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CHAPTER 2/PATHOPHYSIOLOGY OF NERVE ROOT PAIN / 23
retrogradely transported from the site of nerve injury to
the DRG and spinal cord, it may be this proinflammatory
stimulus that activates central glia and neurons (153).
Apart from directly affecting the endoneurially located
axons, TNF may also indirectly interfere with the axons
by compromising the nutritional transport. It is known
that TNF may induce intravascular coagulation, similar to
nucleus pulposus, following local application (73,145,
154,186,187). This reduces the local blood flow in the
intraneural capillaries (75). A nutritional reduction induces ischemia in the nerve root, which may induce neuroischemic pain.
There is evidence that TNF may be an important mediator of nerve dysfunction and pain. The unfortunate circumstance that TNF is produced and released from cells
in the nucleus pulposus, when displaced from its natural
environment in the center of the intervertebral disc out
into the spinal canal in close contact to the nervous structures, may be one key event for the onset of nerve dysfunction and sciatic pain.
CYTOKINE INHIBITORS IN CLINICAL
STUDIES FOR THE TREATMENT OF SCIATICA
Based on the recent experimental findings that TNF
may both mimic nucleus pulposus–induced nerve dysfunction and pain, pilot clinical trials regarding the possible use of TNF inhibition for the treatment of sciatica
have been initiated. Karppinen et al. administered a monoclonal antibody specific for TNF (infliximab, Remicade) to 10 volunteers waiting for surgery for radiologically verified disc herniations with severe sciatica (188).
In this open-label study , infliximab reduced pain assessed
by the Visual Analogue Scale (VAS) by 50% 1 hour after
infusion. After 2 weeks, 60% of the patients were pain
free. Three months after the single infusion, 90% were
pain free. No adverse drug reactions were seen and no
patients required surgery.
Genevay et al. administered a TNF inhibitor in the
form of a soluble TNF-receptor (etanercept, Enbrel
[Immunex Corporation, Thousand Oaks, CA]) by three
subcutaneous injections to 10 patients with severe sciatica (189). Ten days after commencing the treatment, the
patients had a 70% reduction of VASL (leg pain assessed
by VAS). At 6 weeks the reduction was 83%. The results
were statistically significantly better than for seven
patients treated with three intravenous injections of
methylprednisolone.
Taken together, these preliminary, open-label observations strongly indicate a potential clinical effect of TNF
inhibition for the treatment of sciatica. It may be surprising that TNF inhibition seems to be so much superior to
anti-inflammatory treatment by NSAID or methylprednisolone or even morphine. One may conclude that it is
more efficient to act at the responsible mediators directly
than aiming at general anti-inflammatory effects. This
clinical comparison strongly supports the TNF hypothesis
of neuropathic pain (67,125,154). Sciatica has a neuropathic pain component; nonspecific anti-inflammatory
medication and morphine are less eff icient in such conditions. Nevertheless, it must be remembered that clinical
studies so far have only been open label and the role of
TNF inhibition must be evaluated in randomized, prospective studies before any conclusions regarding its efficacy
for the treatment of sciatica may be drawn (190).
SILENT DISC HERNIATIONS AND LOW BACK
PAIN
The relationship between the herniated disc and sciatica may seem well established. However, circumstances
imply that we are still unaware of some mechanisms. For
instance, why do approximately one third of all persons
who have never suffered from sciatica have disc herniations that may be visualized by radiology? If the presence
of a disc hernia is a prerequisite for sciatica, why do not
all patients displaying disc herniations hav e sciatica? Sciatica is a special form of pain, which (unlike low back
pain) is sharp, distinct, and usually located to the distribution area of one spinal nerve root segment. It is most
likely a form of neuropathic pain (i.e., pain resulting from
direct pathology of the involved nerve), and it is likely
that sciatica may occur because of irritation or injury of
the nerve root in the spinal canal adjacent to a herniated
disc. As described, recent research has demonstrated that
the pathology leading to nerve root pain (i.e., sciatica) is
based on the combined action of a sensitization of the
nerve by proinflammatory cytokines derived from the
intervertebral disc cells and simultaneous mechanical
deformation of the nerve root (58,60,191). Thus, from an
experimental standpoint it seems necessary that there is
both a sensitization and mechanical deformation in order
to produce pain, and that disc leakage or mechanical
deformation per se do not produce pain, at least not at
detectable levels.
