Intervertebral Disk Disease

Anatomy of the Intervertebral Disk and Supporting Structures

Related Anatomic Structures of the Spine

The joining of two adjacent vertebrae is facilitated by several types of articulations (syndesmoses, arthroses, and amphiarthroses). The supporting structures of the spine include the various ligamentous structures (syndesmoses), the articular facets (arthroses), and the intervertebral disks (amphiarthoses). The ligaments of the spinal column include the interspinous and supraspinous ligaments, the intertranversarious ligaments, ligamentum flava, transverse intercapital ligaments, and the longitudinal ligaments (ventral and dorsal) (Fig. 46-1a, Fig. 46-1b and Fig. 46-1c) [1]. The intertranversarious ligaments unite the adjacent transverse processes of the lumbar spine. The supraspinous ligament is a thick ligament extending along the apices of the dorsal spinous processes from the first thoracic vertebra to the third sacral vertebra [1]. This ligament plays an important role in preventing excessive separation of the dorsal spinous processes during spinal flexion. The interspinous ligaments blend with the interspinous muscles and connect adjacent dorsal spinous processes of the thoracic and lumbar vertebrae on midline. Some fibers from this ligament blend with the supraspinous ligament. These ligaments play a role in maintaining the relationship between the dorsal spinous processes when the spine is in flexion; however, they are not as strong as the supraspinous ligament [1].

Figure 46.1a. Extrinsic spinal ligaments. a. dorsal spinous ligament; b. interspinous ligament; c. intertransverse ligament; d. joint capsule of the articular facet. (With permission from Wheeler SJ, Sharp NJH: Functional anatomy. In: Small Animal Spinal Disorders: Diagnosis and Surgery. Wheeler SJ, Sharp NJH (eds). London: Mosby-Wolfe, 1994. Illustration by Joseph E. Trumpey, North Carolina State University).

Figure 46.1b. The longitudinal ligaments of the spinal column. a. dorsal longitudinal ligament; b. ventral longitudinal ligament. (With permission from Wheeler SJ, Sharp NJH: Functional anatomy. In: Small Animal Spinal Disorders: Diagnosis and Surgery. Wheeler SJ, Sharp NJH (eds). London: Mosby-Wolfe, 1994. Illustration by Joseph E. Trumpey, North Carolina State University).

Figure 46.1c. The intrinsic ligaments of the spinal column. a., b, and c. course of the dorsal longitudinal ligament over the vertebral body and intervertebral disk; d. transverse intercapital ligament. (With permission from Wheeler SJ, Sharp NJH: Functional anatomy. In Small Animal Spinal Disorders: Diagnosis and Surgery. Wheeler SJ, Sharp NJH (eds). London: Mosby-Wolfe, 1994. Illustration by Joseph E. Trumpey, North Carolina State University).

The transverse intercapital ligaments attach to the rib heads bilaterally by crossing the spinal canal perpendicularly to its long axis at each intervertebral disk beneath the dorsal longitudinal ligament. These ligaments are associated with the second through the tenth thoracic vertebrae in the dog. Although present between the eleventh rib heads, the transverse intercapital ligament is much less developed there. These ligaments aid in maintaining tight opposing rib head attachments to the vertebrae at the costovertebral joints, resulting in minimal cranial to caudal movement of the rib head [1]. The presence of this additional stabilizing ligamentous structure, in addition to the rigidity of the rib cage, is believed to play a role in the small numbers of clinically significant intervertebral disk extrusions observed in the thoracic region.

The dorsal longitudinal ligament courses along the entire length of the floor of the vertebral canal (dorsal to the vertebral body and dorsal annulus fibrosus). It is arranged as a parallel bundle of fibers that is approximately 2 millimeters or less in thickness when healthy. It is firmly attached to the dorsum of the vertebral body at its midline and fans out to blend fibers with the dorsal annulus fibrosus of the intervertebral disk [2]. Its anatomic location and relationship to the intervertebral disk allow it to help contain centrally extruded intervertebral disk material between it and the spinal cord [2]. The ventral longitudinal ligament is a similar type of ligament that traverses the ventral aspect of the vertebral bodies. In the dog, it is thinner than the dorsal longitudinal ligament and is probably of limited significance in support of the spine [1].

