CHAPTER SYNOPSIS:
The functional spine unit is a three-joint complex composed of the intervertebral disc and the paired facet joints. This concept provides a useful template to explore the degenerative process of the spine. As the degenerative process progresses, function limitation and clinical manifestations such as myelopathy, radiculopathy, spinal stenosis, facet joint pain, and discogenic pain may develop. The degenerative process usually begins with intervertebral disc, which, in turn, leads to altered biomechanics of the functional spine unit. This, in turn, may lead to degenerative changes in the facet joints and ligamentous complexes of the functional spine unit.
IMPORTANT POINTS:
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Evidence of degenerative disc disease does not necessarily imply the presence of pain; many people with degenerative spine changes are asymptomatic.
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The primary risk factor for the development of degenerative disease of the spine appears to be linked to genetic rather than environmental and social factors.
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Degeneration of the intervertebral disc may begin at an early age and appears to precede degenerative changes seen in the facet joints and ligaments.
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Continued research into the genetic influences of degeneration of the spine may lead to the evolution of new treatment strategies.
CLINICAL/SURGICAL PITFALLS:
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The intervertebral disc has a tenuous nutrient supply and is one of the first tissues in humans to show degenerative changes.
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Degenerative changes in the intervertebral disc leads to altered biomechanics of the spine “motion segment” and may accelerate facet osteoarthritis.
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The absence of notochordal cells in the nucleus pulposus of human intervertebral discs is in contrast with most animal models available for study; this may confound the conclusions drawn from animal model testing.
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Degenerative changes of the spine may lead to a myriad of clinical presentations including discogenic pain, radiculopathy, myelopathy, and spinal stenosis.
INTERVERTEBRAL DISC
The intervertebral discs are cartilaginous, articulating structures that reside between the anterior elements of the vertebral bodies allowing for movement (flexion, extension, rotation, lateral bending) in this otherwise rigid portion of the vertebral column. The discs form a complex system with an outer annulus fibrosis composed primarily of type I collagen, surrounding a central nucleus pulposus in which type II collagen predominates. Collagen fibrils from the annulus continue into the surrounding tissues anchoring the disc to the vertebral bodies at its rim, the anterior and posterior longitudinal ligaments, and to the hyaline cartilage vertebral end plates. The hyaline cartilage end plates then interlock to the osseous vertebral end plates by calcified cartilage with few, if any, collagen fibers crossing this boundary. In addition to allowing for movement, the intervertebral discs also provide cushioning between the osseous elements of the spine during normal physiologic loads.
Development of the Intervertebral Disc
The spinal column, vertebrae, cartilage end plates, and annulus fibrosis differentiate from a mesoderm origin. The embryonic nucleus pulposus, in contrast, develops from endoderm as a remnant of the notochord. The vertebral column arises from the human embryonic mesoderm at approximately 4 weeks of gestation, requiring both the central notochord and the neural tube for its induction. The centrum of each vertebrae forms from the fusion of the adjacent somites, with an intersegmental artery running horizontally between them. The cells in the outer region of what will become the intervertebral disc align into sheets with adjacent layers orientating to alternating directions to the vertebral axis ( Fig. 3-1 ). Collagen synthesis commences in the orientation of each of the cell sheets, resulting in a highly organized lamellar structure typical of the adult annulus fibrosis. The origin of the adult nucleus pulposus is less understood; some authors attribute it to the notochord, whereas others believe the notochord rescinds, and the nucleus pulposus is formed from the inner border of the annulus and progresses inward. In humans, the number of notochord cells diminishes rapidly after birth, with 2000 cells/mm present at 6 weeks, then 100 cells/mm at 1 year, and none identifiable after the age of 4 years.
At birth, cartilage end plates make up approximately 50% of the intervertebral space (compared with approximately 5% in the adult) and have large vascular channels traversing them. The immature intervertebral disc also has vascular and neural channels running through the lamellae of the annulus fibrosis. Soon after birth, the vascular channels of the cartilage end plates fill in with extracellular matrix so that no vascular channels remain by the end of the first decade of life. This parallels a similar reduction in the vascularity of the annulus fibrosis. Thus, the adult intervertebral disc is often described as the largest avascular tissue in the body. Thus, the cells of the intervertebral disc, especially in the nucleus pulposus, are a long way from a source of nutrients and clearance of metabolites.
