Neurotmesis

Etiology

Etiologies of traumatic peripheral nerve injury include high-velocity trauma, lacerations, bone fractures, penetrating injury, crush, traction, ischemia, and less common mechanisms such as thermal, electric shock, radiation, percussion, and vibration.[4] Neurotmesis will involve any etiology that can completely transect a nerve, but most cases involve sharp lacerations.

During wartime (Iraq and Afghanistan), the nerve lesions were predominantly focal prolonged conduction block/neurapraxia in 116 (45%), axonotmesis in 92 (35%), and neurotmesis in 53 (20%) and were evenly distributed between the upper and the lower limbs.[5]

In the USA and Canada, during non-conflict time, the etiology usually is motor vehicle accidents.

Epidemiology

The exact incidence and prevalence of neurotmesis are not clearly defined as they are combined together with the other types of peripheral nerve injuries (PNIs). Approximately 100,000 patients undergo peripheral nerve surgery in the United States and Europe annually.[6] The majority of peripheral nerve injuries are traumatic, and the incidence of traumatic nerve injuries is approximately 350,000/year.[7] 

In trauma cases, there is a 1.1 to 2.8 prevalence.[8] The majority of those who suffer traumatic nerve injuries are young, with an average age of 32-39.[9][10] Patients in the 20-29 years of age group demonstrate the highest association for injury. Falls involving force in comparison with ground falls, were associated with a higher incidence of peripheral nerve injuries. Ground-level falls were associated with a lower rate.[9]

Female sex is associated with a lower rate of PNIs.[9] 74% were male.[10] In the pediatric population, there is no gender preference.[8]

The upper extremity is involved in 73.5% of the cases, and 83% of them are mononeuropathies.[6][10][11] In the lower extremities, penetrating injuries to the common peroneal nerve are the most frequent lesions.[12] Others differ and considered the sciatic nerve as the most frequently involved, followed by the peroneal nerve.[13] In the upper extremities, the ulnar nerve, alone or in combination, is the most often affected.[6][10][11] Others differ and consider the radial nerve as the most frequently involved, followed by the ulnar nerve, and then, the median nerve.[13] Combined lesions most commonly involved the ulnar and median nerves.[11]

Pathophysiology

Neurotmesis is caused by transection of a nerve and is the worst degree of peripheral nerve injury. In neurotmesis, the entire nerve, including the endoneurium, perineurium, and epineurium, is completely severed. Neurotmesis leads to the rupture of the axon, myelin sheath, and connective tissues. The prognosis for spontaneous recovery is poor without surgical intervention.[2]

Sunderland’s fifth-degree injury corresponds to the definition of neurotmesis in Seddon’s classification and represents the highest degree of nerve injury, with a complete nerve defect. 

Neurapraxia is a nerve injury commonly induced by focal demyelination and/or ischemia and is the mildest type of peripheral nerve injury. In neurapraxia, the conduction of nerve impulses is blocked in the injured area, motor and the sensory connection is lost, but all morphological structures of the nerve stump, including the endoneurium, perineurium, and epineurium, remain intact. Axonotmesis is a comparatively more severe type of peripheral nerve injury and usually is caused by crush, stretch, or percussion. In axonotmesis, the epineurium is intact, while the perineurium and endoneurium may be disrupted. The axon is separated from the soma, and the axon and the myelin sheath are disrupted. Wallerian degeneration occurs in the axon stump distal to the injury site within 24 to 36 hours after peripheral nerve injury. The remaining surrounding stroma benefits axonal elongation along with the intact tissue framework.

After neurotmesis, Schwann cells adaptively respond to axonal interruption, switching from a highly myelinated state to a de-differentiated state. De-differentiated Schwann cells engulf axon and myelin debris and form a regeneration path for axon growth. Moreover, activated Schwann cells secrete a group of cytokines, including tumor necrosis factor-alpha, interleukin-1 alpha, and leukemia inhibitory factor, to recruit macrophages and facilitate debris digestion. Schwann cells also secrete a group of neurotrophic factors, including nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor, to encourage neuron survival and axon elongation.[14][15][16]

Needle electromyography (EMG) is the most sensitive electrodiagnostic study for motor axon loss, and with lesions of great severity, low-amplitude motor responses appear. The motor response amplitude decrement begins around days 2–3 and is complete by day 6. This reflects the fact that neuromuscular junction degeneration precedes axon degeneration, and the motor responses are dependent on neuromuscular junction transmission.[17]

Histopathology

After neurotmesis occurs, there are many cell signals and neurotrophic factors involved. Within 30 minutes after injury, intracellular processes that promote repair and regeneration have already been activated. Schwann cells play an indispensable role in promoting regeneration by producing neurotrophic factors and by increasing their synthesis of surface cell adhesion molecules, and by elaborating basement membrane containing extracellular matrix proteins, such as laminin and fibronectin.

