This session and case studies were provided courtesy of Dr. Donald B. Sanders, Professor of Neurology at Duke University Medical Center, Durham, NC.
 Donald B. Sanders, M.D. Duke University Medical Center |
Circulating antibodies to the acetylcholine receptor (AChR) are found in up to 80% of patients with autoimmune MG.2,3 MG patients who are seronegative for AChR antibodies also clearly have an antibody-mediated disorder, since their serum passively transfers a neuromuscular defect to mice, plasma exchange improves their weakness, and babies born to seronegative mothers can develop transient neonatal myasthenia.
Muscle specific tyrosine kinase (MuSK) is a surface membrane enzyme that is essential in aggregating AChR during the development of the neuromuscular junction. Its role in mature muscle is not yet clear. Recent studies have shown that antibodies to MuSK are present in 40% to 50% of patients with generalized seronegative MG.4-6 Anti-MuSK antibodies have not been found in patients with purely ocular myasthenia nor in those with anti-AChR antibodies.
The reported experience with MMG is still relatively limited, but several interesting clinical observations have been made. Most reported MMG patients are female. The disease may begin from childhood to the seventh decade of life. Some MMG patients have clinical features indistinguishable from non-MuSK MG, but others differ from the usual clinical pattern of MG. Oropharyngeal muscles may be predominantly involved and become severely atrophied in some MMG patients.5,6 (J. Newsom-Davis, M.E. Farrugia, P. Anslow, R. Kennett, A. Vincent - unpublished observations.) Others have weakness predominantly in neck, shoulder and respiratory muscles, with little or no ocular muscle involvement.4 Results of electrodiagnostic testing may be atypical for MG: EMG findings suggest myopathy in some, although muscle biopsy has not shown myopathic features; repetitive nerve stimulation studies are frequently normal in limb muscles; and, unlike most MG, jitter may be abnormal only in muscles that are severely involved.4
Cholinesterase inhibitors produce a variable response in MMG, and may actually exacerbate weakness. Thymectomy does not appear to benefit these patients, but they have consistently improved after plasma exchange, and many respond well to early, aggressive and selected immunotherapy.4
An assay for anti-MuSK antibodies promises to be of greatest value in confirming the diagnosis in seronegative MG. It may be particularly useful when clinical features are not
typical for MG, especially if edrophonium or pyridostigmine produces no improvement. Available information suggests that MMG patients respond differently to some MG treatments, thus an assay for MuSK antibodies may prove to be useful in selecting therapy for seronegative MG. Anti-MuSK antibodies have not been found in patients with purely ocular myasthenia, nor in those with anti-AChR antibodies. Experience with the test is still limited, however, and it will take more widespread use to determine the range of clinical patterns associated with anti-MuSK antibodies.
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Case 1. MMG with typical MG findingsThis woman developed intermittent diplopia, dysarthria, dyspnea, and generalized weakness at age 31. Strength improved after intravenous injection of edrophonium and oral pyridostigmine. Repetitive nerve stimulation was normal in hand and shoulder muscles; jitter was normal in the arm but markedly abnormal, with frequent blocking, in the frontalis. AChR antibody levels were normal by binding, blocking and modulating assay. Plasma exchange produced marked improvement, which was partially maintained during treatment with prednisone. There was no improvement after thymectomy or a prolonged course of azathioprine. Treatment with cyclosporine was followed within three months by complete resolution of all symptoms. Anti-MuSK antibodies were elevated 25 years after disease onset. Comment: This patient had many findings typical for MG, although repetitive stimulation and jitter studies are usually abnormal in the arm when there is severe generalized myasthenic weakness, and most MG patients improve with azathioprine. She improved rapidly and dramatically after taking cyclosporine, having failed to respond well to previous treatment with thymectomy, corticosteroids and azathioprine. |
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Case 2. MMG with weakness in a restricted muscle distributionAt age 26, while pregnant, this woman had difficulty holding her head up and lifting her arms. Two years later, she developed weakness of grip, slurred speech and dyspnea. Examination showed weakness of neck extension, elbow flexion and grip, but normal ocular and facial movements. EMG showed abnormalities consistent with myopathy in shoulder and neck muscles. There was a 10% decrement to repetitive nerve stimulation in hand and trapezius muscles. Jitter studies were normal in forearm and facial muscles, but showed markedly abnormal jitter with frequent blocking in neck extensors. AChR antibody levels were normal by binding, blocking and modulating assay; anti-MuSK antibodies were elevated. There was no improvement after intravenous edrophonium or oral pyridostigmine. All weakness improved after a course of plasma exchange. Treatment with oral prednisone and mycophenolate mofetil induced marked, sustained improvement. Comment: The clinical findings and initial EMG studies were most consistent with myopathy. Failure to improve with cholinesterase inhibitors made the diagnosis difficult until jitter was found to be markedly abnormal in the neck extensors. |
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Case 3. MMG with faciopharyngeal weakness and atrophyThis man had dysarthria and dysphagia at age 20, which became progressively worse over the following 10 years. At 30, he began having intermittent diplopia. Examination then showed severe lingual/palatal dysarthria and facial diplegia. Facial muscles were atrophic, and the tongue had a "triple-furrowed" appearance. Ocular movements were normal. There was minimal weakness of neck flexion, but strength was normal otherwise. Repetitive stimulation was normal in hand muscles, but produced a 40% decrement in the nasalis muscle. Jitter was normal in the arm, but markedly abnormal, with frequent blocking, in the frontalis. AChR antibody levels were normal by binding, blocking and modulating assay; anti-MuSK antibodies were elevated. His symptoms did not improve after the administration of cholinesterase inhibitors. Comment: This clinical pattern, with progressive weakness and atrophy of oropharyngeal and facial muscles and relatively little and late weakness of ocular muscles, is unusual for MG, but has been described in several patients with MMG. |
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The clinical features of Musk-positive patients may be indistinguishable from seropositive MG patients. However, MuSK-positive patients exhibit variable responses to cholinesterase inhibitors, while exhibiting dramatic improvement after plasma exchange. No reported patients have improved after thymectomy. An assay for MuSK antibodies promises to be valuable in confirming a diagnosis in patients with seronegative MG and may be useful in selecting therapy.4
