Degeneration & regeneration of peripheral nerves

  • By: Terri
  • Date: November 11, 2010
  • Time to read: 5 min.

Peripheral nerve injuries


  • Due to
    • Trauma
    • acute compression
  • Signs & symptoms
    • Loss of motor function
    • Loss of sensory function
  • Pathology
    • Demyelination/axonal degeneration
    • Disruption of the sensory/motor function of the injured nerve
    • Remyelination with axonal regeneration
    • Reinnervation of the sensory receptors & muscle end plates

Degenerative changes

  • Axonal injury
    • Degenerative changes at proximal & distal end
      • Anterograde degeneration (Wallerian Degeneration)
        • Affecting the
          1. Injured neuron
          2. Neurons functionally connected to the injured neuron
        • Transneural degeneration
          • also degenerate neurons that synapses with the injured neuron
        • Starts in 24 hours
      • Retrograde Degeneration
        • Extends up to the first node of Ranvier proximal to the injury
        • Changes in the dendritic tree
          • the parent cell body & the part of the axon still attached to the cell body
        • Chromatolytic changes
        • Swelling of the cell
        • Displacement of the nucleus to periphery
          • sometimes extruded out
        • Fragmentation & reduction of Golgi apparatus
        • Disappearance of neurofibrils



  • disintegration of the Nissl substance
    • begins within 24 – 48 hours
    • begins near the axon hillock & spreads to other parts
  • occurs in certain infectious or degenerative diseases of the nervous system
    • poliomyelitis
    • progressive muscular atrophy
  • degree of chromatolysis depends on
    • proximity of the site of injury to the nerve cell
  • more in motor neurons

Wallerian degeneration


Process that results when a nerve fibre is cut or crushed, in which the part of the axon separated from the neuron’s cell body degenerates.

Pre-degeneration reactions – 1st things that happen when there is injury

  • Decentralisation of the nucleus
    • increased ribosomes surrounding the nucleus
  • Immune response
    • Macrophages start attacking the Schwann cells of the distal segment
  • Nervous system reaction
    • All adjacent neurons start extending sprouts of their axons
    • towards the injured neuron
  • Enzymatic Action
    • The axon of the distal segment is broken down by enzymes



  • Axonal degeneration
    • Axis cylinder (axolemma) swells & breaks up into small pieces
      • Enzymatic Action
        • The axon of the distal segment is broken down by enzymes
          • the products of this action is carried by retrograde transport to the soma
      • Debris appear in the space occupied by axis cylinder
    • Myelin sheath disintegrate into fat droplets
    • Neurilemmal sheath intact
  • Myelin clearance
    • Immune response
      • Macrophages start attacking the Schwann cells of the distal segment
      • Macrophages invade & remove the debris of axis cylinder
  • Regeneration ( begins about 20 days after injury)
    • Schwann cells multiply
      • Macrophages produce interleukin-1 which stimulates Schwann cells to secrete substances that promote nerve growth
      • forms a solid cord of elongated cells within the endoneural tube –> towards the target tissue
        • those that did not reach the target tissue will start dying
      • growth path for axon
    • Adjacent basal lamina separate
      • creating an annular compartment
    • Neurilemmal tube becomes empty
      • now filled by cytoplasm of Schwann cells
    • Axonal sprouts (neurofibrils)
      • Neurofibrils grow out in all directions from the proximal axon
      • Sprouts grows into the distal annular compartment
      • All but one axonal sprout degenerate
      • Surviving fibril enlarges to fill the distal tube Regenerated fiber rarely attains a fiber diameter more than 80% of normal
    • Schwann cell form myelin sheath around the reinnervating axonal sprout
      • Sheath begins to develop in about 15 days
      • Myelin sheath is completed in one year
    • Regeneration in the cell body
      • Nissl granules reappear
      • Golgi apparatus reappear
      • The cell regains its normal size
      • Nucleus returns to central position



Transneural degeneration

  • Degeneration of the neuron with which the injured afferent nerve synapses
    • This neuron is not the one that is injured
  • Examples
    • Optic nerve injury leads to degeneration of the lateral geniculate body
    • Injury to posterior nerve root leading to degeneration of dorsal horn of spinal cord
  • Changes in nerve degeneration


