (r = −0.59, p < 0.05). Conclusions: The antioxidant activity in the orbit is enhanced in GO. However, the oxidative stress appears to be severe enough to deplete the tissue antioxidants and leads to oxidative tissue damage. This study may support the possible value of antioxidant treatment in GO.

Oxidative Stress Change by Systemic Corticosteroid Treatment Among Patients Having Active Graves Ophthalmopathy

To measure the 8-hydroxy-2'-deoxyguanosine (8-OHdG) level in patients having active Graves ophthalmopathy (GO) and to compare this oxidative stress biomarker and the clinical evolution of patients after systemic corticosteroid treatment. In 8 euthyroid patients having active GO, we determined the 8-OHdG levels in urine before, during, and after intensive corticosteroid therapy. Clinical activity and ophthalmopathy index scores were assessed. Nine age- and sex-matched healthy volunteers served as control subjects. The mean 8-OHdG level was statistically significantly increased in patients having active GO compared with that of controls (17.47 vs 5.97 ng/mg of creatinine, P < .001). During and after maximal systemic corticosteroid treatment, patients had statistically significantly lower mean 8-OHdG levels (7.19 and 10.18 ng/mg of creatinine, respectively) compared with the mean level before treatment. These changes were accompanied by decreases in clinical activity and ophthalmopathy index scores. The urinary 8-OHdG levels were subsequently elevated in 2 patients having recurrent active GO when corticosteroid therapy was tapered or withdrawn. Oxidative stress may have a role in the pathogenesis of GO. Urinary 8-OHdG level can be used not only as a noninvasive biomarker of oxidative stress in patients having GO but also as an objective and quantitative parameter in the follow-up of patients during immunosuppressive treatment.

HYPERTHYROIDISM

Objective: Thyroid eye disease presents a special challenge to the ophthalmologists withpathogenetic enigma &amp; therapeutic dilemma. The objective of the study is to determine the frequency of mode ofophthalmic manifestation of thyrotoxicosis, rating of all components of “NOSPECS” classification system and todetermine the relative magnitude of low &amp; high index orbitopathies. Design: Cross sectional study. Setting: Thedepartment of ophthalmology Allied Hospital / Punjab Medical College (PMC) &amp; Punjab Institute of Nuclear medicine(PINUM) Faisalabad. Period: From 1 Apr 2004 to 31 st st March.2005. Material &amp; Methods: 100 patients of all age &amp;sex, after having diagnosed as thyrotoxic on the basis of positive laboratory investigations were subjected to a plannedocular examination according to the given protocol. An ophthalmopathy index scoring system was adopted to tabulatethe results. Results: Among 100 thyrotoxic patients, 72 were female &amp; 28 were male with male to female ratio 1:26.The over all mean age was 36.59 ±13.81 years with 77 % of cases lying between 21-50 year of age. Orbitopathy wasfound in 74 % of thyrotoxic patients with relative distribution of eyelid retraction 56 %, soft tissue involvement 38 %,Proptoses 16%, restrictive myopathy 11%, corneal involvement 13 % and sight loss due to optic neuropathy 7 %. Thereis more occurrence of low index orbitopathy 83 % as compared to high index orbitopathy i.e 17 %. Conclusion: Theoccurrence of dysthyroid orbitopathy is not essentially present in all hyper thyroid patients. Only 3 out of 4 develop it.The frequency of manifestation of various eye lesions in descending order is eyelid retraction, soft tissue involvement,Proptosis, corneal involvement, myopathy &amp; vision loss. Low index orbitopathy is more common &amp; males are at morerisk of developing orbitopathy than females.

Early Response to Intravenous Glucocorticoids for Severe Thyroid-Associated Ophthalmopathy Predicts Treatment Outcome

The results for 18 consecutive patients with severe thyroid-associated ophthalmopathy (TAO) treated with high-dose, pulsed intravenous methylprednisolone (MP) are presented in this paper. Eighteen (18) patients with severe TAO, defined as either optic neuropathy, progressive diplopia, or severe soft-tissue swelling accompanied by evidence of NOSPECS class 2b or more severe eye disease, were studied in a prospective, noncontrolled case series. Patients were treated with 1.5 g of intravenous MP, divided over 3 days, followed by a tapering course of oral prednisolone. All patients were examined before treatment, 1 week and 1 month after commencement of treatment and at 2-3 monthly intervals thereafter. Assessment of visual acuity, differential intraocular pressure (IOP), soft-tissue inflammation, diplopia, and exophthalmometry were used to calculate a modified ophthalmopathy index (OI) for each patient at each visit. Median duration of follow-up was 14 months. A statistically significant reduction in OI following treatment with high-dose MP was observed after 1 week of treatment from 10.8 +/- 3.9 standard deviation (SD) to 8.3 +/- 3.4 (SD) (P < 0.001) and between 1 week and the end of the treatment period (OI, 7.2 +/- 3.4 (SD); P < 0.05). A response occurred in 83% of patients within a week but only 66% maintained this response. There was a significant negative correlation between response to treatment (OI before treatment-OI after treatment) and duration of eye disease (P = 0.034, Spearman correlation). High-dose, pulsed intravenous MP is an effective medical treatment for severe TAO. Responders can be identified within the 1st week. Treatment response is inversely related to disease duration.

