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.

Cold Injury

Peripheral nerves are especially prone to damage from excessively cold temperatures (“frostbite” and “trench foot”). In frostbite, tissue freezing occurs through formation of ice crystals in both superficial and deep tissues. The severity of the injury depends on the duration of exposure, the environmental temperature, and the wind chill factor and ranges from mild partial skin freezing to complete tissue mummification (Imray, 2009). Motor weakness develops with prolonged exposure to temperatures around 10°C; sensory fibers withstand temperatures as low as 7°C; and loss of both functions occurs between 0°C and 5°C. Duration of freezing is directly related to severity of injury. With transient or mild exposure, the underlying pathophysiology is primarily that of demyelinating conduction block, but continued exposure to low ambient temperatures causes increasingly severe degrees of axon injury. The endoneurium becomes particularly edematous, which raises intraneural pressure to the point at which blood flow is compromised, thereby further compounding the injury. If the cold-induced injury is not complete, function is restored in the order it was lost—for example, recovery of first sensory and then motor modalities.

Electrical

A severe neurological injury may follow contact with a high-voltage electric current in the home or workplace, or from a lightning strike. Damage is produced mainly by heating, which may cause the tissues to explode. With high-voltage (>1000 V) injuries, frank necrosis of all tissues including nerve may develop, with subsequent loss of the limb or part thereof. Low-voltage (<1000 V) events are associated with a better prognosis, and the injury may or may not include cutaneous burns. Most peripheral nerve injuries occur in association with third- and/or fourth-degree electrical burns and include mononeuropathies, polyneuropathies, and plexopathies, which may be either early or delayed in onset and frequently bilateral. The median and ulnar nerves most frequently are affected. Symptoms and signs may be similar to those of focal compression neuropathies, occurring at sites of minimal limb cross-sectional area where nerves cross bony protuberances. Joule’s law predicts that heat production will be maximal at such sites, and it has been proposed that perineurial fibrosis may occur at these sites, giving rise to neuropathies that may be relieved by surgical decompression (Smith et al., 2002).

Injection

One of the most severe forms of peripheral nerve injury is that due to injection of drug (prescribed or illicit). Unfortunately, these injuries are relatively common and either are a direct effect of needle insertion into the nerve or (more often) are due to the drug itself or its associated buffer and solvent. The presence of drug in and around a nerve may stimulate an intense inflammatory reaction that may lead to extensive epineurial scarring and distortion of the architecture of the nerve trunk. In general, an intact blood-nerve barrier (i.e., an intact perineurial-endoneurial border) will prevent diffusion of drug or toxin into the nerve fibers themselves. Direct injection of drug into nerve, however, may cause severe endoneurial fibrosis with neural ischemia and axon loss (Strasberg et al., 1999). The radial and sciatic nerves are the most frequently affected, but injection injuries also have been described in the median, femoral, and ulnar nerves. The first symptom often is immediate onset of pain, paresthesia, and paralysis, but in some affected persons, the onset apparently is delayed. Patients who fail to show signs of recovery within 3 to 5 months or who have persistent pain may benefit from surgical intervention.

Clinical and Electrodiagnostic Examination

The clinical assessment of traumatic nerve injury should ascertain an account of the injury itself (including the exact circumstance) with details regarding the localization, severity, and particularly the precise time it occurred (Box 50D.1 and Table 50D.2). The electrodiagnostic examination confirms the site of injury and its underlying pathophysiology and severity and may uncover additional information such as subclinical abnormalities or evidence of early recovery. All these elements determine if and when surgical repair is required and provide a timeline for any interventions. For example, if a period of 4 years has elapsed from the time of injury, it is very unlikely that any significant motor recovery will take place despite surgical intervention. The reduction in ability to regenerate following neurorrhaphy or grafting results from several mechanisms. First, the proximal stumps (motor neuron axons) lose the ability to grow. Second, the distal stump loses the ability to support and guide axonal growth. Finally, atrophy in muscle and tendon contractures often limit the impact of the few axons that can reinnervate functioning neuromuscular junctions. Regarding mechanism, intraoperative transection of a nerve by a scalpel is likely to portend a better prognosis than is possible with a laceration by a chain saw. Early (at <3 months) return of motor and sensory function is a good prognostic sign and supports grade I lesions. Elderly patients and those with metabolic disorders such as diabetes and renal failure are less likely to enjoy good functional outcome after nerve injury.