The articular facets are true arthrodial joints that possess a typical synovial joint capsule and articular cartilage on the opposing surfaces [3]. The cranial articular process of the caudal vertebra and caudal articular process of the cranial vertebra forms this joint between two adjacent vertebrae. In the cervical region, the joint is in a nearly horizontal plane and the caudal articular process lies dorsally over the cranial articular process. In the cranial thoracic region, these joints become more perpendicular in their orientation to the longitudinal spinal axis, whereas in the lower thoracic and lumbar regions the cranial articular process is lateral to the medially situated caudal articular process. The facet joints play an important role in the stability of the spine in rotation and flexion. In extremes of spinal motion, it is not uncommon for these joints to fracture.

The Intervertebral Disk

The dog has 26 intervertebral disks excluding those found between coccygeal vertebrae. There are no intervertebral disks between the first two cervical vertebrae or, in a normal situation, between the sacral segments. The intervertebral disk is an amphiarthrodial joint (an articulation between bony surfaces that provides limited movement and is connected by ligaments or elastic cartilage) that binds adjacent vertebral bodies [2,3]. The intervertebral disk is mechanically and structurally required to be extremely strong as it provides for protective alignment of the spinal column and withstands the various physiologic forces imparted to it. In spite of the minimal movement of this type of joint, the multiple vertebral segments impart an overall flexibility to the spine. The disks differ somewhat in size and detail between spinal regions but are essentially identical in structural organization. The disks are widest in the cervical and lumbar area; the caudal cervical intervertebral disks are the widest disks in the dog. The intervertebral disk can be divided anatomically, histologically, and functionally into two sections: the nucleus pulposus (an internal semi-fluid mass) and the annulus fibrosus (an external layer of fibrous connective tissue) (Fig. 46-2).

Figure 46.2. Schematic transverse drawing of a lumbar vertebra at the level of the intervertebral disk. a.annulus fibrosus; b.nucleus pulposus. (With permission from Wheeler SJ, Sharp NJH: Functional anatomy. In: Small Animal Spinal Disorders: Diagnosis and Surgery. Wheeler SJ, Sharp NJH (eds). London: Mosby-Wolfe, 1994. Illustration by Joseph E. Trumpey, North Carolina State University).

The nucleus pulposus develops from the embryonic notochord [1]. In neonates, it is large and contains a large number of cells of notochordal origin [4]. These cells tend to disappear with age, and chondrocyte-like cells then predominate [4-6]. The nucleus pulposus is positioned eccentrically within the confines of the fibrous annulus pulposus. The ventral aspect of the annulus fibrosus is approximately two times the height of the dorsal annulus, thus leaving the nucleus pulposus closer in position to the spinal canal (Fig. 46-2). The nucleus pulposus is composed of loose, delicate fibrous strands in a gelatinous matrix that suspends fibrocyte- and chondrocyte-like cells in an avascular environment [7]. Most of the fibers within the nucleus are not arranged in any fashion, but those closest to the vertebral endplate embed into it at an angle.

The annulus fibrosus forms the confinement of the nucleus pulposus and strongly attaches to the adjacent intervertebral bodies. The primary cell type in this portion of the intervertebral disk has fibrocyte characteristics [8]. The cells are located between bundles of fibrocartilage that is arranged in parallel fiber bundles (lamellae) that course in oblique orientation, crossing at angles of 100 to 120 degrees to each other [7,9,10]. When cut transversely, these fibers have an appearance of concentric rings surrounding the nucleus pulposus [7,9,10]. The lamellae are thinner and more densely packed in the dorsal aspect (closer to the spinal canal) of the annulus fibrosus. By comparison, the lamellar bands are thicker and more distinct in the ventral aspect of the annulus [2]. No definable structural interface exists between the nucleus pulposus and annulus fibrosus; their fibers blend imperceptibly in a transitional zone. In this region, the lamellae of fibrocartilage become less organized and the collagenous and cellular composition begins to change [7]. Cells in the outer annulus fibrosus are similar to fibroblasts but the cells in the transitional zone are more chondrocytic in nature [2]. This region is involved in the postnatal development of the intervertebral disk and has been observed to be broader in immature disks from chondrodystrophic breeds of dogs [11].

