• Understanding peripheral nerve injury and regeneration along with knowledge of factors influencing prognosis is essential for orthopaedic surgeons.
• These injuries may be seen as a result of trauma, degenerative conditions and occasionally surgery. Consequently, in-depth knowledge of the principles of investigation, treatment and potential outcome is vital in both general and specialist practice.

• Traumatic injuries to peripheral nerves are defined by the individual structures that are damaged, including the neuron, Schwann cell or the myelin sheath.

Mechanical injury

• Acute compression injuries that do not involve disruption of any of the neural elements.
• It is believed that both mechanical compression of the neural elements and ischaemia are responsible for the resulting loss of nerve function.
• Causes a focal demyelination that results in a focal conduction block. Large myelinated fibres appear more susceptible to ischaemia than smaller fibres.
• When injury is severe enough or prolonged, axonal damage will occur and recovery will be delayed.

Stretch injury

• Stretch-related injuries are the most common. Nerves have some structural elasticity due to the collagen content in the endoneurium but when forces exceed the nerve’s ability to stretch, injury occurs.
• Commonly, continuity is maintained but in severe trauma, the nerve may either be avulsed from its root or be completely disrupted.
• These may be associated with fractures or tractional injuries (for instance in a birth injury, obstetric brachial plexus palsy).

Crush injury

• Focal compressioninjury to the nerve caused by haematomas and/or compartment syndrome following a fracture.
• Neuromal ischaemia leads to subsequent segmental demylination, periaxonal and intramyelin oedema.

Laceration

• Caused by blunt or penetrating injury.
• Nerves are not cleanly sectioned but are damaged in an irregular pattern over a large distance.
• Nerve ends must be cut back to undamaged fascicles for successful repair.

Transection

• Associated with trauma, sharp edge.
• Direct surgical repair of nerve ends with minimal resection of nerve ends.

High velocity trauma

• Damage secondary to rapid tissue expansion in the tract of a missile wound.
• Nerve injury is a result of a large amount of absorbed energy in the surrounding tissue. Example: gunshot.

Cold injury

• Several hours’ exposure to temperatures between –2.5°C and 10°C will slow or stop axoplasmic transport.
• Prolonged exposure may cause damage to peripheral nerves.

Healing injury

• Adherence of nerves to scar tissue, fracture callus may limit nerve gliding.
• The three commonest mechanisms of nerve injury are: (1) stretching injuries; (2) laceration; (3) compression.

Nerve injury classification systems

• Acute peripheral nerve injuries were initially described by Seddon and later refined by Sunderland.

Seddon divided nerve injuries into three categories:

• Neurapraxia is the mildest, does not involve loss of nerve continuity. It is the result of a temporary block to conduction and causes a transient functional loss. Excellent prospects for recovery. No Wallerian degeneration. Focal nerve block. Histopathology shows focal demyelination of the axon shealth without neuromal injury so that distal neural degeneration does not occur.
• Axonotmesis involves a complete interruption of the nerve axon and surrounding myelin but the surrounding mesenchymal structures including the perineurium and epineurium remain intact. Axon and myelin sheath degeneration (Wallerian degeneration) occurs distal to the point of injury, causing complete denervation. Good prospects for recovery as the connective tissue elements provide a framework for healing. Sprouting axons grow down the intact mesenchymal tube to re-innervate the target organ.
• Neurotmesis involves complete severance of a nerve. Functional loss is complete and recovery without surgical repair does not occur because of scar formation and the loss of the mesenchymal guide that directs axonal regrowth and healing.

Sunderland further subdivides axonotmetic injuries into three categories, depending on the severity of injury to the connective tissue:

• First degree – equivalent to neurapraxia.
• Second degree – equivalent to axonotmesis.
• Third degree – effectively axonotmesis combined with partial injury to the endoneurium (scarring). Most variable degree of ultimate recovery.
• Fourth degree – nerve in continuity but only the epineurium is intact. There is complete scarring across the nerve.
• Fifth degree – complete disruption of nerve. Same as neurotmesis.

• First degree injuries have an excellent chance of recovery, second and third degree injuries retain the possibility of functional recovery, depending on the extent of the endoneurial damage. Fourth and fifth degree injuries have no chance of functional recovery without surgical intervention and limited success with repair.