It can be demonstrated that acute injection (experimental herniation) of nucleus pulposus material into the
spinal canal does not result in nerve root compression.
Instead, the gel-like nucleus pulposus spreads among the
intraspinal nervous structures, almost reaching the adjacent disc levels (Fig. 2-8). This is most likely what happens when there is an acute herniation when the semiliquid nucleus pulposus leaks through a rupture of the
annulus fibrosus (Fig. 2-9A,B). Later, the herniated
nucleus pulposus is partly resorbed and a healing process
around the site of rupture at the surface of the disc is initiated. This may result from a reactive process induced by
the cytokine activity of the disc, which significantly activates fibroblastic processes. The result, based on the
degree of resorption and scar formation, is a slight
rounded scar over the rupture site of the disc (Fig. 2-9C).
This scar is probably what is refer red to as a herniated
24 /SECTION I/BASIC SCIENCE
A
C
FIG. 2-8. Epidural injection of nucleus pulposus in the pig lumbar spine studied by radiology. Nucleus
pulposus was obtained from another pig. A: The abdomen was incised and a needle connected to a
syringe with nucleus pulposus mixed with Mixobar and Urografin was introduced into the disc from the
abdominal side.The tip of the needle was placed in the epidural canal, just penetrating the dorsolateral
annulus fibrosus. B: The nucleus pulposus in an amount approximately corresponding to one intervertebral disc was gently injected into the spinal canal, resembling an acute herniation (black).The injected
material spread in the spinal canal, almost reaching both adjacent disc levels. C: In the antero-posterior view it was seen that the injected material was mainly located on the side of the injection. An asterisk indicates the injection site. D: Thir ty minutes after the injection, the lumbar segment was removed
and the specimen was radiographed in the axial direction.It was seen that the injected material (1) after
injection from the dorsolateral aspect of the disc (2) was located in the epidural space, outside the thecal sac (3). The thecal sac was displaced slightly to the contralateral side to the injection (left). The
nerve root adjacent to the injection site (4) did not seem to be compressed. Instead, it was covered by
the injected material on the dorsal side.
B
D
disc in the clinical setting. Because of the absence of a
mechanical factor, the patient has not experienced any
neuropathic pain (i.e. sciatica) during this process and the
disc hernia is called a “silent disc herniation” when
encountered by radiology. However, because local application of nucleus pulposus is known to induce reduced
nerve function in experimental models, one may assume
that the patient may suffer from various degrees of
reduced sensibility and motor function during the leakage
of nucleus pulposus material, maybe at a subclinical
level. Likewise, if there is already mechanical compres-
sion of the nerve root (e.g., by lateral canal stenosis or an
osteophyte), the sensitization of the nerve root induced by
cytokines from the leaking disc may induce sciatic pain.
However, no disc herniation is seen by radiology or at
surgery in this case. Repeated episodes of leakage may
result in a larger scar at the disc surface and there may be
a build-up of a scar. At some point the scar will be large
enough to interact with the nerve root mechanically. A
new leakage of disc material at this point therefore may
induce both a sensitization of the nerve root and mechanical deformation by the disc herniation scar, and there
CHAPTER 2/PATHOPHYSIOLOGY OF NERVE ROOT PAIN / 25
FIG. 2-9. Formation of a disc herniation.A: The nerve root (1)
and the central thecal sac with nerve roots and at some levels
the spinal cord (2) are located just dorsal to the intervertebral
disc with its connective tissue ring annulus fibrosus (3) and its
semiliquid center nucleus pulposus (4). B: If the annulus fibrosus ruptures there may be a leakage or herniation of nucleus
pulposus, as indicated by the blac k arro w out onto the surface
of the disc and into the spinal canal (5). The surface of the disc
is innervated by local sensory nerve endings (6) and the
nucleus pulposus may irritate and stimulate these nerve endings. Because this leakage is not combined with any compression of the nerve root, there will not be any sciatic pain.