Table 50D.2 Neurological Examination in Patients with Peripheral Nerve Injury

Determining the distance from the injured nerve segment to its muscle helps establish prognosis. For example, if the target muscle is 3 inches from the injury site on the nerve, a good outcome over the next 3 months is reasonably likely. The reverse is true with nerve injuries that occur at a great distance from the target muscle; an axon-loss lower-trunk brachial plexus injury may be 30 inches or more from target intrinsic hand muscles, so any spontaneous recovery would have to occur by means of collateral sprouting. The presence of the Tinel sign, a tingling induced by mechanical distortion of the distal terminus of a regenerating axon (elicited by tapping the nerve with a finger or tendon hammer) supports ongoing axon regeneration; conversely, absence of the Tinel sign distal to a nerve lesion after 4 to 6 weeks have elapsed is strong evidence against axon regeneration.

The electrodiagnostic examination consists of nerve conduction studies (NCSs) and needle electromyography (EMG). The two main components of the NCSs are assessment of sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs). When the study is performed to assess for complex lesions of the brachial plexus or lower-extremity nerve lesions, it is essential that the electrodiagnostician examine particularly relevant NCSs and an expanded EMG in addition to those done in routine studies (Ferrante and Wilbourn, 2002).

Timing of the electrodiagnostic examination is important and has both practical and prognostic implications. If it is performed too early (<5 days) after the injury, sufficient time may not have elapsed for electrodiagnostic signs of motor axon loss to develop, and the physician cannot judge whether a nerve lesion is caused primarily by demyelinating conduction block or by axon loss. In the case of a severe axon-loss injury, CMAPs and SNAPs will be entirely normal for the first 2 days despite the presence of an obvious clinical deficit and the patient’s inability to voluntarily recruit motor unit potentials (MUPs) during EMG examination (an electrodiagnostic observation known as axon discontinuity conduction block). By day 3, however, wallerian degeneration should cause some loss of the distal CMAP amplitude, and by day 7, the CMAP may have reached its nadir, being further diminished or even absent. By day 5, the SNAP amplitude also is decreasing; it reaches its nadir at day 10 or 11 (the reason for the earlier loss of CMAP amplitude relates to the failure of neuromuscular junction transmission). Finally, after at least 3 weeks, clear evidence of active denervation in the form of fibrillation potentials should be observed during EMG. An important EMG feature is the early appearance of MUPs of low amplitude, increased duration, and increased polyphasia, the so-called reinnervational or nascent MUPs that fire at slow to moderate rates. These represent electrodiagnostic evidence of early axon collateral sprouting and may be found as early as 10 days from the time of injury but usually are more evident after 1 to 3 months.

If the lesion is due to focal demyelinating conduction block (grade I injury), and nerve stimulation is applied both distal and proximal to the lesion site, the examiner should detect a lower proximal compared to distal CMAP amplitude. The difference in proximal and distal CMAP amplitude and the reduction in distal motor unit potential voluntary recruitment on EMG are proportional to the amount of motor fibers blocked. Even with primarily demyelinating lesions, a limited amount of axon loss (i.e., fibrillation potentials) may occur if some axons at the site of the conduction block have incurred injury (Wilbourn, 2002).

Imaging Studies

In trauma cases, plain films of skull base, spine, and long bones may disclose fractures at sites that may compromise local nerve structures. Myelography, sometimes with computed tomography (CT), and magnetic resonance imaging (MRI) with gadolinium of the spine is used to diagnose nerve root avulsions (Fig. 50D.6); contrast material may be seen passing through the torn meningeal sheaths of avulsed nerve roots (pseudomeningoceles). Radiology confirmation of nerve root avulsion may be confounded by localized hematoma formation within or around the neural foramina, which may prevent extravasation of contrast material, thereby obscuring the typical appearance of pseudomeningoceles.

