Disorders affecting the neuromuscular junction (NMJ) are generally pure motor syndromes that usually affect the extraocular muscles but also the proximal limb and bulbar or respiratory function. They can be classified into autoimmune, acquired, toxic, and inherited disorders of the NMJ. The most common NMJ disorders are autoimmune and therefore respond to immunosuppressive therapy. These include myasthenia gravis (MG) and, rarely, the Lambert-Eaton myasthenic syndrome (LEMS). A number of genetically determined disorders of neuromuscular transmission, the congenital myasthenic syndromes, are seen in childhood but may rarely present in adult life. Botulism is a toxin-mediated disorder of the NMJ. All NMJ disorders cause generalized weakness and fatigability with a propensity for oculobulbar involvement. Electrophysiologic studies can detect an impairment of neuromuscular transmission in most of these disorders.1 Fortunately, most of these disorders are treatable2–4 (Fig. 74–1).
Disorders of neuromuscular transmission. (Reproduced with permission from Motor Disorders. In: Simon RP, Aminoff MJ, Greenberg DA, eds. Clinical Neurology, 10e New York, NY: McGraw-Hill; 2018.)
MG is the best understood autoimmune disease among these.5 The immune-mediated nature of MG was suspected as early as 1960 when Simpson speculated that it was an autoimmune disease with antibodies directed against the skeletal muscle acetylcholine receptor (AChR).6 A series of breakthroughs in the 1970s confirmed Simpson's hypothesis. Lindstrom et al developed the animal model experimental autoimmune MG by immunizing rabbits and rats with highly purified AChR from the electric organ of the eel.7,8 Subsequently, high AChR antibody titers were found in the serum of MG patients.9,10 Engel et al localized both the IgG antibody and complement to the myasthenia motor endplate.11,12 This implied that circulating IgG antibody directed against the AChR bound to the postsynaptic membrane and activated the terminal complement sequence (C5b-9), or membrane attack complex (MAC), resulting in lysis of the AChR with subsequent degeneration (Fig. 74–2).
Pathogenesis of myasthenia gravis. (Reproduced with permission from Drachman DB, Amato AA. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison's Principles of Internal Medicine, 19e New York, NY: McGraw-Hill; 2014.)
Elevated MAC levels have been demonstrated in the plasma of MG patients.13 AChR antibody has also been shown to block neuromuscular transmission and accelerate turnover of AChR cross-linked by IgG.14 As a result of this process, the postsynaptic membrane becomes simplified with decreased junctional folds and widening of the synaptic cleft15 (Fig. 74–3).
Endplate changes in myasthenia gravis. (Reprinted with permission from Santa T, Engel AG, Lambert EH: Histometric study of neuromuscular junction ultrastructure: I. Myasthenia gravis. ...