Neuromuscular Junction Syndromes

MYASTHENIA GRAVIS

The defect in neuromuscular transmission in myasthenia gravis (see Chapter50 ) produces a pure muscular weakness without the atrophy, fasciculations, or reflex changes seen in motor neuron disease.^ Myasthenia gravis also causes a pattern of weakness in the ocular and cranial muscles that is different from that seen in amyotrophic lateral sclerosis. A weakness of the extraocular muscles and eyelids producing diplopia and ptosis is common in patients with myasthenia gravis but rare in those with amyotrophic lateral sclerosis (see TableJ.,5,-2 ). Facial weakness is also common in myasthenia gravis, and the combination of ptosis and weakness of eye closure may be duplicated only by an acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome), which has a very different temporal profile.

The other characteristic feature of myasthenia gravis is fatigability. The myasthenic muscle rapidly weakens with continued or repetitive use. The physiological counterpart is the decremental response to repetitive stimulation of a peripheral nerve. Rest can temporarily restore the muscle to almost normal strength, but diplopia and ptosis return as the patient uses the eyes, the nasal voice and mushy dysarthric speech resumes as he speaks, and difficulty with chewing and swallowing occurs as he eats. Limb and postural muscles are generally less affected. y

MYASTHENIC SYNDROME (EATON-LAMBERT SYNDROME)

Although weakness reminiscent of myasthenia gravis is the presenting complaint in most people with Eaton-Lambert syndrome, y the phenomenon of fatigability is less prominent, and the distribution of weakness, which affects the limbs and spares the extraocular muscles and eyelids, is also different. Pharyngeal weakness with dysphagia is the only weakness of the cranial musculature regularly encountered. Also in contrast to myasthenia gravis, autonomic

dysfunction and reflex changes develop. Dry mouth and perversion of taste are common. Knee jerks are often reduced or absent. y

Occasionally patients with the Eaton-Lambert myasthenic syndrome describe a warming-up phenomenon, which is the opposite of fatigability; as a muscle is used repetitively, it may gain in strength, although with continued use fatigability returns. The clinical warming-up phenomenon correlates with an incremental increase in the amplitude of the muscle action potential with repetitive stimulation. The initial low amplitude of the muscle action potential occurs because an antibody blocks a calcium channel, slowing the entry of calcium into the presynaptic terminal to initiate vesicular release of acetylcholine. y Because it is only a partial blockade, however, enough calcium eventually enters with repetitive depolarizations to allow the amplitude of response to increase and strength to improve, at least temporarily.^] In many but not all cases, the antibody against the calcium channel is generated by a cancer; thus, the Eaton-Lambert myasthenic syndrome is often a paraneoplastic disorder.y

OTHER DISORDERS OF THE NEUROMUSCULAR JUNCTION

Botulism produces a rapidly developing paralysis. Because it usually affects the ocular and cranial musculature first, and the weakness develops so rapidly, botulism can be confused with a brain stem stroke or encephalitis. It rapidly becomes generalized to include all skeletal musculature and then may be mistaken for AIDP ( . T§ble.15-14 ). In typical cases, these conditions can be distinguished from each other by the fact that botulism starts in the ocular and cranial musculature and produces a descending paralysis, whereas AIDP starts as a weakness in the legs and produces an ascending paralysis that eventually includes the cranial musculature. This rule applies very well to botulism, which almost invariably begins in the ocular and cranial musculature, but may be violated by AIDP, which sometimes begins in the cranial musculature and descends. However, the early loss of pupillary reflexes in botulism and the predilection of AIDP for the facial and lower cranial nerves can clearly distinguish the two disorders. Weakness resulting from botulism is prolonged, lasting months, because the toxin permanently impairs the presynaptic release of acetylcholine from the terminals to which the toxin is bound. Neuromuscular transmission and strength return only after the nerve terminals sprout new endings.

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