C: The disc herniation heals and becomes organized, and a
dense scar will form (7). This dense herniation scar may compress the nerve root (1) mechanically but because the biologic
activity of the herniated intervertebral disc is now reduced,
there is no radicular pain. This is what is called a “silent disc
herniation” when accidentally found at radiologic examination.
D: At later her niations the newly herniated nucleus pulposus
material (8) will reach the ner ve root. In this case, the combined action of the nucleus pulposus and the previous scar tissue (7) induce nerve root pain (i.e., sciatica).
may be neuropathic or sciatic pain in that specific nerve
root (Fig. 2-9D). Radiology at this time reveals the scar
from the previous leakage and, rightfully, is regarded as
the cause of the present problems, although not in the
sense previously assumed.
One also may consider if the so-called silent disc is
silent. As discussed, patients may have discrete reduction
in sensory and motor function in the early phases of a new
disc leakage. How e ver , w e also kno w that there are sensory
nerve endings at the surface of the intervertebral disc
(192–195). Because many of the substances produced and
released from the disc cells may be neurotoxic and neuroirritative, they may stimulate the local nerves at the disc
surface. Cavanaugh et al. sho w ed that silent receptors at the
disc surface are triggered by a proinflammatory substance
such as carrageenan (196). Disc-derived proinflammatory
cytokines may have a similar action. Although pain from
sensitization of a nerve root with locally derived ectopic
nerve impulses from the axons induces a sharp neuropathic
pain in the corresponding dermatome of that specific nerve
root, the pain derived from local stimulation of nerve endings has a different localization and different characteristics. Kuslich et al. sho w ed that local stimulation of the posterior surface of the disc in conscious volunteers results in
a dull pain in the lumbar area, and suggests that the poste-
rior disc surface is the site of low back pain (88). Taken
together, ir ritation of local nerve endings by disc-derived
substances might induce spontaneous discharges that
induce low back pain in relation to a herniation of disc
material into the spinal canal. We speculate that each time
there is a leakage of disc material there is an episode of low
back pain. In relation to the previous discussion about
repeated episodes of disc leakage leading to a disc herniation scar that eventually will mechanically affect the adjacent nerve root, one may assume that there will be repeated
episodes of back pain as well. Repeated episodes of low
back pain are common in patients with sciatica, and low
back pain is in fact the strongest predictor of sciatica (197).
This clinical observation thus may closely relate to this
speculative scenario. It is also common that sciatica is preceded by sev eral days of low back pain, which based on the
previous discussion may be e xplained as direct stimulation
of nerve endings of the disc surface before the sensitization
of the nerve root and the subsequent neuropathic pain
develops. Silent disc herniations (i.e., leakage of nucleus
pulposus without sciatica) may thus be silent with respect
to sciatica, but may be a not pre viously recognized mechanism for low back pain.
CONCLUSIONS
The pathophysiology of sciatica is a complex event
with numerous substances and mechanisms acting at various levels. Recently, these mechanisms have attracted
attention also by basic scientists, and thus a number of
studies looking into neuroimmune events have provided
important insights to the pathophysiologic mechanisms
that account for the human problem. It seems clear that the
intervertebral disc per se has certain biologic effects that
contribute directly to these pathophysiologic processes.
