Nerve root pathophysiology.

1. Nerve Root Pathophysiology
Richard C Rooney, MD, FACS
rrooney@seattlespinegroup.com

2. Symptomatology-Different physiological events
• Pain
• Nerve root dysfunction

3. Mechanisms
• 2 mechanisms at tissue level
• Mechanical deformation of the nerve roots
» Mixter, NEJM ’34
» Bailey, J Nerv Ment Dis ’11
» Goldthwait, Boston Med Surg J ’11
» Sachs, J Nerv Ment Dis ‘00
• Effect of nucleus pulposus on nerve root
» Olmarker, Spine ‘93

4. Mechanical Effects
• Peripheral nerves and nerve roots are different
• Peripheral nerves have greater connective tissue content so
they are more resistant to deformation
» Gelfan, Am J Physiol ’56
» Sharpless, NIH workshop, ‘75

5. Experimental nerve root compression
• Pig cauda equina nerve root compression model
» Olmarker, Spine ’91 & Acta Orthop Scan ‘91
– Occlusion pressure ≈ venous stasis pressure
» Sunderland, J Neurol Neurosurg Psych ‘76
– ↓blood flow ↓ nutrition ↓ function
– Occlusion(ischemia) leads to increase vascular permeability, edema,
and fibrosis
» Rydevik, Scan J Plastic Rec Surg ’76 & ‘77

6. Experimental nerve root compression model. The cauda equina (A) is compressed by an inflatable
balloon (B) that is fixed to the spine by two "L"-shaped pins (C) and a Plexiglas plate (D).
From Olmarker K, et al., Experimental nerve root compression. A model of acute, graded compression of the porcine cauda equina and an analysis of neural and vascular
anatomy. Spine 1991;16(1):61-69.

7. Experimental nerve root compression
• In short term 50-75 mmHg pressure on roots decreases
monophasic action potential
• Sensory more susceptible than motor to compression
» Pedowitz, Spine ’92
» Rydevik, Spine ‘91
• More susceptible if BP is lowered
» Garfin, JBJS Am ‘90

8. Rate of onset
• Rapid onset
– induces more edema
» Olmarker, Spine ’89
– decreases methylglucose transport
» Olmarker, J Spinal Dis ’90
– and decreases impulse propagation more than slow onset
» Olmarker, Spine ‘90
• Reasons and mechanisms of difference are unclear but shear and creep
are implicated

9. Multiple levels of compression
• Substance P (neurotransmitter) increases in compression…no
good studies…may be adaptation
» Cornefjord, Spine ‘95

10. Experimental-Clinical correlation
• 75mm2 cross sectional area correlates with increased root
pressure in cadavers which correlates with CT scans in
symptomatic patients
» Schonstrom, Spine ’84 & ‘85

11. Mechanical deformation and pain
• Nerve root pressure correlates with deficits but not amount of pain with
SLR
» Takahashi, Spine ‘99
• Mechanical nerve deformation
– induces impulses
» Howe, Pain ‘77
– dorsal root ganglion most sensitive
» Cavanaugh, CORR ‘97
– neurotransmitters related to pain increased in DRG
» Cornefjord, Spine ’95
» Weinstein, Spine ‘88

12. Neuropathology and pain
• Apoptosis or necrosis
• Mild ischemia producing demyelination (apoptosis of schwann
cells) generally not painful
» Powell, Lab Invest ’86
» Myers, Anesthesiology ‘93
• Severe ischemia producing necrosis of schwann cells and
wallerian degeneration results in hyperalgesia

13. Neuropathology and pain
• Cytokine driven process of wallerian degeneration is the link
between nerve injury and pain
– Degree and extent of wallerian degeneration relates directly to
magnitude and duration of hyperalgesia
» Myers, Anesthesiology ’93
» Stoll, J Periph Nerv Syst ’02
» Myers, Cytokines and Pain ’99
» Myers, J Neurol Sci ’96

