73 Myasthenia Gravis

Clinical Vignette

A healthy 63-year-old man presented with a 6-week history of the gradual onset of asymmetric eyelid drooping and double vision. His ptosis and diplopia fluctuated in severity, being more noticeable later in the day. His wife noted that his speech sounded slurred near the end of the day or after he had been speaking uninterrupted for a few minutes. Neurologic examination revealed asymmetric, left worse than right, ptosis and dysconjugate eye movements in several directions of gaze with associated weakness of eye closure, neck flexion, and mild proximal limb weakness.

Nerve conduction studies and needle electromyography (EMG) demonstrated normal motor and sensory action potentials. Repetitive motor nerve stimulation testing demonstrated a 35% decrease in the ulnar compound muscle action potential (CMAP) amplitude between the first and fourth stimuli. Acetylcholine receptor (AChR) antibodies were present in significantly abnormal titers. Results of computed tomographic (CT) scanning of the mediastinum were unremarkable. Immunosuppressive and pyridostigmine bromide (Mestinon) treatments were initiated.

This vignette is typical of a myasthenia gravis (MG) patient with fatigable and fluctuating muscle weakness. MG almost always begins with ocular muscle weakness manifesting as ptosis, dysconjugate gaze, and eye closure weakness (Fig. 73-1). The symptoms of MG often spread to involve “bulbar” muscles, causing fatigable and fluctuating dysarthria, chewing weakness, and dysphagia. Respiratory, neck, and limb muscles can also become weak. An autoimmune basis for MG has been recognized since 1960. Overall, women are more commonly affected. Peaks of onset are seen in women in the second and third decades and for men in the fifth and sixth decades. The overall prevalence, estimated at 1 per 10,000, has increased over the past 40 years because of improved recognition, treatment, and survival.

Figure 73-1 Myasthenia Gravis: Clinical Manifestations.

Etiology And Pathogenesis

The most common cause of acquired MG is the abnormal development of antibodies to immunogenic regions (epitopes) on or around the nicotinic AChR of the postsynaptic endplate region at the neuromuscular junction (NMJ) (Figs. 73-2 and 73-3). These AChR antibodies trigger immune-mediated degradation of the AChRs and their adjacent postsynaptic membrane. The loss of large numbers of functional AChRs decreases the number of muscle fibers that can depolarize during motor nerve terminal activation, resulting in a decreased generation of muscle fiber action potentials and subsequent muscle fiber contraction. Blocking of neuromuscular transmission causes clinical weakness when it affects large numbers of fibers.

Figure 73-2 Somatic Neuromuscular Transmission.

Figure 73-3 Neuromuscular Transmission.

The nicotinic AChR contains five subunits arranged radially around a transmembrane ion channel (Fig. 73-4). The antibodies generated in MG are usually directed against the alpha subunit of the AChR. These antibodies may bind at or near the acetylcholine-binding site, directly preventing acetylcholine binding, or may alter receptor function through other mechanisms, such as increased receptor degradation or complement-mediated receptor lysis.