Peripheral Neurological Recovery and Regeneration

Overview and Description

The peripheral nervous system includes all nerves and ganglia located outside of the brain and spinal cord and is comprised of both the somatic and autonomic nervous systems. The somatic nervous system is made up of both motor and sensory nerves. The cell bodies of the motor nerves are located in the brainstem and ventral horn of the spinal cord while those of the sensory nerves are located outside of the spinal cord in the dorsal root ganglia (Fig 1)¹.

Fig 1. Diagram of Central and Peripheral Nervous System

Common signs and symptoms of peripheral nerve injuries include:

• Hyperesthesia
• Hypesthesia
• Paresthesia
• Dysesthesia
• Weakness
• Pain
• Muscular atrophy
• Dystrophic changes
• Hyporeflexia or areflexia
• Bowel or bladder incontinence

Assessment:

• A combination of clinical assessment and electrodiagnostic studies are the standard to assess the location and severity of peripheral nerve injuries.  Injuries to the myelin are usually the least severe, while injuries to the axons and supporting structures are more severe (Fig 2)².
• Severity is classified by pathologic findings: neurapraxia, axonotmesis, and neurotmesis, also known as Seddon Classification.³ It is sometimes difficult to differentiate the severity by clinical findings, because all three lesion types have common neurologic impairments—motor and/or sensory loss—distal to the lesion.
• In neuropraxia (Sunderland grade 1) there is focal demyelination with impaired sensory and motor function distal to the lesion but preserved axonal continuity.
• Axonotmesis (Sunderland grades 2, 3, and 4) develops when axons are damaged.
  • Sunderland grade 2 is only axon damage; Sunderland grade 3 is axon and endoneurium damage; and, Sunderland grade 4 is axon, endoneurium, and perineurium damage.
  • With each increase in Sunderland-grade, regeneration becomes less optimal and recovery-time becomes longer.
• In neurotmesis (Sunderland grade 5), the axon and all surrounding connective tissue (endoneurium, perineurium, and epineurium) are damaged (i.e., transected nerve). Spontaneous recovery is not possible.

Fig 2. An example of a peripheral nerve structure

Table 1 Classification of Peripheral Nerve Injury

Relevance to Clinical Practice

A. Natural history of peripheral nerve injury

• In neurapraxia, diminished muscle strength and/or sensation develop acutely, but because of axon continuity, nerve conduction of the distal segment remains intact regardless of the length of time following injury.
• Both axonotmesis and neurotmesis involve axonal degeneration but there are differences in the process and prognosis of axonal recovery.
  • Degeneration usually proceeds proximally up one to several nodes of Ranvier.
  • Distal axon degeneration (Wallerian degeneration) involves motor and sensory fiber deterioration occurring immediately within 24-36 hours.
  • Paralysis and sensory loss develop acutely, but nerve conduction of the distal segment only remains intact until the distal segment is consumed by Wallerian degeneration.
  • During Wallerian degeneration, Schwann cells both phagocytose the axonal and myelin debris and help regenerate myelin.