The articular surface of the vertebral body, or the vertebral endplate, is concave in its center and covered with cribriform cartilage that renders this region porous [12]. Unlike typical arthrodial joints, the surface of the endplate does not possess compact cartilage tissue between the medullary cavity of the vertebral body and the nucleus pulposus of the intervertebral disk. In this region, the bony trabeculae blend with the chondrous endplate and the fibers of the nucleus pulposus and inner lamellae of the annulus fibrosus [13-17]. Adjacent to the central depression of the endplate, dense compact bone forms the edges of the vertebral body. This region of the endplate serves as an apophysis for attachment of the fibers of the annulus fibrosus and dorsal and ventral longitudinal ligaments [18]. The osseous outer ring provides the firmest attachment of the disk to the vertebral body where the outer lamellar bands of the annulus fibrosus (also referred to as Sharpey's fibers) penetrate it [18-20]. The outermost lamellar fibers of the annulus extend beyond the confines of the disk to blend with the vertebral periosteum and longitudinal ligaments [1,2].

Physiology of the Intervertebral Disk

Macromolecular Composition

The major macromolecular components of the intervertebral disk are collagenous and noncollagenous proteins, proteoglycans, and glycoproteins [7,17,21-24]. Collagen forms the strong structural fibrocartilage network of the disk and anchors it to the vertebral endplates, allowing containment of the cells and extracellular matrix [5,7,25]. It is found in the highest concentration in the annulus fibrosus. The annulus fibrosus possesses mostly type I and some type II collagen; the nucleus pulposus only possesses type II collagen [22,26,27]. In transition from the inner lamellae of the annulus fibrosus to the nucleus pulposus, the concentration of type II collagen increases and type I decreases [27,28]. The type of collagen present in each region is related to its mechanical function. Type II collagen is most suited to load-bearing functions, whereas type I collagen is better at withstanding tensile loads [25,29-31]. Other collagen types are found in much lesser concentrations within the disk [5,28,32]. Elastic fibers are also present within the disk and are oriented parallel to the collagen fibers [5]. They are found in dense concentration between the lamellae of collagen fibers and likely play a role in sliding and recoil of the lamellar fibers during deformation [5,33].

The proteoglycans found in the extracellular matrix are composed of glycosaminoglycans or GAGs (long chains of monosaccharides) covalently bound to a central protein core (Fig. 46-3) [34-39]. Aggrecan is the most abundant of these proteoglycans in the intervertebral disk [4,27,40]. The GAGs present in the intervertebral disk are primarily chondroitin sulfate and keratan sulfate [12,24]. The highest concentration of proteoglycans is found in the nucleus pulposus, which is associated with type II collagen [41], but these proteins are also present in the intercellular matrix of the annulus fibrosus. Proteoglycans are negatively charged macromolecular complexes. Those concentrated in the nucleus pulposus and transitional zones possess polar groups (carboxyl and sulfonyl) that convey a high degree of hydrophilicity. Binding of water to the hydrophilic groups, up to 9 times the volume of the proteins [5,12,26,27,34,40,42,43], is responsible for the gelatinous consistency of the nucleus pulposus [24,27]. The normal intervertebral disk is highly hydrated; the water content of a young intervertebral disk is approximately 80 to 85% in the nucleus pulposus and 60 to 78% in the annulus fibrosus [24,27]. The nucleus pulposus of a young disk has seven to eight times more proteoglycan than the annulus fibrosus, and half as much collagen [44-46]. Proteoglycan turnover varies with age, but in people, the average turnover rate is two to three years [12,40]. With age, the nucleus pulposus becomes more collagenous in structure.

Figure 46.3. Schematic of the glycosaminoglycan aggregate and its associated molecular components. (With permission from Alberts B, Bray D, Lewis J, et al: Molecular Biology of the Cell, 2nd ed. New York: Garland Press, 1989).

