Chapter 29: Disorders of the Neuromuscular Junction

INTRODUCTION

At the neuromuscular junction motor neurons release acetylcholine that binds to acetylcholine receptors on the postsynaptic muscle fibers, causing them to contract. Diseases of the neuromuscular junction can be classified as either presynaptic (e.g., Lambert-Eaton syndrome, botulism) or postsynaptic (e.g., myasthenia gravis) (Fig. 29–1). Congenital myasthenia gravis can be caused by mutations in either presynaptic or postsynaptic neuromuscular junction structures.

MYASTHENIA GRAVIS

Clinical Features of Myasthenia Gravis

Myasthenia gravis is a postsynaptic disorder of the neuromuscular junction in which antibodies are produced against components of the acetylcholine receptors on muscle. These antibodies are most commonly against the acetylcholine receptor itself, leading to blocking and destruction of these receptors.

Weakness in myasthenia fluctuates and is fatigable: It emerges or worsens with exertion and late in the day, and resolves with rest. Imagine the acetylcholine rushing across the neuromuscular junction to synapse on its receptors on the muscles. If these receptors are blocked or diminished in number due to antibody-mediated destruction, the available receptors will quickly be saturated, and no further response to acetylcholine can be elicited. This leads to initial muscular force but subsequent fatigue.

In most patients with myasthenia gravis, one or both eyes are involved at presentation with fluctuating/fatigable ptosis and/or diplopia (due to extraocular muscle weakness). The pupils are not affected. The disease may remain limited to the eyes in a small proportion of patients (ocular myasthenia). In patients whose symptoms are initially isolated to the eyes, about half will ultimately develop signs of generalized myasthenia gravis beyond the eyes over subsequent years. Beyond the eyes, facial weakness, dysphagia, laryngeal weakness leading to a hypophonic and/or nasal voice, jaw weakness, and neck weakness are common, and extremity weakness and respiratory weakness also occur.

Myasthenia gravis has a bimodal distribution in its age of presentation, most commonly presenting in younger women (20s–30s) and older men (≥60). There are several bedside maneuvers that can be used to evaluate for fatigability on clinical examination.

For the eyes:

• Ptosis time assesses the amount of time a patient can sustain upgaze. In patients with myasthenia, one or both eyelids may start to slowly fall like descending curtains due to fatigue of the levator palpebrae muscles.

• Ptosis may improve after applying ice to the eyelids (icepack test), since cold temperatures may facilitate neuromuscular transmission.

• With attempted sustained eye closure, the eyes may start to open (peek sign) due to fatigable weakness of the orbicularis oculi.

• If the examiner lifts the eyelid on one ...