Infections with exotoxin-producing bacteria may be associated with defects in neural transmission and muscle contraction. Clostridium tetani and Clostridium botulinum (Chapter 9) both release extremely potent neurotoxins that interfere with neuromuscular transmission. Tetanus toxin (known as tetanospasmin) blocks the action of inhibitory neurons, leading to the increased release of acetylcholine and sustained muscle contraction and spasm (tetanus). Botulinum toxin, by contrast, inhibits acetylcholine release, producing a flaccid paralysis. The purified toxin (Botox) is remarkably stable after injection, an attribute that has led to its widespread use as an antidote for wrinkles and a variety of other conditions associated with unwanted muscular activity (e.g., blepharospasm and strabismus).
Disordersofneuromuscularjunctionsmanifestwithweaknessthatoftenaffectsfacialandextraocularmusclesandmayshowrapidfluctuationinseverity.
BothmyastheniagravisandLambert-Eatonsyndrome,whicharethemostcommonforms,areimmunemediated,beingcausedbyantibodiesthattypicallytargetpostsynapticacetylcholinereceptorsandpresynapticcalciumchannels,respectively.
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Myastheniagravisoftenisassociatedwiththymichyperplasiaorthymoma.Lambert-Eatonsyndromeisaparaneoplasticdisorderinthemajorityofthecases;thestrongestassociationiswithsmallcelllungcancer.
Geneticdefectsinneuromuscularjunctionproteinsandbacterialtoxinsalsocancausesymptomaticdisturbancesinneuromusculartransmission.
The principal component of the motor system is the motor unit, which is composed of one lower motor neuron together with the associated axon, its neuromuscular junctions, and the skeletal muscle fibers it innervates.
Skeletal muscle consists of different fiber types broadly classified as slow twitch type I and fast twitch type II fibers (
Table 22.2 ). The fiber type is dependent on the innervation. All myofibers of a motor unit therefore share the same fiber type. Normally the fibers of different types are distributed in checkerboard patterns (
Fig. 22.1A ). A number of proteins and protein complexes are crucial for the unique structure and function of skeletal muscles. These include proteins that make up the sarcomeres and the dystrophinglycoprotein complex (
Fig. 22.3 ), as well as enzymes that allow muscle to meet it unusual metabolic requirements.
Primary muscle diseases or myopathies have to be distinguished from secondary neuropathic changes caused by disorders that disrupt muscle innervation. Both are associated with altered muscle function and morphology, but each has distinctive features (
Fig. 22.4 ). Myopathic conditions are often associated with segmental necrosis and regeneration of individual muscle fibers (
Fig. 22.4B ). Some myopathies are also associated with other morphologic features, such as inflammatory infiltrates or intracellular inclusions. Disruption of muscle by endomysial fibrosis and fatty replacement is reflective of disease chronicity that can occur both in myopathic as well as neuropathic conditions.
Both neuropathic and myopathic processes cause muscle fiber atrophy. However, certain disorders are associated with particular patterns of atrophy, as follows: • Neuropathic changes. Loss of innervation causes atrophy of myofibers. The two main morphologic hallmarks of neurogenic changes, grouped atrophy and fiber type grouping (
Fig. 22.4C ), are the result of multiple rounds of denervation and reinnervation. Loss of an axon or lower motor neuron results in atrophy of the myofibers that are part of this motor unit (