Blood Supply and Nutrition of the Intervertebral Disk

The intervertebral disk is the largest avascular structure in the body, but it is biochemically vital. It is characterized by a high rate of metabolic activity [4,47,48] and, unlike arthrodial joints that receive nutrition through synovial fluid, it receives its nutrition and disposes of metabolic waste via diffusion. Nutrition and metabolic waste product removal are brought to and from the disk, respectively, by diffusion from two sources: the bone-disk interface vasculature of the vertebral endplate, which supplies the majority of the disk, and an adjacent peripheral vascular plexus, which supplies the outermost one to two mm of the annulus fibrosus and surrounding soft tissues [5,16,48-52]. In some instances the nutrients may need to diffuse several millimeters to parts of the disk farthest from the endplate capillary system [5,50]. The endplate arterial supply to the disk arises from the same supply as the vertebral body and drains into either a venous network or into bone marrow veins [53]. The endplate capillary system forms terminal loops that penetrate the subchondral endplate [13,54-58], and diffusion of materials to and from the disk occur at this interface. The concentration of capillaries is highest at the center and decreases toward the periphery of the disk [17]. This vasculature, like the systemic vasculature, is regulated by the autonomic nervous system (muscarinic receptors) and is responsive to external stimuli [59].

Like most systems that are dependent on diffusion for equilibrium of solutes, two properties affect this diffusion: the partition coefficient and diffusion coefficient [12]. The partition coefficient defines the equilibrium of solutes between that found in the plasma and the intervertebral disk [12]. It depends on both the size and charge of the particle of interest [12,17,60]. Small uncharged solutes will be near equilibrium between the plasma and the intervertebral disk, whereas large molecules such as albumin and lysozyme are excluded [12,50,60,61]. In regard to ionic solutes, the intervertebral disk matrix possesses a high content of proteoglycans, which behave as fixed, negatively charged aggregates [26,34,42,43,45,60,62]. The concentration of these molecules is much higher in the nucleus pulposus and inner annular lamellae compared with that in the outer annulus fibrosus [17]. Particles or solutes with positive charge diffuse easily into this region, allowing for a higher concentration of cationic particles in the disk compared with that in the plasma [12,17,60]. Negatively charged particles are repulsed by the existing overall negative charge of the disk and tend to be in higher concentration in the plasma [12,14,17]. This differential in ionic permeability has been supported by studies on antibiotic concentrations in the intervertebral disk; negatively charged antibiotics (penicillin and cefuroxime) penetrate much less effectively than positively charged antibiotics (aminoglycosides) [61,63,64]. Because of differential concentrations of proteoglycans, and thus, fixed negative charges throughout the disk, some difference may exist between the sources of diffused solutes based on the partition coefficient. Cationic solutes may diffuse more easily from the endplate interface vasculature and anions from the peripheral vasculature, whereas small uncharged particles are equally distributed from both vascular capillary systems (Fig. 46-4) [12,60].

Figure 46.4. The central portion of the intervertebral disk (nucleus pulposus and inner lamellae of the annulus fibrosus) possesses a predominately negative charge owing to higher concentrations of proteoglycans. Because of the differential charge in the inner and outer regions of the disk, the partition coefficient for charged particles differs between the peripheral vascular plexus and interface vasculature at the vertebral endplate. Cationic solutes more readily diffuse from the interface vasculature than do anionic solutes. Anionic solutes are more likely to diffuse from the peripheral vascular plexus.

The diffusion coefficient characterizes solute mobility [12]. Solute mobility is slower in the intervertebral disk compared with that in the plasma because of the presence of large compact molecules such as collagen and proteoglycans [12]. Without considering solute charge, the diffusion coefficient is 40 to 60% of that in water [12,14]. Mobility is greatest where the water content is higher, as seen in the nucleus pulposus and inner annular lamellae [12].

Movement along the spine may provide a "pumping" action, and likely aids in diffusion of the larger molecules into the disk [12]. This "pumping action" may induce some degree of convective transport by which negatively charged and larger molecules with lower diffusion coefficients may move into the disk [65-68]. Convective transport may also aid in the movement of molecules synthesized by the disk cells [17].