Fig. 50D.6 Cervical spinal root avulsion seen on computed tomographic myelogram. A-B, Avulsion of dorsal rootlets of the cervical spinal cord (arrows). C, Pseudomeningoceles (arrows).

(Image courtesy Nicholas Boulis, MD, Cleveland Clinic, 2006.)

MR neurography of peripheral nerve uses diffusion-weighted, T2-weighted, and short T1/tau inversion recovery (STIR) images based on the longitudinally oriented water diffusion properties of nerve as opposed to surrounding tissues (Grant et al., 2002). Signal hyperintensity can be seen on T2-weighted and STIR images of traumatized nerve segments; abnormal high signal intensity is seen both at and distal to the injury site (Fig. 50D.7).This MRI modality can detect neuroma formation at nerve repair sites, and it may even be possible to identify which fascicles within a nerve trunk are injured and which are spared. These signal changes may be transient in cases of mild nerve injury or may be prolonged (up to many years) in severe preganglionic brachial plexus avulsion injuries. Early (within 1 week) signal hyperintensity also may be seen in denervated muscle on T2-weighted and STIR images, which will persist if nerve discontinuity prevents reinnervation.

Fig. 50D.7 Magnetic resonance neurography images from a 23-year-old woman 1 month after she was diagnosed with a compressive left sciatic neuropathy due to prolonged compression (alcohol-induced coma). A, Large field-of-view axial T-weighted image with fat suppression demonstrates marked T2 signal hyperintensity in left sciatic nerve (solid arrow). Large field of view allows comparison with normal right side, which can be useful in cases of subtle T2 signal hyperintensity to differentiate from normal nerve signal. B, Small field-of-view axial T2-weighted image with fat suppression demonstrates same changes in left sciatic nerve as in A (solid arrow) but with improved spatial resolution, allowing for detection of small mass lesions and subtle signal changes. C, Small field-of-view axial T1-weighted image obtained after injection of intravenous contrast demonstrates minimal nerve enhancement (solid arrow) and enhancement of hamstring musculature (open arrow). Note that although most regions of T2 signal hyperintensity also enhance, signal changes may be subtler than on T2-weighted images. Contrast-enhanced images are most useful for detecting small mass lesions and characterizing solid versus cystic lesions.

(MR images courtesy Joshua Polster, MD, Diagnostic Radiology, Cleveland Clinic.)

Higher-tesla MRI scanners (3.0 T) offer enhanced resolution that may provide images with imaging quality equal to or greater than that of MR neurography. Another emerging technique, diffusion tensor imaging (DTI) and tractography of peripheral nerves (also performed on 3.0 T MRI), is based on the principle that water molecules have anisotropic diffusion properties (or a preferred orientation) in white-matter fiber tracts, compared with isotropic diffusion (equal in all directions) in surrounding tissues (Hiltunen et al., 2005; Sheikh, 2010) (Fig. 50D.8).

Fig. 50D.8 Magnetic resonance (MR) tractography. Peripheral nerves of right wrist, knee, and calf imaged with diffusion tensor imaging and compared to their corresponding MRI anatomy. A, Median, ulnar, and radial nerve of wrist. B, Posterior view of tibial and peroneal nerve at the knee. C, Tibial and peroneal nerve at mid-calf level.

(From Hiltunen, J., Suortti, T., Arvela, S., et al., 2005. Diffusion tensor imaging and tractography of distal peripheral nerves at 3 T. Clin Neurophysiol 116, 2315-2323.)

High-frequency ultrasonography of peripheral nerve and muscle is a relatively inexpensive and accessible diagnostic method to provide further information in the assessment of nerve injury (Umans, 2010; Visser, 2010). Although the resolution of ultrasound imaging is below that of MRI, this test can be performed in the office setting, has the advantage of real-time imaging, and is of particular use in patients who cannot tolerate MRI. Ultrasonography enables more dynamic observation of in vivo nerve segments (e.g., retroepicondylar subluxation of the ulnar nerve) and focal structural changes that accompany nerve injury (e.g., swelling, nerve continuity, neuroma formation).

