Continuing Education Activity
This activity reviews the etiology, epidemiology, anatomy, physiology, and prognosis of peripheral nerve injury with a particular focus on axonotmesis. Considering the diverse etiology of axonotmesis and prolonged course, patients will interface with healthcare providers of diverse training backgrounds. This article will familiarize the interprofessional team with ways to identify and manage axonotmesis.
- Identify the etiology of axonotmesis.
- Review the evaluation of axonotmesis.
- Outline the management options available for axonotmesis.
Peripheral nerve injuries (PNIs) are a relatively uncommon but potentially devastating health concern. As an illustration of patient dissatisfaction with such injuries, litigation following these common procedures, spine surgery, foot/ankle surgery, and arthroplasty is most often for PNI. PNI may result from traumatic or nontraumatic means and can often be iatrogenic in nature. Early identification of injury is of paramount importance as the best neurological outcomes are associated with early intervention.
Axonotmesis is a term that describes the range of PNIs that are more severe than a minor insult, such as those resulting in neurapraxia, yet less severe than the transection of the nerve, as observed in neurotmesis. Ultimately, these terms are used to describe gradations of nerve trunk involvement with a common underlying molecular process. However, the descriptive terms used to categorize the degree of damage to nerve structures permits the practitioner to consider different mechanisms, tailored therapeutic strategies, and appropriate expectations for functional outcomes.
In order to understand each grade of nerve injury, it is important to be familiar with the basic anatomy of the peripheral nerve. From most superficial to the deepest structures, the peripheral nerve contains epineurium, epifascicular epineurium intervening between fascicles, perineurium covering individual fascicles, endoneurium envelops axons that are wrapped by a myelin sheath and Schwann cells.
Sunderland and Dellon elaborated on Seddon's proposed gradations of PNI.
- Grade I is considered neurapraxia. Histological changes may encompass focal segmental demyelination.
- Grades II-IV are considered axonotmesis.
- Grade II - intact endometrium; damaged axons
- Grade III - intact perineurium; damaged axons and endoneurium
- Grade IV - intact epineurium; damaged axons, endoneurium, and perineurium
- Grades V is considered neurotmesis, which is a complete nerve transection.
- Grade VI - multifocal mixed injury of the nerve. This is likely the most common type of injury.
PNIs may be broadly categorized by the status of the adjacent integument. "Closed" injuries involve the nerve trunk with sparing of the integument, while "open" injuries involve damage to both the nerve trunk and the adjacent integument. Open injuries may result from clean, sharp injuries and/or ragged, contusion injuries. An example of a clean, sharp injury would be an incision using a scalpel with a resultant transection of the nerve. A ragged, contusion injury may result from a projectile with nerve involvement. The ragged injuries lead to an increased inflammatory response with nerve fiber disruption, fiber displacement, and potential foreign body contamination.
Closed injuries are the result of strain and/or contusion and may result from mechanisms such as joint dislocation and crush injuries. Missile injuries are considered a subset of closed PNI with aspects of concussive forces, thermal forces, and/or transection.
In general, neurapraxia follows compression or entrapment, axonotmesis is commonly the result of crush and stretch injuries, and neurotmesis is found after sharp, traction, avulsion, and toxic damage to a nerve.
Common traumatic injuries with their commonly affected nerve(s) include the following:
Seat belt - the upper trunk of brachial plexus, stab in 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.
Nontraumatic focal nerve injuries are less common in the population. Compression can be interrupted by repositioning in able-bodied and unimpaired individuals. Spontaneous bleeding, vascular injury, and the mass effect or invasion of solid tumors can cause nerve injury.
Examples of iatrogenic non-surgical injuries include nerve compression from an adjacent hematoma, compression from improper positioning of the surgical patient, neural tension or fibrosis from irradiation, tension, or compression from a tourniquet, direct needle injury, and dressing/device-related injury. Iatrogenic surgical injuries may result from high tension, compression, and/or transection of the involved nerve. Procedures that have been 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 accessory nerve from a lymph node biopsy of the posterior triangle of the neck and the median nerve from a carpal tunnel repair are two of the nerves that are most likely to be iatrogenically injured.
The incidence of PNI following extremity trauma has been reported between 1.64% and 3.4%. The most to least commonly involved upper extremity nerves include radial, ulnar, and median. The lower extremity nerves most likely to be involved include sciatic, peroneal, and tibial/femoral. Truncal nerves include the ilioinguinal, genitofemoral, and the spinal accessory nerve. PNI was most often associated with crush injuries.
