These disorders are discussed together because they cause weakness or changes in salience of the musculature but are not strictly speaking disease of muscle, instead having their origins in problems with the terminal motor axons or neuromuscular junction, the ends of the line in motor transmission, so to speak. Their pathophysiology and clinical features sometimes overlap with immune mechanisms that underlie a number of them. In most ways, however, they stand apart from each other but are most efficiently described together here.
DISORDERS OF THE NEUROMUSCULAR JUNCTION
Included under this category is a group of diseases, the most important of which is myasthenia gravis. Most of these disorders exhibit the characteristic and striking features of fluctuating weakness and fatigability of muscle. Some degree of weakness is usually present at all times but it is made worse by activity. The weakness and fatigability reflect physiologic abnormalities of the neuromuscular junction that are demonstrated by clinical signs and by special electrophysiologic testing. As an aid to understanding the diseases discussed in this chapter, the reader should consult the discussion of the structure and function of the neuromuscular synapse given in Chap. 2.
The cardinal feature of myasthenia gravis, usually referred to simply as myasthenia, is fluctuating weakness of voluntary (skeletal) muscles, particularly those innervated by motor nuclei of the brainstem, that is, ocular, masticatory, facial, deglutitional, and lingual. Manifest weakening during continued activity, quick restoration of power with rest, and dramatic improvement in strength following the administration of anticholinesterase drugs such as neostigmine are the other notable characteristics. Myasthenia is an immune disease in which circulating antibodies against components of the motor postsynaptic membrane and subsequent structural changes in that membrane explain virtually all the features of the disease.
Several students of medical history affirm that Willis, in 1672, gave an account of a disease that could be none other than myasthenia gravis. Others give credit to Wilks (1877) for the first description and for having noted that the medulla was free of disease, in distinction to other types of bulbar paralyses. The first reasonably complete accounts were those of Erb (1878), who characterized the disease as a bulbar palsy without an anatomic lesion, and of Goldflam (1893); for many years thereafter, the disorder was referred to as the Erb-Goldflam syndrome. Jolly (1895) was the first to use the name myasthenia gravis, to which he added the term pseudoparalytica to indicate the lack of structural changes at autopsy. Also it was Jolly who demonstrated that myasthenic weakness could be reproduced in affected patients by repeated faradic stimulation of the motor nerve and that the “fatigued” muscle would still respond to direct galvanic stimulation of its membrane. Interestingly, he suggested the use of physostigmine as a form of treatment but there the matter rested until Reman, in 1932, ...