14. Biological effects of disc tissue
• HNP inflammatory effect and injury to Schwann cells
» Rydevik, Acta Orthop Scan ’83
» McCarron, Spine ’87
» Olmarker, Spine ’96 & ’97
» Kayama, Spine ‘96
• HNP leads to intraneural edema and decreased intraneural blood flow
by 2 hours
» Byrod, Eur Spine J ’98 & J Orthop Res ’02
» Yabuki, Spine ‘98
• Histologic change of nerve roots by 3 hours

15. Biological effects of disc tissue
• Decrease in nerve conduction velocity 3-24 hours after
application
• HNP increases vascular permeability which increases
intraneural edema which increases ischemia via chemotactic
effect
» Olmarker, Spine ’95
» Takino, ISSLS Trans. ‘95
• Pain is mediated by infiltrating leukocytes
» Kawakami, CORR ’00 & J Orthop Res ‘02
» Myers, Exp Neurol ’96

16. Nucleus pulposus and sciatic pain
• Displacement does not cause pain but displacement of nerve
root with an associated HNP does cause pain
» Olmarker, Pain ‘98
• Touching nerve root is not painful but touching nerve root
exposed to NP is painful
» Kuslich, Orthop Clin North Am ’91

17. Nucleus pulposus and sciatic pain
• Vascular impairment of the nerve tissue with a resultant
nutritional deficit that results in ischemia of the nerve seems
to be the likely pain mechanism
– Induced by both biological and mechanical factors

18. Mechanisms and transport routes
• HNP → inflammation
» Olmarker, Spine ’93 & ’95
» Takino, ISSLS Trans ’95
» Kawakami, CORR ’00
» Kang, Spine ’96
» Delcanto, J Neurol Sci ’75
» Hahn, Acta Neuropath ’80
» Bisla, CORR ’76
» Bobechko, JBJS ’65
» Gertzbein, Orthop Clin North Am ’75 & CORR ’77
» LaRocca, Orthop Clin North Am ’71
» Naylor, Ann Roy Col Surg ‘62

19. Seven days after the application of nucleus pulposus. Myelinated nerve fiber with prominent
vesicular swelling of a Schmidt-Lanterman incisure. Note the mononuclear cell (black M) in close
contact with the nerve fiber. A, Well-preserved axon; white M, myelin sheath; S, outer Schwann
cell cytoplasm. Arrowheads indicate myelin sheath layers outside the Schmidt-Lanterman
incisure.
Olmarker K, et al: Ultrastructural changes in spinal nerve roots induced by autologous nucleus pulposus. Spine 1996.

20. Components of the NP of discs
• Proteoglycans, collagen, cells
» Bayliss, The Lumbar Spine and Back Pain ’92
» Eyre, New Perspectives on Low Back Pain ‘88
• Proteoglycans have been implicated as having direct irritating effect on
nerve tissue
» Naylor, Ann Royal Col Surg ’62
» Marshall, Lancet ’73 & CORR ‘77
• Cells- killed(frozen) do not induce any change in nerve conduction
velocity
» Olmarker, Spine ’97
» Kayama, Spine ‘98

21. Cytokines as mediators of nerve dysfunction and
pain
• TNF
– Regulatory proinflammatory cytokine
– Has specific biologic effects
– Up regulates and acts synergistically with other cytokines (IL-1B, IL-6)
» Chao, Brain Behav Immun ’95
» Gadient, Neurosci Letters ’90
» Bluthe, Eur J Pharmacol ’91
» McHale, J Immun ’99
» Siwik, Circ Res ’00
» McGee, Immunology ‘95

22. TNF as mediator of nerve dysfunction and pain
• Immediately after nerve injury, TNF is released and up
regulated by
– Schwann cells
– endothelial cells
– fibroblasts
– mast cells.
» Wagner, Neuroscience ‘96

23. TNF as mediator of nerve dysfunction and pain
• Also produced by chondrocytes and disc cells
» Olmarker, Spine ’98
» Satomi, Jap J Exp Med ’81
» Bachwich, Am J Patho ’86
» Robbins, J Immunology ’87
» Sayers, J Immunology ’87

