Eye Muscle Dysfunction Research Articles

Presence of thyroid-associated ophthalmopathy in Hashimoto's thyroiditis.

To determine the prevalence of ophthalmopathy in Hashimoto's patients and to make a comparison in subgroups of patients. The study involved 110 Hashimoto's thyroiditis patients and 50 control subjects attending to the endocrinology department of the hospital. Subgroup classification of patients was made as euthyroid, subclinic and clinic in Hashimato's thyroiditis. All patients were evaluated by a single experienced ophthalmologist for the prevalence and characteristics of eye signs. The overall prevalences of eye changes were 22.7% (25 patients) in patients and 4% (2 persons) in control subjects respectively (P=0.002). In patients the most common symptom was retrobulbar eye pain with or without any eye movement. Thirteen patients had significant upper eyelid retraction (11.8%). Six patients had eye muscle dysfunction as reduced eye movements in up gaze. In control patients one person had proptosis and another had lid retraction. The clinical activity score and classification of the ophthalmopathy did not show any significant differences among subgroups. The eye signs were mostly mild (22.7%) and the most common eye sign was the presence of upper eyelid retraction (11.8%). Additionally six patients had eye muscle dysfunction as reduced eye movements in up gaze. Therefore we recommend to make a routine ophthalmic examination in Hashimoto's thyroiditis patients in order not to omit the associated ophthalmopathy.

Treating Graves’ orbitopathy: where are we?

Medical management of overt and active Graves’ orbi-topathy is frequently unsatisfactory, both for the patientand the physician [1]. Systemic glucocorticoids, moreefficaciously given intravenously [2], represent the first-line treatment [3, 4], but many patients require a secondcourse of steroids, associated with orbital radiotherapy orcyclosporine, to inactivate the disease [5]. And, eventually,some kind of rehabilitative surgery (orbital decompression,squint surgery, eyelid surgery) is needed in many patientswhen GO is inactive to correct residual invalidating man-ifestations, such as exophthalmos, strabismus/diplopia,eyelid retraction [3].Reasons why glucocorticoids are not always effectiveare not fully understood. They include selection of patientswith long-lasting GO, prevalence of proptosis with limitedinflammatory changes, long-standing eye muscle dysfunc-tion associated with fibrotic changes, smoking habits,mutations in the glucocorticoid receptor causing adecreased sensitivity to the drug. Most importantly, glu-cocorticoids, despite immunosuppressive actions, aremainly anti-inflammatory drugs and cannot be really con-sidered pathogenic drugs. Autoimmune pathogenesis ofGO is extremely complex, involving autoreactive T lym-phocytes, B-lymphocytes, the TSH receptor, the IGF-1receptor, secretion of a number of cytokines automain-taining the reactions occurring in the orbit. Studies areongoing to completely unveil the multiple steps of thecascade of events eventually causing remodeling of theorbital tissue, with an increase in the fibroadipose tissueand swelling of the extraocular muscles [6]. These studiesare essential to define the target of novel (‘‘pathogenic’’)treatments (T-cells? B-cells? Cytokines?). Among clinicalstudies based on better understanding of orbital patho-physiological processes, promising, although preliminary,results come from the evaluation of the CD20? depletingagent, rituximab [7] or some anti-TNFa agents [8]. Inpatients with mild GO, selenium administration for6 months prevented the progression to more severe formsof eye disease [9]. Expansion of the orbital adipose tissue isundoubtedly a key feature of GO under most circum-stances. In this issue of Endocrine, Zhang et al. [10]evaluated the effects of thalidomide on preadipocytes(3T3-L1 preadipocytes) and orbital fibroblasts from fewpatients with GO. This agent was initially used as an oralsedative hypnotic, but it is now used in the management ofseveral autoimmune disorders in view of its anti-inflam-matory and anti-angiogenic features. In Zhang et al.’sstudy, thalidomide dose-dependently inhibited adipogene-sis of 3T3-L1 preadipocytes; this was associated with adecreased expression of PPARc and the TSH receptor [10].These inhibitory effects were also observed on the differ-entiation of preadipocyte fibroblasts from GO orbital tissueinto adipocytes, in which the expression of TNFa and IL-6was also reduced by thalidomide [10]. The main limitationof this ex vivo study is the small size, because tissue fromonly three patients with GO was utilized. However, itseems reasonable to try and reproduce these preliminaryresults in larger studies before envisioning or advocating itspossible use in clinical practice in patients with GO.Pathogenesis of GO is so complex and implies the partic-ipation of so many actors that it is presently hard to believethat a single drug can cure or control the disease. It ishowever worth keep on trying.

Eye muscle antibodies in Graves' ophthalmopathy: pathogenic or secondary epiphenomenon?

