Symposium 4: Neuromuscular junction and related disorders SY4.1. Myasthenia gravis and related disorders

Abstract

Autoimmune myasthenia gravis (MG) results from autoantibodies that bind to the neuromuscular junction (NMJ). Incidence and prevalence vary worldwide; the estimated US prevalence is 20/100,000, or ∼60,000 patients. Women develop MG more often before age 40, men after 50. Drooping eyelids or double vision is the first symptom in 60%; weakness remains limited to periocular muscles in 10–15% – ocular myasthenia. The voice may be nasal or hoarse, especially after prolonged talking, and swallowed liquids may escape through the nose. Weakness typically worsens throughout the day. Spontaneous improvement may occur early on but is rarely permanent. The diagnosis depends on recognizing distinctive patterns of weakness and confirmation by serologic and electrodiagnostic tests. 80–85% of patients have circulating anti-AChR antibodies; repetitive nerve stimulation (RNS) demonstrates abnormal neuromuscular transmission (NMT) in up to 90% of generalized MG and 60% of ocular myasthenia. Increased jitter is found in almost all patients if appropriate muscles are examined. Approximately 10% of patients have antibodies to muscle specific tyrosine kinase (MuSK). Clinical findings resemble non-MuSK MG in some patients; many have predominant weakness in cranio-bulbar muscles with marked atrophy. Others have predominant neck, shoulder and respiratory weakness. With selected treatment most non-MuSK and MuSK-MG patients have only minimal long-term morbidity. Congenital myasthenic syndromes result from genetic defects of muscle endplate molecules involved in NMT; most have autosomal recessive inheritance. The diagnosis is suggested by clinical features and response to cholinesterase inhibitors, or electrodiagnostic findings. Identification of specific genetic or physiologic defects requires genetic studies or specialized morphological and electrophysiological studies. Lambert-Eaton myasthenia results from antibodies to voltage-gated calcium channels (VGCC) on presynaptic nerve terminals, which produces the classic triad of weakness, reduced muscle stretch reflexes and autonomic dysfunction. Approximately 50% have an underlying malignancy, usually small cell lung cancer. The diagnosis is confirmed by a decrementing pattern during low frequency RNS and low muscle responses that increase at least 60% after muscle activation. Antibodies to the VGCC are found in most cases. Treatment is initially directed against any underlying malignancy. Amifampridine produces symptomatic improvement in most patients; immunomodulatory therapy may provide modest benefit in some.