Axonotmesis

Etiology

PNIs may be broadly categorized by the status of the adjacent integuments. Closed injuries involve the nerve trunk without injuring the integument, while open injuries involve damage to both the nerve trunk and the adjacent integument. Open injuries may result from clean, sharp wounds or ragged, contused wounds.

An example of a clean, sharp injury is the transection of a nerve using a scalpel. A ragged, contusion injury may result from a projectile directly impacting the nerve. Ragged injuries lead to an increased inflammatory response, disruption of nerve fibers, fiber displacement, and potential foreign-body contamination.[9]  

Closed injuries are the result of nerve strain or contusion and may result from joint dislocation and crush injuries. Missile injuries are considered a subset of closed PNI, with features of concussive, thermal, and transection forces.[9] In general, neurapraxia follows compression or entrapment; axonotmesis is commonly the result of crush and stretch injuries; and neurotmesis occurs after sharp, traction, avulsion, or toxic damage to a nerve.[5] Common traumatic injuries with affected nerves include the following:

• Seat belt: The upper trunk of the brachial plexus
• Stab wound to the posterior triangle of the neck: Spinal accessory nerve
• Shoulder dislocation: Axillary nerve
• Humerus fracture: Radial nerve
• Elbow dislocation: Median nerve
• Pelvic fracture/hip dislocation: Sciatic nerve
• Knee dislocation/fibular fracture: Peroneal nerve [9]

Nontraumatic focal nerve injuries are less common in the population. Compression can be interrupted by repositioning unaffected individuals. Spontaneous bleeding, vascular injury, and the mass effect or invasion of solid tumors can cause nerve injury. Examples of iatrogenic nonsurgical injuries include:

• Nerve compression from an adjacent hematoma
• Compression from improper positioning during a surgical procedure  
• Neural tension or fibrosis from irradiation
• Tension or compression from a tourniquet
• Direct needle injury
• Dressing- or device-related injury.

Iatrogenic surgical injuries may result from high tension, compression, and transection of the involved nerve. Procedures identified as carrying an increased risk of iatrogenic injury include varicose vein procedures, inguinal hernia repair, Baker cyst removal, carpal tunnel release, posterior cervical triangle biopsy, arthrodesis, osteotomy, and osteosynthesis. The spinal accessory nerve, injured during posterior triangle neck lymph node biopsy, and the median nerve, injured during carpal tunnel release, are among the nerves most likely to sustain iatrogenic injury.[10]

Epidemiology

The incidence of PNI following extremity trauma has been reported to be between 1.64% and 3.4%.[1] The most commonly injured upper extremity nerves are the radial nerve, followed by the ulnar nerve, and then the median nerve. The lower extremity nerves most likely to be injured are the sciatic, followed by the peroneal, and then the tibial and femoral nerves. Truncal nerves that can be injured are the ilioinguinal, genitofemoral, and spinal accessory nerves, in that order. PNI was most often associated with crush injuries.[9][10] 

Results from an analysis of a large database indicated an average annual incidence of upper extremity PNIs of 43.8 per 1 million individuals. The incidence decreased throughout the study, while the compound annual growth rate in cost was 9.6% between 2001 and 2013. Most patients were men, White, and admitted through the trauma and emergency department. The average age was 38.1 years, and the most common injury was a digital laceration. Most patients were discharged from the emergency department following their examination.[11]

Results from another database study indicated that lower-extremity PNIs had an annual average incidence of 13.3 cases per 1 million individuals. The mean age was 41.6 years, and most patients were men, with most admitted through the emergency department. The sciatic nerve was the most commonly injured nerve, and the most frequent injury was a lower extremity fracture. The compounded annual growth rate of the cost was 8.8% from 2001 to 2013.[12] Positioning nerve injuries are most likely to occur in individuals with extremes of body weight, in men, and in those with a history of nerve disease or comorbidities that would predispose them to a nerve injury.[13]

Pathophysiology

In states of axonotmesis and neurotmesis, stretching can lead to patchy ischemia and reduced blood flow within the vasa nervorum. As stretching progresses, intraneural connective tissue destruction, hemorrhage, and necrosis are likely to result. Disruption of trophic factors, degradation of cytoskeletal elements, increased intracellular calcium, and interruption of axonal transport will then progress sequentially.