The extra ocular (eye) muscles are one of the principal tissues involved in the autoimmune-mediated inflammation of Graves' ophthalmopathy (GO). Several eye muscle proteins are targeted by autoantibodies or sensitized T lymphocytes, or both, and include: G2s, which is now identified as the terminal 141 amino acids of the winged-helix transcription factor FOXP1, the flavoprotein (Fp) subunit of the mitochondrial enzyme succinate dehydrogenase, the so-called "64kDa protein", a non-tissue specific membrane protein called 1D and the calcium binding protein calsequestrin. Of these, antibodies against G2s and Fp are the most sensitive markers of eye muscle damage in patients with thyroid autoimmunity even though neither antigen is specific to eye muscle and neither antibody is specific to GO. However, the recent finding that the calsequestrin gene is 4.7 times more expressed in eye muscles than other skeletal muscles suggests that we should reconsider the possible role of anti-calsequestrin autoantibodies in ophthalmopathy. GO may comprise two main subtypes with different pathogenetic mechanisms, namely ocular myopathy in which eye muscle inflammation predominates and congestive ophthalmopathy where inflammatory changes occur in the periorbital connective tissues in the absence of eye muscle dysfunction. Anti-G2s and anti-Fp antibodies are closely associated with the ocular myopathy subtype of GO while antibodies targeting type XIII collagen, the only member of the collagen family to have a transmembrane domain, are closely linked to congestive ophthalmopathy. Since both G2s and Fp are intracellular antigens it is unlikely that either antibody causes eye muscle fiber damage in GO, although a role in the later stages of the disease when the fiber has released its cellular contents has not been excluded. Eye muscle antibodies that are cytotoxic to eye muscle cells in antibody-dependent cell-mediated cytotoxicity (ADCC) are more likely to play a role in eye muscle fiber damage since they target a putative eye muscle cell membrane antigen, the identity of which is currently being investigated. While anti-G2s and anti-Fp antibodies are probably secondary to an underlying reaction, such as cytotoxic T lymphocyte targeting of an eye muscle membrane antigen that has yet to be identified, they are reliable markers of immunologically mediated eye muscle fiber damage in patients with Graves' hyperthyroidism. In conclusion, while a pathogenic role for eye muscle antibodies has not been excluded, they are most likely secondary to cytotoxic T cell reactions in GO and, as such, good markers of this autoimmune disease.

Ophthalmological evaluation in thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is an autoimmune disorder associated with Graves' disease and can seriously decrease quality of life. Current therapeutic regimens have considerable side-effects and are not always able to restore normal function and appearance. Timing and a proper choice of therapy are critical but require careful patient evaluation. The present paper aims to describe clinical symptoms and signs of TAO and their relevance for management. Thyroid-associated ophthalmopathy has an initial active inflammatory phase which usually lasts for 6-24 months but which may not infrequently continue for several years. The severity of the subsequent clinical manifestations is determined by the degree of optic nerve involvement, corneal involvement, eye muscle dysfunction and exophthalmus, and also by the degree of subjective illness and disfigurement. Disease severity is the key determinant of indication for therapy, while inflammatory activity is the key determinant of therapeutic choice. Immunosuppressive therapy may be used in the inflammatory stage, while reconstructive surgery should be postponed to the inactive phase. Emergency surgery may be needed for vision-threatening situations during the active stage.

Orbital radiotherapy for Graves' ophthalmopathy.

Orbital radiotherapy is a well-established method of treatment for severe Graves' ophthalmopathy, because of its anti-inflammatory and locally immunosuppressive effects. It has been used for 60 years. Conventional external x-ray and cobalt therapy have been abandoned, and most groups now use supervoltage linear accelerators (4-6 MeV). Cumulative doses may vary, but in most studies a cumulative dose of 20 Gy delivered over 2 weeks was utilized. Successful outcome depends on the selection of patients, because recent onset, active ophthalmopathy is much more favorably affected than longstanding, inactive disease. Inflammatory signs, recent onset eye muscle dysfunction, and optic neuropathy respond well to orbital radiotherapy, while proptosis and longstanding eye muscle restriction respond poorly. Overall, favorable responses have been reported, with few exceptions, in approximately 60% of cases. Combination of irradiation with high-dose systemic glucocorticoids provides better results than either treatment alone. Orbital radiotherapy is well tolerated and safe. Preexisting retinopathy (e.g., in patients with diabetes) is a contraindication to this treatment for the risk of further retinal damage. No case of radiation-induced tumors has so far been described after orbital radiotherapy for Graves' ophthalmopathy.

Serum antibodies against the flavoprotein subunit of succinate dehydrogenase are sensitive markers of eye muscle autoimmunity in patients with Graves' hyperthyroidism.

