1. Pathophysiology of Peripheral Nerve Lesions
David A. Lake, PT, PhD
Department of Physical Therapy
Armstrong Atlantic State University
Savannah, GA

2. Anatomy of Peripheral Nerves
Peripheral nerves are composed of many nerve fibers (axons) bundled together by connective tissues

3. Anatomy of Peripheral Nerves
Each axon is surrounded by a connective tissue layer called the endoneurium

4. Anatomy of Peripheral Nerves
Axons are grouped together into fascicles, and each fascicle is surrounded by another connective tissue layer, the perineurium

5. Anatomy of Peripheral Nerves
Fascicles are grouped together, covered by an outer connective tissue layer, the epineurium, to form a peripheral nerve

6. Anatomy of Peripheral Nerves
These connective tissue layers protect the nerve axons from injury

7. Damage to Peripheral Nerves
Nerve injury is classified by the extent of the injury to the nerve into one of 3 classification
Neurapraxia
Axonotmesis
Neurotmesis

8. Damage to Peripheral Nerves
Neurapraxia
Defined as failure of conduction in a nerve in the absence of structural changes, due to compression or ischemia
Lack of conduction through the area of compression but conduction above and below the compression
Return of function normally ensues.

9. Damage to Peripheral Nerves
Neurapraxia
Histological analysis shows enlargement at the site of entrapment secondary to  in thickness & amount of perineurial and endoneurial connective tissues.
Normal Nerve
Compressed Nerve

10. Damage to Peripheral Nerves
Neurapraxia
Occasionally compression can result in only slowed conduction through the region due to widened nodal regions (formerly referred to as axonostenosis)
Sites of slowing often just distal & proximal to the site of compression
Symptoms of compression (pain, numbness & paraesthesias) are more common and more intense when compression is combined with peripheral ischemia

11. Damage to Peripheral Nerves
Neurapraxia
Characteristics more associated with the degree of compression include:
Amount of Action Potential slowing
Decrease in sensory evoked potentials and sensory NCV.
Numbness
Amount of muscle denervation
Muscle weakness & wasting

12. Damage to Peripheral Nerves
Neurapraxia
Characteristics more associated with ischemia include:
Acute pain
paraesthesias - particularly those of intermittent character

13. Damage to Peripheral Nerves
Neurapraxia
Pain may be the result of direct irritation of the abnormal spectrum of surviving nerve fibers (small > survival than large)
Paraesthesias may result from spontaneous activity in the entrapped fibers resulting from ischemia

14. Damage to Peripheral Nerves
Neurapraxia - Levels of Severity
Pre-symptomatic -  in perineural and endoneural microvasculature
Minimal - perineurial and epineurial fibrosis without changes in the nerve fibers
Moderate - thinning of myelin in large myelinated fibers
Severe - change in distribution of fiber sizes with dramatic  in large myelinated fibers and proportional  in small unmyelinated fibers

15. Damage to Peripheral Nerves
Axonotmesis
Nerve injury characterized by:
Disruption of the axon and myelin sheath distal to crush
Preservation of the endoneurium, perineurium & epineurium

16. Damage to Peripheral Nerves
Axonotmesis
Conduction block occurs immediately across the site of injury
Followed by irreversible loss of excitability of the nerve impulse beginning at the neuromuscular junction and then spreads proximally over the length of the distal segment
Little change in the proximal segment at least initially

17. Damage to Peripheral Nerves
Axonotmesis
Initially, conduction testing proximal to injury cannot distinguish between neuropraxia & axonotmesis
Once Wallerian degeneration completes its process, proximal nerve conduction velocity can be expected to be decreased by 30-40% of normal.

18. Damage to Peripheral Nerves
Axonotmesis
Wallerian degeneration results and takes 3-5 days
Degeneration lasts for several days prior to any regenerative activity in the distal ends of the damaged nerve
Regeneration occurs at a rate of 1 mm/day on average assuming normal oxygen tissue tensions
Generally the prognosis for recovery is good

19. Damage to Peripheral Nerves
Wallerian Degeneration - characterized by:
Axonal enlargement into an amorphorous mass
Breakdown of the axons, and schwann cell
Ingestion of fragmented myelin to provide clean endoneural tubes for advancement of regenerating axons  

20. Damage to Peripheral Nerves
Wallerian Degeneration 

21. Damage to Peripheral Nerves
Wallerian Degeneration - characterized by:
Cell body increases in size and nucleus migrates to the cell periphery
Proximal nerve segment degeneration extends proximally to the next node of Ranvier and is proportional to the severity of injury

