ANATOMY AND PHYSIOLOGY OF PERIPHERAL NERVE INJURY

The foundation for understanding nerve injury begins with a brief discussion of nerve anatomy and physiology. This topic and its relation to nerve injury have been reviewed extensively.^2,³ Through the classic work of Sunderland (1990), the details of the microstructure of nerve anatomy have been elucidated and have formed the foundation for the development of classification schemata of nerve injury.² The peripheral nerve is composed of several components, each of which plays an integral role in nerve function (Fig. 105-1). The cell body, or cyton, is the metabolic center of the nerve and produces the structural elements and nutrients that are important for maintaining nerve function. The axon is the main transporting segment of the nerve and conducts action potentials and transports proteins from the cell body to the nerve terminal. Most nerves contain a myelin sheath that surrounds the axon and provides a mechanism for rapid conduction of the action potential along the axon.

Figure 105-1 Anatomy of peripheral nerve.

Several supporting structures are important in maintaining the integrity and form of the nerve but do not play a role in action potential propagation. Surrounding each myelinated axon, each group of unmyelinated axons, and their investing Schwann cells and basal lamina is a framework of collagen fibrils formed by fibroblast. These longitudinally directed collagen fibers form a thin sheath immediately external to the Schwann cell basal lamina. This functional unit consisting of the axon or axons, their surrounding Schwann cells, and the basal lamina and collagen makes up the endoneurium, or endoneurial tube. The endoneurial tube makes up the simplest component of the connective tissue sheath of a peripheral nerve. Nerve axons and their endoneurium are grouped into fascicles within the nerve. Each fascicle within the nerve is surrounded by perineurium. The perineurium is composed of a lamellated arrangement of flattened sheaths cells formed from mesodermal, undifferentiated fibroblast-like cells with long cell processes. The perineurial sheath cells are surrounded by a basal lamina and separated and surrounded by layers of collagen fibers arranged in oblique, circular, and longitudinal arrays. The collagen fibers within the perineurium provide most of the elastic and tensile strength of peripheral nerve.

The epineurium is the outermost layer of the nerve and is composed of loose areolar tissue and fat, collagen, elastin, and lymphatic and blood vessels. The collagen bundles within the epineurium and the elastic fibers are oriented primarily longitudinally. This arrangement holds the nerve fascicles together while separating the fascicles from one another and also protects the nerve fascicles by dissipating the stress on the nerve from external pressure.

The number of fascicles of axons contained within the epineurium of a particular compound nerve varies in number from 1 to 100. In a compound nerve containing sensory, motor, and autonomic axons, a single fascicle usually contains many different types of axons. The arrangement of axons in a fascicle is actually very complex. Along the longitudinal course of the nerve. there is a continuous intermixing of axons from one fascicle to another. This interchange of axons between fascicles is most prominent in proximal portions of the nerves and is much less prominent in distal portions below the elbow and knee. The fascicular arrangement within nerves is important when the manifestations of nerve trauma are considered. Incomplete lesions of a peripheral nerve may involve individual fascicles to different degrees, and injury to a peripheral nerve at one site may therefore produce different symptoms, signs, and severity than does damage to the same nerve at different points along the course of a peripheral nerve.

The primary function of a nerve is to conduct information from one site to another in the nervous system. In the peripheral nervous system, the motor nerves conduct impulses from the brainstem or spinal cord to a muscle, whereas the sensory nerves conduct sensory stimulus from a peripheral receptor back to the spinal cord or brainstem. An inability to conduct these impulses produces weakness, sensory loss or disturbance, or autonomic dysfunction. The physiology of propagation of these impulses begins with an action potential generated at the cell body of the motor neuron or peripheral sensory receptor. The action potential then rapidly spreads from the point of origin over the entire axon membrane to the nerve terminal at the neuromuscular junction, in the case of a motor axon, or to the central nervous system, in the case of a sensory axon. Rapid propagation of the action potential along the nerve relies on the integrity of the axon, the transmembrane channels, and the myelin sheath. When nerve injury occurs, interference with action potential development and propagation may occur, leading to neurological symptoms.