Epidural application of nucleus pulposus induces both
structural and functional changes, which relate closely to
the nerve dysfunction seen in radiculopathies such as sciatica. Nucleus pulposus also seems to sensitize the nerve
roots to produce pain when exposed to mechanical deformation, whereas nucleus pulposus application or mechanical deformation alone does not seem to induce significant
pain. These experimental observations cor relate with the
clinical impression that preoperative touching of nerve
roots that have been e xposed to disc herniation under local
anesthesia reproduces the sciatic pain, and that surgical
removal of the mechanical compression of the nerve root
often relieves the symptoms. It thus seems that substances
from the nucleus pulposus, in combination with mechanical deformation, initiate the pathophysiologic events leading to pain and nerve dysfunction. The substance of
importance in this regard clearly seems to be TNF. The
activation and up-regulation of this ubiquitous proinflammatory cytokine produces acute pain and the neuropathologic changes associated with chronic pain states. Tumor
necrosis factor stimulates fibroblast scar formation in a
26 /SECTION I/BASIC SCIENCE
vicious cycle whereby the local presence of TNF stimulates other cells to up-regulate this cytokine. Thus, initiation of this cycle by the leakage of TNF from herniated
nucleus pulposus produces a cascade of tissue injury, scar
formation, and local pain. Superposition of mechanical
injury to the nerve root in this environment exacerbates
the neural immune insult, causing macrophage mediated
wallerian degeneration with significant increases in TNF
concentrations. We suggest that these combined events
explain the problem of sciatica. Interestingly, there is also
ongoing research indicating an immune reactivity in some
patients after disc herniation, which might be involved in
the later pathophysiologic phase, thus contributing to
chronicity of the symptoms. The recent success of human
trials with anti-TNF agents strongly supports this interpretation of the neural immune studies summarized in this
chapter. Although the pathophysiology of sciatica is far
more complex than one might first suspect, we are certain
that future research will reveal both substances and mechanisms of importance to the induction of symptoms in sciatica, and we hope that such research may provide a basis
for improved diagnosis and treatment of this common disorder.
ACKNOWLEDGMENTS
This work was supported by grants from the Swedish
Research Council for Medicine, (8685) the Inga-Britt and
Arne Lundberg Research Foundation, Department of Veterans Administration, USA, and the Fukushima Society
for Promotion of Medicine, Japan.
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CHAPTER 3
Biomechanical Considerations of Disc Degeneration
Allison M. Kaigle Holm and Sten H. Holm
Mobility and stability of the spine are governed by a
complex neuromusculoskeletal system. Panjabi (1) eloquently described the spinal stabilizing system as three
subsystems (Fig. 3-1): passive (disc, ligament, bone,
and passive muscle), active (tendons and active muscle),
and neural (the nervous system and neural components
within the passive and active structures). The biomechanical characteristics of the lumbar spine are dependent upon the integrity of all three subsystems. Under
normal conditions, the musculoskeletal structures interact in a highly coordinated and optimized fashion via
neural networks, to produce the desired movements and
achieve the requirements for stability. However, injury
or degenerative processes disrupt the intricate balance,
and cause a transfer in unfavorable loads onto other
spinal structures. This often leads to pain or dysfunction. With regard to the intervertebral disc, degenerative
processes are believed to alter the disc’s mechanical
properties as well as the surrounding structures. This
underlying belief has fueled an extensive amount of
research aimed at elucidating the biomechanical consequences of disc degeneration.
STRUCTURE AND FUNCTION
It is important to have some basic kno wledge of the individual structures of the lumbar spine, as well as their functions and interactive processes, in order to understand how
disturbances to a single structure can adversely affect secondary structures, and ultimately the spinal system as a
whole. Many examples of this can be found in the literature. Disc degeneration transmits unfavorab le stresses onto
other spinal structures, particularly the facet joints. A radiographic study by Butler et al. (2) found that disc degeneration caused secondary osteoarthritic changes in the facet
joints, most likely due to a shift in the mechanical loading.
Using a sheep model, facet joint arthrosis has been shown
to occur in response to experimentally induced disc degeneration (3). Substantial bone remodeling in vertebrae adjacent to intervertebral discs that sustained lesions of the
annulus has also been observed (4). Changes in muscle
fiber type of the multifidus and erector spinae muscles
(5–7), and structural changes in the connective tissue of the
multifidus (8) have been reported clinically in patients
with lumbar disc herniation.
