Neuromuscular Junction Case File

Neuromuscular Junction Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 10

A 51-year-old male presents to neurosurgery clinic with a 4-month history of sharp, stabbing pain from his low back to the front of his thigh. He has difficulty walking because of the pain which is exacerbated by physical activity. However, he finds relief when leaning forward or sitting, but minimal improvement with rest. He complains of mild weakness when he kicks with his left leg, but denies any difficulty with bowel or bladder control. There is no history of recent trauma. On physical examination, there is mild weakness in his left quadriceps femoris muscle. Muscle stretch reflex in the left patellar tendon is decreased. There is no clonus. Babinski response is negative bilaterally. He has a normal-based gait with appropriate arm swing. It is determined that the patient has a lumbar disk herniation at L3-4.

• What imaging study would the physician obtain to further confirm the diagnosis?
• What treatments are available?

ANSWERS TO CASE 10: NEUROMUSCULAR JUNCTION

Summary: A 51-year-old male presents with pain in his low back and left anterior thigh with mild weakness in the left quadriceps muscle and decreased reflex in his left patellar tendon.

• Further studies: MRI of the lumbar spine
• Treatment: Conservative management versus surgical excision of the herniated disk

CLINICAL CORRELATION

Only 1%-3% of low back pain, one of the most common ailments for which patients seek medical treatment, is caused by lumbar disk herniations. The intervertebral disk is composed of a central nucleus pulposus surrounded by a fibrous annulus which acts to provide support to the spine and allow for stable motion. With aging, the proteoglycans within the nucleus pulposus desiccate and result in a loss of disk space height and become more susceptible to injury. Tears in the annulus allow the nucleus pulposus to protrude or herniate out of the disk space and impinge on the passing nerve root. Impingement of the nerve root can result in symptoms such as pain radiating down an extremity, motor weakness in the distribution of a nerve root, dermatomal sensory changes, and/or decreased muscle stretch reflexes. The most common location for lumbar disk herniations is L5-S1, with second most common being L4-5. The L3-4 level is a less common site of pathology. The herniated disk will most likely impinge on the nerve root from the lower lumbar level, that is, an L5-S1 disk herniation will affect the S1 nerve root. The clinician can use the straight leg raising test or Lasegue’s sign to distinguish possible radicular pain from pain secondary to hip pathology. In this maneuver, the patient is supine and the clinician raises each leg independently while keeping the knee extended. Pain from a herniated disk will generally be reproduced before the leg is raised more than 60 degrees. The FABER test stresses the hip joint and does not elicit radicular pain. The initial treatment of an acute disk herniation and radiculopathy is conservative management, since upward of 85% of patients will improve on their own within 5-8 weeks. If the patient develops a cauda equina syndrome (CES) or a progressive motor deficit, then emergent surgery should be considered. A cauda equina syndrome may develop from a very large midline disk herniation, most commonly at the L4-5 levels. The patient may experience low back pain or radicular pain. There can be significant motor weakness which can progress to paraplegia if not treated. The most common sensory deficit is a saddle anesthesia involving the anus, lower genitalia, perineum, inner thighs, and buttocks. Also, the patient may have difficulty with bladder and bowel control to varying degrees. The surgical treatment of lumbar disk herniations consists of removal of the offending disk material and decompression of the nerve root through a posterior approach called a lumbar diskectomy.

APPROACH TO NEUROMUSCULAR JUNCTION

Objectives

1. Identify the components of the neuromuscular junction.
2. Describe the morphology of the endplate potential waveform.
3. Describe how the endplate potential is converted into an action potential (AP).
4. Describe changes that occur with denervation of a muscle.

Definitions

Motor endplate: The region of the muscle fiber innervated by a motor nerve.

Endplate potential: The postsynaptic potential in the muscle fiber that occurs following release of acetylcholine (ACh) from the nerve terminal.

