Diagnosis and Repair of Peripheral Nerve Injuries

Sameer K. Puri, MD

Margaret E. Cooke, MD

Steve K. Lee, MD

Dr. Lee or an immediate family member has received royalties from Arthrex, Inc.; is a member of a speakers’ bureau or has made paid presentations on behalf of Axogen; serves as a paid consultant to or is an employee of Axogen, Checkpoint, Synthes, and Zimmer; serves as an unpaid consultant to HQRB; has received research or institutional support from Arthrex, Inc. and Axogen, Checkpoint, Integra, and Toyoba; has received nonincome support (such as equipment or services), commercially derived honoraria, or other non-research-related funding (such as paid travel) from Cartiva; and serves as a board member, owner, officer, or committee member of the American Society for Surgery of the Hand. Neither of the following authors nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter: Dr. Puri and Dr. Cooke.

INTRODUCTION

Peripheral nerve injuries present challenges to surgeons in diagnosis and characterization of the injury; prognostication of outcomes with surgical and nonsurgical intervention; and choosing optimal treatment options when intervention is chosen. Suboptimal treatment can leave devastating consequences due to pain and dysfunction. Over one million people worldwide present with a peripheral nerve injury every year. These injuries affect the quality of daily life; 24% to 41% of patients with a major peripheral nerve injury are unable to return to their previous line of work.¹ Despite this, there remains a lack of consensus on optimal treatment strategies for many clinical scenarios.

The authors will attempt to present an up-to-date approach to diagnosis and management of peripheral nerve injuries, with reliance on the best available evidence when available. The goals for treating surgeons should be to (1) accurately describe the injury, (2) make a best available assessment as to the likelihood of improvement without intervention, and (3) choose the optimal intervention at the earliest time point when clarity is available. Clarity is not always obtainable, and intervention in the form of exploration may at times be indicated. Options for treatment of peripheral nerve injuries include direct repair, single or cabled autografts, allografts, conduit-assisted repairs, nerve transfers, and tendon- and muscle-based salvage options.

CLASSIFICATION OF NERVE INJURIES

Seddon described three types of nerve injury based on the histologic structure of nerves—neurapraxia, axonotmesis, and neurotmesis. Neurapraxia describes a conduction block of an otherwise intact nerve.² Axonotmesis describes an injury involving axonal discontinuity. These injures will lead to a degenerative pathway, with variable potential for regeneration, but the macroscopic structure of the visible nerve sheath remains intact. The final category, neurotmesis, describes a complete transection of all neural elements.

SUNDERLAND CLASSIFICATION

Sunderland introduced a classification of peripheral nerve injury in 1989, expanding on Seddon’s classification from 1942, which has been widely accepted and is used to categorize nerve injuries (Table 1). The classification is based on the histologic structure of peripheral nerves, progressing in increasing severity based on the amount of damaged neural elements. When applied accurately, it can help surgeons to accurately prognosticate and make the clinical choice on whether or not to intervene.

TABLE 1 Sunderland Classification of Nerve Injuries With Description of Pathoanatomy and Expected Clinical Course Without Surgical Intervention

Sunderland Grade (and Seddon Classification)	Description and Damaged Elements	Anticipated Clinical Course
1 (Neurapraxia)	A temporary conduction block. Axonal continuity remains; there is damage to the myelin sheath preventing complete or effective conduction.	There may be some sensory, and less commonly motor, sparing. As the myelin sheath repairs, clinical recovery is anticipated.
2 (Axonotmesis)	Stretch or contusion has led to axonal discontinuity and damage to the myelin sheath. The perineurium containing fascicles and endoneurium surrounding axons remain intact.	Due to axonal continuity, a degenerative process distal to the lesion will occur. With the neural structure remaining largely intact, nerve regeneration and spontaneous healing is anticipated.
3 (Axonotmesis)	As above, but with additional damage and scarring of the endoneurium within the fascicles.	Variable chance of recovery based on the amount of endoneurial scarring, and difficult to prognosticate.
4 (Axonotmesis)	Additional damage to the perineurial structure of the individual fascicles. Epineurium remains intact, with the nerve visibly in continuity from a macroscopic perspective.	With all internal neural elements damaged, there is low likelihood of regeneration. Commonly referred to as “neuroma in continuity.”
5 (Neurotmesis)	Complete transection of all neural elements.	Low likelihood of spontaneous regeneration.

PHYSIOLOGIC EFFECTS OF NERVE INJURY

Understanding the physiologic effects of nerve injury helps to form the basis of clinical decision making (Table 2). Axonotmetic nerve injuries lead to predictable changes to the nerve stump proximal to the lesion, the cut nerve distal to the lesion, and in the target muscles and target sensory end organs that the nerve innervates. All of these factors play into clinical decision making, and the treatment choice requires a basic understanding of the physiology of nerve healing.