Within hours of injury, the ends of the severed axons seal over, and the sealed ends swell with cellular organelles as anterograde axonal transport in the proximal stump, and retrograde axonal transport in the distal stump persist for several days.[11] 

Within days after injury, Schwann cells begin to divide and create a pool of de-differentiated daughter cells. These de-differentiated Schwann cells upregulate expression of nerve growth factor, other neurotrophic factors, cytokines, and other compounds that lead to Schwann cell differentiation and proliferation in anticipation of the arrival of a regenerating sprout.[11]

History and Physical

Information regarding the mechanism of injury is extremely important as it will guide decisions about the timing of the nerve repair. The majority of neurotmesis injuries will involve sharp cuts with glass, knife, or sharp metals.

Physical examination of the extremity involved and the muscles innervated will point toward a specific nerve involved. The sensory distribution of the nerve involved is tested. There is complete anesthesia of the sensory distribution of the nerve. All muscles involved will show flaccid paralysis. A flicker of movement or some degree of preserved sensation indicates that the lesion is incomplete. Eliciting a Tinel sign is useful in following patients with a peripheral nerve injury to determine the regeneration of axons across the defect.

Evaluation

After careful examination of the extremity involved, studies to confirm and determine the type of lesion are performed. These include EMG, magnetic resonance imaging (MRI), and ultrasound.

EMG is most useful after a 2- to 3-week delay to permit denervation changes to occur in the affected muscles. In a complete neurapraxia lesion, needle EMG will show no motor unit action potentials (MUAPs) under voluntary control, but fibrillations are not present. In complete lesions (neurotmesis), the appearance of fibrillations and positive sharp waves is time and length-dependent. They do not appear for a number of days after the injury. In proximal muscles, they appear after 10 to 14 days and in distal muscles after 3 to 4 weeks. The presence of MUAPs by EMG examination indicates that reinnervation is occurring. The EMG is more sensitive than the physical examination for detecting early reinnervation, so the return of MUAPs on needle examination in the muscle closest to the injury site is typically the first evidence of reservation.[11]

MRI has become the mainstay of imaging methods to assess peripheral nerve injury. It can display the morphologic changes of nerves and provide quantitative indexes to monitor nerve degeneration and regeneration dynamically.[18]

Recent advancements in MRI, especially diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), and diffusion tensor tractography (DTT) derived from DTI, can provide three-dimensional maps of fiber tracts that intuitively display the orientation and density of nerve fiber bundles within the tissue, have significantly increased the utility of MRI for assessing peripheral nerve injuries, including the connective tissue element.[17][18][19][20][21] 

In acute situations, the ultrasound is most useful to differentiate between nerve axonotmesis and neurotmesis.[4] Differentiation of neurapraxia or axonotmesis from neurotmesis is done by observing nerve continuity and the demonstration of proximal and distal nerve stumps.[4][22][23][24][25][26]. It also provides information for the presence and location of neuromas, the length of any gap, and anatomical continuity after nerve-grafting procedures.

Treatment / Management

The main treatment goal of nerve repair is to allow reinnervation of the target organs by guiding regenerating sensory, motor, and autonomic axons into the environment of the distal nerve with minimal loss of fibers at the suture line. For optimal nerve regeneration, nerve stumps must be precisely aligned without tension and repaired atraumatically with minimal tissue damage and a minimal number of sutures.[6] End-to-end nerve repair techniques include epineural repair and fascicular repair. Two important factors for nerve repair are the timing of the procedure and the technique/material used. The time of repair of the nerve depends on the mechanism of the injury and the condition of the nerve.(B3)

In sharp nerve transections with none or minimal crush component, good blood supply, and clean wound, primary nerve repair is the best option for restoring the function. They are usually repaired within 72 hours when the fascicles are still identifiable.[6] The best results occur with primary end-to-end neurorrhaphy without tension.[11][27](B3)

Blunt transection repairs are usually delayed for 3 to 4 weeks, at which point the nonconducting fibrotic segment of both stumps is appreciable and can be adequately resected before repair. When repair is performed prior to this time, failure rates of 100% have been reported.[17]

For gunshot wounds, nerve regeneration through the neuroma-in-continuity may require three months or so, depending on the severity of the neuroma. Repair is delayed until that time. For stretch/avulsion injuries, if clinical or electrophysiological recovery still has not occurred by 4 to 5 months, then operative repair is indicated.[28](B2)

Lack of clinical and electrophysiological signs of spontaneous recovery after 3 to 6 months imposes surgical intervention. It is essential that endoneurial tubes will be in contact with regenerating axons within 18 to 24 months after injury; otherwise, degeneration will occur. The Schwann cells and the endoneurial tubes remain viable for 18 to 24 months after injury. If they do not receive a regenerating axon within this period, the tubes degenerate. Target muscle atrophy becomes irreversible after 12 to 18 months of denervation, which limits the functional outcome of the repair.[6] Axon regrowth is 1 mm/day from the site of injury or the site of surgical repair. When the regenerative distance exceeds 20 inches, even when the axons successfully reach their target, they are nonfunctional because denervated muscle fibers undergo fibrofatty degeneration at 20 to 24 months.[29](B3)