B. Electrodiagnostic findings⁴

• Injury and electrodiagnostic findings are time dependent and therefore, it is suggested to delay these studies for several weeks to better witness specific findings and delineate injury severity.
• Therefore, most peripheral nerve injuries are initially are managed conservatively, with nerve function evaluation at 3 weeks via nerve conduction study and electromyography (NCS/EMG). 
• Neuropraxia
  • Nerve conduction studies (NCS): Delayed conduction (prolonged distal latency, conduction block, and/or slow conduction velocity) across the lesion but normal conduction distal to the lesion.
  • Needle electromyography (EMG): normal spontaneous activity but may show decreased motor unit action potential (MUAP) recruitment due to conduction block.
  • With recovery, conduction is re-established across the lesion and electrodiagnostic findings will normalize.
• Axonotmesis
  • NCS: In the first few days after the injury, there will be reduced conduction across the lesion but conduction may be normal above and below the lesion until Wallerian degeneration occurs.  With time, partial axonal loss may result in reduced amplitude and slowed conduction, while complete axonal injury results in loss of action potentials.   
  • Needle EMG: Effective immediately, there will be decreased recruitment in partial lesions and unobtainable MUAPs/absent recruitment in complete lesions.  In a manner of weeks, fibrillations and positive sharp waves appear in affected muscles.
  • As axon sprouting and regeneration progress, abnormal spontaneous potentials decrease and MUAPs may appear variable.
  • In the first weeks to months, re-innervation by collaterals may result in polyphasic MUAPs and/or satellite potentials, while the slower axonal re-growth will eventually result in larger amplitude, longer duration potentials.
• Neurotmesis
  • NCS: Loss of NCS waveforms below the lesion once distal axon degeneration (Wallerian degeneration) is complete.
• EMG: Diffuse positive sharp waves and fibrillation potentials will appear in about 3 weeks in affected muscles, with no observable MUAPs. The amplitudes of the spontaneous potentials will diminish over time as the denervated muscle fibers atrophy.  As in axonotmesis, if there is any re-innervation by collaterals, EMG may reveal polyphasic MUAPs and/or satellite potentials, while the slower axonal re-growth will eventually result in larger amplitude, longer duration potentials.
• Extensive axonotmesis cannot be differentiated initially from neurotmesis by either clinical or electrodiagnostic examination.
• Sequential electrodiagnostic examinations may help predict recovery:
  • As noted above, reinnervation by collaterals may result in polyphasic MUAPs and/or satellite potentials, while the slower axonal re-growth will eventually result in larger amplitude, longer duration potentials.

Table 2: Electrodiagnostic Findings at 1 Month following Peripheral Nerve Injury

Table Assumptions and Key:

• This table lists general electrodiagnostic findings.
• In the setting of neuropraxia, this chart assumes that the conduction block is persisting across the lesion and EMG findings listed are distal to the lesion in the relevant nerve territory.
• For axonotmesis and neurotmesis, the EMG findings listed are distal to the lesion in the relevant nerve territory.
• Key:
  • WNL = Within normal limits
  • Abnl = Abnormal
  • NR = No response

C. Imaging

• Imaging studies are not the standard of care for peripheral nerve injuries, but studies such as magnetic resonance imaging (MRI) and ultrasound (US) can be used to identify nerve derangement and rupture, and neuroma formation. ⁵
• Ultrasound (US) – can accurately diagnose various nerve injuries, especially superficial nerves, but it can be limited by anatomy, body habitus, edema, and architecture distortions with deeper structures.⁶
  • US can accurately diagnose transected nerves, but is limited by large hematomas, skin lacerations and soft tissue edema.
  • Types of injuries and US findings⁶
    • Contusion
      • Edema within the nerve bundle
      • Increased distance between hyperechoic lines
    • Stretching
      • Edema over long segment
      • Multiple branches involved with loss of fascicular pattern
    • Laceration
      • Proximal end terminal neuroma, homogenous hypoechoic echotexture
      • May see muscle atrophy
  • US Advantages
    • Time: very quick to do, faster than EMG or MRI ⁶
    • Dynamic: real time assessment, visualize anatomy with movement and manipulation
    • Cost: Relatively low cost compared to other modalities
    • No contraindications
  • US Disadvantages
    • Cannot assess physiological functioning of the nerve
    • Prognosis: cannot distinguish between neurotmetic and neuropraxic lesions
    • Operator-dependent
• MRI – demonstrating promise in both diagnosing and monitoring injury, especially in the surgical setting. 
  • MR neurography can identify nerve discontinuity of a nerve, but over 50% of high-grade nerve transections have minimal to no gap present.⁷
  • Diffusion tensor imaging (DTI), a type of MR, can quantify axon density and myelin thickness. Acute crush nerve injuries and traction injuries can be detected⁸ 
  • Nerves are honeycomb in appearance and mild hyperintense at baseline.
    • T2-weighted images are more helpful than T1. During injury, nerves become more hyperintense on T2 and, given the chronicity, muscle atrophy may be present and localized edema can be seen. 
    • Additionally, high resolution MRI (1.5 and 3 Tesla) can further enhance injury detection. 
  • T2-weighted images can detect axonotmesis and neurotmesis but not neuropraxia.⁷
    • Axonotmesis – presents as enlarged hyperintensity with loss of fascicular structure, edema 
    • Neurotmesis – terminal neuroma, muscle atrophy, fatty replacement⁸
  • MRI Advantages 
    • Time: provider may be able to have study done sooner if a timely EMG is difficult to obtain.
    • Site: if the muscle is very deep or limited by body habitus, MRI could be a better option than EMG. 
    • Patient: if the patient cannot tolerate an EMG (pediatric) 
  • MRI Disadvantages
    • Cost: expensive
    • Contraindications: pacemaker, metal implants, aneurysm clips
    • Setup: may be difficult to obtain if patient is claustrophobic or morbidly obese

