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Show journal of Ni- iin>- 0)> hllitili> n> l<> M 15( 3): ' l66- 170, 1995. < b ]' J95 Lippincotl- Raven Publishers, Philadelphia Acetylcholine Receptor Antibodies in Patients with Graves' Ophthalmopathy Daniel M. Jacobson, M. D. Abstract: Objectives: To determine the frequency and clinical correlates of acetylcholine receptor ( AChR) antibody seropositivity in patients with Graves' ophthalmopathy. Materials and Methods: Fifty consecutive new patients with Graves' ophthalmopathy diagnosed in an outpatient neuro- ophthalmology practice underwent determination of AChR- binding antibodies. Clinical and biochemical thyroid variables were compared between seropositive and seronegative patients. Clinical variables included age, sex, thyroid disorder, and duration and course of illness. Biochemical variables included thyroid hormone levels and thyroid antibodies. Seropositive patients were followed clinically to identify signs of myasthenia gravis. Results: Four of 50 ( 8%) patients had definitely elevated levels of AChR- binding antibodies. No obvious differences existed between the seropositive and seronegative groups in regards to age, sex, underlying thyroid disorder, biochemical thyroid state, presence of thyroid antibodies, or duration and course of their disease. None of the four seropositive patients developed signs of myasthenia gravis during the median follow- up period of 4.5 years. Conclusion: AChR- binding antibody seropositivity occurs in a small proportion of patients with Graves' ophthalmopathy but, by itself, does not necessarily identify an individual with concurrent myasthenia gravis or an individual at risk to develop myasthenia gravis. Key Words: Myasthenia gravis- Graves' ophthalmopathy- Ophthalmoplegia- Acetylcholine receptor antibody- Autoimmune. Manuscript received March 6, 1995. From the Departments of Neurology and Ophthalmology, Mnrshfield Clinic, Marshfield, Wisconsin, U. S. A. Address correspondence and reprint requests to Dr. Daniel M. jacobson, Marshfield Clinic, 1000 N. Oak Ave., M.- irshfidd, Wl 54449, U. S. A. Graves' ophthalmopathy and ocular myasthenia are autoimmune disorders that often present with ophthalmoplegia. Laboratory abnormalities of thyroid function, thyroid antibodies, or acetylcholine receptor ( AChR) antibodies may help support the clinical suspicion of one of these disorders. However, the occasional clinical ( 1- 3) and serological ( 4) overlap of Graves' ophthalmopathy and ocular myasthenia may cause diagnostic confusion when evaluating an individual with diplopia who has minimal or ambiguous findings ( 5). The purpose of the following study was to determine the frequency and clinical correlates of AChR antibody seropositivity in patients with Craves' ophthalmopathy. METHODS Fifty consecutive newly diagnosed patients with Craves' ophthalmopathy were evaluated prospectively in an outpatient neuro- ophthalmology practice during the period December 1987 through August 1990. The diagnosis was established clinically by identifying the cardinal features of this condition ( 6), including some combination of lid retraction and lag, orbital congestion, restrictive ophthalmoplegia, proptosis, and external ocular injection and chemosis. Details regarding associated thyroid disease, if present, were obtained during the initial evaluation. In most cases, patients with thyroid dysfunction had been evaluated by an endocrinologist at my institution. Pertinent records were requested and reviewed for those patients whose thyroid disease was diagnosed and treated by physicians unaffiliated with my institution. Patients were followed at serial intervals so that the course of their orbitopathy could be established. A modified staging scheme suggested by Raikow et al. ( 7) was used to categorize the course 166 GRAVES' OPHTHALMOPATHY 167 of orbitopathy into one of three groups: stable, active, and chronic. Briefly, stable disease implied that no change in signs and no active chemosis or orbital congestion was observed for at least six months. Active disease implied that increasing proptosis, restrictive ophthalmoplegia, chemosis, or orbital congestion was observed within six months. Patients who developed compressive optic neuropathy were also categorized as having active disease. In general, patients with active disease usually had external evidence of orbital congestion and had physical findings whose progressive changes were readily apparent over the course of a few weeks to two months. Chronic disease implied that changes in proptosis, ophthalmoplegia, and external signs of orbital congestion were observed but were much milder and developed much slower than those signs observed with active disease. In general, patients with chronic disease had mild or