Like any organ, the intervertebral disk requires an adequate supply of nutrients and biochemical building blocks to maintain its integrity. Glucose is consumed at a high rate as the primary energy source of the intervertebral disk [69]. Because of low oxygen concentration in the disk, anaerobic glycolysis with production of lactic acid is the primary metabolic pathway [17,27]. The intervertebral disk develops mechanisms by which to survive in an acidic environment [27]. When glucose demands are not met, disk cell vitality is adversely affected [70-75]. In addition, when lactic acid production is decreased, the increasing pH of the intervertebral disk results in reduced production of extracellular matrix components. The production and activation of proteases that breakdown the extracellular matrix is not likewise impaired [76]. Thus, the overall net effect of inadequate energy supply is impaired cellular viability and loss of extracellular matrix components. The disk is not as dependent on oxygen supply as it is on glucose. Under hypoxic conditions, the cells become dormant and synthesis of extracellular matrix is impaired [5,72,76,77]. Long-term, however, this would result in a net loss of extracellular matrix as well.

The diffusion of molecules is regulated by the rate of metabolism leading to diffusional gradients. Gradients for oxygen and glucose exist throughout the disk, especially toward the center of the disk where concentrations are lowest [71,72,77]. For example, glucose consumption is up to 100 times greater than the rate of incorporation of sulfate during proteoglycan synthesis [16]. The diffusional gradient for sulfate is low because it is consumed and replenished easily, whereas the diffusional gradient for glucose is steep because the concentration is low [16]. Accordingly, high cellular density in certain regions of the disk also results in steeper diffusional gradients simply by the nature of higher demand. Cell density tends to be highest where the diffusional distances are the shortest; thus, cell density is dictated by nutrient diffusional constraints [78].

Function of the Intervertebral Disk

The primary function of the intervertebral disk is both to contribute to protective structural alignment and to resist and redistribute stresses along the spine [29]. It must be strong enough to withstand normal physiologic loads (torsion, shear, bending, and compression) [7,10,56,79-85] and yet deformable enough to allow flexibility and mobility [12,23,86-89]. Whereas the spinous ligaments and articular facets tend to withstand torsional, bending, and shear forces, the intervertebral disk is biomechanically best constructed to withstand compressive forces [12,23,86,88,89]. The mechanical properties of the intervertebral disk are conferred upon it by its biochemical nature related to the quantity and quality of its matrix glycosaminoglycans [5,10,40]. Altered biochemistry of the intervertebral disk alters its mechanical properties and ability to withstand axial stresses. The nucleus pulposus is anatomically situated within the intervertebral disk along the center of the axis of movement, which is the equilibrium between tension generated on the convex side and compression on the concave side when the spine is bent [31,90-93]. Because of its gelatinous make up, the nucleus pulposus behaves as a viscous fluid under applied pressure (compression) with considerable elastic rebound and return to its original position on release of the pressure. The nucleus pulposus essentially serves as a "hydraulic shock absorber" allowing disk deformity and dissipation of forces equally over the annulus fibrosus and vertebral end plates [23,29,31,94,95]. Fluid is essentially incompressible; therefore, the internal pressure achieved during compression of the nucleus pulposus pushes the annulus out radially in a horizontal plane of distortion (Fig. 46-5a and Fig. 46-5b) [12,31,84,94-96]. The annulus fibrosus itself is normally highly elastic and readily absorbs axial stresses, but it is constructed to best resist the high tensile forces generated during compression by sliding of the lamellar fibers across one another [12,29,31,40,87,94,95]. The lamellae of the annulus fibrosus are strongest when forces are generated along the direction of its fibers and these forces, therefore, are best counterbalanced by the alternating, oblique arrangement of these lamellae [31,84,97,98]. The tensile forces are the highest in the outer lamellar layers and this is where the majority of injuries to the intervertebral disk occur [31]. Initially, the intervertebral disk is easily deformed, but as compressive force increases, it becomes "stiffer" to prevent structural collapse [90,96,99,100]. With increasing sustained compression, gradual efflux of interstitial fluid out of the disk will result in additional microscopic movement of the disk known as "creep." [96,101]. This is particularly noted as a diurnal effect in people, in whom 25% of the fluid is expressed during the day with loading and reimbibed when they sleep at night when the axial stresses are relieved [5].