DISCUSSION

The neuromuscular junction (NMJ) is the interface between a motor neuron and a skeletal muscle fiber at a region called the motor endplate (see Figure 10-1). The axon of the motor neuron loses its myelin sheath as it approaches the muscle fiber and splits into multiple fine synaptic boutons. The synaptic cleft is approximately 100 nm wide from the bouton to the surface of the muscle fiber which contains multiple deep invaginations called junctional folds. The cleft contains the basement membrane composed of collagen and extracellular matrix proteins which anchor acetylcholinesterases to hydrolyze and inactivate the neurotransmitter ACh. The surface of the postsynaptic membrane contains nicotinic acetylcholine receptors (AChR) at the surface of the muscle fiber and voltage-gated Na+ channels deep within the junctional folds.

Figure 10-1. Schematic illustrations of a myoneural junction. A: Motor fiber

supplying several muscle fibers. B: Cross section as seen in an electron micrograph.

(With permission from Waxman’s Clinical Neuroanatomy. 25th ed,

Fig. 3-11, page 3.)

As the AP travels to the bouton, the synaptic vesicles release ACh into the synaptic cleft in a process described in the previous chapters. ACh rapidly diffuses across the synaptic cleft and binds to the AChR. It is cleared from the cleft by diffusion out of the synaptic cleft and hydrolysis by the acetylcholinesterases.

As previously discussed, the neurotransmitter binds to the inotropic receptors and rapidly depolarizes the membrane at the motor endplate, resulting in a postsynaptic potential called the endplate potential. The amplitude of the postsynaptic potential is greatest at the endplate and diminishes as it passively spreads away because of the leakage of current along the muscle fiber. This is in contrast to the AP which is capable of regeneration along its course.

Recordings of the endplate current demonstrate a rapid depolarization followed by a more gradual repolarization. This wavelike morphology is because of several factors. Stimulation of a motor neuron releases large numbers of ACh molecules which bind to and rapidly open more than 200,000 AChR. This results in a rapid and large depolarization in the postsynaptic membrane. However, ACh is rapidly cleared from the synaptic cleft and receptors and the channels begin to close in a random manner, producing small decreases in the endplate potential in a steplike fashion. But owing to the sheer number of channels involved, the steplike decrease in the magnitude of the current appears more smooth and gradual.

The depolarization that results from the stimulation of a single motor neuron is up to 70 mV at the neuromuscular junction. This is in contrast to the postsynaptic potentials produced in the central nervous system which reach an amplitude of approximately 1 mV. The motor endplate potential is usually sufficient to activate the voltage-gated Na+ channels in the junctional folds. The endplate potential is converted into an AP and is propagated throughout the muscle fiber, which results in an increase in the intracellular Ca2+ ion concentration and the contraction of the muscle fiber.

Injury to a nerve supplying muscle fibers leads to denervation changes to the muscle which occurs in several stages. The distal segment of the axon produces spontaneous injury potentials from hypopolarization of the nerve membrane. These injury potentials travel to and stimulate the muscle fiber resulting in coordinated contractions called fasciculations which are visible to the eye and are one of the earliest indications of denervation. As the distal segment of the injured nerve continues to degenerate, the multiple terminals of the axon are separated. They continue to produce injury potentials and isolated muscle fiber contractions, but in an uncoordinated fashion. These fibrillations are not visible to the eye, but can be detected by an electromyogram. Finally, following complete degeneration of the nerve, the muscle no longer receives any type of potential and is electrically silent. Degeneration atrophy occurs resulting in significant loss of bulk and tone. Denervated muscles will initially upregulate its AChR to serve as targets for the regenerating nerve. However, if reinnervation has not occurred in 2 years, the receptors are lost.

COMPREHENSION QUESTIONS

[10.1] A 27-year-old man is brought into the emergency room immediately after having injected himself with a rather large dose of atracurium (a nondepolarizing skeletal muscle relaxant). He has flaccid paralysis throughout his body, and is being mechanically ventilated by the paramedics who brought him in. Which of the following events at the neuromuscular junction is inhibited by this drug?