In neurapraxia, compression or entrapment results in a temporary interruption of nerve conduction. Increased venous pressure and endoneurial edema result from prolonged compression, leading to Schwann cell fragmentation. Focal demyelination occurs, leading to the leakage of action potentials at the nodes of Ranvier, which most often causes slowing of conduction. However, if the internodal conduction time exceeds 5-600 μs, permanent conduction block may lead to muscle atrophy.[5] Axons are not involved during this process.[4]

In axonotmesis, the axons are disrupted.[5] Recovery in axonotmesis occurs either through collateral sprouting (20% to 30% of axons damaged) or regeneration (greater than 90% of axons damaged).[5][14] Within the first few hours, chromatolysis (breakdown of Nissl bodies) and swelling of the axotomized cell body and nucleus occur.[5]

Over the next few days, anterograde and retrograde Wallerian degeneration ensue. Wallerian degeneration is generally the fate of the distal end of the damaged nerve when over 90% of the axons are injured.[9] Proximal degradation is most often negligible, progressing only up to the nearest node of Ranvier.[9][15]

If the lesion is in close proximity to the cell body, neuronal death alone occurs. Within the distal axons, calcium influx activates calpains that cleave neurofilaments, causing axonal fragmentation.[7][16] The Schwann cell will shift to a phagocytic phenotype upon macrophage recruitment, clearing both axonal and myelin cellular debris (leaving only the basement membrane) within 3 to 6 weeks.[17]

Schwann cells then switch to a regenerative phenotype, releasing growth factors (ciliary and glial-derived neurotrophic factors).[13][15] The bands of Bungner are pivotal in guiding the emerging axonal sprouts into the distal stumps that cross the coaptation site and remain viable for up to 24 months after injury.[5][7][8][17] The sprouting, mediated by actin and guided by lamellipodia and filopodia, cytoplasmic extensions, occurs at a rate of 1 to 3 mm/day.[7][8][18] 

Regeneration of the myelin sheath takes 3 months.[19] Fibrosis and gap, however, impede this healing process, leading to the formation of a neuroma in continuity.[15] Neuroma in continuity results in persistent neuropathic pain.

Regarding the end organs, the remaining motor units in the muscles may initially show hypertrophy. A pruning process later sets in as axons diminish due to inadequate neurotrophic factors.[14] Preganglionic avulsion injuries with the discontinuity of the spinal roots to the central cord lack regenerative neurons, unlike postganglionic injuries that occur distal to the proximal stump.[9]

History and Physical

The diagnosis and treatment strategies for acute nerve injury are determined clinically. For that reason, obtaining a thorough history and physical examination is essential for providing quality patient care.[20] A complete trauma evaluation with a primary survey is indicated in most cases of traumatic PNI. Once the patient is stabilized and the critical aspects of patient care have been addressed, a secondary survey may proceed.

In both traumatic and atraumatic presentations, a complete neurologic examination is warranted. The clinician should test individual muscle strength, myotome performance, and dermatomes, and solicit the patient's subjective concerns regarding the examination. Clinicians should seek an associated trauma or disease state that can explain observed sensory, motor, and autonomic deficits noted on the examination.

In atraumatic presentations, attention should be directed to the patient's medications, oncologic risk, coagulopathy, mobility, and substance use. Electrophysiologic testing and advanced imaging can aid in diagnosis.[20] A baseline assessment is integral for meaningful surveillance because patient abilities may change over time.

