книги студ / Color Atlas of Pathophysiology (S Silbernagl et al, Thieme 2000)

Neuromuscular transmission is a sequence of events (→A) that can be interrupted at various levels. The action potential is carried along by activation of the Na+ channels to the nerve ending, where it depolarizes the cell membrane and thus opens the voltage-gated Ca2+ channels. The Ca2+ ions that enter the nerve ending mediate the fusion of acetylcholine (ACh)-containing vesicles with the presynaptic membrane, whereupon ACh is released into the synaptic cleft. ACh binds to receptors of the subsynaptic membrane and in this way opens nonspecific cation channels. The depolarization of the subsynaptic membrane is transmitted to the postsynaptic membrane where, through opening of voltage-gated Na+ channels, an action potential is initiated that rapidly spreads over the entire muscle membrane. ACh is broken down by acetylcholinesterase; the choline which has been split off is again taken up into the nerve ending and used again for the synthesis of ACh.

Abnormalities can affect any element of this process. Local anesthetics, for example, inhibit the voltage-gated Na+ channels of the neuron and thus interrupt nerve transmission to the end-plate. The Ca2+ channels can be blocked by antibodies (see below). Botulinus toxin inactivates synaptobrevin, the protein responsible for binding the ACh-containing vesicles to the plasma membrane and thus for the release of ACh. The ACh receptors can also, like the Ca2+ channels, be blocked by antibodies which furthermore accelerate the internalization and breakdown of the receptors. The receptors can also be blocked by curare that, without itself having an effect, competitively inhibits the binding of ACh to the receptors.

Succinylcholine (suxamethonium chloride) leads to continuous stimulation of the receptors, continuous depolarization of the postsynaptic membrane, and thus to an inactivation of the postsynaptic Na+ channels. In this way it can, like curare, block neuromuscular transmission. In low concentrations, substances that inhibit acetylcholinesterase (e.g., physostigmine) increase neuromuscular transmission by increasing the availability of ACh in the synaptic cleft. In high doses, however, they inhibit neuromuscular transmission be-

cause high concentrations of ACh, as of succinylcholine, cause continuous depolarization of the subsynaptic membrane and so inactivate the postsynaptic Na+ channels. The re-up- take of choline into the nerve ending can be inhibited by Mg 2+ and hemicholine.

The most important disease affecting the end-plates is myasthenia gravis, a muscle paralysis that results from blockage of neuromuscular transmission (→B). It is caused by antibodies against the ACh receptors in the subsynaptic membrane which accelerate the breakdown of the receptors (→B1). This autoimmune disease can be caused by infection with viruses that have an ACh-receptor-like structure. Myasthenia may also occur in patients with a benign tumor of the thymus. The formation of such antibodies is favored in those who express special subtypes (DR3 and DQw2) of the major histocompatibility complex (MHC class II). In patients with myasthenia gravis, repetitive stimulation of a motor nerve will at first cause the production of a normal summated muscle action potential whose amplitude will, however, decrease through progressively increasing “fatigue” of neuromuscular transmission (→B2).

Another autoimmune disease that impairs neuromuscular transmission is the pseudomyasthenic syndrome of Lambert and Eaton

(→C). This condition often arises in patients affected by a small-cell carcinoma of the lung. Ca2+ channels in the plasma membrane of the tumor cells sensitize the immune system and stimulate the formation of antibodies that also react with the Ca2+ channels of the endplate (→C1). Due to inhibition of the Ca2+ channels, the summated muscle action potential is at first small, but is progressively normalized, because with the repetitive stimulation increasing amounts of Ca2+ are accumulated in the nerve endings (→C2).

The motor unit consists of the motoneuron (α- motoneuron in the spinal cord or the cranial nerves), the associated axon, and all the muscle fibers innervated by its collaterals. The function of the motor unit can be affected by disease of the motoneuron, by interruption or delay of axonal conduction, or by disease of the muscle (→A).

The α-motoneurons can be infected by poliovirus and irreversibly destroyed by it. Also in spinal muscular atrophy, a group of degenerative diseases largely of unknown cause, these cells are destroyed. Amyotrophic lateral sclerosis (ALS) may be caused primarily by a disorder, partly genetic, of axonal transport that secondarily leads to the death of spinal α-motoneurons and supraspinal motoneurons (→A1).

Damage to or death of axons may, among others causes, be due to autoimmune diseases, a deficiency of vitamin B1 or B12, diabetes mellitus, poisoning (e.g., lead, alcohol), or genetic defects (e.g., Charcot–Maire–Tooth syndrome; →p. 302) (→A2).

The musculature (→A3) can also be affected by autoimmune diseases (e.g., dermatomyositis). In addition, genetic defects may involve the musculature, for example, in myotonia or dystrophy (see below).

Lesion of a motor unit causes paralysis of the affected muscles, regardless of whether it is localized in an α-motoneuron, axon, or the muscle itself (→A). In primary death of an α- motoneuron fasciculations typically occur. They are the result of synchronous stimulation and contraction of the muscle fibers of a motor unit. In ALS the destruction of the supraspinal neurons may result in hyperreflexia and spasticity (→p. 310), as long as some of the α-mo- toneurons are still intact. A lesion of a peripheral nerve which has reduced the thickness of the myelin layer will result in a slowing of the nerve’s conduction velocity (→p. 302). As a rule, sensory parts of the nerve are also affected. This leads to abnormal sensory functions as well as spontaneous action potentials in the damaged nerves, resulting in corresponding sensations (paresthesias). In primary death of muscles fibrillations often occur, i.e., uncoordinated contractions of individual muscle fibers.