no chemosis or soft tissue congestion and had physical findings whose changes were apparent only with prolonged comparison between follow- up evaluations of no less than six months. The biochemical state of thyroid function was determined at the time Graves' ophthalmopathy was diagnosed by assessing levels of thyroid hormones, including total thyroxine ( Emit Assay; Syva Co., Palo Alto, CA, U. S. A.), and a supersensitive assay for thyrotropin ( IMo- Rad CoTube Assay; Bio- Rad Laboratories, Hercules, CA, U. S. A.), as suggested by the American Thyroid Association's guidelines for use of laboratory tests in thyroid disorders ( 8). While it is recognized that performing thyrotropin- releasing- hormone stimulation assays may be more sensitive for detecting subclinical hyperthyroidism in patients with Graves' ophthalmopathy and normal baseline thyroid hormone levels, this test was not routinely performed on all patients. In addition, patients underwent determinations of microsomal antibodies and thyroglobulin antibodies using a commercially available microagglutination assay ( Sera- Tek; Miles, Inc., Elkhart, IN, U. S. A.). Normal titers are e UOO. AChR- binding antibody levels were determined by an immunoprecipitation assay using AChR complexed with radioactively labeled a- bunga-rotoxin ( 9,10). All samples were submitted to the Neuroimmunology Laboratory, Mayo Clinic ( Rochester, MN, U. S. A.) for analysis, where normal values are « 0.03 nmol/ L. A case control design was felt to be unnecessary since the patients in this study underwent the exact assay performed by Lennon and Howard ( 9), who found that values of AChR- binding antibody were 0.03 nmol/ L or less in all of their 48 normal control subjects. Furthermore, false positive results using this assay in neurological control subjects are rare and only occurred in two of 22 subjects with amyotrophic lateral sclerosis ( 0.11 and 0.12 nmol/ L), and one of 17 subjects with unexplained ptosis unassociated with myasthenia gravis whose AChR- binding antibody level was only 0.04 nmol/ L ( 10), RESULTS Six patients with Graves' ophthalmopathy had levels of AChR- binding antibodies above the 0.03 nmol/ L cut off. However, the level of seropositivity in two of these patients was so low ( 0.04 nmol/ L) that they were considered insignificant. The levels in three of the remaining four seropositive patients ( Table 1) were elevated within the low end of the range typically observed in patients with generalized myasthenia gravis ( 9,10). The value in a fourth seropositive patient { Table 1, patient 3) was markedly elevated. Accordingly, the frequency of definite AChR- binding antibody seropositivity in this population of Graves' ophthalmopathy was four of 50 ( 8%) patients. The number of seropositive patients was too small to apply meaningful statistical comparisons between the seropositive and seronegative groups. However, there were no obvious differences between these two groups of patients in regards to their age, sex, and underlying thyroid disorders ( Table 2). Likewise, the clinical and laboratory correlates of the seropositive and seronegative groups with Graves' ophthalmopathy were similar ( Table 3). Pt./ age ( yr)/ sex 1/ 42/ F 2/ 67/ F 3/ 29/ M 4/ 61/ F TABLE 1. Summary o Thyroid disorder Diffuse toxic goiter Diffuse toxic goiter None Diffuse toxic goiter > f four acetylcholine receptor seropositive patients with Graves' ophthalmopathy Current thyroid state Hypothyroid Hypothyroid Euthyroid Euthyroid AChR- binding antibody ( nmol/ L) 0.25 0,11 7.96 0.21 Microsomal antibody titer 1: 600 < 1: 100 1: 409,600 < 1: 100 Thyroglobulin antibody titer < 1,100 < 1.100 1: 102,400 < 1: 100 } Neino- Oi> hl) inhmit, Vol. 15, No. 3, 1995 168 D, M. JACOBSON TABLE 2. Clinic Age ( yr) Range Median Sex ( n) Female Male Thyroid disorder ( n) Diffuse toxic goiter Primary hypothyroid ism Nontoxic ( euthyroid) goiter Benign ( nonfunctioning) nodule Subacute thyroiditis Chronic lymphocytic None/ euthyroid ( hypothyroid) al characteristics of patients with Graves' ophthalmopathy thyroiditis ( hyperthyroid) Total group ( n = 50) 23- 79 56 38 12 19 3 2 2 2 1 21 AChR- seropositive group ( n = 4) 29- 67 51 3 1 3 0 0 0 0 0 1 AChR- seronegative group ( n = 46) 23- 79 56 35 11 16 3 2 2 2 1 20 None of the seropositive patients were receiving penicillamine, had relatives with myasthenia gravis, or had tardive dyskinesia, primary biliary cirrhosis, or known thymic tumors, other conditions that have been associated with elevated levels of anti- AChR ( 11). None of the four seropositive patients had other autoimmune disorders at the time of diagnosis or during the follow- up period. Anti- nuclear antibody assays were performed in three seropositive patients ( patients 1, 3, and 4) and were negative in all three. All