24. TNF as mediator of nerve dysfunction and pain
• The local production of TNF is the stimulus that attracts macrophages to
injury site which up regulates pro-inflammatory cytokines to the injured
tissue
» Stoll, J Peripher Nerv Syst ‘02
• Several studies have shown that blocking TNFα results in reduced or
delayed neuropathologic change and reduced hyperalgesia
» Myers, Exp Neurol ’96
» Sommer, Pain ‘98

25. TNF as mediator of nerve dysfunction and pain
• TNF induces axonal and myelin injury similar to NP application
» Wagner, Neuroreport ’96
» Igarashi, Spine ’00
» Liberski, Acta Neurobiol Exp ’94
» Madigan, Neurol Research ’96
» Redford, Brain ’95
» Selmaj, Ann NY Acad Sci ’88
» Stoll, J Neuroinnumol ‘93
– Intravascular coagulation
» Nawroth, J Exp Med ’88
» van der Poll, Blood ’96
» Watts, British J Cancer ‘96
– Increased vascular permeability
» Watts, British J Cancer ‘96

26. TNF as mediator of nerve dysfunction and pain
• TNF is neurotoxic
» Madigan, Neurol Res ’96
» Selmaj, Ann NY Acad Sci ’88
» Viviani, Toxicol Appl Pharmacol ’98
» Wuthrich, Am J Pathol ‘90
– Induces painful behavioral changes
» Wagner, Neuroreport ’96
» Sommer, Neurosci Lett ‘97
– Ectopic nerve activity
» Igarashi, Spine ’00
» Sorkin, Neuroscience ‘97

27. TNF as mediator of nerve dysfunction and pain
• TNF is sequestered in membrane bound form and is activated
after shedding by certain enzymes
– MMP-9, MMP-2 which are up regulated immediately after a nerve
injury
» Shubayev, Brain Res ‘00
• TNF is also in disc cells

28. TNF mechanism of action
• TNF induces an activation of endothelial adhesion molecules (ICAM and
VCAM) which adhere circulating immune cells to vessel walls
» McHale, J Immunol ’99
» Mattila, Scand J Immunol ’92
» Pober, Ciba Found Symp ‘87
• TNF induces vascular permeability which allows WBC’s to migrate to
endoneurial space where axons are located
» Creange, Eur Cytokine Network ’97
» Munro, Am J Pathol ’89
» Oku, J Biochem ‘87

29. TNF mechanism of action
• The cells release TNF
– Myelin injury
– Accumulation of Na channels
– Induction of allodynia
» Kagan, Science ’92
» Baldwin, Proc Natl Acad Science USA ’96
» Wei, Am J Physi Renal Phys ‘’03
• Na channels allow K+ and Na+ which results in spontaneous discharge
and discharge of ectopic impulses following mechanical stimulation
• TNF can cause spontaneous electrical activity in A-delta and C-
nociceptors
» Sorkin, Neuroscience ‘97

30. TNF mechanism of action
• These discharges regardless of whether they came from pain fiber or
another sensory fiber are interpreted by the brain as pain
» Woolf, Acta Neurochir Suppl ’93
» Attal, Acta Neurol Scand Suppl ’99
» Zimmermann, Eur J Pharmacol ’01
» Wall, Br Med Bulletin ‘91
• This mechanism may relate to the sensitization of nerve roots to
mechanical stimuli

31. TNF mechanism of action
• TNF disintegrates the myelin sheath
» Wagner, Neuroreport ’96
» Creange, Eur Cytokine Network ’97
» Selmaj, Ann Neurol ’88 & ’91
» Villarroya, J Neuroimmunology ‘96
– So does nucleus pulposus
» Olmarker, Spine ’96
» Kayama, Spine ‘96

33. Questions?
Thank you
rrooney@seattlespinegroup.com
Confidential