• The success of nerve regeneration or healing is dependent upon the severity of the injury sustained. Other factors that affect nerve healing:

• Age of patient – younger patients have a greater chance of functional recovery.
• Type of injury – a clean laceration is more likely to be repairable than a stretch injury or extensive area of nerve damage.
• Surrounding tissues – deep wounds with surrounding tissue damage, sepsis, scar tissue or contracture may adversely affect nerve regeneration.
• Type of nerve injured – pure motor or pure sensory nerves have better healing potential. Mixed nerves may suffer axon transposition during regeneration, resulting in improper end-organ re-innervation and therefore a poor functional recovery.
• Level of nerve injury – proximal injuries place a greater metabolic burden upon the nerve cell body and may result in cell death and thus poor recovery.
• Timing of repair – as time from injury to repair increases, irreversible changes occur both in the nerve cells and trunk, combined with fibrosis in the denervated muscles and joint contractures, leading to poor functional recovery potential.
• Associated injuries – number of arteries involved.
• Surgical technique.

• Meta-analysis review article of prognostic factors for outcomes following nerve injuries.¹

• Injury to a peripheral nerve results in structural and biochemical changes within each component of the nerve:

• Ventral cell body in the spinal cord
• Proximal nerve stump
• Distal stump
• Associated end organs

Ventral cell body

• Undergoes hypertrophy during the healing process to accommodate greater biosynthesis of metabolites necessary for nerve regeneration.
• The neuron shifts from nerve conduction mode to repair mode.
• The cell nucleus migrates to the periphery of the cell body and chromatolysis occurs.
• Chromatolysis corresponds to disappearance of basophilic material from the cytoplasm.
• The production of ribonucleic acid (RNA) and regeneratic enzymes increases with a corresponding decrease in neurotransmitters and neurofilament proteins.

Proximal nerve stump

• If the nerve has been completely severed, retraction occurs.
• Haemorrhage and clot formation with intraneural swelling are evident for around 10 days.
• The extent of proximal degeneration is dependent on the cause of injury. Sharp lacerations result in minimal degeneration while tractional or jagged lacerations result in a greater extent of degeneration.
• The myelin sheath becomes less well defined and macrophages invade to remove damaged tissue. Schwann cells proliferate along the axis of the axoplasm and digest remaining debris.
• Between 2 and 20 days from injury, axoplasmic regeneration may begin, associated with the increased biosynthetic activity in the cell body.
• Synthesis of new axoplasm occurs at between 1 and 3 mm per day while Schwann cell elements attempt to bridge the gap and connect with elements on the distal stump with the regenerating axon following these Schwann tubules.
• Without surgical repair, a meshwork of organised clot elements, mainly fibrin strands, provides an errant scaffolding framework for axonal migration, potentially leading to neuroma formation.

Distal nerve stump

• In the process known as Wallerian degeneration, the axon thickens and disintegrates due to increased degradative enzyme production and the surrounding myelin sheath undergoes degeneration with macrophages removing debris. This activity lasts up to 30 days from injury, leaving only Schwann cells and connective tissue with total atrophy expected by 18 months.

Associated end organs

• End organs undergo changes after nerve injury. Complete atrophy occurs within 2–6 weeks of denervation. Fibrosis occurs in motor fibres at 1–2 years and fragmentation and disintegration occur by 2 years.
• It is generally accepted that functional recovery is suboptimal if the nerve does not reach the motor end plate by 12 months.
• Sensory end organs are less sensitive to denervation than motor end organs.
• Functional recovery after nerve injury involves a complex series of steps, each of which may delay or impair the regenerative process.
• The sequence of regeneration can be divided into anatomical zones:

• Neuronal cell body
• Segment between the cell body and the injury site
• Injury site itself
• Distal segment between the injury site and the end organ
• End organ itself

Neuronal cell body

• The earliest signs of recovery are visible changes in the cell body that mark the reversal of chromatolysis.
• The nucleus returns to the cell centre and nucleoproteins reorganise into the compact Nissl granules.
• Post-injury, many subcellular metabolic functions were altered during chromatolysis.
• Chromatolysis heralded a fundamental shift in cell function from synaptic transmission to cellular repair.
• The metabolic machinery was reprogrammed so that the cell would be able to produce the vast amount of protein and lipid needed for axonal regrowth during the regeneration phase.

Segment between the cell body and the injury site

• Axonal regeneration occurs from the most distal node of Ranvier.
• As many as 50–100 nodal sprouts appear, mature into a growth cone, and elongate responding to directing signals from local tissue and denervated motor and sensory receptors (neurotrophic and neurotropic factors).

Injury site itself

• Scar tissue density increasing gap length and axonal misdirection all affect regeneration.

Distal segment between the injury site and the end organ

• Regeneration of axons in the distal stump occurs at a rate of 1–3 mm per day. Regeneration rate depends on the site, with more rapid regeneration seen in the body of the distal nerve stump. Nearer the zone of injury and at the motor endplate, growth is slower.
• Extension of Schwann cells and connective tissue elements provides a scaffold for the migration of axoplasm filaments into the tubules of the distal stump. As the axoplasm regrows, the Schwann cell envelope undergoes myelination with associated increased metabolic activity.