Double-Blind, Placebo-Controlled Trial of Octreotide Long-Acting Repeatable (LAR) in Thyroid-Associated Ophthalmopathy

Several uncontrolled studies suggest octreotide is beneficial in thyroid-associated ophthalmopathy (TAO); however, the natural tendency of TAO to improve mandates randomized, controlled trials. We report results of a double-blind, placebo-controlled trial of octreotide long-acting repeatable (LAR). Fifty euthyroid patients (11 males, 39 females; age 22-74 yr, median 50 yr) with active TAO [clinical activity score (CAS) > or =3, NOSPECS (no signs or symptoms; only signs, no symptoms; signs only; proptosis; eye muscle involvement; corneal involvement; sight visual acuity reduction) 2a-5a] of median duration 0.9 yr received either 30 mg LAR or placebo every 4 wk for 16 wk; both groups then received 30 mg LAR for wk 16-32 and were followed up without treatment for a further 24 wk. Objective assessments included all individual parameters of TAO, CAS, and derived scores for soft tissue inflammation (STI) and ophthalmopathy index (OI). During wk 0-16 there was significant reduction in STI, subjective diplopia, and CAS in LAR-treated patients; STI and CAS were also reduced with placebo. The OI reduced by -1.12 in LAR (P = 0.0017) vs. -0.23 in placebo (P = 0.33), giving a barely significant treatment effect by Wilcoxon (P = 0.043), but analysis of covariance failed to confirm this (P = 0.16). During wk 16-32 there was no significant change in OI in either group. The overall results (wk 0-32) showed reduction in STI and CAS in both groups. In this double-blind, placebo-controlled trial, no significant therapeutic effect of octreotide LAR was seen in patients with moderately severe TAO. The improvements in both treated and placebo groups emphasize that the results of open studies must be viewed with caution.

The effect of etanercept on Graves' ophthalmopathy: a pilot study

To assess the effect of etanercept, an antitumour necrosis factor (anti-TNF) drug, on clinical signs in Graves' ophthalmopathy (GO). A total of 10 consecutive patients (seven female, three male) with recent-onset, active, mildly-to-moderately severe GO were treated with subcutaneous injections of 25 mg etanercept (Enbrel) twice weekly during 12 weeks. The average age was 50 years (range: 39-59 years). The average duration of GO was 4 months (range: 2-6 months). All patients were at least 2 months euthyroid with medication. The mean pretreatment clinical activity score (CAS) was 4 (range: 3-6). The mean CAS prior to treatment was 4, at 6 weeks 2.6, and at 12 weeks 1.6. The mean ophthalmopathy index (OI) prior to treatment was 5.8, at 6 weeks 4.8, and at 12 weeks 4.4. Thus, after 12 weeks of treatment the mean CAS had decreased by 2.4+/-1.3 (60%), and the mean OI had decreased by 1.4+/-1.2 (24%). The main decrease of the CAS and OI was noted at 6 weeks of treatment. The difference was particularly evident on soft-tissue changes, including periocular chemosis and redness. The mean exophthalmometry values did not change. In all, 60% percent of patients reported moderate to marked improvement. In three patients, the GO flared up again after cessation of treatment. There were no serious adverse events or side effects during a mean follow-up time of 18 months. This study strongly suggests that etanercept may suppress the clinical signs in GO, but randomized controlled trials are needed to further evaluate the effect of anti-TNF treatment and to compare its side-effects with those of corticosteroids.

Radiotherapy only in severe, progressive endocrine orbitopathy: long-term results and comparison of various classification systems

Therapeutic results after radiotherapy in thyroid associated orbitopathy (TAO) often are not comparable, because either different therapeutic methods at the same time or different scores were used in the evaluation. This study focuses on radiotherapy alone by means of different evaluation scores. 60 patients (49 women, 11 men) received standard external beam radiotherapy (20 Gy: 10 fractions of each 2 Gy) as ultima ratio after failing different other therapies of thyroid associated orbitopathy. The mean interval from beginning of the symptoms to the radiotherapy was 17 +/- 36 months (between 6 and 240 months). The follow up was documented--classified by means of 4 different scores--before radiotherapy, 6-12 weeks, 1 year after radiotherapy and at last follow up. The changes of symptom categories or grades of the different scores were analysed. Significant changes of the ophthalmic scores were observed when comparing the endpoints at 6-12 weeks, and at 1-year follow up after radiotherapy. The "classical" Werner score at 12 months follow up did not correlate well with the other TAO scores: American thyroid association (ATA) scoring system, Stanford scoring system, International ophthalmopathy index, while all other TAO scores revealed a high correlation among each other. According to the Orbitopathy Index (OI) of Grussendorf an improvement from 14.2 points to 6.0 points was achieved. Soft tissue involvement and corneal involvement demonstrated the highest response rate (83/87%), extraocular muscle involvement and proptosis a good response rate (69/70%). No long-term complications were observed. According to this study there are indications that external beam radiotherapy is a suitable therapy even after pretreatment and a longer course of TAO. The OI, the ATA and the Stanford scoring systems lead to similar results in the assessment of thyroid orbitopathy.

