PNS

• Pathology of peripheral nerves and skeletal muscles
• Complex group of disorders that typically present with


  • Weakness
  • Muscle pain
  • Sensory deficits
• May be inherited or acquired
• Grouped according to anatomy, disease course, and pathogenesis
• Two components of peripheral nerves involved in impulse transmission


  • Axons
  • Myelin sheaths made by Schwann cells

  
• Injury to these two components


  Result in a peripheral neuropathy
• Components of the somatic motor function


  • Lower motor neuron located in the anterior horn of the spinal cord or in the brainstem
  • An axon that travels in a nerve to a target
  • Neuromuscular junctions
  • Multiple innervated myofibers (muscle fibers)

  
• Components of the somatic sensory function


  • Distal nerve endings – may contain specialized structures that serve to register specific sensory modalities
  • A distal axon segment – travels as part of a peripheral nerve to the dorsal root ganglion
  • Proximal axon segment – synapses on neurons in the spinal cord or brainstem

  
• Autonomic nerve fibers transmit all visceral motor and sensory functions and outnumber somatic fibers in the peripheral nervous system
• Signs and symptoms related to autonomic nerve fiber involvement are generally not prominent features of peripheral neuropathies, with a few important exceptions (e.g., cases of diabetic neuropathy)
• Axons distinguished by diameter


  • Thin unmyelinated fibers - mediate autonomic functions, pain and temperature sensations, have slowest conduction speeds
  • Large diameter axons - with thick myelin sheaths transmit light touch and motor signals, have fast conduction speeds
• Myelinated axons


  Individual Schwann cells make exactly one myelin sheath that wraps around a single axon to create a myelinated segment called internode
• Nodes of Ranvier


  Internodes are separated by unmyelinated gaps, uniformly spaced along the length of the axon
• Relationship between lipid bilayers and associated proteins in myelin within internodes. Mutant forms of certain proteins cause some forms of Charcot-Marie-Tooth disease, a hereditary demyelinating neuropathy.
• Unmyelinated axons are intimately associated with Schwann cells but in a different arrangement in which one cell surrounds segments of multiple axons
• Most peripheral nerves carry out both motor and sensory functions and thus contain axons of varying diameter and myelin thickness
• Axons are bundled together by three major connective tissue components


  • Epineurium - encloses the entire nerve
  • Perineurium - a multilayered connective tissue sheath that groups subsets of axons into fascicles
  • Endoneurium - surrounds individual nerve fibers
• Axons are the primary target of damage in this large group of peripheral neuropathies
• Wallerian degeneration


  • Portions of axons distal to the point of transection degenerate
  • Distal axons fragment, associated myelin sheaths unravel and disintegrate
• Macrophages are recruited to remove axonal and myelin debris
• Axonal regeneration


  1. Formation of a growth cone

  2. Outgrowth of new branches from the stump of the proximal axon

  3. Schwann cells and their associated basement membranes guide the sprouting axons

  4. Continuous pruning of the sprouting axons removes misguided branches

  5. Schwann cells create new myelin sheaths around the regenerating axons
• Regeneration is successful only if the two transected ends remain closely approximated
• Traumatic neuroma


  Pseudotumor, failure of the outgrowing axons to find their distal target, a nonneoplastic haphazard proliferation of axonal processes and associated Schwann cells that results in a painful nodule
• Changes observed following experimental nerve transections only partially resemble those seen in various axonal neuropathies

  
• Electrophysiologic hallmark of axonal neuropathies: Reduction in signal amplitude owing to the dropout of axons from affected peripheral nerves, with relative preservation of conduction velocity
• Demyelinating neuropathies


  • Schwann cells with their myelin sheaths are the primary targets of damage
  • Axons are relatively preserved
  • Individual myelin sheaths degenerate in a seemingly random pattern
  • Schwann cells or Schwann cell precursors proliferate and initiate repair through the formation of new myelin sheaths, which tend to be shorter and thinner than the original ones
• Electrophysiologic hallmark of demyelinating neuropathies: Slowed nerve conduction velocity, reflective of the loss of myelin
• Neuronopathies


  Result from destruction of neurons, leading to secondary degeneration of axonal processes
• Examples of insults that may lead to neuronopathies


  • Infections like herpes zoster
  • Toxins like platinum compounds
• Damage in neuronopathies is at the level of the neuronal cell body, so peripheral nerve dysfunction is equally likely to affect proximal and distal parts of the body
• Anatomic patterns of peripheral neuropathies


  • Mononeuropathies - affect a single nerve
  • Polyneuropathies - involve multiple nerves, usually in a symmetric fashion
  • Mononeuritis multiplex - damages individual nerves in a haphazard fashion
  • Polyradiculoneuropathies - affect nerve roots as well as peripheral nerves

  
• Symptoms of peripheral neuropathies


  • Numbness
  • Painful "pins and needles" sensations
  • Weakness, most often in the distal portions of the extremities
• Causes of peripheral nerve damage


  • Inflammatory diseases
  • Infections
  • Metabolic changes
  • Toxic injury
  • Trauma
  • Paraneoplastic disease
  • Inherited gene defects
• Guillain-Barré syndrome


  An immunologically mediated demyelinating peripheral neuropathy that can lead to life-threatening respiratory paralysis
• Guillain-Barré syndrome has an incidence of approximately 1 case per 100,000 persons
• Clinical manifestation of Guillain-Barré syndrome


  • Weakness beginning in the distal limbs that rapidly advances to affect proximal muscle function ("ascending paralysis")
• Histologic features of Guillain-Barré syndrome: Inflammation and demyelination of spinal nerve roots and peripheral nerves (radiculoneuropathy)
• Pathogenesis of Guillain-Barré syndrome


  Thought to be an acute-onset immune-mediated demyelinating neuropathy, often preceded by an acute, influenza-like illness
• Epidemiologic associations of Guillain-Barré syndrome


  • Campylobacter jejuni
  • Cytomegalovirus
  • Epstein-Barr virus
  • Mycoplasma pneumoniae
  • Prior vaccination
• No infectious agent has been demonstrated in affected nerves, so an immunologic reaction is favored as the underlying cause of Guillain-Barré syndrome