four seropositive patients were followed to identify any clinical features of myasthenia gravis. The follow-up period ranged from two and one half to five years ( median, four and one half years). Patient 1 ( Table 1) developed mild proptosis and redness of both eyes at the same time she developed thyrotoxicosis seven years before her evaluation. She was treated with radioactive iodine and subsequently required thyroid replacement for iatrogenic hypothyroidism. Her orbital symptoms remained stable during the next seven years. She had mild bilateral proptosis, lid retraction, and lid lag, but no signs of ocular or generalized myasthenia gravis. She has been followed for two and one half years without any progression of Graves' ophthalmopathy and without any signs of myasthenia gravis. Patient 2 ( Table 1) experienced proptosis of her left eye for the preceding four months. She developed thyrotoxicosis two years earlier, which was treated with radioactive iodine. She then required thyroid replacement for iatrogenic hypothyroidism. One year prior to recognition of her thyroid disorder she experienced vertical diplopia which has since remained stable. A repetitive nerve stimulation study was normal at the time she presented with diplopia. She had a small incomitant vertical ophthalmoplegia, mild bilateral lid retraction, and mild proptosis of her left eye. Orbital TABLE 3. Summary of clinical and laboratory Years present Range Median No, Unknown Current thyroid state ( n) Euthyroid Hyperthyroid Hypothyroid Thyroid antibody positive ( n) Microsomal Thyroglobulin Course Stable Active Chronic Graves' ophthalmopathy Total group ( n = 50) 1 wk- 25 yr 1 yr 11 33 4 13 18 6 37 10 3 correlates of AChR- seropositive group ( n = 4) 0.5- 7 yr 3yr 0 2 0 2 2 1 3 1 0 AChR- seronegative group ( n = 46) 1 wk- 25 yr 0.9 yr 11 31 4 11 16 5 34 9 3 / Nettm- Ofihtltiilitio), Vol 15. No. 3, 1995 GRAVES' OPHTHALMOPATHY 369 computed tomography confirmed enlargement of the extraocular muscles of both orbits in a pattern consistent with Graves' ophthalmopathy. Her or-bitopathy has remained stable during the subsequent four and one half years. She has not developed any clinical signs of myasthenia gravis. A plain chest radiograph obtained one year following her initial evaluation did not show a mediastinal mass. Patient 3 ( Table 1} noted " ptosis" of his left upper eyelid for the preceding six months. His examination revealed normal position of the left upper eyelid, mild retraction and lag of the right upper eyelid, minimal injection around the horizontal rectus muscle insertion sites, and minimal propto-sis of the right eye. He had no signs of myasthenia gravis. Orbital computed tomography showed mild enlargement of the medial and inferior rectus muscles of both orbits. When his AChR- binding antibody titer returned markedly elevated ( Table 1), the possibility of superimposed ocular myasthenia was entertained as a cause for his eyelid asymmetry. Intravenous injection of edrophonium did not change the resting position of the left eyelid. Single- fiber electromyography was normal. Antibody determination at a different laboratory also returned markedly elevated at 7.4 nmoI/ L ( normal range, less than 0.8 nmol/ L). Assay for anti- striated muscle antibody was negative. He has been followed for four and one half years without any progression of Graves' ophthalmopathy and without any signs of myasthenia gravis. Patient 4 ( Table 1) developed thyrotoxicosis and was treated with radioactive iodine five years before her evaluation. She then required thyroid replacement for iatrogenic hypothyroidism. She experienced vertical diplopia and nonfluctuating mild ptosis of her left upper eyelid three years before her evaluation. Her examination revealed mild bilateral restrictive ophthalmoplegia, mild right eyelid retraction and lag, mild nonfatigable left upper eyelid ptosis, and mild proptosis of the left eye. Computed tomography confirmed thick extraocular muscles in both orbits in a pattern consistent with Graves' ophthalmopathy. She had no other symptoms or findings of myasthenia gravis. In addition to her elevated AChR- binding antibody level ( Table 1), she also had an abnormal AChR- modulating antibody assay of 64% ( normal values, 0- 20%), but a normal AChR- blocking antibody assay of 1% ( normal values, 0- 25%). The course of her orbitopathy was characterized by progressive restriction of ocular motility, increasing nonfatigable ptosis and levator function impairment of the left upper eyelid, and progressive proptosis. A foliow- up AChR- binding antibody level three and one half years after the initial determination remained elevated at 0.13 nmol/ L. During this period of time, two intravenous edrophonium tests produced no improvement of her ptotic left upper