CLASSIFICATION OF PERIPHERAL NERVE INJURY

Different classifications of stages of nerve injury have been developed.^2,⁴ One scheme, proposed by Sunderland (1990), separates nerve injury into five stages on the basis of the extent of anatomical disruption of the nerve (Table 105-1).² In this classification, the higher stages of nerve injury represent a greater degree of damage to the nerve and the surrounding structures, and therefore the potential for nerve regeneration and regrowth diminishes, leading to a poorer prognosis. The other classification scheme, developed by Seddon, consists of fewer stages that also reflect the degree of damage to the different components of the nerve and supporting structures. Seddon proposed three stages of nerve injury: neurapraxia, axonotmesis, and neurotmesis.⁴

TABLE 105-1 Classification Schemata of Nerve Injury

Neurapraxia in Seddon’s classification scheme corresponds to Sunderland’s first-degree injury. In neurapraxia, there is a block of conduction of the action potential across the region of nerve injury. The axon and supporting structures remain structurally intact, but conduction of the action potential across the abnormal area of the axon is blocked. Conduction of action potentials and the structural integrity of the proximal and distal portions of the axon are maintained. When the inciting cause is removed, recovery occurs within hours to months, and the prognosis for recovery is good. Focal demyelination is the predominant pathological alteration of this stage, although alteration of the cell membrane or channels, such as that produced by local anesthetic, may also produce this type of injury.

Axonotmesis in Seddon’s classification scheme is a more severe stage of injury. In this stage, the continuity of the axon is disrupted and the portion of the axon separated from the anterior horn cell or dorsal root ganglia undergoes wallerian degeneration. For the first week after an axonotmetic injury, the distal portion of the axon that is separated from the cell body still has the ability to propagate an action potential when stimulated electrically. After 1 week, wallerian degeneration of the axon occurs, and the disconnected segment of the axon can no longer conduct an action potential when stimulated. Axonal regeneration and regrowth along the endoneurial tubes is possible. Sunderland divided axonotmetic lesions into three separate degrees, on the basis of the amount of damage to the connective tissue. In Sunderland’s stage 2 injuries, the axon is disrupted but the endoneurial tube, and remainder of the connective tissue is intact. In stage 3, the axon and endoneurial tube are disrupted, but the perineurium and epineurium are intact. In stage 4 lesions, the axon, endoneurial tube, and perineurium are damaged, and only the epineurium is preserved. The duration and extent of axonal regrowth and regeneration depend on the degree of disruption of the nerve and the distance required for the nerve to regrow. The amount and speed of recovery are worse with higher grades of injury in Sunderland’s classification.

Neurotmesis, or Sunderland’s fifth-degree injury, is the most severe stage, in which the axon, myelin, and connective tissue sheath, including the epineurium, are disrupted and the two ends of the nerve are separated. In this stage, effective recovery is very unlikely or impossible, depending on the amount of separation of the two ends of the nerve. The axonal sprouts may grow between the separated ends and form a neuroma but are unlikely to find an endoneurial tube to grow down.

EVALUATION OF NERVE TRAUMA

The evaluation of the patient with nerve trauma relies on a careful and thorough neuromuscular history and examination and is supplemented by electrophysiological studies, imaging studies, and, on occasion, intraoperative exploration.

Clinical Evaluation

The type and cause of injury is an important historical point to determine, because stretch, blunt trauma, or crush injuries typically produce more diffuse nerve injury than do penetrating injuries. The timing from the trauma to the development of neurological deficits is important. In most cases, the onset of neurological deficits occurs at the time of trauma, and delayed deficits may indicate injury from other complications, such as hemorrhage or edema. The neurological examination is crucial for determining the degree and distribution of deficits. However, in many instances, such as with multiple fractures of the extremity or alteration of consciousness with concomitant closed-head injury, it may be difficult to perform a reliable neurological examination. When possible, the examination should include careful assessment of motor function, including distribution and severity of weakness and atrophy, and of sensory loss, as well as of injury to associated soft tissue and supportive structures.