22. Damage to Peripheral Nerves
Wallerian Degeneration - characterized by:
Distal nerve segment has:
Schwann cell proliferation
Collapse of endoneurium
Entire axonal material is phagocytosed from the site of injury to the endplates

23. Damage to Peripheral Nerves
Wallerian Degeneration - Regeneration
Within 96 hours of the injury, the proximal end of the nerve fiber sends out sprouts towards distal connective tissue tubes
The sprouts are attracted by growth factors produced by Schwann cells in the tubes

24. Damage to Peripheral Nerves
Neurotmesis 
Partial or complete severance of a nerve
Disruption of the axon and its myelin sheath and the connective tissue elements
Regeneration may occur if peripheral distruption is incomplete but often the pattern and rate of regeneration in those cases amy be abnormal

25. Damage to Peripheral Nerves
Neurotmesis 
With complete severance of a nerve regeneration does not occur
If regeneration does not occur often the nerve endings bundle up to form a neuroma

26. Damage to Peripheral Nerves
Cell Body Changes 
Large neurons have abundant rough endoplasmic reticulum (RER) which forms aggregates, the Nissl granules
If the axon is transected, the RER disaggregates and neuronal cell body swells
Normal Neuron
Neuron with Transected Axon

27. Damage to Peripheral Nerves
Cell Body Changes 
Cytoplasm becomes smooth and the nucleus is displaced toward the periphery
This appearance is called retrograde or central chromatolysis
Neurons can die if damage is substantial
Normal Neuron
Neuron with Transected Axon (chromatolysis)

28. Radiculopathy
Damage along a peripheral nerve is often secondary to entrapment
Entrapment can occur at particular places along a peripheral nerve where the nerve is in a confined space where pressure can be applied
This begins with the nerve roots and trauma to the nerve roots is called radiculopathy

29. Radiculopathy Anatomy of the Spinal Nerves
Dorsal and ventral roots leave the spinal cord and merge to form the spinal nerve
31 pairs:
8 cervical
12 thoracic
5 lumbar
5 sacral
1 coccygeal

30. Radiculopathy Anatomy of the Spinal Nerves
Spinal nerves pass out through the intervertebral foramina (IVF)
Cervical nerves exit above their similarly numbered vertebra
C8 nerve exits below C7 vertebra

31. Radiculopathy Anatomy of the Spinal Nerves
Thoracic & lumbar nerves exit below their similarly numbered vertebra
Sacral nerves exit through the sacral foramina
Coccygeal nerves exit just lateral to the coccyx bone

32. Radiculopathy Anatomy of the Spinal Nerves
In cervical & thoracic spinal segments the spinal roots and nerves exit the IVF almost immediately upon arising from the spinal cord
However the spinal cord ends between L1 and L2 vertebrae

33. Radiculopathy Anatomy of the Spinal Nerves
At that point spinal nerves must descend in the spinal canal to their level of exit
The descending spinal nerves form the cauda equina (horse tail)
Spinal nerve length from spinal cord to foramen varies widely

34. Radiculopathy Anatomy of the Spinal Nerve
As it exits the IVF the spinal nerve bifurcates into dorsal and ventral rami
Dorsal ramus passes dorsal to ligament of the transverse process to innervate the muscles and skin of the back
1. Spinal Nerve Sympathetic
2. Intervertebral foramen Ganglion
3. Pedicle
4. Superior articular facet
5. Transverse process
6. Spinous process
7. Ligament of the transverse process
8. Dorsal ramus of spinal nerve
9. Ventral ramus of spinal nerve
10. Vertebral body
11. Intervertebral Disc

35. Radiculopathy Anatomy of the Spinal Nerve
Ventral ramus runs ventral to ligament of the transverse process to innervate the muscles and skin anterior trunk and extremities
1. Spinal Nerve Sympathetic
2. Intervertebral foramen Ganglion
3. Pedicle
4. Superior articular facet
5. Transverse process
6. Spinous process
7. Ligament of the transverse process
8. Dorsal ramus of spinal nerve
9. Ventral ramus of spinal nerve
10. Vertebral body
11. Intervertebral Disc

36. Radiculopathy
Contents of inter-vertebral foramen (area of picture where 1 & 2 are):
Spinal nerve
Dorsal root ganglion when more laterally located
Connective tissue - dural sleeve & loose areolar connective tissue
Fat
1. Dorsal root ganglion Gray matter
2. Ventral root White matter
3. Pia mater Spinal Nerve
4. Arachnoid
5. Dura mater
6. Dorsal root
7. Subarachnoid space