Thyroid-associated ophthalmopathy is an autoimmune disorder of the extraocular muscles and orbital connective tissue, which is usually associated with Graves' hyperthyroidism. Well-studied markers of ophthalmopathy are eye muscle membrane antigens, reportedly of approximately 64-kDa molecular mass. One, originally identified only as the 64-kDa protein, has recently been shown to be the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, which has a correct molecular mass of 67 kDa. We have used purified beef heart Fp as antigen in an enzyme-linked immunosorbent assay for cross-reactive human autoantibodies. Sera have been screened from patients with thyroid-associated ophthalmopathy classified according to activity and presence or not of eye muscle disease, and from those with Graves' hyperthyroidism without eye involvement. Also examined were serum samples taken periodically from 20 patients with Graves' hyperthyroidism during 24 months of treatment of their hyperthyroidism with antithyroid drugs. Four of these patients had ophthalmopathy at the onset, 12 developed ophthalmopathy, and 4 did not develop any eye signs during treatment. Anti-Fp subunit antibodies were detected in 73% of patients with active ophthalmopathy and evidence of eye muscle involvement but only in 25% if there was only congestive ophthalmopathy. These values were 0% and 11% for patients with chronic ophthalmopathy, with or without eye muscle dysfunction, respectively. The antibodies were also detected in 14% of patients with Graves' hyperthyroidism without evident ophthalmopathy, 11% of patients with nonimmunologic thyroid disorders, 12% of type I diabetics, and 12% of age- and sex-matched normal subjects. Significantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves' hyperthyroidism, who developed eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient. Antibodies were not detected in any of 6 patients who developed congestive ophthalmopathy without evidence of eye muscle damage or in 4 patients who did not develop any eye signs. In conclusion, we have shown a close relationship between eye muscle disease and serum antibodies against the Fp subunit of succinate dehydrogenase in patients with Graves' hyperthyroidism.

Treating severe Graves' ophthalmopathy

Most patients with Graves' disease have some evidence of ocular involvement, but this is commonly mild, requiring only local measures. A minority of patients (3-5%) have severe Graves' ophthalmopathy, for which the three main treatment procedures are represented by high-dose glucocorticoids, orbital radiotherapy and orbital decompression. Favourable results with medical treatment have been reported in approximately 60% of patients, with particular regard to inflammatory changes, newly developed eye muscle dysfunction and optic neuropathy. Orbital decompression is indicated in severe eye disease not responsive to glucocorticoids and/or irradiation, particularly in the presence of marked proptosis and optic neuropathy. Not conclusive or unsatisfactory results have been obtained with other medical treatment procedures, including immunosuppressive drugs, intravenous immunoglobulins and plasmapheresis. Recently favourable responses have been reported with somatostatin analogues. Rehabilitative surgery involving either the eye muscles or the eyelids is not infrequently required after medical treatment or decompression. Permanent control of thyroid hyperfunction by radioiodine or thyroidectomy is advisable when severe ophthalmopathy is present. Exacerbation of ophthalmopathy following radioiodine may occur but can be prevented by concomitant administration of glucocorticoids. Smoking deleteriously influences the course of ophthalmopathy and its response to treatment.

Localization and clinical significance of thyrotropin receptor mRNA expression in orbital fat and eye muscle tissues from patients with thyroid-associated ophthalmopathy.

We have studied the cellular localization of thyrotropin receptor (TSH-R) mRNA in orbital fat and extraocular muscle tissues from patients with thyroid-associated ophthalmopathy (TAO) using Northern blot, reverse transcriptase polymerase chain reaction (RT-PCR), and in situ hybridization, and we correlated the findings with clinical estimates of ophthalmopathy. Although we failed to detect TSH-R mRNA in orbital tissues by Northern blot, TSH-R cDNA was amplified in orbital fat tissue from 13 of 25 patients with TAO and from 2 of 4 control subjects, in eye muscle tissue from 2 out of 7 patients with TAO, and in cultured orbital fibroblasts and subcutaneous fibroblasts from TAO patients. In situ hybridization showed that TSH-R mRNA was detected in cultured orbital fibroblasts as well as skin fibroblasts obtained from the patient. Furthermore, the expression of TSH-R mRNA in orbital fat tissue from patients with TAO significantly correlated with the orbital fat volume and the severity of ophthalmopathy, especially the extent of eye muscle dysfunction. These results suggest that the expression of TSH-R in the orbit, especially fibroblasts, may play a role in the pathogenesis and clinical manifestations of the ophthalmopathy in patients with TAO, although a secondary effect, involving fibroblasts in TAO is also possible.

