Axon

The core element of the nerve is the axon, a thin tube of axoplasm that extends from the nerve cell body to the target organ. Unmyelinated axons are partially ensheathed by invaginations of the Schwann cell membrane, whereas myelinated axons are enveloped in concentric lamellae of myelin composed of compacted spiraled Schwann cell membrane to form a sheath (Fig. 50D.2). The myelin sheath is laid down in segments called internodes, each derived from one Schwann cell. The small gap of uncovered axoplasm between sheaths is called the node of Ranvier, the site where the largest part of ion flow takes place to transmit the action potential. In saltatory conduction, action potentials leap from node to node, rather than traveling in a continuous conduction process along the entire length of the axolemma. In this way, a myelinated large-caliber axon in human adults may conduct electrical impulses at up to 73 meters per second, whereas a small unmyelinated axon may conduct as slowly as 0.5 meter per second (Kimura, 2005).

Fig. 50D.2 Anatomy of a peripheral nerve. The motor nerve cell body lies within the anterior horn of the spinal cord. A single axon extends from the anterior horn cell to its target muscle, making contact at the neuromuscular junction. Local support cells called Schwann cells generate a myelin sheath that is laid down at regular intervals around the axon; each interval is called an internode, and the intervening gap is called the node of Ranvier.

Peripheral Nerve Trunks

The connective tissue within a peripheral nerve trunk is composed of the endoneurium, perineurium, and epineurium (Fig. 50D.3). These tissues provide structure, tensile strength, and elasticity.

Fig. 50D.3 Classification of peripheral nerve trauma (see text).

(Image courtesy Cleveland Clinic, 2006. Illustrator, David Schumick, BS, CMI.)

The endoneurium is a thin layer of collagenous connective tissue that surrounds individual nerve fibers and is continuous with the fine layer of connective tissue of the nerve roots. In the nerve trunk, bundles of myelinated and unmyelinated nerve fibers are arranged into fascicles (or funiculi). These fascicles, which vary greatly in size and number, are arranged in an intertwining pattern (sometimes called the Sunderland plexus) in the more proximal portion of the nerve trunk but are arrayed in a more parallel pattern in the distal parts of the nerve. Each fascicle is surrounded by perineurium, which consists of perineurial cells that interlock to form tight cell junctions, creating the blood-nerve barrier that maintains an immunologically privileged endoneurial environment. A typical spinal nerve trunk consists of a variable number of fascicles separated by inter- and extrafascicular epineurium that constitutes an extension of the dura mater. Finally, the nerve trunk melds into surrounding structures via a loose layer of protective areolar tissue, or the mesoneurium, which allows the nerve passive movement in the transverse and longitudinal planes.

Peripheral nerves have an abundant and anastomotic blood supply. The arterial arrangement is composed of extraneural arteries (arteriae nervorum) that enter the nerve proper at various sites and angles along the length of the nerve. Longitudinally arranged arterioles travel along the interfascicular epineurium before they branch off to pierce the perineurium. The endoneurial or intraneural capillaries are larger in diameter than typical capillaries in other organs and resemble end-arterioles in size, although they are surrounded only by pericytes. Venous drainage is conducted along postcapillary venules.

Segmental Demyelination

Segmental demyelination occurs when a focal segment of nerve is subjected to a relatively mild compressive or traction force. The nerve segments that lie distal and proximal to the site of injury are not affected and function normally. Conduction across the injured segment is impaired, however, when distortion of the myelin sheath causes degeneration of one or several internodes thereby reducing the ability of the sheath to act as an electrical insulator. If the myelin is only slightly damaged, the only local consequence may be a widening of the node of Ranvier that causes a slowing of conduction velocity across the nerve segment. Focal demyelination of axons within a nerve fascicle may affect some but not all fibers, resulting in asynchronous conduction across the affected nerve segment. In this case, impulses eventually reach their destination after a delay measured in milliseconds, but the slowing may affect certain nerve functions that rely on highly synchronous firing (e.g., deep tendon reflexes, vibration sense), resulting in paresthesia.