37. Radiculopathy Contents of inter-vertebral foramen: Radicular artery
Veins vertebral foramen
Veins communi -cating between internal and external venous plexuses
2-4 recurrent meningeal nerve branches
Not labeled are the radicular artery & communicating veins which are the large red and smaller blue objects respectively just below 1) Dorsal root ganglion and 2) the ventral root.
Not shown are the recurrent meningeal nerves branches

38. Radiculopathy Meningeal Coverings
Dural sleeve (dura & arachnoid) and pia mater with CSF in subarachnoid space extend most of the length of the spinal nerve as it passes through the IVF
Dural sleeve ends and is contiguous with epineurium of spinal nerve
1. Dorsal root ganglion Gray matter
2. Ventral root White matter
3. Pia mater Spinal Nerve
4. Arachnoid
5. Dura mater
6. Dorsal root
7. Subarachnoid space

39. Radiculopathy Dorsal Root Ganglion Variable positioning within IVF
Most sensitive to injury if medially located from osteophytes & posterolateral disc herneation
Highly vascularize so exposured to mediators of inflammation
1. Dorsal root ganglion
2. Ventral root
3. Pia mater
4. Arachnoid
5. Dura mater
6. Dorsal root
7. Subarachnoid space
8. Gray matter
9. White matter
10. Spinal Nerve

40. Radiculopathy Dorsal Root Ganglion
Peripheral nerve fibers of different sizes are mixed within the nerve
As peripheral nerve approaches DRG
Large caliber fibers are more dorsomedial
Small caliber fibers are more anterolateral
1. Dorsal root ganglion
2. Ventral root
3. Pia mater
4. Arachnoid
5. Dura mater
6. Dorsal root
7. Subarachnoid space
8. Gray matter
9. White matter
10. Spinal Nerve

41. Radiculopathy Primary causes of compression include: Protruding discs
Osteophytes of uncovertebral region
Posterior narrowing
Superior articular process
Ligamentum flavum
Periradicular fibrous tissues

42. Radiculopathy Factors that contribute to pain with disc herniation:
protrusion of disc material
Distention secondary to water-polyglycan content
Inflammatory interface between fragment and the nerve root

43. Radiculopathy
Compression of spinal nerve influenced by head & trunk posture
IVF volumes  with flexion
IVF volumes  with extension
Most pronounced in the cervical spine
Extension
Flexion

44. Radiculopathy
Compression of spinal nerve influenced by head & trunk posture
Cervical rotation further  IVF volume ipsilateral to the rotation direction
 IVF volume contralateral to the rotation direction

45. Radiculopathy
Compression of spinal nerve influenced by head & trunk posture
Spurling's test for radiculopathy is a reproduction of pain with rotation and extension of the neck

46. Radiculopathy
Compression of spinal nerve influenced by head & trunk posture
Extension of the cervical spine relaxes the spinal nerve root
Relaxing the nerve  its diameter
The nerve dural sleeve is relaxed and thicker so fills more of the IVF
 compression is applied to the spinal nerve
Flexion stretches, straightens and thins nerve and the sheath and thus  spinal nerve compression

47. Radiculopathy Inflammation similar to seen elsewhere:
 phospholipid A activity which produces PGE2 & leukotrienes
 Nitric oxide
 Cytokine release - such as interleukins, TNF-
Macrophage invasion into inflamed site

48. Radiculopathy Sequence of Events    
COMPRESSION  edema  fibroblast invasion
 
INJURY TO THE NERVE  fibrotic tissues
 
 risk of  adhesion of
traction injuries  the nerve which
to the nerve immobilizes it

49. Radiculopathy Classic Signs and Symptoms Sensory Abnormalities Pain
Paresthesia
hypesthesia & numbness
hypesthesia and numbness often follow dermatomal patterns
pain & paresthesia may of may not follow dermatomal patterns depending upon if there is paraspinal muscle involvement

50. Radiculopathy Classic Signs and Symptoms Sensory Abnormalities
Progression from neuropraxia to axonotmesis from conduction block to discontinuity of the axons
There may be regeneration if axonotmesis, but if spouting occurs locally without regeneration can form neuromas which may be the cause of "electric pain" sensations
 nerve irritability - hypersensitivity of the nerve to compression and stretch

