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Show Journal of Clinical Neuro- ophthalmology 10( 3): 201- 205, 1990. © 1990 Raven Press, Ltd., New York Penicillamine- Induced Ocular Myasthenia Gravis in Rheumatoid Arthritis Grant T. Liu, M. D., and Don C. Bienfang, M. D. We report a case of a 47- year- old woman with rheumatoid arthritis who developed ocular myasthenia gravis during penicillamine treatment. Her serum contained elevated titers of acetylcholine receptor antibodies, and her symptoms resolved 8 weeks after discontinuation of penicillamine. We review the clinical and laboratory features of this syndrome of penicillamine- induced myasthenia gravis and discuss its pathophysiology and treatment. Key Words: Penicillamine- Myasthenia gravisRheumatoid arthritis. From the Divisions of Neurology ( G. T. L.) and Ophthalmology ( D. CB.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Address correspondence and reprint request~ to Dr.. G. T. Liu, Division of Neurology, Brigham and Women s Hospital, 75 Francis Street, Boston, MA 02115, U. S. A. 201 In 1973 a controlled English trial proved 0penicillamine to be effective in the treatment of rheumatoid arthritis ( 1). Its mechanism of action is still unclear ( 2), but penicillamine is known to decrease serum titers of immunoglobulin ( Ig) M rheumatoid factor ( 3), perhaps by depolymerization ( 4). The side effects in early trials ( 1,5) were listed as rash, proteinuria, nausea and vomiting, and thrombocytopenia. Bucknall and colleagues ( 6) in 1975 first described the association between myasthenia gravis and penicillamine treatment of rheumatoid arthritis. They reported four patients receiving penicillamine who developed myasthenia gravis clinically indistinguishable from the idiopathic type but whose symptoms improved upon withdrawal of the drug ( 6). Since then there have been several similar case reports ( 7- 23). A recent trial ( 23) involving a larger cohort than in previous studies ( 1,5) showed that 2% of patients receiving penicillamine for rheumatoid arthritis develop myasthenia gravis. In addition, myasthenia gravis has been reported in association with penicillamine treatment of Wilson's disease ( 24,25), primary biliary cirrhosis ( 26), and systemic sclerosis ( 27,28). We report a typical case of penicillamineinduced myasthenia gravis and then discuss the clinical and laboratory features, pathophysiology, and treatment of this syndrome. CASE REPORT A 47- year- old woman with an 8- year history of rheumatoid arthritis was evaluated at this hospital for a sudden complaint of diplopia. Her medications included 5 mg/ day prednisone and 750 mgl day penicillamine. She had been started on penicillamine at 250 mg/ day 9 months prior to her presentation, and her dose had been gradually 202 G. T. LIU AND D. C. BIENFANG increased to 500 mg then 750 mg/ day over the next 4 months. The physical exam was notable for arthritic changes in the hands, knees, and ankles, and mild right blepharoptosis as well as paresis of the right superior rectus muscle. Her pupils were normal, and there was no systemic weakness. The erythrocyte sedimentation rate, glucose, glycosylated hemoglobin, Lyme antibody titer, and computerized tomography ( CT) and magnetic resonance imaging ( MRI) of the brain were all normal. Chest radiography showed no evidence of thymoma. An edrophonium ( Tensilon, Roche Laboratories, Nutley, NJ) test was negative although acetylcholine receptor antibodies were positive at 0.6 nmollL ( normal 0- 0.5 nmollL). The penicillamine was stopped on September 22, 1989. Three weeks later the patient complained that her diplopia had not improved and that it had " changed." Exam at that time showed resolution of the symptoms in her right eye and eyelid and a new weakness of the left medial rectus muscle that worsened with fatigue ( Fig. 1). She fused in left lateral gaze, but she had a 12- diopter left exotropia in primary position and a 23- diopter left exotropia in right lateral gaze. There was an 8- diopter left hypertropia. During a Lancaster- type diplopia test, i. v. injection of 5 mg Tensilon resolved the diplopia completely within 1 minute. The patient was diagnosed as having ocular myasthenia gravis, but given no further medication. After 3 more weeks she fused in primary position, and there was no hypertropia. In right lateral gaze there was 7 diopters of left extropia. On November 14, 1989, 8 weeks after discontinuation of penicillamine, she fused in all fields of gaze. Acetylcholine receptor antibody level at this time was negative « 0.5 nmollL). The patient's HLA haplotype was A2- A23- B7- Cw4- Bw4- Bw6- Drl- B44Dqw1- Drw53. FIG. 1. Center: Primary gaze, before Tensilon injection. Top: Right ( left) and left ( right) lateral gazes before Tensilon injection. Bottom: After Tensilon injection, right ( left) and left ( right) lateral gazes with improvement of left eye adduction. I Clin Neuro- aphthalmol, Vol. 10, No. 3, 1990 DISCUSSION This patient's clinical presentation and course were typical of previously reported cases of penicillamine- induced myasthenia gravis in rheumatoid arthritis (&- 23). Seventy- seven