High-dose intravenous steroid pulse therapy in thyroid-associated ophthalmopathy.

To evaluate the efficacy of high-dose intravenous steroid pulse followed by oral steroids in the treatment of thyroid-associated ophthalmopathy, we performed clinical assessment and measurement of retroorbital muscle enlargement in 27 patients before and after the therapy, and followed them up longitudinally. The mean duration of follow up is (mean +/- SD) 29.8 +/- 23.8 months (range 4-92). Diplopia disappeared in 10 patients and ameliorated in 11 patients. The degree of proptosis decreased in 15 patients and the fall in visual acuity improved in a third of the patients. The total ophthalmopathy index (OI) decreased from 7.0 +/- 1.9 to 3.0 +/- 1.5. The extraocular muscle enlargement (EME), expressed as the maximal ratio of extraocular muscle thickness to the diameter of the optic nerve, decreased from 2.33 +/- 0.56 to 1.27 +/- 0.26. No major side effects were found in any patient. The improvement in the eye disease was found immediately after the pulse therapy, prior to the start of the following therapy by oral steroids and/or orbital irradiation. Both of OI and EME decreased with time after the therapy and did not get worse after withdrawing oral steroids. The efficacy of the therapy evaluated by degrees of improvement in OI and in EME was significantly greater in females than in males. Although there was a significant positive correlation between initial OI and EME values and initial TBII and TSAb activities, a significant correlation was seen only between the degrees of improvement in EME and changes in TBII activity due to the therapy. The duration of eye disease, thyroid status, treatment with anti-thyroid drug, smoking and experience of previous treatment did not affect the efficacy of the present therapy. We conclude that high-dose intravenous steroid pulse therapy is effective and safe for thyroid-associated ophthalmopathy.

Thyroid stimulating antibody in sera of Graves' ophthalmopathy patients as a possible marker for predicting the efficacy of methylprednisolone pulse therapy.

Nine patients with Graves' ophthalmopathy (GO) were treated with intravenous methylprednisolone pulse therapy and followed up by ophthalmological assessment, magnetic resonance imaging, and thyroid-associated autoantibody (thyroid stimulating antibody (TSAb), TSH binding inhibitor immunoglobulins (TBII), and anti-eye muscle antibody (EMAb)). Ophthalmological assessment was performed by the ophthalmopathy index (OI) which was made on the basis of the system recommended by the American Thyroid Association Committee. EMAb was expressed as the ratio of density of the 64 kDa band of eye muscle membrane to that of 92 kDa non-specific band found with all normal sera when assessed by western blotting. Five patients with mild ophthalmopathy (OI < 4) did not show progressive improvement in OI. Three of 4 patients with severe eye disease (OI > 4) showed a progressive and distinct improvement in OI. These 3 patients had high TSAb levels before methylprednisolone pulse therapy. One patient with severe ophthalmopathy did not respond to this pulse therapy; this patient's TSAb was negative. A significant positive correlation was observed between the activity of TSAb before treatment and the improvement in OI (delta OI) (r = 0.86, P < 0.01, n = 9). The relationship between delta OI and EMAb did not reach significance. These results suggest that TSAb in sera of GO patients can be a useful marker for predicting the efficacy of methylprednisolone pulse therapy.

Therapy of Graves' Ophthalmopathy with Intravenous High-Dose Steroid followed by Orbital Irradiation

We investigated the effects of intravenous high-dose steroid therapy followed by orbital irradiation for Graves' ophthalmopathy in eight patients. All patients presented with diplopia or fixed globes. Extraocular muscle dysfunction showed excellent improvement after the combined therapy; diplopia disappeared completely in five of them, and one patient with fixed globes showed normal eye movement. Two other patients also exhibited great improvement, although their diplopia persisted. Their ophthalmopathy index was decreased from (mean +/- SD) 4.25 +/- 0.82 to 0.75 +/- 1.48. Extraocular muscle enlargement, assessed by magnetic resonance imaging study after the radiotherapy, was also reduced after the combined therapy, although two patients did not show remarkable enlarged extraocular muscles. There was no change in extraocular muscle thickness 6-9 months after the therapy, and the ophthalmopathy index did not show change in a long follow-up (maximum 37 months after the therapy). These results suggest that high-dose methylprednisolone followed by orbital radiotherapy is a good therapeutic design for Graves' ophthalmopathy and justify a prospective randomized trial.

