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It is known that cytokine-stimulated glycosaminoglycans (GAG) production
plays a role in development of OGD. Tan et al., Rochester, MN, USA, studied
the in vitro effect of soluble IL-I receptor on GAG production in orbital
fibroblasts from OGD patients. They found an inhibitory effect and suggest
that soluble IL-I receptor may be used in humans in prevention and/or treatment
of OGD.
Kiljanski et al., Pittsburg, PA, USA, found in 31% of patients with OGD, but only in 8% of those with Hashimoto and no patients with Graves' hyperthyroidism without OGD, antinuclear antibodies, mostly consistent with anti-Sm or anti-Rnp antibodies. Anti-interstitial tissue antibodies and ANA crossreacted with all tissues tested. The authors query if OGD is a collagen disorder. Wengrowicz et al., Barcelona, Spain, studied serum antibodies reactive against different proteins from pig eye muscle membrane (PEMM) proteins in 27 patients with OGD, 13 patients with Graves' disease without OGD, and 12 normals. They found a strong association between OGD and antibodies to a 55 kDa PEMM protein. Furthermore, clinically active and recent eye disease was related to the presence of antibodies against a 64 kDa PEMM protein. Philippou et al., Athens, Greece, studied the relationship between serum antibodies against TG and acetylcholine-esterase in patients with OGD, Graves' hyperthyroidism without OGD, and controls. They found increased expression of these antibodies only in the patients group with OGD, suggesting that these antibodies might have a pathophysiological significance in this group of patients. Kahaly et al., Mainz, Germany, studied autologous organ specific T cell reactivity to protein fractions extracted from retroorbital adipose tissue, eyemuscle and fibroblasts from patients operated for OGD. They found increased reactivity to protein fractions 6-10 kD and 19-26 kD in 8/9 OGD patients in fat tissue, in 3/4 OGD patients in eyemuscle and 2/4 OGD patients in cultured retrobulbar fibroblasts. The authors conclude that 2 orbital autoantigens reacting with organ specific T-cells, may play a role in the immunopathogenesis of OGD. Production of oxygen free radicals has been suggested to play a role in the generation of autoimmune processes. During production of oxygen free radicals increased production of superoxide dismutases (SOD) is seen in order to reduce free radicals and thus reduce tissue damage. Barsouk et al., Pittsburg, PA, USA, studied the concentration of SOD in lacrimal secretions from patients with OGD and found increased SOD activity as compared to controls. Furthermore there was a significant negative correlation between SOD activity and duration of OGD, and a significant positive correlation with disease activity. They conclude that, although increased SOD activity in tears is not specific for OGD, it's measurement may be useful for early demonstration of OGD. Burch et al., Washington, DC, USA, found increased expression of a similar enzyme (manganese superoxide dismutase) in retroorbital fibroblasts of 2 patients and suggest a potential role of oxidative damage in the pathogenesis of OGD. Marino et al., Pisa and Cagliari, Italy, found an increased prevalence of OGD in patients with Graves' disease when this was associated with myasthenia gravis, that is of 78%, whereas OGD prevalence in Graves' disease without association with myasthenia gravis was 56%. Moncayo et al., Innsbruck, Austria, evaluated the sensitivity of octreoscanning to detect clinical activity of eye symptoms in patients with OGD. They found a high correlation with accumulation of octreotide in retroorbital tissue in 20 patients with strong signs of clinical activity. Also a positive uptake was found about 50% of scans of patients with negative or intermediate clinical activity, indicating activity of the immune process that is not always clinically aparent. Octreoscanning appeared to be more sensitive than CT or MRI. Octreoscans were also positive during immunosuppressive therapy, but were negative in disease of long duration. It is concluded that this technique provides a sensitive method to assess clinical activity in OGD. Krenning et al., Rotterdam, The Netherlands, performed thyroidal and orbital octreoscanning during treatment (methimazole and L-T4, mean follow-up 9 months) in 12 hyperthyroid patients with Graves' disease. Thyroidal octreotide uptake decreased in all patients and normalized at an average of 9 months after treatment was started. It appeared that neither initial nor the decrease in thyroidal octreotide uptake was correlated with thyroid size in these patients. Eleven consecutive patients with OGD were treated with retrobulbar irradiation and 7 responded to therapy. In these patients normalization of orbital octreotide uptake and of clinical activity score (CAS) occurred both at an average of 8 months. It was also found that a high pretreatment early (5h) orbital uptake of octreotide is correleted with a favourable response to orbital irradiation. Bartalena et al., Pisa, Italy, conducted a prospective randomized controlled study involving 443 patients with Graves' disease with slight or absent OGD to evaluate the effects of RAI treatment on development of eyesigns. 