One analysis from a large database indicated an average annual incidence of upper extremity PNIs to be 43.8 per 1 million individuals. This number decreased throughout the study, while the compound annual growth rate in cost was 9.6% between 2001-2013. Most patients were male, Caucasian, and admitted through the trauma/emergency department. The average age was 38.1 and the most common injury was digital laceration. Most patients were discharged following their encounter.
Another database study concluded that lower extremity PNIs occurred with an annual average incidence of 13.3 cases per 1 million individuals. The mean age was 41.6, most were male, and most were admitted through the emergency room. The sciatic nerve was most commonly injured, 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.
Positioning nerve injuries are most likely to occur in those with extremes of body weight, males, and with a history of nerve disease or morbidities that would predispose an individual to nerve injury.
In neurapraxia, compression/entrapment results in a temporary interruption of nerve conduction. Increased venous pressure with endoneurial edema is the result of prolonged exposure to compression with resultant Schwann cell fragmentation. There is no involvement of the axons during this process.
In states of axonotmesis and neurotmesis, stretching can result in patchy ischemia with decreased vasa nervorum flow. As stretching progresses, necrosis, intraneural connective tissue destruction, and hemorrhage are likely. Disruption of trophic factor transportation, increased intracellular calcium, and degradation of cytoskeletal elements proceeds. The Schwann cell phenotype switches to a phagocytic state with the recruitment of macrophages. Once myelin is cleared by phagocytosis, Schwann cells encompass the endoneurium to create the nerve conduit known as bands of Büngner. Branching to re-establish axonal connection occurs when neuronal damage results in <30% of axonal damage.
Wallerian degeneration is generally the fate of the distal end of the damaged nerve when over 90% of the axons are injured. During Wallerian degeneration, both injured ends retract with the proximal end, generally proceeding with degeneration to the closest node of Ravier. However, the distal end degenerates completely. Following the degeneration of the proximal stump, the Schwann cell converts to a regenerative phenotype and releases growth factors. An axonal growth cone with filopodia begins to develop at the distal end of the proximal stump and is guided by actin and myosin distally. The optimal outcome is to make contact with the endoneurial conduit of the degenerated distal nerve segment and grow along the original trajectory to re-innervate the end organs. The growth of a proximally damaged nerve is 2-3mm/day and 1-2mm/day for distal segments.
Regarding the end organs, the remaining motor units on muscles increase in size with hypertrophy of the innervated muscle fibers. A pruning process later takes place when axons receiving inadequate neurotrophic factors diminish. This process begins within 4 days following the insult with healing requiring 3 to 6 months.
Pre-ganglionic avulsion injuries with the discontinuity of the spinal roots to the central cord lack regenerative neurons, unlike in postganglionic injuries distal to the proximal stump.
History and Physical
The diagnosis and management strategies for acute nerve injury are clinically-based. Therefore, a thorough history taking and physical exam are essential to providing quality patient care. A complete trauma work-up with a primary survey is indicated in many 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 exam is warranted. The provider should test muscle strength of individual muscles, myotome performance, dermatomes, and solicit subjective concerns about the patient's performance. A provider should seek an associated trauma or disease state that can explain observed sensory, motor, and/or autonomic deficits noted on the exam. 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. A baseline assessment is integral to meaningful surveillance as patient abilities may change over time.
Evaluation begins with a comprehensive history and physical exam. A thorough neurologic exam is warranted with careful attention to the impairment of autonomic functions, myotomes, and dermatomes.
If the injury is open, it may be immediately explored to determine the extent of damage and address it with surgical intervention, if indicated. For cases with possible spontaneous recovery (lower grade axonotmesis and neurapraxia), patients should be monitored weekly for regain of function. If spontaneous recovery does not occur within a few months, surgery is warranted.
Technology is helpful to evaluate nerve injury if immediate surgical intervention is not indicated, the injury is closed, or surgery was performed, and monitoring is desirable. Although, electrodiagnostic studies may have normal results 2-3 days post-injury and may not reveal the full extent of the injury until 2-3 weeks post-injury.
Nerve conduction studies help determine the location, severity, and progression of nerve injury via motor and sensory conduction studies. When the electrodes are placed proximal to the lesion with recording distally (muscle for motor and nerve for sensory), the amplitude is decreased, velocity is decreased, and conduction is impaired or inhibited with axonotmesis and neurotmesis. Findings remain normal for these studies or slightly diminished until approximately 11 days post-injury for sensory nerve action potentials (SNAPs) and seven days post-injury for compound motor action potentials (CMAPs). Preserved distal responses with a conduction block over 12 days post-injury is characteristic of neuropraxia.