NERVE PROXIMAL TO THE INJURY

Proximal to axonal injury, both the nerve and the cell body undergo histologic and transcriptional changes to switch the nerve from transmission to growth mode.² Macrophages are recruited to the cell bodies and mediate changes in the nuclear transcriptional activity of the cell.³^,⁴^,⁵^,⁶ In the ganglia, a group of regeneration-associated genes (RAGs) are upregulated, increasing transcription of neurotrophic factors, their receptors, and structural components necessary for growth such as tubulin and actin.⁷^,⁸^,⁹^,¹⁰^,¹¹^,¹² These RAGs are upregulated initially after nerve injury and decline over time.¹³^,¹⁴ However, if an injured nerve is repaired or reaches a target, it is exposed to growth factors from the target which help to maintain the regenerative growth response.¹⁵^,¹⁶

NERVE DISTAL TO THE INJURY

Distal to axonal injury, the nerve undergoes a process known as Wallerian degeneration. Negative connotations of the word notwithstanding, Wallerian degeneration refers to a process by which the transected nerve actively becomes more receptive to regrowth. After transection, the distal stump continues to transmit signals for hours to days, likely due to lag time from the slow pace of anterograde axoplasmic transport.¹⁷^,¹⁸^,¹⁹ Quiescent Schwann cells dedifferentiate, upregulate expression of RAGs, recruit additional macrophages, and together phagocytose the preexisting myelin and axonal tissue.²⁰^,²¹^,²²^,²³^,²⁴ The dedifferentiated Schwann cells line up along the basal lamina of the distal transected nerve in bands of Bungner, which help to guide and target regrowing axons.²⁵^,²⁶^,²⁷^,²⁸ Schwann cells continue to play an important role in keeping the nerve alive as well, which will eventually cease in the absence of neurotrophic factors.

NERVE INJURY EFFECTS ON TARGET ORGANS

Target muscle and sensory organs undergo changes when they lose neural input. The neuromuscular junction—made up of terminal Schwann cells and motor axons in the nerve and the motor end plate with its acetylcholine receptors in the muscle fiber—will degenerate and disperse acetylcholine receptors as it loses the neurotrophic factors from the efferent axon.²⁹^,³⁰ Atrophy of the muscle and collagen infiltration begins within weeks of denervation, but the architecture can remain intact for up to a year. By two years, fibrosis and degeneration of the muscle is likely irreversible, leading to the generally accepted guideline that a muscle must be reinnervated by 12 to 18 months from injury to hope for functional recovery.³¹^,³² Sensory organs are more resistant and may remain reinnervatable for 2 to 3 years.³³

TABLE 2 Important Growth Factors, Pathways, and Proteins Associated With Nerve Injury and Regeneration

Growth Factors	Effect
Vascular endothelial growth factor (VEGF)	Secreted by macrophages in response to hypoxia at the injury/repair site, stimulates angiogenesis
CCL2	Released in response to nerve injury, recruits macrophages to injury site, an essential step in promoting regeneration-associated genes (RAGs)
CSF1	Secreted by fibroblasts, recruits macrophages to dedifferentiated Schwann cells
ERK signalling pathway	Pathway for dedifferentiation of Schwann cells, driving their transition to role in postinjury state
LIF/STAT3 pathway	Utilized by macrophages to upregulate RAGs in the cell body of an injured nerve
Sox11	Transcription factor upregulated after injury, promotes neurite branching, elongation, and myelination
EphB2	Receptor upregulated by Schwann cells in distal nerve, responds to Ephrin B secreted by fibroblasts, relocalizing N-cadherin to cell surface. This drives attraction between cells, and aids in formation of bands of Bungner in distal nerve during Wallerian degeneration
N-cadherin, NCAM	Adhesion molecules upregulated by Schwann cells that may aid in migratory behavior, both for formation of bands of Bungner and to drive directionality of regrowth of axons
Chondroitin sulfate glycoproteins	Along with other breakdown products and debris, can play inhibitory role in axon regrowth and migration
Choline acetyltransferase, acetylcholine esterase	Transmission-related genes that are downregulated as RAGs become upregulated
Tubulin, actin	Cytoskeleton proteins upregulated by RAGs essential for growth cone extension from the proximal stump
BDNF, GDNF	RAG-associated neurotrophic factors
GAP-43, CAP-23, SGC-10	Growth-associated proteins upregulated by RAGs, correlated with regeneration capacity of injured neurons
IL-1, IL-6	Schwann cells upregulate production of cytokines that recruit macrophages across blood nerve barrier
BDNF = Brain-derived neurotrophic factor, GDNF = Glial derived neurotrophic factor, NCAM = Neural cell adhesion molecule