Figure 46.5a. The nucleus pulposus (NP) absorbs axial compressive forces along the spine. The nucleus is fluid by its nature and, thus, incompressible.

Figure 46.5b. The nucleus (NP) transmits the forces radially across the disk to the annulus fibrosus (AF) which is elastic and can expand to accommodate the tensile forces.

The spine is loaded both by external forces and internal forces generated by muscles (preload) [5,102]. Regular movement and normal physiologic loads are necessary for extracellular matrix composition; metabolic activity of the disk cells is regulated in response to these loads [103-109]. Nucleus pulposus cells primarily respond to changes in hydrostatic and osmotic pressure, whereas the annulus fibrosus responds to tensile strains that originate from flexion or extension [5]. Dynamic compression of the spine has been shown to result in alterations of gene expression and histochemistry within 2 hours to 1 week of loading [110,111]. Biomechanical stresses modulate the maintenance and remodeling of the connective tissue and extracellular matrix of the disk. In turn, the quality and quantity of these components are responsible for the effectiveness of these tissues to withstand these loads [109].

Aging and Pathology of the Intervertebral Disk

Degeneration is a deterioration of the physical properties of a tissue with changes in cellular function and tissue content that result in destruction or inhibition of function. Degeneration is an ultimate consequence of aging. Although aging is the most common cause of tissue degeneration, genetics, nutrition, and external factors (i.e., lifestyle) also play a role [50,59,112-123]. Aging and degeneration of the intervertebral disk usually occur in parallel and may be a continuum of the same process [17,27,124]. Distinguishing aging from degeneration is difficult; separating these two processes may be the key to understanding degenerative changes that are not age-related [17,25,27,124]. With degeneration, alteration of the intrinsic structure, biochemical characteristics, and cellular function and apoptosis ensues [27]. The biochemical and biomechanical alterations that occur lead to further progression of degeneration of the intervertebral disk [38,125-130].

Although the cellular component is only about 1% of the disk composition [5], these cells are responsible for the production and maintenance of all the macromolecules. Not only do they produce the extracellular matrix, but they also produce enzymes that break it down. In the healthy disk, the rates of synthesis and catabolism are in equilibrium [5]. Matrix degradation occurs when the rate of production decreases and/or rate of breakdown increases [5]. With a limited cell density, it is not surprising that the cells cannot maintain the health of the disk indefinitely. Degeneration is associated with both an alteration in cellular activity and cellular density [124,131]. The chondrocytic cells change the characteristics and decrease the synthesis of new extracellular matrix components [132,133]. Initially, clusters of cells involved in a reparative process may be present within the disk, but cells undergo limited cell division [17]. As degeneration progresses, cells undergo both apoptosis and necrosis [17,134,135].

Several cytokines have been implicated in intervertebral disk degeneration. The role of cytokines in health and in the cause or effect of degeneration of intervertebral disks is not yet understood. Implicated cytokines include tumor necrosis factor (TNF), interleukin-1a and 1b (IL-1), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and matrix metalloproteinases (MMPs). Ingrowth and proliferation of nerve fibers [136], endothelial cells [137,138], and fibroblasts have been observed in relation to the degenerative disk, suggesting that biochemical events are occurring that have autocrine and paracrine effects [25]. Expression of VEGF has been demonstrated in the intervertebral disk [139]. Synthesis of NGF by vessels growing into the disk has been demonstrated [25], suggesting that the neovasculature is influencing the ingrowth of nerve fibers. IL-1 has been shown to be involved in cartilage homeostasis [140] and is associated with a switch from anabolic to catabolic metabolism in the chondrocyte [141,142]. IL-1 has been shown to regulate angiogenesis, potentially by activating VEGF [143,144]. It has also been implicated in both the initiation of extracellular matrix degeneration and pain associated with disk disease [145]. The release of prostaglandins involved with the mediation of pain, such as prostaglandin E2α (PgE2α), and production of degradative enzymes, such as matrix metalloproteinases (MMPs), have been shown to be increased under the influence of IL-1b [145]. Concentrations of interleukin-6 (IL-6) and PgE2α were shown to be higher than normal in culture of herniated disks [145]. The stimulus for production of these cytokines has not been identified. In cartilage, these molecules may be intermediaries in the suppression of proteoglycan synthesis by interleukin-1 (IL-1) [146], promoting a net loss of proteoglycans. Conversely, IL6 is a tissue inhibitor of MMP (TIMMP) in articular cartilage and may actually serve a protective role by inhibiting matrix degeneration [147].