Compound muscle action potential (CMAP) is the summation of the response of the motor endplate potentials; the electrode stimulation is motor conduction studies. It reflects the volume of intact axons. In Wallerian degeneration, CMAP decreases significantly approximately ten days post-injury. In neurotmesis, the reading will be 0 mV when electrodes are placed proximal to the injury site. The nerve conduction block occurs at 50% to 75% amplitude reduction.
EMG is helpful 2-3 weeks post-injury for determining whether the source of weakness is from the muscle or nerves. Needles are placed intramuscularly with the observation of muscle response during placement, abnormal spontaneous activity, and motor unit potentials during contraction. In complete denervation, there are absent motor evoked potentials and low amplitude sharp waves and fibrillation during rest. The nature of abnormal spontaneous activity informs the provider about the time of injury, location, nature, and severity.
Somatosensory evoked potential (SSEP) and motor evoked potential (MEP) may be helpful intraoperatively to confirm the integrity of a sensory or motor nerve, respectively.
Additional modalities include ultrasound, magnetic resonance myelography, CT myelography, magnetic resonance neurography, and other radiologic studies.
Treatment / Management
Patients should be coached on appropriate expectations regarding regaining function, and that full recovery may not be attainable despite providing the standard of care.
In all cases of nerve injury, continued use and engagement of the affected end organ is crucial for the plasticity of the sensorimotor and cortical neurons. Activity maximizes compensatory mechanisms, aids in avoiding the development of contractures and desensitizes the patient to neuropathic pain.
In cases of neurapraxia, closed injuries, and lower grade axonotmesis, a baseline assessment with serial exams is warranted to observe for spontaneous regeneration. If the regain of function does not occur within 3-6 months, surgical intervention should be considered.
Surgical intervention is founded upon the principle of action before irreversible damage. Surgical options include primary repair, secondary repair, (internal or external) neurolysis, nerve graft, and nerve transfer (repair types). When neurophysiologic monitoring detects intact signaling to the nerve segment distal to the damaged site, neurolysis alone is indicated as further surgical intervention does not increase the likelihood of a successful outcome.
Primary end-to-end, tension-free repair is indicated for clean, sharp injuries to the nerve and should occur within 3 hours of injury. Both nerve segments continue to retract after the initial injury and thus it is important to repair before the process of retraction precludes primary repair due to consequent ischemia-inducing tension.
Direct repair may be between epineural substance, perineural substance, or group fascicle repair. It is recommended when nerves are tension free. Immunohistochemistry and intraoperative electrophysiology will aid in coapting sensory to sensory axons and motor fibers to the motor, which is important for improved recovery.
Secondary repair is attributed to less desirable outcomes but is necessary for ragged, contusion injuries. Ragged, contusion injuries fail to demonstrate the extent of nerve damage until approximately 2-3 weeks following injury. Considering its presentation, the primary repair is not indicated. Instead, the nerve endings are attached to the surrounding 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 larger than 2 cm, an intervening graft is indicated. Likewise, regardless of the gap size, if the nerve appears to be under tension during repair, an intervening graft may be indicated.
If the gap is too large for primary or secondary repair, the neurosurgeon has other options available. End-to-side neurorrhaphy is the juxtaposition of a healthy nerve to the degenerated distal stump. Axons branch from the nearest node of Ranvier toward the endoneurial conduit of the damaged, degenerated nerve. Means of creating a path for nerve growth from the proximal stump to the distal nerve include graft repairs (auto- or allo-) and conduits (numerous biologic and artificial options).
Some patients will suffer disability and pain syndromes despite the best efforts of their care team. Therefore, it is important to take a multidisciplinary approach with physical therapy, neurology, neurosurgery, plastic surgery, psychiatry, orthopedic surgery, and pain medicine to address the needs of these patients. Such needs may include prostheses, therapy for chronic pain, and cosmetic solutions for muscle atrophy. The extent of services required for PNI is beyond the scope of this paper.
PNIs are diagnosed through careful history taking and a thorough neurologic exam with the aid of electrophysiologic testing and imaging modalities such as ultrasound and MRI. Other conditions that will be considered differential diagnoses include those that interfere with sensory, autonomic, and motor responses. Without an identified event that would explain focal PNI, the provider must use additional tools to hone in on the etiology of the patient's deficit(s).
