Physiology of nerve injury and regeneration

Summary box

1

Worldwide prevalence of brachial plexus/peripheral nerve injuries continues to increase as the rates of motor vehicle collisions and “extreme sporting” accidents increase.
2

Brachial plexus injuries can be classified in several ways: supra – versus infraclavicular; pre- versus postganglionic; closed versus open; neurapraxia, axonotmesis, or neurotmesis.
3

Lower elements of the brachial plexus are more susceptible to preganglionic (avulsion) injuries than upper elements.
4

After nerve injury, the proximal portion undergoes apoptosis with neuronal cell death, and if the neuronal cell body survives, it undergoes chromatolysis prior to regeneration.
5

After nerve injury, the distal portion undergoes Wallerian degeneration.
6

Denervation leads to a series of structural and electrical changes resulting in atrophy of the muscle if neural regeneration does not occur.
7

Fibrillations result from the acquired supersensitivity of muscle fibers to acetylcholine, which manifests clinically as spontaneous uncoordinated muscle activity.
8

Restoration of function after nerve injury comprises several arbitrarily divided processes: (a) survival of the neuronal cell, (b) axonal elongation, (c) axonal extension through the area of injury, (d) proper targeting to re-establish the neuromuscular junction, and (e) preservation of the integrity of the end organ muscle.
9

Following axonal regeneration, remyelination must occur for optimal functional recovery.
10

Functional recovery relies upon regenerating axons that can grow to reach their target muscle before the denervated muscle degenerates. Unfortunately, the rate of axon growth is only approximately 1 mm/day, so much research is underway to expedite nerve regeneration.

Introduction

In this chapter, we review the key physiological concepts underlying nerve injury and regeneration relevant to the clinical treatment of complex peripheral nerve disorders, such as brachial plexus palsies that manifest as paresis or paralysis of the upper extremity. Motor vehicle accidents cause approximately 70% of adult brachial plexus palsies (BPP). Young adult males comprise a significant proportion of patients suffering traumatic palsies, and they encounter substantial socioeconomic difficulty as a result of their disability. As the number of “extreme” sporting events and high-speed motor vehicle collisions increase, so does the worldwide prevalence of BPP. For countries such as Thailand, Vietnam, and India that rely on motorcycles as the main mode of transportation, the incidence of BPP is remarkably high. As the medical and surgical treatment of patients with BPP continues to improve, outcomes will be enhanced by increasing our knowledge of nerve and muscle pathophysiology after nerve injury and during neural regeneration.

Classifications of nerve injury

Injuries leading to brachial plexus palsies can be classified in several ways. They can be open or closed, sharp or ragged, clean or dirty. Consideration of the pathophysiology of these injury types led Dubuisson and Kline to propose an algorithm for the timing of nerve repair ( Figure 2.1 ). Nerve injury can occur in either or all of the supraclavicular (roots, trunks), retroclavicular (divisions), and/or infraclavicular (cords, terminal branches) regions. Most injuries affect the nerve roots and trunks in the supraclavicular region. Supraclavicular injuries can be classified as preganglionic or postganglionic ( Figure 2.2 ), but this seemingly simple classification has profound implications. In preganglionic lesions, the nerve roots are avulsed from the spinal cord, making nerve repair essentially impossible. In contrast, postganglionic lesions imply that the cell body is anatomically preserved so the nerve can be repaired with expectation of nerve regeneration.

The nerve roots contributing to the trunks exit from their neural foramina and run along the bony groove between the anterior and posterior tubercles of the vertebrae. These bony “chutes” are well-formed and underlie the nerves comprising the upper trunk (C5, C6); however, these “chutes” are less well-defined for nerves comprising the lower trunk. In addition, there is less connective tissue binding the lower nerve roots to the bony chutes when compared to the upper nerve roots. Consequently, the lower nerve roots (C8, T1) are prone to preganglionic (avulsion) injury, whereas the nerves comprising the upper trunk tend to sustain postganglionic injury. A preganglionic injury results in permanent paralysis of the muscles innervated by the avulsed roots and complete sensory loss of the corresponding dermatomes. Spontaneous nerve regeneration is unlikely. A postganglionic injury allows potential retention of function of the cell body within the ventral horn of the spinal cord, and these neurons may regenerate axons under appropriate conditions.

At the microscopic level, Seddon proposed a system for classifying nerve injury in 1943 that is still useful today. This classification system consists of neurapraxia, axonotmesis, and neurotmesis ( Figure 2.3 ). Neurapraxia refers to segmental interruption of the myelin sheath, which leaves the axons and surrounding connective tissues intact; this type of injury recovers spontaneously within a few weeks. Axonotmesis refers to interruption of both the myelin sheath and the axons, but with sparing of the surrounding connective tissues (intact Schwann cell basal lamina); this injury may recover spontaneously within months to years if axonal regeneration is able to progress across the injury zone. Neurotmesis refers to interruption of all elements including the axons, myelin sheaths, and surrounding connective tissues; spontaneous recovery does not occur.

Classifications of nerve injury

Injuries leading to brachial plexus palsies can be classified in several ways. They can be open or closed, sharp or ragged, clean or dirty. Consideration of the pathophysiology of these injury types led Dubuisson and Kline to propose an algorithm for the timing of nerve repair ( Figure 2.1 ). Nerve injury can occur in either or all of the supraclavicular (roots, trunks), retroclavicular (divisions), and/or infraclavicular (cords, terminal branches) regions. Most injuries affect the nerve roots and trunks in the supraclavicular region. Supraclavicular injuries can be classified as preganglionic or postganglionic ( Figure 2.2 ), but this seemingly simple classification has profound implications. In preganglionic lesions, the nerve roots are avulsed from the spinal cord, making nerve repair essentially impossible. In contrast, postganglionic lesions imply that the cell body is anatomically preserved so the nerve can be repaired with expectation of nerve regeneration.

The nerve roots contributing to the trunks exit from their neural foramina and run along the bony groove between the anterior and posterior tubercles of the vertebrae. These bony “chutes” are well-formed and underlie the nerves comprising the upper trunk (C5, C6); however, these “chutes” are less well-defined for nerves comprising the lower trunk. In addition, there is less connective tissue binding the lower nerve roots to the bony chutes when compared to the upper nerve roots. Consequently, the lower nerve roots (C8, T1) are prone to preganglionic (avulsion) injury, whereas the nerves comprising the upper trunk tend to sustain postganglionic injury. A preganglionic injury results in permanent paralysis of the muscles innervated by the avulsed roots and complete sensory loss of the corresponding dermatomes. Spontaneous nerve regeneration is unlikely. A postganglionic injury allows potential retention of function of the cell body within the ventral horn of the spinal cord, and these neurons may regenerate axons under appropriate conditions.

At the microscopic level, Seddon proposed a system for classifying nerve injury in 1943 that is still useful today. This classification system consists of neurapraxia, axonotmesis, and neurotmesis ( Figure 2.3 ). Neurapraxia refers to segmental interruption of the myelin sheath, which leaves the axons and surrounding connective tissues intact; this type of injury recovers spontaneously within a few weeks. Axonotmesis refers to interruption of both the myelin sheath and the axons, but with sparing of the surrounding connective tissues (intact Schwann cell basal lamina); this injury may recover spontaneously within months to years if axonal regeneration is able to progress across the injury zone. Neurotmesis refers to interruption of all elements including the axons, myelin sheaths, and surrounding connective tissues; spontaneous recovery does not occur.