Peripheral neurological recovery and regeneration

Author(s): David Haustein, MD; Mariko Kubinec, MD; Douglas Stevens, MD; and Clinton Johnson, DO

Originally published:09/20/2013

Last updated:08/03/2017

1. 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.

Click Link to view the Figure: Nervous system diagram-en.svg. (2016, August 5). Wikimedia Commons, the free media repository. Retrieved 13:25, July 24, 2017 from

https://commons.wikimedia.org/w/index.php?title=File:Nervous_system_diagram-en.svg&oldid=203196192

Common signs and symptoms of peripheral nerve injuries include:

  • Hyperesthesia
  • Hypesthesia
  • Paresthesia
  • Dysesthesia
  • Weakness
  • 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.
  • Severity is classified by pathologic findings: neurapraxia, axonotmesis, and neurotmesis.1 It is sometimes difficult to differentiate the severity by clinical findings, because all three lesions have common neurologic impairments–motor and sensory loss–distal to the lesion.

http://training.seer.cancer.gov/module_anatomy/unit5_3_nerve_org2_pns.html#

  • 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 Sunderland-grade increase, 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)
Classification of Peripheral Nerve Injury
Sunderland Classification Grade Seddon Classification Pathology
Myelin
Injury
Axonal loss Endoneurial Disruption Perineurium
Disruption
Epineurium
Disruption
1 Neurapraxia X
2 Axonotmesis X
3 X X
4 X X X
5 Neurotmesis X X X X

2. Relevance to Clinical Practice

A. Natural history of peripheral nerve injury

  • In neurapraxia, paralysis and sensory loss 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, and distal axon degeneration (Wallerian degeneration) proceeds with motor and sensory fiber deterioration occurring after 3-5 days and 6-10 days, respectively.
    • 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 findings

  • Neuropraxia
    • Nerve conduction studies (NCS): Delayed conduction (prolonged distal latency, conduction block, and/or slow conduction velocity) across the lesion but normal conduction through the intact axon distal to the lesion.
    • Needle 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: May demonstrate reduced amplitude and mildly slowed conduction.
    • Needle EMG: fibrillations and positive sharp waves confirms axonopathy and decreased MUAP recruitment is expected.
    • As axon sprouting and regeneration progress, the number of abnormal spontaneous potentials decrease and MUAP’s appear as polyphasic potentials
    • As the new axons myelinate, the muscle fiber firing within each motor unit becomes more synchronous and polyphasia merges to become larger-than-normal-amplitude MUAPs.
  • Neurotmesis
    • NCS: loss of NCS waveforms below the lesion once Wallerian degeneration is complete.
    • EMG: diffuse positive sharp waves and fibrillation potentials with complete absence of motor unit action potential (MUAP) recruitment. The amplitudes of abnormal spontaneous resting potentials will diminish over time as the denervated muscle fibers atrophy.
  • Extensive axonotmesis cannot be differentiated initially from neurotmesis by either clinical or electrodiagnostic examination.
  • Sequential electrodiagnostic examinations may help predict recovery:
    • Axonotmesis: axon sprouting/regeneration and re-innervation show improved electrodiagnostic findings over time
    • Neurotmesis: no improvement and continued complete absence of conduction and recruitment

C. Imaging

  • Imaging studies are not the standard of care for peripheral nerve injuries
    • Ultrasound can accurately diagnose transected nerves, but is limited by large hematomas, skin lacerations and soft tissue edema
    • MRI (conventional T2) would demonstrate hyperintensity at the site of injury
    • MR neurography can identify nerve discontinuity of a nerve, but over 50% of high-grade nerve transections have minimal to no gap present
    • Diffusion Tensor Imaging, a type of MR, can quantify axon density and myelin thickness. Acute crush nerve injuries and traction injuries can be detected2