to 88% of patients were women, and the typical age of onset ranges from 39 to 67 years with a mean of 47 years ( 14,20). The duration of rheumatoid arthritis varied from 5 to 34 years ( 14), and prior to the onset of symptoms the patients usually had received penicillamine for 3 months to 5 years ( 14,20). In one report, however, a patient developed myasthenia gravis within 2 days after starting treatment, but the authors feel this may have been the result of direct toxicity of penicillamine ( 9). Patients typically had been given 250- 1,500 mg penicillamine daily ( 14,20) though a case developing on a dose of 125 mg/ day has been documented ( 23). As in our case, all reported patients whose clinical findings were recorded presented with ocular symptoms: diplopia, blepharoptosis, or both ( 14,17). Within a group of 18 patients studied by Delamere ( 20), five ( 28%) initially presented with diplopia alone, three ( 17%) with ptosis alone, and 10 ( 55%), the majority, with both diplopia and ptosis. Nine ( 50%) developed no further symptoms, and two ( 11 %) subsequently experienced dysarthria or dysphagia. However, seven ( 39%) went on to have generalized weakness; of these, two developed respiratory difficulty ( 20). Lang ( 19) reported two patients who developed severe lifethreatening weakness. No predisposing factors have been identified that could predict progression from ocular to systemic myasthenia ( 20). Our patient presented with right superior rectus weakness, which resolved, then later with left medial rectus difficulty. The pattern of ophthalmoparesis commonly changes in patients with myasthenia gravis ( 29). In fact, the character and distribution of the fatigable muscle weakness in our patient and the previously reported cases with penicillamine (&- 23) were indistinguishable from that of idiopathic myasthenia gravis ( 30). Similarly, the diagnosis of myasthenia gravis in the individuals taking penicillamine was confirmed by the improvement of symptoms upon injection of acetylcholinesterase inhibitors Tensilon or neostigmine ( 6,7,10- 14,17- 19,21,22), which is felt to be diagnostic ( 3D), and characteristic decremental response ( 30) during electromyography ( EMG) ( 13- 15). The pathophysiology of the muscle weakness in idiopathic myasthenia gravis is related to a reduction in available acetylcholine receptor sites at neuromuscular junctions and impairment of neuro- PENICILLAMINE- INDUCED MYASTHENIA 203 muscular transmission ( 30,31). Antibodies directed against acetylcholine receptors can block acetylcholine receptor sites, but more importantly there seems to be increased degradation and synthesis of acetylcholine receptor molecules ( 30-- 32). Acetylcholine receptor antibodies have been found in 87% of patients with idiopathic myasthenia gravis ( 32) and in about 50% of patients with weakness restricted to ocular muscles ( 33). They are entirely specific for the disease ( 32). In addition, the rise and fall of serum antibody levels in some cases correlates with the status of clinical weakness ( 30,34). The mechanism of weakness in myasthenia gravis associated with penicillamine treatment of rheumatoid arthritis is very similar. The deeremental muscle response to repetitive stimulation ( 1315) and the clinical response to acetylcholinesterase inhibitors ( 6,7,10-- 14,17- 19,21,22) demonstrated in these patients point to an identical defect in neuromuscular transmission. Many authors were also able to document the presence of elevated serum titers of acetylcholine receptor antibodies ( 8,10,12,15,16,18,19,21,22). Conversely, patients receiving penicillamine without clinical myasthenia gravis have normal antibody levels ( 15). In our patient the presence then absence of acetylcholine receptor antibodies followed her clinical course. Vincent and Newsom- Davis ( 8) and then others ( 10,19,22) have indeed correlated clinical improvement with decreasing acetylcholine receptor antibody levels. Furthermore, in a detailed immunopathological study, Kuncl and colleagues ( 22) demonstrated an increased rate of acetylcholine receptor degradation as well as a decreased number of available acetylcholine receptors, both of which resolved 8 months after stopping penicillamine. The fact that the myasthenia gravis usually resolves after discontinuation of penicillamine differentiates this syndrome from the idiopathic type. Only 8% of patients with idiopathic myasthenia gravis experience clinical remission within the first year ( 14), whereas in Delamere's series ( 20) 78% of the penicillamine- induced cases showed resolution of symptoms within 6 months after stopping the drug. In Albers' review of cases reported in the literature ( 14), 70% of the patients experienced total remission in less than 8 months after discontinuing penicillamine. Of note, there did not seem to be any correlation with the severity or distribution of weakness, ocular or generalized, and the likelihood of improvement off penicillamine ( 20). Patients with rheumatoid arthritis in general do not have a higher incidence of myasthenia gravis ( 16,35), so this temporal relationship between the penicillamine