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.

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:

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  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.

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

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

  
  
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  If the examiner lifts the eyelid on one side to relieve ptosis, ptosis may emerge on the other side. This is because the eyelids are controlled to move conjugately, so the force to attempt to overcome a ptotic lid is distributed to both lids. When the examiner relieves the ptotic lid of the force being required to lift it, the other lid also has less force directed toward it and may droop.

  
  
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  After asking the patient to close the eyes gently and then look up rapidly, the affected eyelid may move rapidly upward and then fall back to a ptotic position (Cogan’s lid twitch). Resting the lid presumably allows for a “rebound” of the lid before it again fatigues.

  
  
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  Saccades may undershoot their goal (hypometric saccades), but may be more rapid than normal. The increased rapidity of saccades presumably reflects some sort of central adaptation attempting to overcome the weakened extraocular muscles: An extra burst of energy makes the eye move quickly over a small distance rather than at normal speed over the intended distance.

Fatigable weakness can also be elicited in the extremities. After testing bilateral deltoid strength to assure that it is symmetric at baseline, the patient is asked to abduct one arm 100 times (“like a flapping wing”). The examiner then retests the deltoids to look for whether exercise has caused weakening of one side, leading to asymmetric strength.

Myasthenic Crisis

The most feared complication of myasthenia gravis is myasthenic crisis. This is an acute exacerbation in myasthenia causing respiratory failure requiring intubation. Myasthenic crisis can be triggered by any physiologic stress (e.g., infection, surgery) or by medications including:

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  Antibiotics: quinolones, macrolides, aminoglycosides

  
  
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  Cardiac medications: beta blockers, calcium channel blockers, quinidine, procainamide

  
  
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  Magnesium

  
  
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  Anesthetic agents

  
  
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  Neuromuscular blocking agents

Rarely, myasthenic crisis may occur as the first presentation of myasthenia gravis. It should also be considered in the differential diagnosis of failure to extubate a patient following surgery.

Treatment of myasthenic crisis is with steroids and immunomodulatory therapy (IVIg or plasma exchange), treatment of any potential triggers (e.g., treating infection, discontinuing any potential medication triggers), and mechanical respiratory support until respiratory muscle weakness improves with treatment.

Diagnostic Testing in Myasthenia Gravis

Electrodiagnostics in the Diagnosis of Myasthenia Gravis: Repetitive Nerve Stimulation and Jitter

Just as the muscles fatigue with exertion in myasthenia gravis, repetitive electrical stimulation leads to a diminution in muscle activity. When a motor nerve is stimulated at 2–3 Hz in patients with myasthenia gravis, a decrement in compound motor action potential (CMAP) is observed (See “Low Frequency and High Frequency Repetitive Nerve Stimulation in Myasthenia Gravis And Lambert-Eaton Myasthenic Syndrome” below).