Electrophysiological Evaluation

Electrophysiological evaluation is a useful adjunctive test, performed in conjunction with the neurological examination, to assess peripheral nerve trauma. Electrophysiological studies generally consist of a combination of nerve conduction studies (NCS) and needle electromyography and are helpful in

1. Identifying localization of nerve trauma (e.g., single nerve branch, single nerve, plexus, or root).

2. Ruling out subclinical injury to other adjacent nerves.

3. Determining the pathophysiology and stage of nerve injury.

4. Determining the severity of injury.

5. Determining prognosis for recovery.

6. Determining extent of ongoing recovery.

7. Assessing the need for intraoperative exploration.

Basic NCS are designed to evaluate the function of peripheral sensory and motor axons, striated muscles and the neuromuscular junction. NCSs are performed in two ways: (1) by stimulating a motor or mixed motor-sensory nerve and recording the action potentials of the muscle fibers innervated by the nerve or (2) by stimulating a mixed or pure sensory nerve at one site and recording the sensory nerve action potential at a distal or proximal site along the nerve. The combination of abnormalities in motor and sensory NCS allows identification of the site and pathophysiology of nerve injury.

Motor NCS are often more useful than sensory NCS in identifying the degree and stage of nerve injury. In a normal nerve, supramaximal electrical stimulation of a nerve depolarizes all of the motor axons within the nerve, which subsequently produce action potentials within all muscle fibers innervated by that nerve. This produces a summated compound muscle action potential (CMAP), or M wave, recorded from a muscle innervated by the nerve. When the nerve is stimulated at a proximal and distal site, the CMAP amplitudes and areas of the two sites are similar, inasmuch as all axons within the nerve are similar in size and conduct at a similar rate. In most motor nerves, there is never more than a 20% reduction in amplitude and area between the two sites of stimulation (Fig. 105-2).

Figure 105-2 Normal result of a motor nerve conduction study of the median nerve.

In nerve trauma characterized by neurapraxia or early axonotmesis, the evoked action potential initiated at a site proximal to the injury is unable to propagate through the lesion. Thus, the lesion produces a “conduction block” of the action potential. However, because the axonal segment and supporting structures distal to the injury remain intact, stimulation distal to the lesion produces a normal response. In the most severe cases in which all axons within a nerve are affected, such as with complete nerve transection or a neurapractic lesion involving all motor axons, no response is obtained with proximal stimulation (complete conduction block) (Fig. 105-3). Stimulation distal to the site of nerve injury produces a propagated action potential and a normal CMAP. In cases of incomplete nerve injury, only some axons are affected, and a partial conduction block may occur (Fig. 105-4). Stimulation proximal to the lesion produces action potentials in all the motor axons. Some percentage of these action potentials are propagated by motor axons that are damaged, and these action potentials do not spread through the lesion. There, action potential spread is blocked. Other motor axons in the nerve may be spared by the lesion, and these spread across the lesion to reach the muscle and produce a CMAP. The amplitude and area of the CMAP are a rough guide to the number of axons spared in an acute to subacute lesion. In more superficial nerves, or with near-nerve stimulation with a monopolar needle, the precise site of the nerve injury can be localized to within 2 cm by short-segment incremental stimulation (“inching”) studies.

Figure 105-3 Ulnar motor nerve conduction study with short segmental incremental stimulation technique demonstrates complete focal conduction block at the medial epicondyle.

Figure 105-4 Ulnar nerve conduction study (NCS) demonstrating partial conduction block in the forearm. ADM, abductor digiti minimi.

In neurapractic lesions, the conduction block persists until the underlying process is reversed. However, in lesions characterized by axonotmesis or neurotmesis, subsequent events produce further changes on NCS. Within the first 5 to 7 days after injury, the NCS simulates a focal conduction block that is indistinguishable from a neurapractic lesion, with normal conduction distal to the injury but block of conduction with stimulation proximal to the lesion. However, after 5 to 7 days, wallerian degeneration of the axons in the distal segment of the nerve occurs, leading to inexcitability of the distal nerve. This is manifest on NCS by a low or absent CMAP response with stimulation proximal and distal to the site of the lesion. Therefore, within the first week after injury, NCS is useful in localizing the lesion but not in determining severity or prognosis. However, after approximately 2 weeks, NCS can help the clinician distinguish neurapractic from axonotmetic lesions and better determine severity, pathophysiology, and prognosis, but in the case of axonotmetic lesions, it may be less helpful in precisely localizing the injury.