Normal Adult Intervertebral Disc
The normal human adult intervertebral disc consists of a large amount of extracellular matrix interspaced by a small number of cells. These cells make up approximately 1% of the volume of the disc and are of at least two distinct phenotypic populations. The cells of the annulus fibrosis and cartilage end plates are fibroblast-like and elongated. This is in contrast with those of the nucleus pulposus, which are more rounded and chondrocyte-like in shape. These apparently simplistic cells play an important role in the modulation of the intervertebral disc. Integrins are important linking proteins that communicate changes in the physical environment to the cells. Long, thin cellular processes extend from these cells sensing changes in mechanical strain, and the response is the synthesis of matrix proteins. Nucleus pulposus cells generally synthesize only type II collagen, whereas cells of the annulus produce both type I and II collagen.
Macroscopically, the healthy adult intervertebral disc consists of two regions, the central nucleus pulposus and the outer annulus fibrosis. When sections of the disc are viewed under polarized light, the orientation of the collagen bundles is clearly demonstrated. Discs from the adult annulus have between 15 and 25 lamellae in the annulus. Initially, these lamellae are discrete bundles of collagen fibers, but as aging occurs, the organization become increasingly complex with bifurcations and interdigitations accompanying a thickening of the lamellae ( Fig. 3-2 ).
The innervation and vascular contribution to the intervertebral discs are unique. Small nerve endings are detectable surrounding the small capillaries of the peripheral annulus. It is still unclear whether this nerve tissue is present only as capillary vessel wall innervation or whether they possess the ability to relay sensory and pain information. Evidence exists that, in the adult disc, the central portion lacks both innervation and vascular channels. With the exception of the capillary bed permeating the outer annulus, the majority of nutrient transport seems to occur through diffusion. Studies suggest that it is the central portion of the vertebral end plate that is primarily responsible for the metabolic processes of the disc, with a maximum diffusion distance approaching 1 cm from the central portion of the end plate to the nucleus pulposus. Aging and pathologic processes may interrupt this tenuous route for cell metabolism, resulting in an acceleration of the disc degeneration process. End plate sclerosis, calcifications of the disc, and decreased marrow vascularity may all contribute to the compromise of the diffusion process.
Biochemical analyses of the discs have identified the molecular components and provided qualitative measurements of the amounts present. Aggrecan is the most abundant proteoglycan in the disc, comprising approximately 70% of the dry weight of the nucleus pulposus and about 25% of the annulus in young healthy discs. Aggrecan molecules are surrounded by negatively charged sugar chains that serve as an ionic gradient. This gradient creates an osmotic gradient, thus attracting positively charged ions and maintaining disc height under physiologic loads. In addition to aggrecan, many other members of the proteoglycan family of proteins have been identified, but in smaller amounts. Examples of these proteins include decorin, biglycan, fibromodulin, and lumican, as well as other small proteoglycan molecules. Significant variation of the distribution of these components exists within the disc as evidenced by histochemical, immunohistochemical, and electron microscopic techniques. For example, elastin comprises only 2% of the dry weight of the annulus, suggesting that it is quantitatively not a major component of the disc. It may, however, contribute greatly to the function of the disc because it has a specific and discrete location within the disc, namely, between the collagen lamellae of the annulus. This may play a role in linking the layered collagen sheets.
The main structural component of the disc extracellular matrix is collagen with variable distribution of its isoforms. Several different collagen types have been identified in the intervertebral discs (types I, II, III, V, VI, IX, and XI). Collagen type I predominates in the annulus, whereas type II collagen is abundant in the nucleus pulposus, and together they account for 80% of the collagen in the disc. In addition to the collagen types I and II, other types of collagen are preferentially located within certain regions of the disc. Type III and VI collagen comprise a small biochemical proportion of the disc but are found predominantly pericellularly; this likely reflects their function as playing a role in fibril formation. Nerve endings and blood vessels are also present but are limited to the outer few millimeters of the annulus fibrosis. A small number of mechanoreceptors are also present and have the morphology of Golgi tendon organs, scant Ruffini receptors, and a few pacinian corpuscles.
DISC CHANGES WITH AGE
Major age-related changes in the cartilage end plates and intervertebral discs may bee seen by the end of the first decade of life. Even as early as 2 years of age, mild microscopic degenerative changes may been seen, including decay and/or proliferation of nucleus pulposus cells, mild cleft formation, alteration in cell density, and matrix degeneration of the cartilage end plates. These changes coincide with and may be related to the regression of the blood vessels in the annulus, cartilage, and vertebral end plates. Cadaver studies demonstrate that the number of vascular channels perforating the osseous vertebral end plates diminishes drastically between 6 and 30 months of age. It has been observed that intervertebral discs undergo degenerative changes earlier in life than other tissues in the body, and this is likely related to the rapid reduction in its nutrient supply.