More severe compression may involve most or all myelinated nerve fibers at the injury site and several internodes. In this situation, blockade of conduction across that segment results in weakness or sensory disturbance. Study of nerve segments that have been subjected to tourniquet compression reveals that the nodes of Ranvier located at the edge of the tourniquet are subjected to greater pressure and are deformed to a greater degree than the segment lying directly beneath the tourniquet. This pressure gradient causes the underlying axon and myelin to telescope into neighboring segments, which greatly distorts the paranodal segment of myelin, resulting in conduction slowing or demyelinating conduction block.

Wallerian Degeneration

Injury to a peripheral nerve triggers a complex process that involves the axon, its cell body, its cellular connections, and the surrounding connective tissues. Wallerian degeneration follows grade II to grade V injuries and can be divided into changes that involve the segments of nerve distal and proximal to the zone of injury (Fig. 50D.4).

Fig. 50D.4 Wallerian degeneration. After axotomy, axon and myelin sheath distal to transection begin to degenerate. Within a few days, macrophages are recruited into injury site and digest debris. Changes also occur proximal to site of injury. A degree of wallerian degeneration takes place up to the first encountered node of Ranvier, and cell body undergoes chromatolysis, which represents a switch in function of cell body from axon maintenance to axon regeneration. If regeneration does not take place, target tissue is not reinnervated, and degeneration of target organ eventually occurs.

Nerve Regeneration

The method of nerve regeneration depends on the type of injury sustained: remyelination after grade I lesions and collateral axon sprouting and proximal-to-distal nerve regeneration after grade II to grade V lesions.

With focal demyelinating lesions, recovery of clinical and electrodiagnostic function occurs as the Schwann cell divides and initiates remyelination. Conduction, and thereby strength, are reestablished within a few weeks or months, but the new myelin sheath usually is thinner and has several internodes for each original internode.

When only some of the axons supplying a muscle are damaged, the intact motor axons produce sprouts that reinnervate the denervated muscle fiber; this is referred to as collateral sprouting. These nerve sprouts originate from the nodes of Ranvier (nodal sprouts) or the nerve terminals (terminal sprouts) as early as 4 days from the time of injury. By adopting denervated muscle fibers, collateral innervation increases the size of the remaining motor units and results in increased contractile force. Clinical recovery due to collateral sprouting takes up to 3 to 6 months from the time of injury. During this same period, compensatory hypertrophy of muscle fibers that have retained their axons occurs, although the muscle as a whole atrophies. Enhanced synchronization of motor unit firing contributes to improved strength.

In contrast with partial or mild nerve injury, in which the surviving motor axon begins the process of collateral sprouting almost immediately, in severe or complete injury, neuronal regeneration starts from the proximal stump only after wallerian degeneration is completed (Burnett and Zager, 2004). Schwann cells play a key role in neuronal regeneration. They dedifferentiate and up-regulate the expression of adhesion molecules and neurotrophins (i.e., cadherins, immunoglobulin superfamily factors, laminin) which promote the migration of nerve sprouts that form at the regenerating axon tip. These sprouts then form cords aligned around the original basal lamina tubes of the myelinated axons (bands of Büngner) that provide a pathway along which new axons are destined to grow. The contribution of axon regeneration to clinical recovery overlaps with collateral sprouting at approximately 3 months, but axon regeneration is the main recovery mechanism from 6 to 24 months after the injury, depending in part on the distance the nerve must grow to reach its target muscle.

The tip of the axon sprout, called the growth cone, travels by way of filopodia and lamellipodia (Fig. 50D.5). Neurotropism, the term used to describe guidance of a regenerating axon, is accomplished by guidance molecules (i.e., semaphorins, ephrins, netrins, slits) that act to attract or repulse the growth cone to prevent misdirected growth of axon sprouts (Marx, 1995). To pass through endoneurial tubules plugged with cellular debris, the growth cone secretes plasminogen activators that dissolve cell-cell and cell-matrix adhesions. Axonal sprouts grow from the proximal to the distal stump at a rate of approximately 1 to 2 mm/day (or approximately 1 inch/month). This rate of regrowth varies depending on the location of the lesion; with proximal lesions, growth may be as fast as 2 to 3 mm/day, while that with distal lesions is about 1 mm/day.