treatment and the myasthenia gravis strongly suggests a causal relationship. Furthermore, the onset then resolution of the acetylcholine receptor antibody response and other immunological parameters of myasthenia gravis may indicate that penicillamine induces new myasthenia gravis rather than enhances subclinical disease ( 22). It is not known exactly how penicillamine induction might occur, but the mechanism is likely related to immunomodulation. In vitro studies have shown that penicillamine binds to acetylcholine receptors ( 36); however, except for one case ( 9), a direct toxic effect of the drug is unlikely clinically, given the delay of months to years before the onset of muscle weakness, as well as the usual delay of months after discontinuation before the symptoms resolve entirely ( 14,20). Alternatively, Bever, Chang, and Penn have proposed that penicillamine's binding of acetylcholine receptors alters the receptors' immunogenicity and perhaps induces acetylcholine antibody formation ( 36). Other autoimmune diseases have in fact been reported to develop during penicillamine treatment: polymyositis ( 37), systemic lUpus erythematosis ( 38), and Goodpasture's syndrome ( 39). Penicillamine treatment of rheumatoid arthritis has also been shown to induce production of antistriatal antibodies ( 25) as well as initiate thymic hyperplasia ( 8). Therefore, penicillamine may have a propensity for initiating autoimmune diseases. Patients with this syndrome may be genetically predisposed to developing it, based on histocompatibility testing. Rheumatoid arthritis is associated with HLA haplotype Dr4 ( 40), and idiopathic myasthenia gravis with HLA- Al, A8, B8, and Dr3 ( 30,41). Several investigators have shown an increased incidence of HLA- Bw35 and Drl ( 12,1921,40) and a decreased incidence of Dr3 ( 40) and Dr4 ( 20) in patients with penicillamine- induced myasthenia gravis. Our patient's haplotype was notable for the presence of Drl and the absence of Dr4, consistent with this pattern. Whether genetic susceptibility is relevant to penicillamine- related autoimmunity and the development of acetylcholine receptor antibodies needs to be studied further. The best treatment has neither been standardized nor formally studied. In most of the cases the penicillamine was stopped and neostigmine or pyridostigmine ( Mestinon, Roche) used only temporarily. The acetylcholinesterase inhibitors were withdrawn months to years after the patient's weakness had been controlled, and then the pa- J Clin Neuro- ophthalmol. Vol. 10. No. 3. 1990 204 G. T. LIU AND D. C. BIENFANG tient was observed for signs of regression ( 6,1114,17,20,22). In our patient and in two other previously reported ones ( 13,21), however, stopping the penicillamine without acetylcholinesterase inhibitor treatment was sufficient for the complete resolution of symptoms. In one case the ptosis, dysarthria, and masseter fatigue resolved within 8 weeks ( 13) and in the other the ptosis and diplopia within 3 months ( 21), so it is not clear whether Mestinon is necessary for full recovery or whether it shortens the duration of weakness. Steroids or other immunosuppressive agents were not used specifically for the treatment of the myasthenia gravis, but in many instances ( 9,15,19,22), they were used for the management of the rheumatoid arthritis. One patient underwent thymectomy ( 8), and two others required plasma exchange when they developed respiratory insufficiency ( 19). Therefore we propose the following guidelines. Patients receiving penicillamine for the treatment of rheumatoid arthritis should be observed for signs of the characteristic fatigable weakness. Routine screening with acetylcholine receptor antibody titers is of no value in patients without symptoms ( 15,16). In suspected cases the diagnosis of penicillamine- induced myasthenia gravis can be confirmed by the presence of at least diplopia and! or ptosis ( in all cases), elevated acetylcholine receptor antibody titers, improvement with Tensilon, and in cases of generalized weakness, decremental response on EMG. The penicillamine then should be discontinued. Because of Mestinon's and neostigmine's muscarinic side effects, diarrhea and abdominal cramping ( 30), we suggest limiting acetylcholinesterase inhibitor treatment to those patients who develop extraocular symptoms of weakness. Patients with diplopia can be treated with an eye patch alone. This treatment plan relies on the usual ( 14,20) self- limited nature of the myasthenia after penicillamine withdrawal. Of course, this regimen has not been studied, and it needs formal evaluation. Thymectomy, steroids, plasmapheresis, azathioprine, or cyclophosphamide ( 30,33) should be reserved for severe or refractory cases. CONCLUSION In summary, we have described a typical case of penicillamine- induced ocular myasthenia gravis. Patients with this syndrome clinically appear similar to those with idiopathic myasthenia gravis, and they also develop elevated acetylcholine receptor antibody titers and respond to acetylcholinesterase inhibitors. All have ocular symptoms. 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