Other Diagnostic Modalities

Somatosensory evoked potentials (SSEPs) are cortical potentials elicited by the stimulation of a sensorimotor nerve trunk or cutaneous nerve. SSEPs obtained by stimulation above the level of nerve injury may give information about the integrity of posterior sensory tracts in the spinal cord and the presence or absence of posterior nerve root avulsion. The presence of an intact SSEP, however, does not reliably indicate that the nerve roots are intact, because SSEPs are so sensitive they may yield positive waveforms in the presence of only a few hundred intact nerve root axons (Spinner and Kline, 2000). Furthermore, they do not provide enough localizing information to be of great assistance in postganglionic peripheral nerve injuries and do not provide information about injury to anterior (motor) rootlets in the spinal canal.

Indications for and Timing of Surgical Repair

A treatment algorithm for traumatic nerve injuries has been proposed by Spinner and Kline (2000) and is presented in Fig. 50D.9. Surgical intervention is not indicated in patients with neurapraxic (or grade I) nerve lesions, because spontaneous recovery with an excellent outcome is likely. However, for axon-loss lesions (grades II to V), this algorithm divides peripheral nerve injury into two major categories: open and closed. The open category is further divided into early repair (within 72 hours for primary repair) and limited initial exploration to tack the proximal and distal nerve stumps to an adjacent structure such as fascia to allow easier identification at definitive repair carried out within 3 to 4 weeks (delayed primary repair). The closed category, which comprises a majority of nerve injuries seen in the outpatient setting, is subdivided into delayed repair (3 to 6 months) and nonsurgical management. The decision to use surgical repair is made on a patient-to-patient basis and depends on the mechanism and degree of injury, the timing of injury, and the presence or absence of spontaneous clinical or electrodiagnostic improvement.

Fig. 50D.9 Diagnostic treatment algorithm for peripheral nerve trauma (see Surgical Repair of Nerve Trauma in text).

(Adapted from Dubuisson, A., Kline, D.G., 1992. Indications for peripheral nerve and brachial plexus surgery. Neurol Clin 10, 935-951.)

Immediate repair (within 72 hours) is indicated with injuries involving a clean transection of a nerve from a scalpel blade or other sharp object; this creates a small, relatively debris-free, well-perfused gap. Primary end-to-end repair is performed in this setting. When the injury results in blunt contusion or ragged epineurial tears (e.g., from a propeller blade), the surgeon performs initial surgical débridement of the wound and tacks the proximal and distal nerve stumps to local healthy fascial and muscular tissue. When the wound is explored 2 to 3 weeks later, the stumps have retracted, and easily detectable neuromas can be resected before end-to-end or nerve graft repair.

A rapidly worsening neurological deficit in a closed wound may require early intervention; considerations should include vascular lesions such as pseudoaneurysms, expanding hematomas, or arteriovenous fistulas that may damage the nerve in the wound site. A compartment syndrome may cause a rapidly worsening neurological deficit requiring emergency fasciotomy.

Delayed repair is indicated when closed injury creates an extensive gap between healthy nerve stumps in the context of associated damage to surrounding affected tissues and blood vessels. A majority of axonotmetic nerve injuries are lesions in continuity. These do not require repair and usually should be observed for a period of 3 to 6 months before the true extent of injury, and thus the potential for natural recovery, can be determined. During this period, repeat clinical (every 1 to 3 months) and electrodiagnostic (every 3 to 5 months) assessments are necessary. The interval for repeat testing is dependent on the time of initial examination and the distance of the nerve-injury site to affected muscles. For instance, paralysis of a muscle in the proximity of the injured nerve site requires assessments at 1-month intervals to document clinical or electrodiagnostic recovery. For muscles that are more than 4 to 5 inches from the site of nerve injury (e.g., proximal infraclavicular lesion), follow-up intervals may have to span up to 3 to 5 months to allow sufficient time for axon regeneration. For example, if a patient with a severe but incomplete axon-loss radial nerve injury from a fractured humerus is assessed 2 months after the injury, and little or no improvement can be detected on clinical and electrodiagnostic testing, it is too early to appreciate the full potential for nerve regeneration. A repeat clinical and electrodiagnostic evaluation, preferably just less than 6 months from the time of injury (or 4 months after the initial evaluation) would be indicated. If reinnervation is minimal or absent at 5 months, neurolysis with intraoperative nerve monitoring is indicated.