Fig. 50D.5 Schematic diagram of axonal regeneration. Axon sprout grows out from proximal stump and proceeds toward degenerated distal axon stump via the bands of Büngner (formed by proliferating Schwann cells and bounded by intact basal lamina). Macrophages migrate through basal lamina into injury site to phagocytose myelin ovoids and axonal debris, clearing the way for the axon sprout to progress distally. The motile tip of the axon sprout is called the growth cone, which bears receptor-rich lamellipodia (sheet-like) and filopodia (finger-like). These structures are guided through the bands of Büngner to their target by multiple signals in the microenvironment.

Peripheral axons and non-neuronal cells contain growth-inducing and trophic molecules that provide the fertile milieu required for nerve regeneration. These include the neurotrophins (nerve growth factor, brain-derived neurotrophic factor, neurotrophins 3 and 4), glial cell line–derived neurotrophic factors (neurturin, artemin, persephin), insulin-like neurotrophic factor, interleukin-6, leukemia inhibitory factor, ciliary neurotrophic factor, fibroblast growth factors, and several transcription factor activators (Dieu et al., 2005; Tucker and Mearow, 2008).

The condition of the endoneurial tube at the injury site determines the efficiency of nerve regeneration. If the tube is intact, regrowth of the proximal axon has a greater chance of success. With severe or complete disruption of the endoneurial tube, the proximal axon may stray into the surrounding connective tissue, which increases the chance of disorganized nerve sprouts or neuroma formation. Misplaced axons produce ectopic hyperexcitability that results from the accumulation of sodium channels and generates neuropathic pain. Once the advancing axon has crossed the injury gap and entered the distal endoneurial tube, the nerve has a reasonably good chance of successfully reaching its target end-organ. If it takes the axon longer than 4 months to reach the gap, however, the distal endoneurial diameter shrinks to perhaps 3 µm or less, further impeding complete recovery. Nevertheless, some degree of reinnervation can occur for up to 2 years after injury.

Successful axon regeneration also relies on the presence of a viable end-organ. Denervated muscle fibers quickly undergo atrophy, and collagen deposition occurs within the endomysium and perimysium, but the overall muscle architecture is maintained, along with end-plate integrity, for at least 1 year after nerve injury. Irreversible muscle fibrosis and degeneration, however, often has occurred by 2 years. Sensory cross-reinnervation is common, and pacinian and meissnerian corpuscles (mediating rapidly adapting light touch) and Merkel cells (mediating slow-adapting touch and pressure) are able to survive in a denervated state for a period of years. Thus, even late reinnervation on the order of 2 to 3 years may restore useful protective sensory function to a limb.

Compression

Compressive nerve injuries most commonly affect large-caliber myelinated nerve fibers in nerves that cross over bony surfaces or between rigid structures, such as the ulnar nerve in the ulnar groove at the elbow and the radial nerve at the spiral groove. Compression neuropathies may occur in patients who have been sedated or unconscious in a single position for an extended period. Because the primary underlying pathophysiology is that of demyelinating conduction block, an excellent recovery generally can be expected in the following days to weeks. A similar problem can be recognized in the postoperative setting. In classic postoperative brachial plexopathy, the patient awakens from general anesthesia with complete upper limb paralysis due to compression and stretch of brachial plexus elements between the clavicle and first rib while the arm is extended and hyperabducted intraoperatively. Electrophysiological examination may reveal a combination of upper trunk demyelinating conduction block and a lesser component of axon loss. The deficit characteristically reduces to a pure upper trunk distribution within the first few days, and within 2 to 3 months has fully resolved.

Mechanical compression may lead to secondary ischemic injury, as in the case of acute compartment syndromes that compromise nerve microcirculation while sparing distal-extremity pulses. When the intracompartmental pressure exceeds intraarterial pressure, nerve (and muscle) ischemia results in axon-loss lesions of variable severity. An example is the medial brachial fascial compartment syndrome after axillary arteriography or axillary regional block. Severe or irreversible single or multiple axon-loss mononeuropathies can occur within 4 hours if untreated by immediate exploration of the puncture site and decompression (Tsao and Wilbourn, 2003).

Stretch and Traction

Peripheral nerves are vulnerable to serious injury from excessive stretch or traction. As the stretching force increases, the elastic properties of the nerve are overcome, and myelin sheaths, axons, and connective tissue may rupture. In addition, it has been shown in an in vivo rat sciatic model that an 8% elongation of a nerve increases intraneural pressure to the point that blood flow is reduced by half.