Interest has been intense over the last 10 years in the role of matrix metalloproteinases (MMPs) in degenerative joint disease. Less is known about their role in intervertebral disk metabolism and degeneration; however, herniated disks cultured in vitro have been shown to produce relatively high levels of MMPs, primarily gelatinase and stromelysin (which degrade gelatin and the core proteins of proteoglycans, respectively) [145,148-153]. Matrix metalloproteinase expression is highly regulated by cytokines and proinflammatory mediators such as TNF, IL1, IL8, and prostaglandins [151,154-156]. The exact role of MMPs is not known, but they have been shown to be involved in the inflammatory cascade and may play a role in radiculopathy and disk matrix degeneration. This is especially true of disk matrix proteoglycans [151]. Because the production of these enzymes in normal intervertebral disks is low, MMPs may also play a role in disk maintenance by acting as a stimulus to remodel and by partially resorbing herniated disk [151]. One problem with previous studies evaluating MMPs is that healthy "control" disk material was not compared with degenerative herniated material [149,157]. Two possibilities exist for the production of MMPs during intervertebral disk degeneration:

1. Degenerating disks make more matrix degenerative enzymes and cytokines, resulting in breakdown of the disk matrix; or

2. The herniated disk itself stimulates the production. However, it is possible that both events are concurrent. The degenerative cells may be biochemically altered, which is followed by disk herniation, which further promotes the production of matrix degenerative enzymes and cytokines [151].

Many macromolecular changes occur with normal aging and with degeneration of the intervertebral disk. Some of these changes are likely "preprogrammed" events during development such as loss of notochordal cells, mesenchymal apoptosis, and loss of the congenital vasculature [27]. With these events, the characteristics of homeostasis within the disk change dramatically [27]. The most significant of these in aging and degeneration of the disk are alterations in the structure and function of the proteoglycans and collagens. Alterations in these macromolecules subsequently lead to loss of hydration and impairment of biomechanical function of the disk. As the disk ages, aggrecan is proteolyzed by matrix metalloproteinases and cleaved by free radicals [23], and its concentration decreases within the disk [23,158]. This is particularly prominent in the nucleus pulposus [159]. In addition to proteolysis of aggrecan, the chain length of chondroitin sulfate is shortened on the proteoglycan, and a shift occurs from chondroitin sulfate to keratan sulfate as the predominant glycosaminoglycan [127]. The synthesis of chondroitin sulfate, but not keratan sulfate, requires oxidation of glucuronic acid. The alteration in chain length and ratio of these GAGs may reflect decreased supply of oxygen as the disk grows in size and the nuclear cells move farther away from the vasculature [160]. With degeneration, loss of nutrient and oxygen supply to the disk results from altered diffusion through the endplate, further contributing to the altered GAG ratio. It is the aggregate negative charge of the proteoglycans and their GAGs that maintains adequate hydrostatic pressure within the disk. Proteolysis results in a high concentration of nonaggregating proteoglycans that are too large to diffuse from the disk [7,27]. These retained nonaggregating proteoglycans may still contribute to the hydrostatic pressure of the disk, but are not as functional [5,7,27]. Therefore, the disk, losing as much as 20% of its water content, becomes dehydrated and the disk height decreases [7]. In addition, there is an increase in collagen type II production in the nucleus pulposus [161,162], with more relative decreases in water and proteoglycan content [132]. The nucleus begins to become more fibrocartilaginous in structure and less distinct grossly from the annulus fibrosus. The fluid-like behavior of the nucleus pulposus transforms into more solid-like properties [163], and the function of the nucleus pulposus in dissipating compressive forces fails.