In axonotmesis, large myelinated A-α nerve fibers mediating fast pain, temperature, light touch, and motor functions are most often affected. Smaller unmyelinated fibers, which modulate vasomotor and sudomotor autonomic function and slow pain C fiber conduction, are mostly spared. Wallerian degeneration leads to a positive Tinel sign. Following regeneration, resolution of autonomic dysfunction usually precedes motor and sensory recovery. Nonprogression of the Tinel sign, allodynia, and the presence of vasomotor and sudomotor signs most often suggest nerve transection.[19]

Evaluation

Evaluation begins with a comprehensive history and physical examination, including careful attention to autonomic function, myotomes, and dermatomes. If the PNI is open, the wound may be explored immediately to determine the extent of damage and provide surgical intervention if indicated. For cases with a possibility of spontaneous recovery (lower-grade axonotmesis and neurapraxia), patients should be monitored weekly to assess functional recovery. If spontaneous recovery does not occur within a few months, a surgical procedure is warranted.

Electrophysiologic Findings

Electrophysiological findings are time-dependent. The axons remain excitable up to 7 to 11 days after injury, so sensory nerve action potential and compound muscle action potential (CMAP) results will be normal during this period.[9] Conduction may also be normal until complete Wallerian degeneration sets in.[15] Thereafter, a conduction block with preserved distal electromyographic responses is suggestive of neuropraxia.[21] Nerve conduction block occurs at an amplitude reduction of 50% to 75%.[15][21] 

CMAP is the summation of the response of the motor endplate potentials. Electrode stimulation during motor conduction studies reflects the volume of intact axons. In Wallerian degeneration, CMAP values decrease significantly approximately 10 days after injury.

Within 2 to 3 weeks, fibrillations and positive sharp waves appear in the needle electromyography. In the first weeks to months, reinnervation via sprouting and collaterals shows polyphasic, unstable motor unit action potentials and satellite potentials (thin, unmyelinated sprouts with immature neuromuscular junctions). The slower-healing phase of axonal regrowth eventually sets in, resulting in larger-amplitude, longer-duration potentials.

Conversely, in neurotmesis, lesion patterns show no motor unit action potential recruitment. Intraoperative electrophysiological studies are also valuable adjuncts to surgical planning, such as in the repair of a neuroma in continuity.[5] Bridge grounding is recommended during intraoperative neuromonitoring to limit the loop effect from the lifting method.[22]

Imaging studies

Ultrasonography may show altered echogenicity, edema, a distorted fascicular (honeycomb) pattern, a neuroma, and muscular atrophy (compared to healthy counterparts).[23][24][25][26][27][28][29][30] Ultrasonography is cost-effective, fast, easily reproducible, and allows real-time assessment. However, ultrasonography is operator-dependent, limited to superficial nerves, and does not provide physiological data.

T2 magnetic resonance images reveal a loss of fascicular pattern and edema in axonotmesis. Conversely, neuroma, muscle atrophy, and fatty replacement are observed in neurotmesis. Although high-resolution magnetic resonance neurography has been used to assess nerve continuity, 50% of transections paradoxically may show no gaps. The average dispersion coefficient in diffusion tensor imaging and tractography also helps dichotomize injury and predict recovery.[31][32][33] Cost, claustrophobia, pertinent contraindications, and availability are limiting factors.[17]

Treatment / Management

In cases of neurapraxia, closed injuries, and lower-grade axonotmesis, a baseline assessment with serial examinations is warranted to observe for spontaneous regeneration. If functional restoration does not occur within 3 months, surgical intervention should be considered.[9] Clinical photography and detailed descriptions of the injury are of paramount importance in treatment.[19] Surgical intervention is based on the principle of providing treatment before irreversible damage occurs.[34] 

The time aspect plays a paramount role in the management of PNI. Open injuries with clean, sharp lacerations are treated within 3 hours of injury. Both nerve segments will continue to retract after the initial injury; thus, the nerve should be repaired before retraction precludes primary repair due to consequent ischemia-inducing tension. Direct repair may be between epineural substance, perineural substance, or group fascicle repair at a time when nerves are tension-free. Immunohistochemistry and intraoperative electrophysiology will aid in coaptation of sensory axons with sensory fibers and motor axons with motor fibers, which is important for improved recovery.

Open injuries with dirty, blunt lacerations are delayed to allow better demarcation of the injury and to avoid infection. Ragged, contusion injuries fail to demonstrate the extent of nerve damage until approximately 2 to 3 weeks following the injury. Given this presentation, primary repair is not indicated.