If possible, repair should be performed before 6 months. For the reasons listed earlier (proximal and distal stump deterioration and muscle atrophy), repairs performed before 6 months have a better prognosis. Grade V injuries have a very low likelihood of meaningful spontaneous recovery. In these cases, neurolysis as a prelude to potential nerve repair is often indicated within 2 to 3 months of the injury. The increasing application of nerve transfers is likely to extend this time window. Nerve transfers involve transecting fascicles in a functioning healthy nerve and grafting them into the distal stump of the compromised nerve. Nerve transfers can often be performed at a position that is much closer to the neuromuscular junction, hence reducing the impact of deterioration in the distal stump. Also, the use of healthy donor fascicles eliminates the impact of deterioration in the proximal stump axons. Despite these advantages, transfers are not always possible and carry some risk to the donor nerves.

Intraoperative Nerve Monitoring

Intraoperative nerve action potential (NAP) recording enables the surgeon to locate abnormal sites of mixed sensory and motor nerve conduction caused by axon loss and to define the healthy margins of nerve. After external neurolysis, stimulating and recording electrodes are placed directly onto the nerve surface proximal and distal to an obvious or suspected site of nerve trauma that has remained in continuity. The NAP is proportional to the number of functioning axons. Thus, a 5-µV NAP elicited in the distal nerve segment indicates continuity of at least 3000 to 5000 moderate-diameter myelinated axons at the recording site, the presence of which correlates with good spontaneous recovery (Spinner and Kline, 2000). Such incomplete lesions usually are treated with external or internal neurolysis. Conversely, the absence of a NAP at 6 weeks or more after the injury generally portends poor spontaneous recovery and constitutes an indication for surgical repair.

Intraoperative NAPs can be used to determine whether nerve root avulsion is present. With a plexus lesion in which nerve roots are injured at a preganglionic level but intact postganglionically, a NAP can be recorded because the large myelinated sensory fibers have been spared wallerian degeneration. In contrast, an absent NAP suggests injury to the postganglionic segment. When preganglionic injury is suspected, stimulation of the proximal portion of the spinal nerve to obtain a somatosensory evoked response can be performed. With preganglionic injury, these evoked responses are absent (Kline and Hudson, 1995). Finally, when NAPs and SEPs initially are absent or reduced, reassessment after several months may show regenerating responses. NAP and SEP amplitudes typically recover earlier than those of CMAPs, because the latter type requires maturation of the motor end plate (Harper, 2005).

Direct recording of motor evoked potentials by transcranial magnetic or electrical stimulation of the motor cortex and recording from distal muscles or motor nerves is another method of assessing anterior root or proximal nerve integrity (Burkholder et al., 2003; Sutter et al., 2007; Turkof et al., 1997). This technique has several limitations, including sensitivity to inhaled anesthetics or boluses of intravenous anesthesia, large stimulation artifact, submaximal stimulation, and contraindication with cochlear implants and open skull fractures. With further refinement, however, motor evoked potentials may play a greater role as a routine intraoperative recording technique.

Surgical Techniques

Peripheral nerve surgery has continued to advance since the introduction and refinement of microsurgical techniques in the last half century. The basic techniques currently employed in most specialty centers are reviewed next.

Primary Neurorrhaphy

Primary repair (primary neurorrhaphy) of a grade V lesion involves the direct suturing of the proximal to the distal stump and is the procedure of choice (Fig. 50D.10). Emphasis is placed on the reduction of tension on the site of neurorrhaphy, because this is thought to undermine regeneration through scar formation. The role of early exploration, particularly with nerve laceration, is to tack the nerve (thus preventing nerve retraction) and then to facilitate future approximation of nerve ends. In addition, with early exploration, individual fascicles have not yet atrophied and thus are easier to reanastomose. Delayed exploration, by contrast, allows for better demarcation of the injured nerve endings because the damaged segment of nerve will undergo fibrosis, making identification of healthy nerve easier.

