Degeneration & regeneration of peripheral nerves

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

Chromatolysis

• 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

Pathophysiology

• 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

Summary:

Transneural degeneration

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

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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)

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
y

• 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