NERVE HEALING

The space between the proximal and distal stump of nerve is initially characterized by a macrophage-rich inflammatory response.³⁴ Local hypoxia drives migration of regional dedifferentiated Schwann cells and, with them, their neurotrophic factors and factors of angiogenesis. At the distal aspect of the nerve proximal to the injury, growth cones are formed which respond to and are led by neurotrophic factors primarily derived from the Schwann cells in the bridge between proximal and distal nerve.³⁵ Schwann cells progressively organize into cords that can lead regenerating axons across the gap from the proximal to distal nerve stump.³⁶^,³⁷ This process, especially initially, is imperfect with staggering of the crossing axons and frequent misdirection.³⁶^,³⁸ Upon reaching the distal stump, axons are guided by the bands of Bungner along the path of the distal nerve toward the target organ. While initially random, over time, neurotrophic factors sort the fibers appropriately toward motor and sensory end organs.³⁹

MODALITIES OF DIAGNOSIS

The goals of diagnosis are to understand the location, level, and extent of the zone of a nerve injury and to understand the severity of nerve injury. When these features are known, the surgeon can make a hypothesis as to whether the patient will recover function with or without intervention. History and physical examination, along with knowledge of the patient’s clinical progression since the injury, provide a groundwork for understanding the injury. Electrodiagnostic studies can be invaluable in confirming a diagnosis, assessing severity, and tracking recovery. Increasingly, imaging modalities are utilized that may aid in clinical decision making.

HISTORY

The mechanism of injury and the time when the injury occurred are paramount to the history. Peripheral nerve injuries occur from trauma and can be open from sharp laceration,
crush, gunshot wounds, blast, or closed traction injuries. Injuries can also be iatrogenic from direct laceration, compression by plates or suture, and stretch. When the injury occurred is particularly important to motor nerve injuries because distal nerve, motor end plates, and target muscle degenerate and are not reinnervatable 12 to 18 months after injury.

Three essential pieces of information must be taken from history.

1. What was the mechanism of injury? Nerve deficit after sharp laceration implies high likelihood of complete neurotmesis with minimal surrounding zone of injury, and should lead to a low threshold for surgical intervention based on history alone. Open injury due to crush, gunshot, or blast mechanisms can have highly variable clinical progressions. These injuries can cause neurapraxia due to concussive trauma to the nerve, or transfer more significant amounts of energy to the nerve resulting in a degenerative pathway with a wide zone of injury. The energy imparted from the mechanism of injury is a clear prognostic factor, with worse outcomes seen in higher energy injuries.⁴⁰^,⁴¹
2. When did the injury occur? The timing of presentation relative to injury is key. As detailed above, there is a physiologic window with regard to potential for nerve regeneration. For motor recovery, the reinnervated nerve must reach its target before 12 to 18 months, likely closer to 12 months, especially in patients older than 40 years. However, outcomes are optimized with early intervention when possible depending on clinical circumstances.
3. What has the clinical course been since injury? A conduction block or neurapraxia should be expected to improve by 6 to 12 weeks from injury. Nerve regeneration after axonotmesis should be expected to progress along its anatomic course at approximately 1 mm/d after an initial latent period of 2 to 4 weeks. While there is likely variability in this rate between nerves, individual patients, and at different time points over the course of a single nerve’s recovery, this estimate can be useful in evaluating likelihood of recovery without further intervention.⁴²

PHYSICAL EXAMINATION

In cases of laceration, open wound, or surgical incision, the area of skin scar is palpated and percussed to attempt to elicit painful Tinel. Tenderness and positive severely painful Tinel at the site of previous open injury is a sign of neuroma and nerve injury. A Tinel sign that advances away from the site of injury or repair is a sign of nerve regeneration.

The patient’s active range of motion should be compared with their contralateral extremity, and their motor strength for all pertinent muscles should be assessed. The British Medical Research Council (BMRC) method of motor grading is usually used. The sensory examination performed differs depending on the body part examined. For hand examination and digits, static two-point discrimination, a measure of innervation density, is useful.⁴³ Normal values are <6 mm, and protective sensation is defined as <15 mm, but typically a lacerated nerve will lead to sensation being indeterminate <10 mm.⁴⁴ For other body parts, usually light touch is used and graded by the patient reporting if the sensibility is normal, altered (paresthesia, hyperesthesia, hypoesthesia), or none (anesthetic).