Tension at the repair site will cause scarring that blocks the advance of regenerating sprouts.[11] In the case of nerve gaps, which cannot be approximated without tension, the current gold standard of repair is autologous nerve grafting. Autologous nerve grafts are the ideal nerve conduit because they provide a permissive and stimulating scaffold, including Schwann cell basal laminae, neurotrophic factors, and adhesion molecules. Donor sites include the medial antebrachial cutaneous nerve, lateral antebrachial cutaneous nerve, superficial sensory branch of the radial nerve, dorsal cutaneous branch of the ulnar nerve, and sural nerve.[6] Autologous nerve grafts heave some difficulties, including donor nerve sacrifice and nerve mismatch.[6][16] (B2)

Tissue-engineered nerve grafts can be used as supplements or even substitutes for autologous nerve grafts to bridge peripheral nerve defects. The biomaterial-based scaffold offers physical structural support for the growth of injured nerves. Allografts provide an alternative for short grafts and can yield similar outcomes without the associated risks of harvesting autologous graft.[30] Several allograft and medium are used to improve the functional outcome, including tubing technique with biomaterials, fibrin conduit and sealant, silicone conduit, and platelet-rich plasma (PRP).[31][32][33] The influence of PRP in enhancing axon regeneration has been proposed to result from platelet-released neurotrophic and other factors like vascular endothelial growth factor, which induces enhanced axon regeneration by inducing rapid vascularization of the entire nerve gap.(A1)

Incorporated seed cells and neurotrophic factors further enhance the therapeutic effect of the biomaterial-based scaffold.[33] The incorporation of stem cells, such as embryonic stem cells, neural stem cells, bone marrow mesenchymal stem cells, adipose stem cells, skin-derived precursor stem cells, and induced pluripotent stem cells has enhanced the therapeutic effects of tissue-engineered nerve grafts.[16] Despite the encouraging repairing effects of neural stem cells, the clinical use of neural stem cells may be limited by the difficulty in collecting them, and the possibility of tumor formation. Bone marrow mesenchymal stem cells can differentiate to Schwann-like cells and boost neurite outgrowth when co-cultured with neurons.[34] (B2)

Adipose stem cells can be induced into spindle-shaped cells that express Schwann cell markers, secrete neurotrophic factors, stimulate neurite outgrowth and form myelin sheaths, skin-derived precursor stem cells, and induced pluripotent stem cells. The downsides of induced pluripotent stem cells are that they exhibit some similar characteristics to embryonic stem cells, including malignant potential. Immunomodulation to promote myelin debris clearance during Wallerian degeneration and promote subsequent axon regeneration via enhanced macrophage recruitment in neurotmesis has been used in combination with mesenchymal stem cells.[18]

Control of pain is a challenge in the management of peripheral nerve injury. The pain is typically neuropathic, characterized by burning and dysesthesias, and requires medications that are specific for neuropathic pain, such as tricyclic antidepressants, serotonin reuptake inhibitors, anticonvulsants (carbamazepine, phenytoin, lamotrigine, gabapentin, and pregabalin), antiarrhythmics, and baclofen. The mechanism of action of these drugs is thought to be the peripheral or central reduction of neuronal hyperexcitability. Although traditional analgesics are not regarded as first-line drugs for treating neuropathic pain, agents such as nonsteroidal anti-inflammatory drugs, tramadol, and opioids may be useful for short-term use.[11](B3)

Differential Diagnosis

• Neurapraxia
• Axonotmesis
• Inflammatory neuritis
• Infectious neuropathy (HIV, leprosy)
• Paraneoplastic neuropathy
• Metabolic (diabetic neuropathy)

Prognosis

There are several factors favoring a good functional outcome:

• Younger age
• Distal injury in the nerve (shorter distance to the muscle, and a more discrete separation of motor and sensory fascicles that can be matched).
• End-to-end repair
• Early repair[11]

The return of function following nerve repair is best for patients less than 20 to 25 years of age, and the extent of recovery decreases significantly with increasing patient age.[33] Pediatric patients had a 95.4% partial or complete sensorimotor recovery.[35] In adults, injuries that underwent immediate repair obtained functional improvement in 78% of cases. Those that underwent delayed repair obtained 70% functional improvement.[28] Graft repair of these injuries reduced the outcome to 63 to 77%.[28][30]

Peripheral nerve injuries can lead to long sick-leave periods, long-term disability, and in 30% of the cases to a permanent disability pension.[36]

Complications

• Failed regeneration
• Muscle atrophy
• Contractures
• Neuropathic pain
• Ulcers
• Economic losses
• Psychological issues