Muscular disease, central nervous system impairment, electrolyte abnormalities, vascular compromise, autoimmune disease, toxin exposure, and infectious causes should be considered. Notably, with the aid of electrophysiologic studies, muscular injury and inflammatory neuritis can be differentiated from focal nerve injury. Weeks following injury, electrophysiologic testing can differentiate between axonotmesis and neurotmesis. Serial exams with an observation of spontaneous recovery and documented mode of injury can help differentiate neurapraxia from higher-grade injuries.
The prognosis of axonotmesis relies on the underlying condition of the patient and the nature of the injury. In the best circumstances, the nerve can regenerate within a timely manner by axonal branching or through the expansion of the proximal segment of the damaged nerve.
Nerve regeneration becomes more likely with limited damage to axons and the structural units of the neural trunk. Spontaneous recovery frequently occurs, generally within days to weeks, when only the Schwann cells are damaged (neurapraxia). Complete recovery within three years is predicted for 90% of patients suffering from positional nerve injury. Spontaneous regeneration is still possible with axonotmesis if the perineurium and epineurium provide an intact tubule. Distal lesions have a better prognosis.
However, nerve regeneration does not equate to functional recovery. The function also depends on the effective communication of the regenerated axons with the end-organ. Therefore, early intervention on the damaged nerve is suggested before progressive scarring and atrophy of the end-organ renders it nonviable.
Muscle architecture and motor endplates are considered viable for up to 1-year post-injury. Merkel cells, Pacinian corpuscles, and Meissner's corpuscles may endure denervation for 2-3 years post-injury. Considering the growth of the damaged peripheral nerve at approximately 1-2 mm/day, it is prudent to intervene within the first 3-6 months of PNI without signs of spontaneous recovery. Communication with the end-organ must be re-established within a limited timeframe.
Prognostic factors for regain of 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 nerve(s) involved (the spinal accessory nerve is most robust), the location of injury along the nerve (distal injuries have a better prognosis), concomitant injuries, the timing to surgery, the type of surgery, and the patient's age.
Without an intact tubule for the guidance of neuronal regeneration, aberrant nerve growth into a neuroma is a possible outcome. Any foreign body used for suturing, conduit, or graft has the potential to elicit an immune response with resultant scarring, pain, and failure of nerve regeneration. Allografts are seldom used, but the patient is vulnerable to the dangers of immunosuppression when placed. 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 and hematoma.
Deterrence and Patient Education
The prevalence of traumatic causes for PNI emphasizes the importance of patient safety education and patient use of personal protective equipment. Furthermore, patients should be encouraged to have a low threshold to seek care should they develop abnormal sensory, motor, or autonomic responses.
To decrease iatrogenic PNI, healthcare providers should be familiar with the local anatomy where the provider may be placing a needle, an orthotic device, a bandage, a tourniquet, positioning a patient, or performing a procedure. Patients should undergo informed consent before interventions that include divulging the risk of unintended tissue damage, including nervous tissue.
Providers should be conscientious and cautious when positioning patients and performing procedures. Detailed documentation regarding nerve preserving technique is highly recommended. However, not completely protective against successful litigation.
Pearls and Other Issues
The rule of 3's for nerve injury:
- Sharp, clean nerve injuries should be explored and repaired within 3 hours
- Ragged, contusion injuries should have the ragged ends bound to a nearby anatomical structure immediately, then be repaired within three weeks
- Closed injuries should be repaired within three months.
Enhancing Healthcare Team Outcomes
The Walter Reed National Military Medical Center Peripheral Nerve Program (WRNMMCPNP) was established to address PNIs and their associated complications. The team consists of mental health providers, pain physicians, physical therapists, occupational therapists, neurologists/clinical neurophysiologists, neurosurgeons, physical medicine and rehabilitation physicians, plastic surgeons, and orthopedic hand surgeons.
The purpose is to maximize efficiency and eliminate fragmented care by providing a tumor board-like review of patient cases and a monthly comprehensive clinic during which providers from the aforementioned disciplines are available. This program has enabled the institution to serve a large volume of patients, maintain dynamic training programs, and produce PNI-related research.
The major concerns of this organization are mismanaged patients and delays in the intervention for PNIs. It is well-documented that delays relate to worse functional outcomes for patients. Therefore, WRNMMCPNP offers a telemedicine option to their patients to provide a direct route to PNI providers. Additionally, consolidation of PNI resources facilitates a faster response to injuries and rapid communication amongst involved healthcare providers, thereby prioritizing patient safety and outcomes.