51. Radiculopathy Classic Signs and Symptoms
 DTRs - muscle stretch reflexes
Paresis - muscle weakness
Muscle atrophy
Dysautonomia & trophic changes (pilomotor, sweating, skin changes) are most associated with peripheral nerve damage but can also occur with radiculopathy

52. Radiculopathy Classic Signs and Symptoms Complex pain patterns
Can be myotomal or sclerotomal as well as dermotomal patterns
 incidence of peripheral pain syndromes such as complex regional pain syndrome - CRPS (previously called reflex sympathetic dystrophy - RSD)

53. Radiculopathy
Diagnosis
Most commonly diagnosed using needle EMG

54. Radiculopathy Diagnosis
Only useful in diagnosis of motor nerve disturbances - not seen with dorsal root lesions (sensory only)
Seen as abnormal EMG activity in two or more muscles along same spinal nerve distribution (segmental innervation)
Abnormal EMG activity in the paraspinals

55. Radiculopathy Diagnosis Abnormal EMG activity is characterized by:
Prolonged or enhanced "insertional" activity

56. Radiculopathy Diagnosis Abnormal EMG activity is characterized by:
Spontaneous sharp positive waves and fibrillation of fasciculation potentials
Altered morphology of motor unit action potentials
Poor recruitment of MUAPs
If dorsal root disorder, normal MUAPs but slowed or blocked H-wave evoked reflex or diminished somatosensory evoked potentials

57. Radiculopathy Diagnosis Abnormal EMG activity is characterized by:
Spontaneous sharp positive waves and fibrillation potentials when normally not seen

58. Radiculopathy Diagnosis Abnormal EMG activity is characterized by:
Spontaneous fasciculation potentials when normally not seen

59. Radiculopathy Diagnosis Abnormal EMG activity is characterized by:
Altered morphology of motor unit action potentials from normal biphasic to polyphasic potentials
Normal biphasic motor unit action potentials (MUAP) superimposed upon motor endplate potentials (MEPP)

60. Radiculopathy Diagnosis Abnormal EMG activity is characterized by:
Altered morphology of motor unit action potentials from normal biphasic to polyphasic
Abnormal polyphasic MUAPs

61. Radiculopathy Diagnosis Abnormal EMG activity is characterized by:
Poor recruitment of MUAPs seen as decreased maximal activity (interference pattern) when maximal voluntary contraction
Normal
Reduced

62. Radiculopathy Diagnosis Abnormal EMG activity is characterized by:
If dorsal root disorder, normal MUAPs but slowed or blocked H-wave evoked reflex
Normal H-reflex
Slowed H-wave
Blocked H-reflex

63. Radiculopathy What is an H-reflex? Electrical stretch reflex
Stretch reflex - stretched muscle reflexively contracts

64. Radiculopathy What is an H-reflex?
Electrically stimulate nerve to muscle so stimulate both sensory afferent (Ia) and motor efferent
Record from muscle
Stimulate nerve to muscle which includes both motor & sensory fibers
Record electrical activity in the muscle

65. Record electrical activity in the muscle
Radiculopathy
What is an H-reflex?
When stimulate motor fibers there is a short distance traveled
A short distance traveled will produce a short latency potential recorded from muscle
Stimulate motor fibers
Record electrical activity in the muscle

66. Record electrical activity in the muscle
Radiculopathy
What is an H-reflex?
When stimulate sensory fibers there is a long distance traveled
A long distance traveled will produce a long latency potential recorded from muscle
Stimulate sensory fibers
Record electrical activity in the muscle

67. Radiculopathy What is an H-reflex?
So when you stimulate the nerve from a muscle, stimulation of the motor fibers will produce a short latency potential recorded in muscle (M-wave)
M-wave
Stimulus

68. Radiculopathy What is an H-reflex? Motor  M-wave Sensory  H-wave
Short distance
Short latency (time from stimulus to recorded potential)
Sensory  H-wave
Long distance
Long latency
M-wave
H-wave
Stimulus

69. Radiculopathy If damage is along the dorsal root
There should be no effect on the motor response (M-wave)
However the sensory response (H-wave) should be blocked X
M-wave
Site of Damage X
H-wave
Stimulus

70. Radiculopathy
Loss of only H-wave is seen with damage along the dorsal root
Before Damage intact M-wave & H-wave
Site of Damage X
After Damage loss of only H-wave X

71. Radiculopathy What is an H-reflex?
So when you stimulate the nerve from a muscle, stimulation of the motor fibers will produce a short latency potential recorded in muscle (M-wave)