Nerve Root Pathophysiology

Richard C Rooney, MD, FACSrrooney@seattlespinegroup.com

Symptomatology-Different physiological events• Pain• Nerve root dysfunction

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

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

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

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.

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

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

Multiple levels of compression• Substance P (neurotransmitter) increases in compression…no good studies…may be adaptation

» Cornefjord, Spine ‘95

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

Questions?

Thank you

rrooney@seattlespinegroup.com

Confidential