Fig. 50D.10 Basic techniques in surgical repair. Schematic diagram illustrating basic concepts of epineural, fascicular, and graft repair. Direct end-to-end neurorrhaphy of small distal nerves is usually carried out using an epineurial repair approach (upper panel), which entails placing sutures through epifascicular epineurium and bringing nerve stumps into approximation. Fascicular repair (upper panel) is preferred for more proximal nerves that have a more complex interlaced fascicular pattern. Stumps are approximated using sutures that have been placed through the perineurium. Graft repairs (lower panel) are performed when direct end-to-end neurorrhaphy would cause excessive tension on repair site. Graft material is harvested from a “nonessential” sensory nerve (e.g., sural nerve), which is then sutured between fascicles.

In cases of short gaps, two primary techniques are used to relax the tension on nerves: mobilization and transposition. Mobilization is external neurolysis, freeing the nerve from its natural connection to surrounding tissue and scar tissue. In the brachial plexus or at branch points (the distal sciatic), internal neurolysis may be used to free the fascicle, giving rise to the proximal stump from the body of the nerve. Reducing nerve anchor points results in a mobilized nerve segment with more elasticity and less tension for a given length of stretch. Transposition refers to moving the nerve into a shorter pathway, thereby reducing tension and gaps. The best example of transposition is the movement of the ulnar nerve from the cubital tunnel to a position anterior to the medial epicondyle.

If the parent nerve trunk contains relatively few fascicles that are easy to align, an epineurial repair often is the preferred option. Consequently, this kind of repair usually is carried out on the distal segments of smaller nerves in the distal upper and lower extremities (e.g., digital nerves). Sutures are placed through the epineurium of the proximal and distal stumps, which are then tightened into approximation without causing undue tension on the newly repaired nerve. Local landmarks such as the orientation of blood vessels are used to ensure correct alignment of the nerve endings.

In fascicular repair, the preferred technique in proximal extremity nerve injuries, the surgeon coapts the proximal and distal ends of individual fascicles rather than the entire nerve trunk. Sutures are placed through the fascicular perineurium using loop magnification or microsurgical techniques. Bringing fascicles directly together in this manner will provide the most direct route for regenerating axonal growth cones. Pairing proximal and distal fascicles remains a significant challenge, however, and is a potential barrier to successful functional restoration. If proximal stump sensory fascicles are paired with distal motor fascicles and vice versa, functional reinnervation will not occur. Most proximal fascicles are mixed, thus preventing this problem. Nevertheless, every effort should be made to maintain fascicular matching. Although it is critical that motor axons arrive at end plates to achieve functional recovery, an individual axon need not find its original synapse or even its original muscle group. Plasticity in the CNS motor system is capable of reorganization that allows for meaningful control even if the original peripheral wiring configuration becomes disorganized during regeneration.

There has been a general trend away from placing many microsutures at the time of repair. Some evidence supports the idea that sutures induce scarring and retard regeneration. Fibrin glue or other sealants have been used to augment the stability of these sutures minimizing anastomosis. Indeed some surgeons advocate the use of glue alone without suture. We have not eliminated sutures entirely, usually preferring to use at least two sutures with glue augmentation.

Overall, good functional outcome is achieved in approximately 70% of primary neurorrhaphies but may range as high as 80% to 90% (Kim et al., 2001a, 2001b; Murovic, 2009). The end-to-side repair technique can be employed to repair facial motor nerve injuries and may also be helpful in the repair of brachial plexus injuries that lack a proximal stump. In this technique, the donor nerve is partially transected and grafted to the recipient nerve; it has been shown that sensory nerve sprouts will form spontaneously from the donor nerve, but it requires a deliberate surgical injury to motor axons to generate motor axon sprouts (Siemionow and Brzezicki, 2009).