eyelid or ophthalmoplegia. Single- fiber electromyography and repetitive nerve stimulation studies were normal. Four and one half years after her initial evaluation, she developed left- sided compressive optic neuropathy treated with corticosteroids and then orbital decompressive surgery. The ptosis of her left eyelid did not improve during the six- week period that she received corticosteroids. She never developed other signs of myasthenia gravis. The progressive left upper eyelid ptosis and levator impairment was thought to result from mechanical compression of the levator palpebrae by her massively enlarged superior rectus muscle. Annual plain chest radiographs failed to identify a mediastinal mass. DISCUSSION This study confirms that AChR- binding antibody seropositivity occurs in a small proportion of individuals with Graves' ophthalmopathy. Because of the low frequency of false seropositivity, and the low concentration of AChR- binding antibody in three of the four seropositive patients identified, one must consider whether seropositivity occurs in patients with Graves' ophthalmopathy simply because of a failure of the assay's specificity, or occurs because of some specific immunological relationship between Graves' ophthalmopathy and myasthenia gravis. Unfortunately, this study was not designed to specifically address this issue. Few other studies have tried to address the issue of AChR antibody seropositivity and Graves' ophthalmopathy. Robb et al. ( 4) identified three of 40 ( 7.5%) elderly patients with thyroid antibodies who had elevated AChR antibody levels using a similar assay technique. However, these investigators did not report whether their patients with thyroid antibodies had other laboratory or clinical features of thyroid disease or Graves' ophthalmopathy ( 4). Howard et al. ( 10) failed to identify AChR- binding seropositivity in 84 patients with Graves' thyroid disease; the presence of orbitopathy was not mentioned in this report. Tanaka and Miyatake ( 12) found elevated levels of AChR antibodies in nine of 50 ( 18%) Japanese individuals older than 70 years of age. They suggested that false- positive results may occur in elderly individuals on the basis of altered cell-j Nanv- Ovlittialmol, Vol. IS, No. 3, 1395 170 D, M. JACOBSON mediated immunity associated with aging ( 12). This association is unlikely to explain the seropos-itivity of the four patients described in this study since all were less than 70 years of age ( range 29- 67 years; median 51 years). In fact, the youngest patient in the study ( patient three) had the highest AChR- binding antibody level. Robb et al. ( 4) were unable to confirm a relationship between increasing age and false- positive AChR antibody levels in Caucasians. Other techniques to measure AChR antibodies using other assay systems exist ( 9,10) but were not routinely performed in this study. The AChR-blocking antibody assay, as described by Lennon and Howard ( 9), was designed to detect antibodies that react with the ACh binding region of the AChR. Such antibodies are not detectable in the AChR- binding assay because the neurotransmitter binding region of the AChR has such high affinity for a- bungarotoxin, the substrate used in the AChR- binding assay. The AChR- blocking antibody assay is less sensitive than the assay employed in this study ( 10). The AChR- modulating antibody assay, also described by Lennon and Howard ( 9), was designed to assess the degree of degradation of the AChR that results from antibodies binding to multiple extracellular sites, a process that causes cross- linking and subsequent endocytosis of the AChR. The AChR- modulating antibody assay demonstrates a frequency of sero-positivity in myasthenia gravis very similar to the AChR- binding antibody assay, but has the advantage of occasionally identifying patients with myasthenia gravis who are seronegative using the AChR- binding antibody assay ( 10). Accordingly, it is possible that the frequency of seropositivity identified in this study might have been higher had the AChR- modulating antibody assay been used instead of the AChR- binding antibody assay. None of the four seropositive patients in this study developed clinical signs of myasthenia gravis during their median follow- up period of four and one half years. Electrodiagnostic assessment of neuromuscular transmission performed in three of the seropositive patients ( patients 2- 4) failed to provide evidence for subclinical myasthenic involvement. AChR- binding antibody seropositivity occurs in a small proportion of patients with Graves' ophthalmopathy but, by itself, does not necessarily identify an individual with concurrent myasthenia gravis or an individual at risk to develop myasthenia gravis. 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