150 Patients were treated with RAI alone and 145 patients with RAI and 0.5 mg prednisone/kg bodyweight. Also 148 patients were treated with methimazole for 1.5 years. Results: RAI only; no change in eyesigns in 127/150 patients and worsening of eyesigns in 23/150 patients. RAI + prednisone; no change in 95/145 patients, no worsening, improvement in 50/145 patients. Methimazole; 141/148 no change, 4/148 worsening, 3/148 improvement. It is concluded that RAI treatment is associated with exacerbation of OGD, but that glucocorticoids may prevent exacerbation and cure mild OGD. Methimazole does not influence the course of OGD. (Comment: This is an important study with a great number of patients and of high scientific quality, because the authors did not find any differences with regard to duration of hyperthyroidism and OGD prevalence and degree of ocular involvement in the three patient groups. The results suggest that eyesigns may develop after RAI, even if not present before, and the question should therefore be raised if glucocorticoids should be given as a routine irrespective of absence or presence of eyesigns in patients with Graves' disease who are going to be treated with RAI. Before an answer can be given to this question, more details should be revealed about the study, for instance about the degree of newly developed OGD. At present however, it seems advisable to treat all those patients with glucocorticoids when treated with RAI, when active eyesigns are already present.) Boucher et al., Montreal, Canada, studied the effects of treatment with propylthiouracil (PTU) or RAI in patients with Graves' disease on the development of serum antibodies against eye muscle (EM Abs). 14 Patients were treated with RAI and 13 patients with PTU. TSI and EM Abs were similar before treatment. RAI induced an increase in EM Abs and also of TSI whereas PTU induced a sustained decrease in EM Abs, while TSI did not change. (Comment: These studies suggest that RAI may release autoantigens to which autoantibodies like EM Abs and TSI are being developed and the results are in line with the previous report i.e. exacerbation of eyesigns after RAI without concomitant administration of glucocorticoids.) Ringel et al., Washington, DC, USA, studied the development of antibody dependent cellular cytotoxicity against human orbital muscle cells (ADCC) in 15 patients with Hodgkin's disease (HD) treated with external beam irradiation and 5 patients with HD treated with chemotherapy. ADCC was significantly elevated in the whole group of patients with HD as compared to controls and HD patients who were irradiated were more likely to have positive ADCC than those treated with chemotherapy. Also HD patients had more anti-TPO antibodies, but no difference with regard to anti-TG antibodies, TSI, and TBII as compared to controls. Bartley, Rochester, MN, USA, did an epidemiological and clinical study of OGD in a population based setting. During a 15 year interval 120 incident cases of OGD were diagnosed among residents of Olmsted County, MN, USA..14.3% of patients were male and 85.8% female. All patients were white. The ageadjusted incidence rates for females and males were 16.0 cases and 2.9 cases per 1.00,000 population per year respectively. Peak incidence rates occurred in age groups 40-44 years and 60-64 years in females and 45-49 years and 65-69 years in males. Approximately 90% of patients had Graves' hyperthyroidism, 1% primary hypothyroidism, 3% Hashimoto's thyroiditis, and 5% were euthyroid. The median age at diagnosis of OGD was 53 years. Nagy et al., Debrecen, Hungary, compared ultrasound and CT scanning of 315 extraocular muscles in patients with OGD and found a poor correlation between the two techniques (r = 0.25). From their studies they conclude that MRI is the best technique to estimate muscle thickness in OGD and that ultrasound tends to underestimate muscle diameter. Yeung et al., Hongkong, performed a prospective study to evaluate the effect of somatostatin (200 ug 3xd) versus corticosteroids (prednisone 1 mg / kg / d in decreasing doses) in the treatment of mild/moderate eye disease in patients with OGD. In the somatostatin group complete improvement occurred in 1/7, partial improvement in 3/7, no improvement in 3/7. In the corticosteroid group the results were 3/9, 2/9, and 4/9 respectively. Matsumoto et al., Fukuoka and Kobe, Japan, evaluated OGD in 20 patients, who underwent total thyroidectomy followed by RAI ablation for malignant OGD, 10 years after treatment. A decrease inproptosis of 2 2 mm was considered to be represent improvement. Twenty-one eyes (52.2%) showed improvement, 16 eyes (40%) were unchanged, and 3 eyes (7.5 %) worsened. The goiter size in the improved patients was significantly smaller before treatment (31 ml) than that in the unchanged and worsened groups (60 ml). (Comment: No information is available about visual acuity in these patients before and after treatment. Total thyroidectomy with RAI ablation is not a standard therapy for malignant exophthalmus, although it may be necessary in some cases. Often acute administration of corticosteroids in high doses in combination with orbital irradiation may suffice in many patients.) Hamada et al., Osaka and Tokyo, Japan, studied 22 patients with Graves' disease without proptosis or orbital CT abnormalities, 57 patients with extraocular muscle (EOM) enlargement and 125 patients with enlargement of orbital fat (OF). Patients with EOM had significantly smaller thyroids and a lower degree of hyperthyroidism than the two other groups. These findings were parallelled by a lower TBII value in the EOM group than in the other two groups. |