Nerve Grafting

If a significant gap exists between the proximal and the distal stumps, it may not be possible to perform primary neurorrhaphy. Such gaps can occur in severe neurotmesis lesions such as high-velocity gunshot wounds or in axonotmetic stretch injuries in which long regions of the nerve may be damaged. Excessive stretch leads to scar formation, especially with passive stretch across bony protuberances and joints. In such situations, nerve grafting is the preferred choice. This repair strategy entails suturing a piece of nerve harvested from elsewhere between the proximal and distal stumps of the injured nerve. In most centers, an autologous nerve graft is used—a healthy segment of nerve is removed from the patient’s body and sutured between the stumps at the trauma site (Siemionow and Brzezicki, 2009). Although vascularized (pedicled) grafts have been described, conventional grafts are obligatorily devascularized. Accordingly, a longer graft means a longer distance traveled in entirely devascularized tissue. Thus, the surgeon continually balances the need to minimize tension on the anastomosis with the desire to minimize graft length and mobilization. In general, grafts are sutured using a fascicular rather than an epineurial approach. Common donor nerves are those that are “nonessential” and largely sensory in function, such as the sural nerve, the lateral antebrachial cutaneous nerve, and the lateral femoral cutaneous nerve. It is important to counsel the patient that once such a nerve is sacrificed, an area of permanent sensory loss in the sensory distribution of the donor nerve may result. The harvest of an autologous graft often leaves a long scar and carries the risk of painful end-neuroma formation.

In the case of large gaps in proximal nerves, it is often difficult to find sufficient autologous graft material to perform long polyfascicular repairs, and it is equally frustrating to sacrifice a sensory nerve to repair short gaps in small distal nerves. These concerns have motivated a search for alternatives to conventional grafts. Creative approaches have used muscle tissue, with an interposed segment of the distal stump to serve as a source for Schwann cells, or allografts accompanied by immunosuppression (Mackinnon, 1996). Cadaveric grafts have also been introduced and do not require immunosuppression but add expense. The main alternative to autologous grafts is manufactured nerve substitutes. A variety of these have been made available in the last decade; they can broadly be divided into collagen-based graft material and synthetic aliphatic polyesters.

To prepare the stumps for grafting, they are sectioned perpendicular to the long axis of the nerve. Smaller soft nerves may be wrapped with polyethylene film or paper to lend substance to the nerve. Under the microscope, the epineurium is dissected away with microscissors, leaving the fascicles free. The remaining gap is measured, and the harvested graft is cut to fit in order to minimize graft length. We prefer to perform anastomosis with two 8-0 nylon sutures positioned 180 degrees from each other. This maintains the alignment of the graft with individual fascicles and prevents rotation. Use of more sutures may lead to increased scarring at the anastomosis. At the completion of polyfascicular grafting, we apply fibrin glue to stabilize and protect the anastomosis (Fig. 50D.11).

Fig. 50D.11 Peroneal nerve graft. A, Proximal stump neuroma on cut peroneal nerve with 3-cm gap on rubber background. Sciatic, sural, and tibial nerves and proximal part of cut peroneal nerve are encircled in a yellow vessel loop. B, Polyfascicular graft with fibrin glue at anastomosis. Note that gap increases with removal of neuroma.

(Image courtesy Nicholas Boulis, MD, Cleveland Clinic, 2006.)

The success rate of nerve grafting depends on the experience and skill of the nerve trauma team, the particular nerve involved, the distance between the proximal and distal stumps, and the type of nerve graft or conduit used. The single most important prognostic factor is the time interval between the nerve injury and reinnervation of the target motor or sensory organ. A primate study showed that the optimal time to successful reinnervation of the target organ using nerve grafts is within 100 days of sustaining the nerve lesion (Krarup et al., 2002).

Overall, a satisfactory functional outcome is achieved in about 50% of nerve graft cases. This is an approximate figure, however, and many factors are involved. For example, at one major nerve trauma center, good functional recovery of motor function was observed in 68% to 75% of median and 80% of radial nerve injuries that were repaired by nerve grafting (Kim et al., 2001a, 2001b). Retrospective review of functional outcomes after repair of sciatic nerve injuries at the same center reported good outcomes after repair of tibial but not peroneal (less than 36%), division injuries (Kline et al., 1998).