Genetic ionic channel defects (→B) are the cause of a group of functional muscle diseases. Normally (→B1) depolarization of the muscle cell membrane is triggered on excitation by a voltage-gated Na+ channel that causes the opening of a voltage-gated Ca2+ channel (→ p. 304) and a Ca2+ channel of the sarcoplasmic reticulum. As a result, intracellular Ca2+ is increased, mediating muscular contraction. Repolarization is achieved by inactivation of the Na+ channels, by Cl– influx, and K+ efflux. This causes the inactivation of the Ca2+ channels so that the intracellular Ca2+ concentration again falls and the muscle relaxes.

Delayed inactivation of the Na+ channel due to mutation in the gene for the channel protein can lead to delayed relaxation, increased excitability, and cramps (Na+ channel myotonia and congenital paramyotonia; →B2). Cold further slows Na+ channel inactivation such that cramps occur, particularly in paramyotonia when the muscle gets cold. An additional defect of the Na+ channel or a defective K+ channel (?) can cause paralysis when the extracellular concentration of K+ is high (hyperkalemic periodic paralysis). A genetic defect of the volt- age-gated Ca2+ channel also leads to hypokalemic periodic paralysis. If there are defects in the Cl- channels, myotonia occurs. Depending on the severity of the molecular defect, inheritance of the disease is dominant (congenital myotonia, Thomsen’s disease) or recessive (Becker’s myotonia). In certain defects of sarcoplasmic Ca2+ channels the volatile halogenated anesthetics may bring about potential-inde- pendent activation of these channels with an increase in intracellular Ca2+. The resulting massively increased energy metabolism causes hyperthermia (malignant hyperthermia;

→p. 22).

In Duchenne’s or Becker’s degenerative muscular dystrophy (→C; →p. 307) dystrophin, an element of the cytoskeleton, is defective. The responsible gene is on the short arm of the X chromosome. The disease occurs practically only in males, because in females with one defective gene the dystrophin formed from the normal gene is sufficient. In Duchenne’s dystrophy only short, completely functionless dystrophin fragments are formed

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Spinal α-motoneurons are controlled by several supraspinal neuronal tracts (→A1):

–the pyramidal tract (violet) from the motor cortex;

–the rubrospinal tract from the red nucleus (red);

–the medial reticulospinal tract from the pontine reticular formation (orange);

–the lateral reticulospinal tract from the medullar reticular formation (brown); and

–the vestibulospinal tract (green).

The medial reticulospinal and the vestibulospinal tracts predominantly promote the activity of the so-called antigravity muscles, i.e., the muscles that flex the arms and stretch the legs. The pyramidal, rubrospinal, and lateral reticulospinal tracts, on the other hand, predominantly promote the activity of the flexors of the leg and extensors of the arms.

If the motor cortex or the internal capsule is damaged (e.g., by bleeding or ischemia in the area supplied by the middle cerebral artery), impulse transmission in the immediately adjacent descending cortical tracts is interrupted. These make up the pyramidal tract and other connections of the motor cortex, such as those to the red nucleus and to the medullary reticular formation. The result is a reduced activity not only of the pyramidal tract but also of the rubrospinal and medial reticulospinal tracts. The vestibulospinal and medial reticulospinal tracts are less affected, because they are under stronger noncortical influence, for example, from the cerebellum. An interruption of transmission in the area of the internal capsule thus ultimately results in an excessive activity of the extensors in the legs and the flexors in arms (→A2).

At first, however, spinal shock will set in due to cessation of supraspinal innervation of α- motoneurons (→A3a). The antigravity muscles are also affected, less so than the other muscles though, by the reduced supraspinal activation of the α-motoneurons. In spinal shock the muscles are flaccid and no reflexes are elicited (areflexia).

However, partial “denervation” of the α- and γ-motoneurons as well as of interneurons leads to a gradual increase in sensitivity of these neurons. In addition, the endings of su-

praspinal neurons that are out of action are replaced by synapses with the spinal cord neurons (→A3b). As a consequence, the reflexes gradually gain a stronger influence on the activity of the α-motoneurons, and hyperreflexia occurs.

Another consequence is spasticity. After loss of function of the descending tracts, the activity of the α-motoneurons comes under the increasing influence of the muscle spindles and Golgi tendon organs (→A4). Stretching the muscle spindles stimulates the α-motoneu- rons of the same muscle via a monosynaptic reflex; the increased influence of the muscle spindles results in massive contraction on stretching. Nevertheless, the response of the muscle spindles is mainly phasic, i.e., if they are stretched slowly or continuously their activity slowly decreases. As a result, the influence of the Golgi tendon organs becomes dominant: when the muscle is stretched they inhibit muscle contraction via an inhibiting interneuron. It is also under the influence of the Golgi tendon organs that on slow or continuous stretching the muscle will suddenly become flaccid after initial increase in tone (clasp-knife effect).

The predominance of the stretching muscles leads to extension of the big toe on stroking the sole of the foot (→A5), instead of its normal plantar flexion. This is called Babinski’s sign or the Babinski reflex. It is taken as evidence for a lesion in the pyramidal tract. In fact the Babinski reflex is the result of a lesion of several descending cortical tracts, including the pyramidal tract. Isolated damage of the pyramidal tract (extremely rare) results in neither spasticity nor the Babinski reflex, but only minor disturbance of fine movement.

If the red nucleus has been destroyed (e.g., due to ischemia of the mid-brain or in Wilson’s disease [→p. 252]), coarse tremor will result. Neurons of the red nucleus are, among other functions, important for the dampening of oscillations that can occur as a result of a negative feedback in the control of α-motoneurons. In lesions of the vestibular nucleus abnormalities of balance with vertigo, nystagmus, and nausea predominate (→p. 330).