End organ itself

• Numerous axonal extensions elongate from the growth cone until they connect with a receptor. Axonal pruning then occurs with the remaining neurites. If a receptor or endoneurial tube is not reached, growth cone branches continue to grow in a disorganised manner producing a neuroma, which can manifest clinically as a painful lump.
• Axonal development and maturation are aborted if the end organ, due to prolonged denervation, has undergone degenerative changes that do not allow the establishment of functional connections.

• Examination of a peripheral nerve requires detailed anatomical knowledge of the course of the nerve and the muscles and sensory organs it innervates.
• Assessment includes testing of motor function in all muscles and grading according to MRC grading (in comparison to contralateral muscle).

0: No contraction

1: Flicker/trace contraction

2: Active movement with gravity eliminated

3: Active movement against gravity

4: Active movement against resistance

5: Normal/full power

• Sensory testing may be performed as a brief “screening” test of relevant areas of skin or more in depth, including assessment of light touch, pin-prick/pain, temperature and vibration sensibility.

• Tinnel’s test: light tapping over a nerve to elicit tingling or pins and needles in the specific distribution of the nerve. This is characteristic of a nerve trunk compression or injury causing demyelination. Negative Tinnel’s suggests nerve is intact or neurapraxia. A Tinnel’s that progresses along the course of a nerve suggests nerve regeneration

• The primary goal of nerve repair is to allow re-innervation of the target organs by guiding regenerating sensory, motor and autonomic axons into the environment of the distal nerve with minimal loss of fibres at the suture line.

• This is controversial and may involve:

• Expectant treatment (with regular clinical examination ±nerve conduction studies).
• Early decompression (to remove haematoma/debris compressing a nerve in continuity).
• Early end-to-end repair (with a clean laceration). Dissection should be carried out proximally from normal nerve to identify the area of damage. Handle nerve tissue with care and debride any necrotic tissue. Mobilisation of the nerve may aid tension-free repair. Ends are then approximated and repaired with 9-0 or 10-0 interrupted sutures in the epineurium. The use of microsurgical instruments and image magnification may aid in avoiding malrotation of the repair. This may also be aided by identification of the longitudinal intramural blood vessel.
• Grafting (due to extensive injury and nerve gapping) – typically with autograft from a sacrificial sensory nerve (superficial radial nerve or aural nerves are commonly used). A fine network of capillaries exists at the endoneurial level and this is easily disrupted when there is tension at the nerve repair. In the face of tension at the repair site, nerve grafts or conduits have better outcomes than direct repair.
• Delayed repair (often in polytrauma or severe tissue injury at the site of nerve damage).
• Delayed muscle/tendon transfer to return some function to the limb.
• Delayed joint fusion.
• Amputation (in the case of severe unremitting pain and functionless/dangerous limb).

Nerve repair

• Epineural repair is performed when a tension-free coaptation in a well-vascularised bed can be achieved. Gross fascicular matching between the proximal and distal nerve ends results from lining up both the internal nerve fascicles.
• Other repairs include grouped fascicular repair requiring intranerve dissection and direct matching and suturing of fascicular groups.
• This is more practical distally in a major peripheral limb nerve.
• However, the theoretical advantages of better fascicle alignment with this technique are offset by more trauma and scarring to the healing nerve internally due to the presence of permanent sutures.
• Despite its anatomical attractiveness, overall group fascicular repair is no better than epineural repair in functional outcomes.

Nerve grafts

• When there is a gap between the nerve ends with excessive tension for direct epineural repair, reversed interposition autologous nerve grafts are required.
• Donor nerve grafts are harvested from expendable sensory nerves including the sural and medial antebrachial and are reversed in orientation to maximise the number of axons successfully regenerating through the graft by funneling them distally.
• British Orthopaedic Association, BOAST 5 guidelines include that thorough neurological examination must be documented with all injuries. Fractures associated with nerve injuries should be stabilised and the nerve explored, urgent repair must be undertaken in the advent of iatrogenic nerve injury during surgery and that painful paraesthesia or paralysis must be explored urgently. In the acute setting, neurophysiology testing is rarely necessary and that all brachial plexus injuries must be discussed with the local expert within 3 days (https://www.boa.ac.uk/wp-content/uploads/2014/12/BOAST-5.pdf).

• Despite significant advances in surgical techniques for nerve repair in recent years, functional recovery after a severe lesion is often unsatisfactory. Current research is looking into modification of other factors that may alter healing, including reduction of local and systemic inflammation (dexamethasone has been shown to improve nerve healing in rats), hormonal manipulation (growth hormone and thyroid hormone have both been shown to enhance nerve healing in rats), manipulating signaling proteins to stimulate nerve growth (for example the protein retinoblastoma can be switched off) and drugs that target inhibitors to remyelination.