Antibody-dependent cell-mediated cytotoxicity against orbital target cells in thyroid-associated ophthalmopathy and related disorders; close relationship between serum cytotoxic antibodies and parameters of eye muscle dysfunction.

We have carried out tests for antibody-dependent cell-mediated cytotoxicity (ADCC) against extra ocular muscle (EOM), Müller's muscle, orbital fibroblasts and skeletal muscle in patients with thyroid-associated ophthalmopathy (TAO) and related eye disorders. Cytotoxicity was measured as lactate dehydrogenase (LDH) release and results expressed as % cytotoxicity. Tests were positive, with EOM cells, in 65% of patients with TAO, 75% with ocular myopathy, a variant of TAO in which periorbital inflammation is minimal, 50% with euthyroid Graves' disease defined as ophthalmopathy associated with subclinical thyroiditis and in 50% of patients with stable lid lag and retraction but no other signs of progressive ophthalmopathy, but in only 13% of patients with Graves' hyperthyroidism without ophthalmopathy, 10% with Hashimoto's thyroiditis and 14% of patients with other thyroid disorders. Tests were positive, with Müller's muscle cells, in 40% of patients with TAO, 25% with ocular myopathy, 40% with euthyroid Graves' disease, 44% with lid lag, 19% with Graves'hyperthyroidism, 50% with Hashimoto's thyroiditis and in 37.5% of patients with other thyroid disorders. When skeletal muscle cells were used as target, tests were positive in 13% of patients with TAO, 31% with lid lag, 25% with Graves' hyperthyroidism and in 29% of patients with Hashimoto's thyroiditis, but in no patient with euthyroid Graves' disease or other thyroid disorders. Tests were negative in all patients and normals tested when EOM-derived fibroblasts were used as targets in ADCC. A significant positive correlation between % cytotoxicity against EOM cells and the severity of the eye muscle dysfunction expressed as an eye muscle index, was observed in patients with TAO. There was a significant negative correlation between the duration of eye disease and % cytotoxicity against EOM cells, suggesting higher titers of cytotoxic antibodies in the early stages of TAO. There was no correlation between % cytotoxicity and serum level of anti-TSH receptor antibodies, measured in a radioreceptor assay. These findings suggest that autoimmunity against Müller's muscle may play a role in the pathogenesis of persistent lid lag and retraction. The nature of the EOM and Müller's muscle autoantigens recognized by cytotoxic antibodies in the serum of patients with TAO and related eye disorders is unknown.

The ophthalmopathy of Graves' disease.

Ophthalmopathy is an integral component of Graves' disease. It usually appears at the same time as hyperthyroidism, and is characterized by proptosis (exophthalmos), periorbital and conjunctival edema, eye muscle dysfunction, and on occasion corneal ulceration or optic neuropathy. Graves' ophthalmopathy, like Graves' hyperthyroidism, is an autoimmune disease, but the mechanisms that initiate and maintain it are not known. Most patients can be treated conservatively, but a few require anti-inflammatory or surgical therapy to relieve symptoms and preserve vision.

Orbital cobalt radiotherapy and systemic or retrobulbar corticosteroids for Graves' ophthalmopathy.

Orbital radiotherapy and corticosteroids are two well-established medical treatments for severe Graves' ophthalmopathy. In this report we analyze the results obtained by the combination of orbital radiotherapy and systemic or retrobulbar corticosteroids in patients with severe Graves' ophthalmopathy. Orbital cobalt radiotherapy was carried out by a cobalt unit, delivering a total of 2,000 rads to each eye in 10 daily doses. Systemic corticosteroid treatment was started with 70-80 mg methylprednisolone/day for 2-3 weeks with subsequent progressive reduction of the dose until discontinuation of the drug after 5-6 months. Retrobulbar corticosteroid therapy was performed by 14 bilateral injections of 40 mg methylprednisolone acetate at 20- to 30-day intervals. Results were evaluated both on clinical grounds and by numerical scoring (ophthalmopathy index, OI). Excellent or good responses were obtained in the majority of 72 patients by combined treatment with orbital cobalt radiotherapy and systemic corticosteroids. Soft tissue changes, newly developed eye muscle dysfunction and optic neuropathy showed the most beneficial effects from treatment, whereas proptosis, corneal lesions and long-standing eye muscle abnormalities responded to a lesser extent. The results of a controlled clinical trial showed that the combined treatment was more effective than the administration of systemic methylprednisolone alone. Because relevant side effects of systemic corticosteroid therapy were observed in 4 cases, the clinical validity of retrobulbar corticosteroids in substitution for systemic corticosteroids was evaluated in 44 patients. Excellent or good responses were observed in 25% of these patients, slight responses being obtained in 55% and no change in 20%.(ABSTRACT TRUNCATED AT 250 WORDS)