An important example of a closed traction or stretch injury is neonatal Erb-Duchenne palsy due to excessive traction forces applied to the infant’s C5-C6 roots and fibers of the upper trunk of the brachial plexus during a difficult delivery. Significant axonal injury characteristically occurs, which may leave the child with permanent paralysis of upper arm flexors and forearm supinators, causing the arm to be held in the “waiter’s tip” position.

Sufficient stretch produced by distraction of the neck from the shoulder results in avulsion injury of the intraspinal rootlets from the spinal cord. Avulsion injuries most often are due to motor vehicle and motorcycle accidents. The typical scenario is that of a motorcycle rider being thrown off the motorcycle; the head and shoulder strike the pavement, laterally flexing the neck away from the shoulder, stretching the brachial plexus, and pulling the rootlets out of the spinal cord. Another example is a heavy object falling from a height onto a person’s shoulder. Avulsion particularly affects the intra- and extraforaminal portions of the cervical root fibers and the proximal brachial plexus fibers. Lesions of the lumbosacral plexus and roots are uncommon. The prognosis with avulsion of motor and preganglionic sensory fibers is poor. Avulsion is associated with particularly severe and lasting neuropathic pain.

Laceration

In laceration, the nerve is partly or completely severed by a sharp object. Common laceration injuries are knife wounds and injuries from broken glass, metal shards, chainsaw blades, wood splinters, and animal bites. In general, the sharper the injurious object, the neater the injury and the shorter the distance between proximal and distal nerve stumps, with a greater likelihood of a satisfactory functional recovery. An iatrogenic example is the inadvertent transection of branches of the spinal accessory nerve during surgical removal or biopsy of a mass in the posterior triangle of the neck.

Crush

A crush injury may arise from a sudden significant force applied to the nerve from a blunt object such as a surgical clamp, lead pipe, baseball bat, or motor vehicle component. Mild degrees of crush may cause a predominantly demyelinating conduction-block injury, but axon loss usually is prominent in most cases. Experimental work on animal nerves using smooth-tipped forceps has shown that axon and myelin debris is displaced longitudinally by the crush force, whereas the Schwann cell and its membranes remain intact. After removal of the crush force, axon and myelin tissues flow back into the crush site. Nerve regeneration may be quite satisfactory if the distance between the proximal and distal healthy margins is not too great and continuity of the axon structure is maintained. Neuroma formation is common at injury sites with longer wounds.

Gunshot

It is important to distinguish between low-velocity and high-velocity gunshot injuries. Low-velocity weapons more often are used in the civilian setting, and their missiles typically cause laceration, compression, and stretch injuries to localized segments of nerve and tissue. High-velocity weapons are used in both military and civilian settings. Missiles fired from such weapons are surrounded by a high-pressure gas zone, and the associated explosive force causes extensive damage to both local and distant nerves, together with other tissues such as muscle, bone, organs, and blood vessels. As a consequence, all grades of nerve injury may occur concurrently within and around the wound site. Although neurotmesis lesions may be clearly apparent on first inspection of the wound, the very real likelihood of additional areas of neurapraxia and axonotmesis must be considered. Therefore, it is vital in these patients to perform serial clinical evaluations and electrophysiological studies after the injury, prior to making the decision to attempt graft repair.

Radiation

One of the most frequently encountered radiation-induced nerve injuries is that to the infraclavicular brachial plexus (initially involving the lateral cord) after radiotherapy of the axillary chain of lymph nodes for breast cancer. Supraclavicular brachial plexus involvement is seen less often but may follow mantle radiation (or delivery of a downward cone beam) for lymphoma of the cervical, peritracheal, or supraclavicular regions. A delay in onset between 6 months and 35 years after therapy is typical, and the neuropathy most commonly starts with paresthesia in the index or middle finger, followed by weakness in muscles mainly derived from the lateral cord. Progression over time is the rule; a flail deformity eventually may develop in the involved limb. This form of plexopathy is initially characterized by the development of persistent demyelinating conduction block, which actually portends a poor prognosis and makes this plexopathy considerably different from the neurapraxias associated with acute compression injuries.