Disorders of the neuromuscular junction and muscle are pure motor phenomena. The underlying pathophysiology can result in distinctive patterns of weakness that narrow the list of potential causes. In addition to laboratory studies including genetic assays, nerve conduction studies and electromyography can be particularly helpful in diagnosing neuromuscular junction and muscle disorders (see Table 24-1).

DESCRIBING THE NEUROMUSCULAR JUNCTION

The neuromuscular junction (NMJ) is an electrical–chemical–electrical link between nerve and muscle. More specifically, electrical action potentials in the nerve can be communicated and then transmitted through muscle to cause a contraction via the neurotransmitter acetylcholine in a well-choreographed cascade. An action potential propagates down the entire length of a motor nerve axon to the axon button. Depolarization then triggers voltage-gated calcium channels (VGCCs) to open and, in turn, the influx of calcium causes a proportional release of acetylcholine from the presynaptic terminal; when more calcium is present, more acetylcholine is released. Acetylcholine then travels across the synaptic cleft and binds to receptors on the muscle membrane, stimulating sodium channels to open (see Fig. 24-1). The resultant depolarization creates end-plate potentials with amplitudes proportional to the amount of bound acetylcholine. If the end-plate potentials are great enough, an action potential is transmitted through the muscle fiber. Acetylcholinesterase metabolizes acetylcholine in the synaptic cleft.

Neuromuscular dysfunction can arise from abnormalities in key points along this multistep path. The resultant disorders can be classified pathophysiologically as presynaptic, synaptic, or postsynaptic. NMJ diseases can be further characterized by their etiologies. Some are congenital and affect the packaging, metabolism, and receptors of acetylcholine. Toxic and metabolic causes include snake and black widow spider venom, organophosphate poisoning, botulism, and hypermagnesemia. The most commonly encountered disorders, however, are immune-mediated: Lambert–Eaton myasthenic syndrome (LEMS) is a presynaptic disorder, while myasthenia gravis (MG) is a postsynaptic disorder of the NMJ.

DISORDERS OF THE NEUROMUSCULAR JUNCTION

MYASTHENIA GRAVIS

Several identified antibodies play a role in the pathogenesis of MG. In the most common form of antibody-positive MG, there is an IgG-directed attack on postsynaptic nicotinic acetylcholine receptors (Fig. 24-1). The antibody binding effectively limits the number of functioning receptors to which acetylcholine can bind. Therefore, even though the amount of acetylcholine released from the nerve axon button into the cleft is sufficient, it is not ultimately sensed in adequate quantities by the motor endplate. Patients with MG may also have elevated MuSK or LRP4 titers, although some patients do not have any detectable antibodies. Nevertheless, “seronegative” MG presents in a manner indistinguishable from seropositive MG.

The characteristic symptom is “fatigable weakness,” a loss of power that becomes more pronounced with the use of the affected muscles, and at the end of the day. Although some patients have symptoms limited to the ocular region, most develop some combination of weakness involving ocular, bulbar, respiratory, and limb muscles. On exam, patients may have asymmetric ptosis or extraocular abnormalities, nasal voice, limited palate elevation, impaired gag reflex, slurring of speech, head drop, proximal weakness, or combinations of these.

Several specialized bedside examination maneuvers can be done to assess for fatigable weakness. To test sustained up-gaze, the examiner asks the patient to look upward at a fixed target for about 60 seconds. Findings supportive of MG include the subjective experience of double vision or the objective development of ptosis, eye misalignment over time, or both. If there is detectable ptosis at baseline, ice can be applied to the affected eye for at least 2 minutes, as tolerated; a transient decrease in the degree of ptosis suggests MG. Checking neck muscle strength is also important, because weakness there may be accompanied by diaphragmatic weakness; nerve roots C3, 4, and 5 serve both neck and diaphragmatic muscles—the latter through the phrenic nerves. Asking the patient to count as high as possible during a single exhalation can also provide a rough idea of respiratory function; an inability to count to 40 should raise concern, as should shortness of breath that increases in the supine position (when the mechanical advantage of gravity is lost). Limb strength can be checked before and after a brief exercise task. For instance, after checking deltoid strength, have the patient perform 20 “arm pumps” in which the arm is repeatedly abducted to shoulder level and then adducted to the torso. A subsequent reduction in deltoid strength indicates fatigable weakness.

FIGURE 24-1. The neuromuscular junction: key components of the NMJ are depicted, including the motor axon and muscle endplate, the synaptic cleft, and the muscle fiber. When an action potential reaches the terminal, ACh is released into the synapse and binds to the nicotinic ACh receptors on the sarcolemma, triggering a muscle fiber action potential and contraction. The antigenic targets in MG and LEMS are indicated, as is the site of action of botulinum toxin. [NMJ, neuromuscular junction; ACh, acetylcholine; MG, myasthenia gravis; LEMS, Lambert–Eaton myasthenic syndrome]. Reprinted with permission from Louis ED, Mayer SA, Rowland LP. Merritt’s Neurology. 13th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015. Figure 89.1.

The diagnosis of MG is made largely on the clinical evaluation. It can be confirmed by the identification of elevated acetylcholine receptor, MuSK, or LRP4 antibody titers. Elevated anti-striated muscle antibody titers may also be present and have been linked with a higher incidence of thymoma. All patients with a new diagnosis of MG should have chest imaging to assess for thymic tumors.

In the absence of characteristic antibodies, electrodiagnostic tests can be very helpful. Specifically, a “decremental” (decreasing) response on slow repetitive nerve stimulation may occur. The most sensitive electrodiagnostic test, however, is single-fiber electromyography (SF-EMG) when performed on a weak muscle; this test is abnormal in 95% to 99% of patients with generalized MG. Of note, increased “jitter” on SF-EMG is not specific and can be seen in other neuromuscular conditions, including LEMS.

Treatment with antiacetylcholinesterase agents, such as pyridostigmine (Mestinon), can provide relief of symptoms, but it is important to remember that pyridostigmine does not address the underlying cause of MG. Rather, immunomodulatory therapies such as prednisone and steroid-sparing agents may be necessary. In the setting of myasthenic crisis, with pronounced respiratory distress potentially requiring intubation, intravenous immunoglobulin (IVIG) and plasmapheresis are indicated because they act much more quickly.

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