Pharmacological Options

Table 50D.3 summarizes various medications used in the treatment of neuropathic pain. A pharmacological strategy is to establish effective longer-acting antiepileptic or antidepressant monotherapy, while breakthrough pain is judiciously treated with shorter-acting medications. Refractory pain may require the addition of another antiepileptic or antidepressant medication, preferably with a different mechanism of action (e.g., mixing a sodium channel blocker, γ-aminobutyric acid (GABA) inhibitor, and serotonin-norepinephrine reuptake inhibitor). More aggressive pain control, particularly in the acute setting, may require the use of narcotics (e.g., morphine, fentanyl patches).

Interventional Strategies

Refractory neuropathic pain (e.g., after avulsion of preganglionic posterior nerve roots) can be treated through a variety of interventions. These approaches can involve ablation of pain pathways (e.g., neurectomy, nerve lesioning) or neuromodulation (e.g., implantation of electrodes in the PNS and CNS).

Neurectomy is most commonly applied in the case of end-neuromas that cause persistent neuropathic pain. In this case, the nerve is sectioned with a sharp incision proximal to the neuroma. An attempt is made to push the nerve away from the region of dissection to limit scarring around the stump. Alternatively, the end can be implanted in muscle. Although these procedures are associated with a high rate of recurrent pain, they are worth attempting to avoid the need for implanted hardware systems. Varieties of CNS ablative procedures exist, but all are largely employed in cancer pain (cordotomy and cingulotomy). The dorsal root entry zone (DREZ) procedure, however, should be included in the armamentarium of pain procedures for the traumatized PNS. DREZ is most effective when applied to root avulsion. For this procedure, the DREZ is exposed above and below the level of avulsion. Various means have been devised to destroy the dorsal horn, but the most common technique uses high-radiofrequency ablation. The electrode is inserted at 1- to 2-mm intervals between the rootlets for individual lesioning.

Neuromodulation includes the implantation of pumps and electrodes with internalized power sources or antennae for the delivery of external power. The goals of neuromodulation are to achieve at least 50% pain relief, a reduction in analgesic drugs, and improvement in quality of life. Before the implantation of a neuromodulation device is considered, patients should be screened by a pain psychologist to identify those with a significant emotional overlay and secondary gain issues that would contraindicate this management approach. Pump catheters most commonly are implanted into the intrathecal space. Although narcotic analgesics frequently are employed, a variety of drugs that are more selective for neuropathic pain, including bupivacaine, clonidine, and ziconotide can be used. Catheters have been implanted along individual peripheral nerves, with the advantage of maintaining MRI compatibility. The longevity and effectiveness of this technique, however, have not been proved. We prefer the use of implanted electrodes to that of pumps, because they tend to provide more durable relief and are subject to fewer complications.

With peripheral neuromodulation, electrodes most commonly are implanted directly on the peripheral nerve or in the epidural space (Fig. 50D.12). Epidural electrodes referred to as spinal cord stimulators or dorsal column stimulators are positioned over the lower thoracic cord to treat lower-extremity neuropathic pain and over the cervical cord for upper-extremity pain. Alternatively, in cases of partial denervation, they can be implanted subdermally in the region of subjective pain. Once a device is implanted, a controller is given to the patient that allows adjustment of the amplitude of the stimulation. More complex programming is performed in the physician’s office, including adjustments to the frequency, pulse width, voltage window, and specific active leads in the system. In cases of severe refractory causalgia, deep brain stimulation electrodes can be implanted within important brain relay nuclei in the pain pathways. Motor cortex stimulation also has been employed with some success to manage refractory appendicular pain. Nonetheless, the efficacy of motor cortex stimulation currently is a subject of considerable debate. In our experience, direct implantation of stimulators on damaged peripheral nerves is the most effective means to modulate pain from these nerves.

Fig. 50D.12 Median nerve stimulator. Persistent neuropathic pain secondary to proximal median nerve injury from a medial brachial fascial compartment syndrome is treated with a peripheral nerve stimulator implanted deep to the nerve.

(Image courtesy Nicholas Boulis, MD, Cleveland Clinic, 2006.)