A. Influx of calcium into the presynaptic terminal as a result of depolarization

B. Release of synaptic vesicles as a result of calcium influx

C. Depolarization of the postsynaptic membrane by AChR activation

D. Removal of ACh from the synaptic cleft by acetylcholinesterase

[10.2] A 35-year-old woman presents to your office with complaints of weakness and diplopia, both of which are worse at the end of the day. She is concerned that she may have myasthenia gravis (MG), and you order a Tensilon test. In this test a short-acting acetylcholinesterase inhibitor is administered to see if it results in improvement of symptoms. In what location in the neuromuscular junction does this drug act?

A. Presynaptic membrane

B. Inside the synaptic vesicle

C. Synaptic cleft

D. Postsynaptic membrane

[10.3] In what way is the motor end plate potential (EPP) different from the AP?

A. Involves the opening of sodium and potassium channels

B. Results in membrane depolarization

C. Decreases as it travels down the length of the cell membrane

D. Occurs as a result of normal depolarization of the motor nerve

Answers

[10.1] C. Atracurium (and all nondepolarizing skeletal muscle relaxants) work by binding to AChR in the neuromuscular junction and preventing their activation by ACh, thus preventing AChR-mediated depolarization of the postsynaptic membrane. This results in total flaccid paralysis, which can result in death secondary to paralysis of the respiratory muscles unless mechanical ventilation is continued until the patient has recovered from the effects of the drug. Calcium influx into the presynaptic terminal is impaired in Eaton-Lambert myasthenia, synaptic vesicle release is impaired in botulism, and removal of ACh by acetylcholinesterase is blocked by a number of therapeutic drugs and also by nerve agents such as sarin gas.

[10.2] C. Acetylcholinesterase is the enzyme primarily responsible for the degradation of ACh and its removal from the synaptic cleft. The enzyme is located within the synaptic cleft. The defect in MG is a

paucity of AChR on the postsynaptic membrane, resulting in impaired neurotransmission at the neuromuscular junction. By inhibiting acetylcholinesterase within the synaptic cleft, the concentration of ACh is increased, which increases the amount of neurotransmission. This results in symptomatic improvement in a large number of cases.

[10.3] C. The EPP only depolarizes in the area of AChR, so it decreases in amplitude as it travels along the length of the cell membrane. The motor EPP triggered by the release of ACh from the presynaptic motor nerve is very similar to an AP but has some important differences. Both potentials are the result of opening of both sodium and potassium channels in the membrane, and both serve to depolarize the membrane from its normal negative resting potential. The ion channels involved, however, are different. The EPP arises from opening of ligand-gated channels, while the AP arises from the opening of voltage-gated channels. An important consequence of this is that the AP is selfpropagating. The depolarization of the membrane causes the opening of more voltage-gated channels, so it spreads rapidly throughout the postsynaptic cell. The EPP only depolarizes in the area of AChR, so it decreases farther away in the cell. In a normal cell, however, the depolarization from the EPP is sufficient to trigger an AP, which then propagates throughout the muscle cell, so both types of potential normally occur following the depolarization of a motor nerve.

NEUROSCIENCE PEARLS ❖ Injury to a nerve leads to distal segments of the axon producing spontaneous injury potentials, manifested as fasciculations. ❖ As the distal segment of the injured nerve continues to degenerate, the multiple terminals of the axon separate and produce uncoordinated muscle fiber contractions. These are called fibrillations and can only be detected by an electromyogram. ❖ If reinnervation does not occur within 2 years, the postsynaptic AChR are lost.

REFERENCES

Bear MF, Connors B, Paradiso M, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 

Purves D, Augustine GJ, Fitzpatrick D, et al., eds. Neuroscience. 3rd ed. Sunderland, MA: Sinauer Associates, Inc.; 2004. 

Zigmond MJ, Squire LR, Bloom FE, Landis SC, Roberts JL, eds. Fundamental Neuroscience. 2nd ed. San Diego, CA: Academic Press; 1999.

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