Detailed knowledge of innervation patterns from root to terminal branch can help the surgeon focus the examination. Based on preserved function, identified deficits, and location of Tinel sign, the nerve and level of injury can often be identified.

ELECTRODIAGNOSTIC STUDIES

Nerve conduction testing is performed by stimulating nerves and recording their response and tests only the large, myelinated fibers of a nerve. Sensory nerves are recorded directly, whereas motor nerves are recorded in the innervated target muscle of the tested nerve. Compound muscle action potentials (CMAPs) provide a summation of the motor response to stimulation and represent the number of conducting axons. Because it is measured as a muscle response, CMAPs have larger amplitude than sensory nerve action potentials (SNAPs), which are smaller and more prone to error. Both sensory and motor nerves can be tested for their latency (time from stimulus to response) and conduction velocity (distance/time). Normative values vary by laboratory, age of patient, and environmental factors including temperature of the room.

In the setting of nerve injury, a transected nerve, or nerve fibers distal to a site of axonotmesis, will continue to conduct for, sometimes, several days after injury, prior to the onset of Wallerian degeneration. CMAPs must be recorded in an anterograde fashion and will be absent distal to axonotmesis or decreased in amplitude if there is a decrease in efferent axon count. SNAPs can be recorded antero- or retrograde. SNAPs will also be absent across the site of axonotmesis, but in the setting of preganglionic avulsion, they will be preserved in an anesthetic limb because the nerve is still in continuity with its cell body, despite being disconnected from the brain.⁴⁵ Conduction velocity and latency slowing is likely due to inefficient conduction due to demyelination or ongoing compression. Severe conduction block can lead to dispersion of the individual axonal transmission, mimicking loss of axons by decreasing the amplitude of the signal.

Needle electromyography (EMG) measures the electrical signal directly in a muscle. There is both an involuntary and voluntary portion of the test. A needle is inserted into muscle and elicits insertional activity—usually a short burst followed by silence. In the setting of muscle denervation, there is increased insertional activity followed by spontaneous fibrillations and positive sharp waves. Voluntary recruitment on needle electromyography demonstrates presence or absence of functioning motor axons and relies on patient effort and compliance. EMG recruitment categories (in order of ascending activity) are graded as none, low discrete (1-2 motor units on maximum recruitment), high discrete (3+ motor units on maximum recruitment), decreased, and full.⁴⁶ (Figure 1). Motor unit configuration patterns
categories included none, nascents, increased polyphasics, and di-/triphasics. Nascent wave configurations can be thought of as immature waves with capacity to mature to di-/triphasic waves.⁴⁷

FIGURE 1 Electromyographic (EMG) recruitment grading is categorized as (A) full when there is there is complete voluntary activation and filling of the EMG screen, (B) decreased when there is less complete filling, but individual motor units are not discernible, (C) discrete when individual motor units can be distinguished, and (D) none when no motor units are activated despite full voluntary effort. (Reproduced with permission from Schreiber JJ, Feinberg JH, Byun DJ, Lee SK, Wolfe SW: Preoperative donor nerve electromyography as a predictor of nerve transfer outcomes. J Hand Surg Am 2014;39(1):42-49.)

ULTRASONOGRAPHY

Ultrasonography (USG) is gaining popularity as a cost-effective modality to evaluate peripheral nerve injuries. USG has the ability to evaluate for fascicular continuity, areas of compression or kinking, focal areas of nerve enlargement, and complete nerve discontinuity with end neuroma formation.⁴⁸ It is particularly useful for visualization of neuromas. High rates of clinical correlation between USG and intraoperative findings have been reported.⁴⁹

Ultrasonography-guided local anesthetic injections are a very useful diagnostic tool to confirm pain relief of a neuroma or scar-tethered nerve. Ultrasonography is limited if the nerve is very deep or underneath bone or under devices such as metal plates.

MRI

Magnetic resonance neurography (MRN) is useful to determine continuity of nerves and presence of neuroma and examine for neuritis. Features that can be seen include in evaluating nerve continuity, nerve caliber, signal intensity, perineural edema, and enhancement. An examination of the regional anatomy can aid in clinical decision making, for example, by showing the absence or presence of signs of denervation atrophy in target muscles.⁵⁰ T1, turbo spin echo T2-weighted, and diffusion tensor imaging have all been utilized and found to be useful, with higher level magnets (3T) likely yielding more useful information.⁵¹^,⁵² Diffusion tensor imaging (DTI) has been previously used for brain imaging and is showing promising results in visualizing neuronal microstructure.⁵³

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