 D. Recovery and Prognosis

• The prognosis, in general, is more favorable for a demyelinating lesion than for a lesion producing axonal loss.
• In addition, recovery of injury is highly dependent on the severity of injury. For instance, the less severe injuries (i.e. neuropraxia) recover in shorter amount of time and to a better degree. On the contrary, axonotmesis and neurotmesis take longer to recover and may not recover as well, or at all.
• Two mechanisms of nerve recovery resulting in re-innervation of end-organs occur simultaneously:
  • Collateral branching/sprouting of intact axons
    • Primary mechanism when 20-30% of axons injured
    • Starts within 4 days of injury and proceeds for 3-6 months
  • Axonal regeneration
    • Primary method when greater than 90% of axons injured
    • Begins within hours of injury and takes months to years to complete.
    • Requires an intact endoneurial tube to re-establish continuity between the cell body and the distal terminal nerve segment.⁹
    • Generally, the axon re-grows at the rate of 1 mm/day (i.e. approximately one inch per month), but individual nerves may have different speeds (ulnar, 1.5 mm/day; median, 2-4.5 mm/day; and radial, 4-5 mm/day).³  Sensory nerve regeneration is often less successful than motor-nerve regeneration. ¹⁰ 
    • Axonal regeneration is faster in the beginning and becomes slower as it reaches the nerve end. When the regenerating axon reaches the end organ, the axon matures and becomes myelinated
    • If neural regeneration is successful, the conduction velocity of the injury returns to 60% to 90% of pre-injury level (but this does not usually adversely affect clinical recovery).
    • Scar formation at the injury site will block axonal regeneration. If the axons fail to cross over the injury site, the distal segment is permanently denervated and the axonal growth from the proximal segment forms a neuroma.
• NCS can demonstrate the resolution of conduction block or remyelination
• EMG can demonstrate reinnervation via collateral sprouting and axonal regrowth.

Rehabilitation management of peripheral nerve injury

• Because peripheral neuropathy most frequently results from a specific disease or damage of the nerve, or as a consequence of generalized systemic illness, the most fundamental treatment involves prevention and control of the primary disease. Rehabilitation is directed toward improving or compensating for weakness and maintaining independent function.
• Exercise, stretching, splinting, bracing, adaptive equipment, and ergonomic modification are usual components of the rehabilitation prescription.¹¹
• If surgery is warranted to the nerve injury, the type of surgery could dictate healing and outcomes.¹²
  • Muscle and tendon transfers can lead to adhesive scarring in the antagonist muscle and prevent proper tendon function.
  • Repairs with grafts can sometimes result in poor functional outcomes as a consequence of fibrosis and endplate degeneration.
• No matter which surgery, postoperative nerve repairs should be immobilized for 10 days to 6 weeks depending on the injury severity. After this, full passive and active range of motion may be introduced for rehabilitation.⁵  
• Muscle fatigue, or the decline of performance during an exercise or task, after muscle reinnervation is one limiting factor in the rehabilitation process.¹²
  • Reinnervated fibers develop an increase in type II motor fibers (fast twitch, anaerobic fibers)
  • Reinnervated fibers have been shown to fatigue earlier compared to non-injured fibers, especially during isometric repetitive actions. This is relevant and applicable not only during physical and occupational therapy, but also to the patient’s daily activities.