The intervertebral disc is a deformable connective
structure, with a very low capacity for remodeling and
repair due to its avascularity in the mature state. This
makes it particularly vulnerable to fatigue failure. A
turgescent central nucleus pulposus exists in the healthy
state; it is designed to sustain and transmit pressure while
surrounded by an annulus fibrosus, a highly organized
arrangement of collagen fiber layers that can resist movements in all directions due to the fibers’ alternating
oblique orientation. Due to the arrangement of the annulus fibers and regardless of the type of loading, the disc
annulus, partly or in whole, is subjected to tensile
stresses. The three major constituents of the intervertebral disc are water, collagen, and proteoglycans. Their
proportions vary radially within the disc, as well as with
aging and degeneration (9,10). The outer annulus has the
highest collagen content and the lowest water and proteoglycan contents, whereas the nucleus has high water and
proteoglycan contents and low collagen content (11). The
biomechanical properties of the intervertebral disc depend largely on the tissue’s hydration. The collagen fibrils
provide the tensile strength of the intervertebral disc. The
turgid action of the water-binding proteoglycans surrounded by the collagenous framework provides the loadbearing capacity (12). The principal functions of the
intervertebral disc are to allow joint mobility and transfer
axial loads between the vertebrae. Together with the vertebrae, the disc resists approximately 80% of the compressive force acting on the spine in the upright standing
31
32 /SECTION I/BASIC SCIENCE
FIG. 3-1. Schematic of the bilateral active and passive structural arrangement and sensory innervation
on the L3-L4 level.
posture (13). The intervertebral disc allows rotations
(flexion-extension, lateral bending, and axial) between
the vertebrae, as well as translational movements caused
by compressive or shear forces.
A cartilaginous end plate, which joins the vertebral body
and intervertebral disc, provides a nutritional pathway to
the avascular intervertebral disc. The end plates deflect
when sufficient axial loads are transferred between the
intervertebral disc and vertebral body. Disruption in the
nutritional pathways through the end plate is belie v ed to be
a key mechanism for disc degeneration (14).
The zygapophysial joints, or commonly called facet
joints, are synovial joints formed between the superior and
inferior articular processes of adjacent vertebrae. These
cartilage-covered articulating processes or facets, along
with the fibrous capsule that encloses the joint, provide a
locking mechanism that can resist shear translation and
axial rotation between the vertebrae. Bony impact, as well
as tension of the joint capsule, play major roles in providing passive stability during bending of the lumbar spine.
According to Adams and Hutton (15), the facet joints normally bear approximately 20% of the spinal compressive
force, but if there is a loss in disc height due to degenerative changes, load bearing can be as high as 70%. In a
lumbar motion segment, the intervertebral disc provides
approximately 40% to 50% torque strength, while the
remaining strength is attributed to the posterior elements
and the interspinous ligaments (16).
The ligaments of the lumbar spine provide passi ve tensile
resistance to external loads. The amount of stability provided by a particular ligament depends not only on its
strength, but also on its architectural arrangement and the
loading circumstances. Ligaments are most effective in
resisting loads along the same direction of their fibers. With
disc degeneration, narrowing of the disc space can reduce
the ligamentous tension, and thus decrease its effectiveness
in providing passive translatory or rotatory stability.
Devoid of the muscles, the osseoligamentous spine is
inherently unstable at low loads (approximately 90 N)
(1,17). Therefore, the neuromuscular system must fulfill
the supplementary and adaptive role of maintaining postural stability in vivo. Disturbances in the precise motor
control strategies, particularly those of repetitive nature,
may have detrimental effects on the lumbar spinal structures (e.g., cause pain or dysfunction). The lumbar spine is
directly influenced by a number of bilateral muscles, both
intersegmental and polysegmental, acting in a well-coordinated manner in order to balance the actions of gravity or
execute controlled movements, as well as provide passive
elastic tension. The muscles not only produce movements,
but also generate compressive and shear forces that contribute to the high internal forces to which the lumbar spine