Age and gender influence the severity of thyroid‐associated ophthalmopathy: a study of 101 patients attending a combined thyroid‐eye clinic

The pathogenesis of thyroid-associated ophthalmopathy is thought to be autoimmune, although environmental and genetic factors are also considered to be important. As the morbidity of thyroid-associated ophthalmopathy is considerable and treatment often unsatisfactory, there a need to identify possible predisposing factors. The study was undertaken in order to ascertain the relationship between age, gender and severity of thyroid-associated ophthalmopathy. One hundred and one consecutive patients with thyroid-associated ophthalmopathy who presented over a period of 5 years to a combined thyroid-eye clinic. Patients were assessed by grading their inflammatory signs and degree of diplopia, and by measurement of exophthalmos, palpebral aperture, differential intraocular pressure, and visual acuity. On the basis of the above an ophthalmopathy index was devised to grade the overall severity of eye disease. The mean age was 49.2 years (SD 13.4), the female-to-male ratio was 4.05, and mean ophthalmopathy index 6.49 (SD 3.3). Optic nerve compression was present in 9.9% of patients. There was a positive relationship between age and ophthalmopathy index (P < 0.001); after correcting for age, males had an average ophthalmopathy index 41% greater than that of females. There is an association between severity of thyroid-associated ophthalmopathy and (i) advancing age and (ii) female-to-male ratio, which has not been previously described. Patients over the age of 60 (particularly males) with Graves' disease appear to be at risk of developing severe eye disease.

High-dose intravenous immunoglobulin treatment in Graves' ophthalmopathy

We have evaluated the efficacy of high-dose intravenous immunoglobulin treatment in Graves' ophthalmopathy, and have carried out a prospective randomized clinical trial, including a single-blind evaluation, whereby 14 patients were assigned to two different treatment groups: 7 patients were treated with intravenous immunoglobulin and orbital radiotherapy (Group 1) and 7 patients were given intravenous immunoglobulin alone (Group 2). The results of the intravenous immunoglobulin treatment were also compared with those obtained in a Historical Control Group (12 patients) treated with systemic methylprednisolone and orbital irradiation. Degree of ocular involvement and response to treatment were assessed by ophthalmopathy index. The mean initial and final ophthalmopathy index showed no significant difference among the three groups. Comparison between the mean initial and final ophthalmopathy index showed a statistically significant reduction (p less than 0.005) in all three groups, the observed changes being confirmed by orbital computerized tomography in Groups 1 and 2. Corticosteroid treatment was associated with major and minor side effects, while no important adverse reactions were observed during intravenous immunoglobulin treatment. Even considering our results as preliminary, we conclude that intravenous immunoglobulin treatment is effective and safe in improving Graves' ophthalmopathy.

Role of magnetic resonance imaging in thyroid-associated ophthalmopathy: its predictive value for therapeutic outcome of immunosuppressive therapy.

To investigate the efficacy of magnetic resonance imaging (MRI) in the assessment of thyroid-associated ophthalmopathy (TAO), 51 patients with TAO were evaluated by ophthalmologic examinations and MRI at 0.5 T. Thickness of extraocular muscles (EM) was measured by T1-weighted image. Signal intensities of EM and orbital connective tissue (OCT) were measured by short inversion time inversion recovery (STIR) image and expressed as a ratio by comparison to the signal intensity of cerebral substantia alba (SI, signal intensity ratio). Significant enlargement of one or more EM was observed in 86% of patients with TAO, and SI of EM (2.15 +/- 0.63, mean +/- SD) was significantly increased compared with control values (n = 16; 1.35 +/- 0.33; t test, p < 0.01). SI of OCT tended to be greater than that in the control group, although the difference was not significant. There was a significant positive correlation between thickness of EM and severity of ophthalmopathy, assessed as an ophthalmopathy index (p < 0.05). SI of neither EM nor OCT correlated with the severity of the eye disease. To investigate whether MRI findings could predict the outcome of methylprednisolone pulse therapy, we studied 23 patients with TAO who received this treatment. SI of EM and OCT in the 12 patients giving favorable responses were significantly greater than those in the 11 patients without good response (t test, p < 0.01). On the other hand, the thickness of eye muscles did not correlate with the outcome of treatment except for that of medial rectus muscle. There was a significant correlation between SI of EM and that of OCT (r = 0.78, p < 0.01), suggesting possible similar pathologic processes in these tissues in TAO.(ABSTRACT TRUNCATED AT 250 WORDS)