Surgical repair of peripheral nerve injury

• Surgical repair criteria are based on open or closed injuries and nerve continuity.¹⁴
• Open versus closed injuries:
  • Open injuries with complete nerve transection are repaired based on the laceration type.
    • Open injuries with sharp laceration are managed with immediate repair within 3-7 days.
    • Open injuries with dirty, blunt lacerations are delayed in surgical repair to better allow demarcation of injury and avoid complications such as infection.
  • Open injuries with nerve in-continuity (epineurium intact), and all closed-injuries, initially are managed conservatively, with nerve function evaluation at 3 weeks via nerve conduction study and electromyography (NCS/EMG).  This testing can further determine Sunderland grade. Sunderland grades 1-3 are treated with conservative measures while grades 4-5 usually require surgical repair.^13-15 If clinical or electrical recovery is not evident by 3 months, surgical intervention is recommended.
• Surgical repair is further classified based on the size of the nerve gap and include primary repair, conduits, allografts, and autografts.^5;16;17
• The type of surgery can be guided by the size of the gap of injury:
  • <1cm: End-to-end neurorrhaphy. ^17;18
  • >1cm:
    • Autologous graft to provide a conduit for axonal regrowth
    • Donor nerve is usually a sensory nerve

Cutting Edge/Unique Concepts/Emerging Issues

Promising new developments are under investigation that may help to suppress symptoms and restore function. These require further exploration and clinical trials:

1. Pharmacological Agents

• Currently, there are no FDA-approved pharmacological treatments for nerve regeneration.
• Various possibilities have been studied to improve/accelerate nerve repair/regeneration via neuronal-death reduction and axonal-growth enhancement.
• All agents have been tested only in cell-culture or animal models. Some of the agents include erythropoietin, tacrolimus, acetyl-L-carnitine, N-acetylcysteine, testosterone, chondroitinase ABC, dimethylsulfoxide, transthyretin (pre-albumin), ibuprofen, melatonin, and polyethylene glycol.
• Polyethylene glycol (PEG) has proven successful in animal models and was applied to human trials.¹⁸
  • PEG helps fuse cells, develop desired cell lines, remove water at the injured lipid bilayer, and increase the fusion of axolemmal ends.
  • One study found that during a surgical repair of a sharp, complete resection, the application of PEG for 2 minutes after surgical connection of the injured ends, helps to decrease inappropriate calcium-mediated vesicle formation, promote fusion, enhance axonal continuity with nerve healing, and improve sensory recovery, based on static two-point discrimination.¹⁸
  • Benefits: affordable, readily available, low risk of toxicity
  • Limitations: not been tested in mixed nerves, motor nerves, or jagged injuries

2. Modalities

• Acute, brief, low-frequency electric stimulation following post-operative peripheral nerve repair has been shown in human models to improve motor and sensory re-innervation. This is thought to be due to increased production of neurotrophic factors by Schwann cells, as well as increased production of cytoskeletal proteins ^10;19

Gaps in Knowledge/Evidence Base

The current standards of care for peripheral nerve injury is based on serial examinations and/or electrodiagnostics. There is significant room for improvement in the development of more formal diagnostic tools, aiding prognostication for these difficult and sometimes severe injuries. In addition, cost-effective approaches to following progress to recovery are needed.  For the treatment of traumatic nerve injuries, future research in pharmacologic interventions and gene therapy needs to be expanded to human subjects.