Boos et al. have described progressive histologic changes in the disc. These changes include an increased number and extent of clefts and tears, the presence of granular material, and neovascularization from the outer aspect of the annulus inward. Increased cell death, cluster formation, and some extent of cell proliferation also occur. From the second decade of life onward, a loss of demarcation between the annulus and nucleus is increasingly observed. As aging continues, structural changes in the cartilage end plate are seen: cracks, thinning of the end plate, altered cell density, microfracture of the adjacent subchondral bone, and bone sclerosis. These changes in the end plates are accompanied by changes in the annulus (particularly the outer region) and typically precede degenerative changes seen in the nucleus pulposus.
Changes with Disc Degeneration
Histologic and Cellular Changes
Disc degeneration is typified histologically by changes at the cellular level. Increased cell proliferation and cell cluster formations are seen, as well as molecular changes such as increased production of cytokines and matrix-degrading enzymes (matrix metalloproteinases). Alterations of structural matrix proteins such as collagen types I, III, VI, and X, as well as elastin, fibronectin, and amyloid are observed. Glycosaminoglycans are reduced in disc degeneration, as well as normal aging.
The most significant biochemical changes that occur in the degenerating disc are seen with the proteoglycans. The normally large aggrecan molecules degrade in response to various enzymatic influences (matrix metalloproteinases, aggrecanase). The degradation and loss of glycosaminoglycans lead to fragmentation of the large molecules, which, in turn, leads to a loss of hyaluronan binding sites. This decreases the number of negatively charged molecules and reverses the osmotic gradient, allowing “leaching” to occur. The result is a decrease in hydration of the disc and a loss of resistance to compressive loads.
Gross matrix changes, including increased lamellar disorganization with fissures, are features of degenerating discs. A neovascularization and reinnervation of the aging disc is observed. This neovascularization is more pronounced around the annulus and can also bee seen with disc herniations. These changes are also seen in the “normal” aging disc, and researchers are challenged with differentiating these changes as pathologic as opposed to a part of the normal aging process. Schmorl nodes (vertebral end plate lesions that can be seen in up to 75% of the population) represent this type of challenge. It is not clear whether these represent normal aging or a pathologic degeneration of the disc. It has been suggested that thoracolumbar nodes may be related to disc degeneration, whereas lower lumbar nodes seem to be related to simple aging. Beadle suggests that morbid changes are simply the early appearance degenerative changes brought on by increased functional strain. Clarification of the role of these histochemical changes as “pathologic” or part of the aging process is the focus of continuing research ( Fig. 3-3 ).
Alterations in Disc Function
The primary role of the intervertebral disc is to act as a load-sharing cushion for the osseous elements of the spine. The collagen and aggrecan of the extracellular matrix create an osmotic gradient, and load deformation is primarily resisted by hydrostatic pressure within the disc. Increasing loads, as with standing, cause a fluid displacement from the disc until a balance is achieved between the external physiologic loads and the osmotic/hydrostatic pressure inherent to the disc. The extrusion of fluid from the disc leads to a loss of disc height. This is readily restored when the deforming loads are discontinued. Magnetic resonance imaging (MRI) studies have demonstrated a diurnal pattern to disc height. Daytime measurements of disc height demonstrate a decrease of up to 25% with physiologic loading. This reduction in height is due to a combination of collagen deformation, as well as displacement of fluid from the disc. Nocturnal examination of the disc demonstrates a restoration of the disc height. In vivo analysis has also demonstrated that loads applied to a disc result in a subsequent increase in intradiscal pressures. The same analysis also demonstrates decreased intradiscal pressures in degenerative discs.
Early in the degenerative process, the concentration of aggrecan decreases, leading to a necessary decrease in the osmotic pressure gradient. The loss of hydration impairs the ability of the disc to resist loads. Additional stresses normally absorbed by the disc are transferred to other elements of the spine. The loss in disc height increases the flexion moment of the spine, which alters the loads normally applied to the facet joints. This may serve to hasten the pattern of osteoarthritis of the facet joints. Loss of disc height also increases the forces seen across the vertebral end plates and annulus. This may lead to cartilage wear and sclerosis of the end plates, and place the annulus at risk for fissures. Also seen with disc space narrowing is a decrease in tension forces on the ligamentum flavum. These decreased tension forces may lead to remodeling and hypertrophy of the flavum characteristic of degenerative spinal stenosis ( Fig. 3-4 ).