Sensory NCSs are less helpful in localizing nerve injury because of the wide variation of conduction velocities from different fiber sizes within sensory nerves. As a result, there is more dispersion of the response with distal to proximal stimulation. In nerve injuries, this normal dispersion in sensory nerve action potentials makes it difficult to identify conduction block in sensory axons. Sensory NCSs are useful in attempts to distinguish injury to the brachial plexus from root avulsion. In axonotmetic lesions localized distal to the dorsal root ganglion (e.g., brachial or lumbosacral plexus), sensory fibers undergo wallerian degeneration, which leads to low-amplitude or absence of sensory responses. However, in root lesions in which the dorsal root ganglia remain intact, the sensory NCS responses remain entirely normal despite profound sensory loss. Sensory NCSs are also very important in the study of injuries to pure sensory nerves.

Needle electromyography is used in conjunction with NCS to determine the pathophysiology, localization, and severity of nerve injury. Needle electromyography assesses spontaneous electrical activity arising from muscle fibers and the firing characteristics and structure of voluntary motor unit potentials. Fibrillation potentials are spontaneous action potentials from individual muscle fibers that are separated from the nerve terminal. Fibrillation potentials arise within 2 to 4 weeks after nerve injury and occur in muscles that are nearest the site of nerve injury before more distal muscles.

Each limb motor axon innervates hundreds of muscle fibers, and each limb muscle is innervated by several hundred motor axons. A basic concept of reinnervation that is often not understood requires some explanation. After motor axonal loss and denervation, reinnervation of skeletal muscle may occur in two basic ways. The loss of motor axons to a muscle may be incomplete or complete. If the axonal loss or denervation to a skeletal muscle is incomplete with some intact motor axons remaining, the surviving motor axons give off collateral sprouts from the nerve terminals near the muscle fibers that have lost their innervation. These collateral axonal sprouts from the surviving motor axons begin to reinnervate muscle fibers within a matter of days to weeks. Therefore, after incomplete lesions, reinnervation by collateral sprouting begins quickly. On the other hand, if all of the motor axons to a muscle are severed, reinnervation must occur by regrowth of axonal sprouts from the distal end of the proximal stump down the nerve to the end organ. This form of reinnervation takes much longer. Axonal sprouts grow at 1 mm per day, or 1 inch per month. In the case of complete axonal loss, the time to the beginning of reinnervation is determined primarily by the distance that the axonal sprouts have to travel to reach the end organ, and this takes months to years.

Electromyographic assessment of voluntary motor unit potentials is helpful in identifying whether reinnervation by regrowth or collateral spouting is occurring. In pure neurapractic lesions, the needle examination reveals a reduced number of voluntary motor unit potentials recruited when the patient attempts to produce a more forceful activation of the muscle under examination. There are no fibrillation potentials or change in the amplitude, duration, or structure of the motor unit potentials. In axonotmetic or neurotmetic lesions, the disintegration of the motor axons extends to the nerve terminal at the neuromuscular junction, and the muscle fiber is separated from its innervation. Immediately after the injury, the needle examination reveals reduced recruitment if the lesion is partial or no motor unit activity if the lesion is complete. In partial lesions, the structure of the motor unit potentials should be normal. Fibrillation potentials appear in the denervated muscles after 2 to 3 weeks. In partial or incomplete axonotmetic lesions, the nerve terminals of surviving motor axons begin to produce axonal sprouts 4 days after the injury. These effectively reinnervate some denervated muscle fibers after 3 weeks. At that time, the structure of the surviving motor unit potentials begins to change. There is an increased number of turns or phases on the motor unit potential. As more and more collateral sprouts from a motor neuron reinnervate muscle fibers, the motor unit potentials become more complex, larger in amplitude, and longer in duration.