Instead, the nerve endings are anchored to the adjacent muscle or fascia to mitigate retraction. Once reassessed weeks following the initial injury, devitalized tissue is excised, followed by a tension-free repair. Should the gap between the proximal and distal nerve segments be significant, an intervening nerve graft is indicated.

Likewise, regardless of the gap size, if the nerve appears under tension during repair, an intervening nerve graft may be indicated.[15] Open injuries with nerve discontinuity (but epineurium intact) and all closed injuries are initially treated conservatively, and nerve function evaluation is performed at 3 weeks.[17] If clinical or electrical recovery is not evident even at 3 months, surgical intervention is required.[17](B2)

Surgical Management in Peripheral Nerve Injuries

• Neurolysis: When neurophysiologic monitoring demonstrates an intact nerve segment distal to the damaged site
• Nerve repair: Nerve repair consists of epineurial (most important in tension-free repair), perineurial repair (high risk of fibrosis, fascicular discontinuity), and group fascicular repair.[35][36] Either end-to-end or end-to-side neurorrhaphy can be performed. Minimal use of nonabsorbable monofilament sutures is recommended. Fibrin sealant can also be used to reduce the need for sutures and mitigate granuloma and neuroma formation. Tension and misalignment need to be avoided.
• Nerve reconstruction: Nerve reconstruction is performed via the use of nerve grafts or cables and conduits (silicon tube, spider silk). Autologous sensory nerve grafting is the gold-standard option. However, limited supply, donor-site morbidity, size mismatch, and the fact that only 40% to 50% show notable improvement due to fascicular mismatch are inherent limitations. Nonneural grafts, such as blood vessels and freeze-thawed skeletal muscle, can also be used.[7][15] Allograft use requires concurrent immunosuppression.[15][36]
• Nerve transfer and neurotization: For delayed cases, nerve transfer should be performed within a critical 6- to 9-month window.[15][17][19][37]
(B2)

Surgical dictum during nerve repair

• Viable nerve ends
• Proper fascicular alignment to prevent pruning-induced preferential motor reinnervation and denervation-induced atrophy
• Tension-free coaptation
• Microsurgical repair under magnification [7][20]
(A1)

Adjuvant Management Modalities

• Epigenetics and gene therapy: Examples include the delivery of ciliary neurotrophic factor using an adenoviral-associated vector.[16] However, ethical, biosafety, and mutagenesis concerns remain.[38]
• Cell-based therapy: Stem cell therapy, secretome–Schwann cell therapy, cell-seeded scaffolds, aided recently by 3-dimensional (3D) and 4D printed conduits, and nanomedicine.[17][36][39][40] Mesenchymal stem cells can differentiate into Schwann cells, secrete neurotrophic factors, exhibit self-renewal, migrate to sites of injury, prevent apoptosis, form the extracellular matrix, and enhance angiogenesis. Mesenchymal stem cells can be obtained from bone marrow, adipose tissue, dental pulp, amniotic fluid, and umbilical cord.[16]
• Platelet-rich plasma (PRP): PRP promotes tissue regeneration by releasing bioactive growth factors that stimulate angiogenesis and connective tissue remodeling. Emerging evidence indicates that PRP exerts neuroregenerative and analgesic effects. Its therapeutic potential has been demonstrated in the repair of various nerves.[41]
• Stimulation via electrical, ultrasonographic, magnetic, or laser photobiomodulation methods increases the number and diameter of regenerated axons.[7][16]
• Pharmacotherapy includes corticosteroids (minimize scarring), androgens, erythropoietin (promotes myelin), 4-aminopyridine (facilitates calcium influx and synaptic transmission), L-carnitine, tacrolimus, melatonin, citicoline, gabapentin, and polyethylene glycol.[17] 
• Restorative medicine: Niclosamide reprograms glial scarring and extracellular matrix stiffening. [42]
  • Phytochemicals [36]
• Nutritional therapy includes polyunsaturated fatty acids, vitamin B_6, vitamin B_12, and vitamin C.
• Physical therapy
(A1)

Some patients will experience disability and pain syndromes despite the best efforts of their care team. An interdisciplinary approach encompassing physical therapy, neurology, neurosurgery, plastic surgery, psychiatry, orthopedic surgery, and pain medicine is therefore essential to address the needs of these patients. Such needs may include prostheses, chronic pain therapy, and cosmetic solutions for muscle atrophy.