 D. Recovery and Prognosis

  • The prognosis, in general, is more favorable for a demyelinating lesion than for an axonal-loss lesion.
  • The two mechanisms of nerve recovery (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 segment3
      • 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; median, 2-4.5 mm; and radial, 4-5 mm/d).1  Sensory-nerve regeneration is often less successful than motor-nerve regeneration4
      • 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
Prognosis and Mechanism of Recovery
Sunderland Classification Grade Seddon Classification Mechanism of Recovery Prognosis
1 Neurapraxia Re-myelination and resolution of conduction block Complete functional recovery is expected in the vast majority of cases typically occurring between 2 weeks and 6 months
2 Axonotmesis Collateral sprouting

Axonal regeneration

Diminished prognosis with each higher Sunderland grade
3
4 Axonotmesis Little to no recovery possible Guarded – Surgery is usually required
5 Neurotmesis


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 diseaseRehabilitation 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.5
  • 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 proteins4,6

Surgical repair of peripheral nerve injury

  • Surgical repair is required in most Sunderland Grade 4 and 5 injuries.
  • Timing of open versus closed-injuries:
    • Open-injuries with complete nerve transection are managed with immediate repair within 3-7 days.
    • Open-injuries with nerve in-continuity (epineurium intact), and all closed-injuries, initially are managed conservatively, and nerve function is re-evaluated clinically at 4-6 weeks. If improving, conservative management is continued, but if worsening or no change, electrodiagnostic testing is obtained to determine Sunderland grade. Sunderland grades 1-3 are treated with conservative measures while grades 4-5 usually require surgical repair.7,8,9
Surgical Repair Options
Gap between

stumps

Surgical Technique Comments
< 2 cm Microsuture epineurial repair

(end-to-end)

> 2-3 cm Nerve grafting

(autologous or allograft)

Autologus: Provide a supportive structure for regenerating axons, Schwann cells, neurotrophic factors, and adhesion molecules; but, autografts risk donor-site morbidity

Allograft (cadaver): Plentiful and avoid donor-site morbidity, but increased cost and require immunosuppression for approximately 2 years until the allograft has been repopulated with host Schwann cells.  Decellurized allografts can be used to avoid immunosuppression, but expensive and limited to short gap lengths of less than 3 cm

Proximal stump unavailable or when prior nerve repair has failed End-to-side nerve transfers No documented randomized clinical trials

Nerve fascicles considered less-needed are dissected from a donor nerve and anastomosed to the distal segment of the injured nerve.

Used for proximal nerve injuries when proximal stump is unavailable or inaccessible (e.g. brachial plexus injuries)

Advantages: places regenerating axons much closer to target muscles thus ‘converting’ a proximal nerve injury to a distal nerve injury; and, also avoids autograft donor-site morbidity.

Disadvantages: possible donor-nerve loss of function, and precludes use of donor-nerve muscle for muscle transfer.

Examples: thoracodorsal nerve to axillary nerve; anterior interosseous nerve to ulnar nerve at wrist; anterior interosseous nerve to median recurrent motor branch; medial pectoral nerve or thoracodorsal nerve to long thoracic nerve.8

3. Cutting edge/unique concepts/emerging issues

Promising new developments are under investigation that may help to suppress symptoms and restore function:

Pharmacological Agents

  • 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 tested only in cell-culture or animal models. Some of the agents studied: erythropoietin, tacrolimus, acetyl-L-carnitine, N-acetylcysteine, testosterone, chondroitinase abc, ibuprofen, melatonin, and transthyretin (pre-albumin)
  • Observed effects include increased: axonal density and caliber; number of myelinated axons; myelin thickness; axon sprouting; and, sensory and motor axon growth across the repair site8

Stem cells

  • Nerve regeneration potential of stem cells has been demonstrated in cell-cultures and animal models
  • As in any use of stem cells, numerous issues remain ranging from autologous versus allogenic, risk of tumorigenicity/immunogenicity, preferred tissue harvest site, pre-differentiation of stem cells in vitro vs undifferentiated in vivo, and method of delivery of stem cells (e.g. injected around nerve stumps/grafts, injected into conduit lumen, suspended in a mechanical construct or ‘scaffold’, or injected systemically) 7,8,9,10