In the case of reinnervation by regrowth of axons, the earliest motor unit consists of only one or a few muscle fibers, and as a result, the motor unit potential of those motor units is very small. These potentials have been called nascent motor unit potentials. As the reinnervating axons give off more branches that reinnervate more motor fibers, the number of muscle fibers innervated by each motor unit increases, and the amplitude and duration of the motor unit potential increase.

The needle examination is performed on different muscles innervated by different nerves, different components of the plexus, and different nerve roots and anterior horn cells. A systematic approach allows determination of the site of the lesion, the age and severity of the lesion, the type of pathology, and the prognosis for recovery.

In cases with electromyographic evidence of reinnervation, surgical intervention is often delayed or postponed, as described later.

Imaging of Peripheral Nerve Trauma

Historically, the sensitivity of imaging studies for identifying the anatomy of the peripheral nerve in detail was low, and imaging studies had low utility in the evaluation of peripheral nerve trauma. However, as the quality of imaging has improved, these studies are becoming increasingly useful adjunctive measures for assessing peripheral nerve trauma. Imaging studies can provide important information regarding the continuity of a nerve after trauma. Magnetic resonance imaging with short-time inversion recovery sequences can demonstrate denervated skeletal muscle, which is high in extracellular water content and thereby produces increased signal on short-time inversion recovery and T2-weighted images.⁵ The distribution of muscle involvement can be extrapolated to determine which nerve or nerves are affected by trauma. More recently, magnetic resonance neurography has evolved to allow for visualization of large peripheral nerves.^6,⁷ Indications for magnetic resonance neurography include the need to visualize roots and nerves for entrapments, adhesions, or the effects of trauma.⁸ In some cases, magnetic resonance neurography can identify discontinuity of the nerve and therefore is helpful in determining prognosis of recovery.⁸

Ultrasonography provides less detail of nerve anatomy than does magnetic resonance neurography, but it has been evaluated for its utility in monitoring patients who have undergone direct nerve repair after peripheral nerve injury.⁹ In a group of 11 patients, reliable identification of the nerve was made with ultrasonography, and neuroma formation, scarring with compression of underlying nerve, and partial discontinuity of nerve fascicles could be identified.⁹

In cases of injury to the brachial plexus in which root avulsion may have occurred, myelography and computed tomographic myelography are the imaging modalities of choice.¹⁰ The myelogram may demonstrate several findings to indicate root avulsion, including pseudomeningocele, poor root sleeve filling, and spinal cord edema or atrophy (Fig. 105-5). Although magnetic resonance imaging may also demonstrate findings suggestive of root avulsion, the findings on computed tomographic myelogram were correlated better with such injury at surgery than were the findings on magnetic resonance imaging.¹¹

Figure 105-5 Computed tomographic myelogram demonstrating pseudomeningocele after traumatic root avulsion.

CAUSES OF PERIPHERAL NERVE TRAUMA

There are many different causes of nerve trauma, each of which presents distinct issues related to nerve function, recovery, and treatment (Table 105-2). Much of the early information related to nerve trauma was derived from wartime injuries during the American Civil War and the World Wars. Currently, the most commonly encountered cause is blunt or stretch injury related to high-speed motor vehicle accidents, followed by falls, penetrating trauma, and industrial accidents.¹² Population studies have estimated that 5% of patients admitted to level I trauma centers have sustained peripheral nerve injuries.¹³ In many instances of injury related to major trauma, the precise mechanism of nerve injury may not be identified, or several mechanisms may have contributed. For example, in a severe motor vehicle accident, compression, crush, and stretch injury may occur, as may ischemia from arterial damage related to the injury.

TABLE 105-2 Causes and Types of Nerve Trauma

Type of Trauma	Examples
Acute transection	Glass or knife wound, surgically induced
Chronic compression	Carpal tunnel syndrome
Stretch injury (stretch, rupture, avulsion)	Traction from motor vehicle accidents
Injection	Intraneural injections
Ischemic	Compartment syndromes
Radiation	Post-irradiation plexopathy
Temperature (cold)	Frostbite, trench foot