References

1. Nervous System Diagram: https://commons.wikimedia.org/w/index.php?title=File:Nervous_system_diagram-en.svg&oldid=292675723.  3-18-2018.Ref Type: Online Source.
2. Nerve Structure: https://commons.wikimedia.org/w/index.php?curid=1298429.  10-21-2006.
3. Dumitru D, Amato A, Machiel Z. Electrodiagnostic Medicine. 2nd ed. 2001.
4. Preston D, Shapiro B. Electromyography and Neuromuscular Disorders: Clinical-Electrophysiologic Correlations. 2013.
5. Griffin M, Malahias M, Hindocha S, Khan WS. Peripheral nerve injury: principles for repair and regeneration. Open Orthop J 2014;8:199-203.
6. Visalli C, Cavallaro M, Concerto A et al. Ultrasonography of traumatic injuries to limb peripheral nerves: technical aspects and spectrum of features. Jpn J Radiol 2018;36:592-602.
7. Marquez Neto OR, Leite MS, Freitas T, Mendelovitz P, Villela EA, Kessler IM. The role of magnetic resonance imaging in the evaluation of peripheral nerves following traumatic lesion: where do we stand? Acta Neurochir (Wien ) 2017;159:281-290.
8. Boyer RB, Kelm ND, Riley DC et al. 4.7-T diffusion tensor imaging of acute traumatic peripheral nerve injury. Neurosurg Focus 2015;39:E9.
9. Rodrigues MC, Rodrigues AA, Jr., Glover LE, Voltarelli J, Borlongan CV. Peripheral nerve repair with cultured schwann cells: getting closer to the clinics. ScientificWorldJournal 2012;2012:413091.
10. Gordon T, English AW. Strategies to promote peripheral nerve regeneration: electrical stimulation and/or exercise. Eur J Neurosci 2016;43:336-350.
11. Delisa J, Gans B, Walsh N. DeLisa’s Physical Medicine and Rehabilitation: Principles and Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005.
12. Wilcox M, Brown H, Johnson K, Sinisi M, Quick TJ. An assessment of fatigability following nerve transfer to reinnervate elbow flexor muscles. Bone Joint J 2019;101-B:867-871.
13. Grinsell D, Keating CP. Peripheral nerve reconstruction after injury: a review of clinical and experimental therapies. Biomed Res Int 2014;2014:698256.
14. Panagopoulos GN, Megaloikonomos PD, Mavrogenis AF. The Present and Future for Peripheral Nerve Regeneration. Orthopedics 2017;40:e141-e156.
15. Sullivan R, Dailey T, Duncan K, Abel N, Borlongan CV. Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer. Int J Mol Sci 2016;17.
16. Bassilios HS, Bond G, Jing XL, Kostopoulos E, Wallace RD, Konofaos P. The Surgical Management of Nerve Gaps: Present and Future. Ann Plast Surg 2018;80:252-261.
17. Ducic I, Fu R, Iorio ML. Innovative treatment of peripheral nerve injuries: combined reconstructive concepts. Ann Plast Surg 2012;68:180-187.
18. Bamba R, Waitayawinyu T, Nookala R et al. A novel therapy to promote axonal fusion in human digital nerves. J Trauma Acute Care Surg 2016;81:S177-S183.
19. Willand MP, Nguyen MA, Borschel GH, Gordon T. Electrical Stimulation to Promote Peripheral Nerve Regeneration. Neurorehabil Neural Repair 2016;30:490-496.

Original Version of the Topic

Chong Tae Kim, MD, Jung Sun Yoo, MD. Peripheral neurological recovery and regeneration. 09/20/2013.

Previous Revision(s) of the Topic

David Haustein, MD; Mariko Kubinec, MD; Douglas Stevens, MD; and Clinton Johnson, DO. Peripheral neurological recovery and regeneration. 08/03/2017.

Author Disclosure

David Haustein, MD, MBA
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C. Alex Carrasquer, MD
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Stephanie M. Green, DO
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Michael J. Del Busto, MD
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