The full extent of services required for PNI is beyond the scope of this article. Significant gaps in knowledge and evidence remain.[17] Animal study models and lab-on-a-chip neural modeling might provide newer insights into the treatment of PNI.[43](B2)

Differential Diagnosis

PNIs are diagnosed through careful history-taking and a thorough neurologic examination, with the aid of electrophysiologic testing and imaging modalities such as ultrasonography and MRI. Other conditions in the differential diagnosis include those that interfere with sensory, autonomic, and motor responses. Without an identifiable event to explain focal PNI, the clinician must use additional tools to determine the etiology of the patient's deficits.

Muscular disease, central nervous system impairment, electrolyte abnormalities, vascular compromise, autoimmune disease, toxin exposure, and infectious causes should be considered in the differential diagnosis. Most notable considerations include neuropraxia and neurotmesis.[15] Please see StatPearls' companion reference, "Peripheral Nerve Injury," for further information.

Prognosis

The prognosis of axonotmesis depends on the patient's underlying condition and the nature of the nerve injury. In axonotmesis, though Wallerian degeneration occurs due to axonotomy, the intact perineural sheaths most often redirect growing axonal buds to the distal stumps, thereby ensuring good functional recovery. Paradoxically, in neurotmesis, the protective coats are also damaged, and scarring imprisons the axonal buds, leading to neuromas in continuity. Therefore, recovery without therapy is almost impossible.[16] The regeneration process slows down at the distal nerve end.[17] The recovery of conduction velocity is also limited to 60% to 90% of the preinjury level despite neural regeneration.

Injury characteristics primarily determine clinical outcomes. Secondary reconstruction after damage-control surgical interventions has not been demonstrated to negatively affect clinical outcomes.[44] Neural function also depends on effective communication between regenerated axons and the end organ.

Muscle architecture and motor endplates are considered viable for up to 1 year after injury. Merkel cells, Pacinian corpuscles, and Meissner corpuscles may persist for 2 to 3 years after denervation. Given that the damaged peripheral nerve grows at approximately 1 to 2 mm per day, clinicians should intervene within the first 3 to 6 months after PNI if there are no signs of spontaneous recovery. Communication with the end organ must be reestablished within a limited timeframe.[9][13][14] Therefore, early intervention for the damaged nerve is suggested before progressive scarring and atrophy of the end organ render the tissue nonviable.    

Prognostic factors for regaining nerve function include a patient's baseline health, the mechanism of injury, the degree of injury, the length of the nerve gap (in axonotmesis and neurotmesis), the type of injury, the nerves involved (the spinal accessory nerve is most robust), the location of injury along the nerve (distal injuries have a better prognosis), the presence of concomitant injuries, the timing to surgical intervention, the type of surgical procedure, and the patient's age.[5][9][10][13][14][15] Activated transcription factor 3, bridging integrator 2, Fc fragment of immunoglobulin G receptor IIb, and urocortin are critical biomarkers of nerve injury and play roles in neurotrophic signaling and neuronal recovery.[45]

Complications

Without an intact tubule to guide neuronal regeneration, aberrant nerve growth into a neuroma is possible. Any foreign body used for suturing, conduits, or grafts can elicit an immune response, leading to scarring, pain, and failure of nerve regeneration. Allografts are seldom used, but patients who receive them are at risk of immunosuppression-related complications.

Autografts may increase morbidity from injury to structures related to the extraction site. The maximal neural deficit will occur within days following the injury. Should improved nerve function relapse or progressively decline, other atraumatic etiologies should be investigated, such as pseudoaneurysm or hematoma formation.[9]