    • There will be neurogeneic rearrangement
      • the growing axon does not necessarily follow the expected growth path
      • incomplete nerve regeneration
    • Criteria for complete nerve regeneration
      • Gap between cut ends of neuron
        • should not be greater than 3mm
      • Neurilemma should be present
      • Nucleus must be intact
        • should not be extruded
      • Two cut ends should remain in the same line
        • or else there will be rearrangement
      • Nerve regeneration is generally limited
        • because axons become entangled in the area of tissue damage
      • Neurotropins
        • nerve growth factors – influence nerve regeneration
        • Growth factors produced by neurons, glial cells, Schwann cells, and target cells


    Classification of nerve injuries

    Seddon’s classification (3 types)

    1. Neuropraxia
      • Caused by
        • minor nerve stretch/pressure
          • causing ischemic injury to the nerve
          • Results in conduction block
            • without any structural damage
      • Electrodiagnostic study
        • normal – above and below the level of injury
        • No denervation muscle changes are present
      • Recovery
        • Once remyelinated, complete recovery occurs
    2. Axonotemesis
      • Caused by
        • excessive stress injury to the nerve
      • Pathology
        • The basal lamina of Schwann cells & other sheaths are intact
        • The epineurium & other supporting structures are not disrupted
          • internal architecture is relatively well preserved
        • Cause Wallerian degeneration distal to the injury
        • Endoneural tubes remain intact
      • Electrodiagnostic studies
        • denervation changes in the affected muscles
      • Recovery
        • In cases of reinnervation
          • motor unit potentials (MUPs) are present
        • Once remyelinated
          • complete recovery with axons reinnervating their original motor and sensory targets
    3. Neurotemesis
      • Caused by
        • penetrating injury to the nerve
      • Pathology
        • All the sheaths are disrupted
        • Physical gaps in the nerve may occur even though an epineurial sheath appears in continuity – after traction or crush
      • Recovery
        • No recovery unless repair is undertaken
        • Unrepaired nerve will be completely replaced by fibrous tissue
          • there is complete loss of anatomic continuity

    Sunderland’s classification (6 degrees of nerve injury)

    1st degree (neuropraxia)
    • most common
    • caused by
      • pressure, occlusion of blood flow, hypoxia
    • mild demyelination occurs
      • without axonal damage
      • there is conduction block
    2nd degree (axonotemesis)
    • Caused by
      • severe prolonged pressure on the nerves
    • May cause Wallerian deneration
    • Repair & regeneration of nerve takes a long time
    3rd degree
    • Endoneurium interrupted
      • epineurium & perineurium intact
    • Incomplete recovery at 3 months
      • recovery slow
      • regeneration is incomplete
    4th degree
    • Endoneurium, epineurium & perineurium interrupted
    • No recovery at 3 months
      • requires surgery to restore neural continuity
      • regeneration is incomplete
    5th degree
    • Complete transaction of the nerve
    • Requires surgery to restore neural continuity
    6th degree
    • Mixed nerve injury
      • that combines other degrees of nerve injuries


    Tinel sign

    • Light percussion on the nerve with a patellar hammer
      • from distal to the proximal end
    • A tingling sensation is experienced at the level of regeneration
      • As the regeneration of the axon grows, the level of tingling sensation also shifts
    • Absent in neuropraxia

    Denervation hypersensitivit


    • Following a section (cut) of a motor nerve
    • Pathology
      • A deficiency of chemical messenger (due to denervation) generally produces an up-regulation of its receptors
      • Acetyl choline receptors increase
        • more than 10 folds in number
        • dispersed over the entire surface of the sarcolemma
      • Sensitivity of the receptors towards acetylcholine increases
        • (desperate to be innervated)
    • Denervation also lowers the membrane potential
      • Muscles more prone to fibrillations
    • After regeneration
      • functional innervation of the muscle is reestablished and sensitivity to acetyl choline decreases
      • resting membrane potential is restored
        • fibrillation disappears after regeneration
    • Other muscles
      • Smooth muscle
        • does not atrophy when denervated
        • becomes hyperresponsive to the chemical mediator that normally activates it
      • Denervated exocrine glands [except sweat glands]
        • become hypersensitive
        • due to the synthesis or activation of more receptors
        • A deficiency of chemical messenger generally produces an up-regulation of its receptors
          • Lack of reuptake of secreted neurotransmitters because pre-synaptic nerve is not present
          • Therefore excess neurotransmitters in the ‘synaptic space’ –> hyperreactivity of muscles
      • Multiple sclerosis
        • Demyelination of oligodendrocytes in the central nervous system & Schwann cells in the peripheral nervous system
        • Disruption of connection between upper motor neurons & the lower motor neurons
        • Can cause
          • increased muscle tone
          • difficulty controlling muscles
          • exaggerated reflexes
          • muscle spasms

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