Gene therapy

  • Successfully applied in rat-models to counteract spinal motor neuron atrophy after root avulsion
  • Theoretically would target Schwann cells, fibroblasts, and denervated muscle.
  • Goal is to generate more neurotrophic factors, cell adhesion or extracellular matrix molecules, and transcription factors9
  • Numerous obstacles prevent translation into humans, such as vector-safety, choosing the correct gene and cell to target, and risk of mutagenesis7,8,9,10

Nanothechnology

  • One approach is to develop nanoscaffold surfaces into tridimensional structured conduits to facilitate axon regeneration via physical stimuli associated with topographic signals (i.e. a scaffold mimicking those architectures/surfaces to optimize axon regeneration)
  • Another approach is to coordinate the internalization of magnetic nanoparticles into cells. These cells would then be guided by external magnetic fields to stimulate and direct axon growth
  • The goal is to develop each approach in parallel and then use in combination11

4. Gaps in knowledge/evidence base

N/A

REFERENCES

  1. Dumitru D, Zwarts MJ, Amato AA. Peripheral nervous system’s reaction to injury. In: Dumitru D, Amato AA, Zwart MJ 2nd, eds., Electrodiagnostic Medicine. Philadelphia, PA: Hanley & Belfus; 2002:115-156.
  2. Boyer R, Kelm N, Riley C, et al. T Diffusion Tensor Imaging of Acute Traumatic Peripheral Nerve Injury. Neurosurg Focus. 2015:39(3): E9.
  3. Rodriques M, Rodriques A Jr, Glover L, Voltarelli J, Borlongan C. Peripheral nerve repair with cultured Schwann cells: getting closer to the clinics. Scientific World Journal. 2012;2012:413091.
  4. Gordon T and English A. Strategies to Promote Peripheral Nerve Regeneration: Electrical Stimulation and/or Exercise. Eur J Neurosci. 2016: 43(3):336-350.
  5. Delisa, Gans, Walsh. Physical Medicine and Rehabilitation. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
  6. Willand M, Nguyen M, Borschel G, et al. Electrical Stimulation to Promote Peripheral Nerve Regeneration. Neurorehabilitation and Neural Repair. 2016: 30(5): 490-496.
  7. Grinsell D, Keating CP. Review Article: Peripheral Nerve Reconstruction after Injury: A Review of Clinical and Experimental Therapies. BioMed Research International. Vol 2014. http://dx.doi.org/10.1155/2014/698256.
  8. Panagopoulos G, Megaloikonomos P, Mavrogenis A. The Present and Future for Peripheral Nerve Regeneration. Orthopedics. January/February 2017: 40(1): 1-67.
  9. Sullivan R, Dailey T, Duncan K, Abel N, Borlongan CV. Review: Peripheral Nerve Injury: Stem Cell Therapy and Peripheral Nerve Transfer. International Journal of Molecular Sciences. 2016, 17, 2101.
  10. Jones S, Eisenberg HM, Jia X. Review: Advances and Future Applications of Augmented Peripheral Nerve Regeneration. International Journal of Molecular Sciences. 2016, 17, 1494.
  11. Poggetti A, Battistini P, Parchi PD, Novelli M, Raffa S, Cecchini M, Nucci AM, Lisanti M. How to Direct the Neural Growth Process in Peripheral Nerve Regeneration: Future Strategies for Nanosurfaces Scaffold and Magnetic Nanoparticles. Surg Technol Int. 2017 Feb 7;30 (Epub ahead of print)

Original Version of the Topic

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

Author Disclosure

David Haustein, MD
Nothing to Disclose

Mariko Kubinec, MD
Nothing to Disclose

Douglas Stevens, MD
Nothing to Disclose

Clinton Johnson, DO
Nothing to Disclose

Related Articles