Collagenous tissues change structure with age, wear, and time [25]. As the disk collagen ages, collagenase damages the fibrillar collagen [132,164]. Damage to the collagen increases with age and becomes more extensive. Accumulation of these damaged fibers reflects the slow metabolic rate and repair of collagen in the intervertebral disk [27,132,164]. Damaged collagen fibers fray and fibrillate [114], resulting in loss of lamellar organization [124]. In addition to collagen damage, the fibril diameter tends to increase over time by cross-linking via glycation [23]. Thickening of the fibrils results in impaired sliding of the lamellae and adversely affects the biomechanical properties of the disk [165]. As these injuries accumulate over time, the mechanical strength of the disk eventually weakens [27]. With the concurrent degenerative changes in the nucleus pulposus, the annulus bears higher percentage of the compressive forces than normal, further contributing to injury [25,166]. Both radial and concentric fissures begin to develop, and the disk may bulge. With progressive degeneration and injury, the annulus may eventually fail and collapse [7,167]. Microfractures in the vertebral endplate also occur and may actually precede the disk pathology as a consequence of increased intradiscal pressure and altered nutrition [20,167-169].

Alterations in normal motion and mechanical loading of the intervertebral disk may also play a role in accelerating degeneration [40,102]. The cells can exhibit both catabolic and anabolic responses depending on type, magnitude, duration, and localization of the forces exerted on the intervertebral disk. With low to moderate magnitude of static compression, anabolic activity increases in the inner AF and NP. For example, normal tensile forces have been shown to induce type I collagen synthesis [10,162], promoting maintenance of disk function. Abnormal intradiscal pressures, either too high or low, have a catabolic effect, inhibiting prostaglandin synthesis and increasing synthesis nitrous oxide and matrix metalloproteinases [10,170]. Most likely, magnitudes and frequencies of forces exist that are physiologically healthy for each cell type within the intervertebral disk to promote maximal biosynthesis and repair [102,171].

The effects of both overload and immobilization have been studied by Stokes et al. [102]. In vitro motion segment testing revealed that annular tears can occur with both excessive static or repetitive loading [172,173]. The annulus fibrosus is damaged by both fiber disruption and separation of lamellar layers. Multiple fissures and microfailure occur before complete failure. Periods of static compression induced changes in the cell synthesis and gene expression for collagen, PGs, and proteases as well as increased cellular apoptosis [161,174-181]. Overload to the spine results in "wear and tear," with localized trauma to the intervertebral disk, which is difficult to heal because of slow metabolic turnover [7]. Accumulation of injury continues to weaken the disk until its ability to repair is overcome by recurrent injury.182 Conversely, hypomobility may not necessarily be beneficial for the intervertebral disk. Most of what is known about hypomobility of joints has been studied in articular cartilage and is not yet proven for the spine [102,183-188]. Stokes et al. [102] postulated that hypomobility will also lead to degeneration of the intervertebral disk. In a state of hypomobility, the stimulus to cellular activity is altered as is transport of nutrient metabolites, which alters the viability of the disk.

Both hypermobility and hypomobility may occur in the early and late stages of disk degeneration, respectively. Degeneration initially results from increased movement and excessive loading, which ultimately leads to pain, resulting in tissue stiffening owing to limitation of motion. People with low back pain develop altered muscle activation patterns that change the physiologic loading of the spine, which ultimately results in even more axial compression and shear loading [189]. Altered muscle activation patterns with resultant change in forces generated on the intervertebral disk likely occur in animals as well, as evidenced by abnormal postures (e.g., kyphosis).

Adequate blood supply is necessary for continued health of the intervertebral disk; derangements in nutrient supply are associated with disk degeneration [17,50]. The integrity of the vasculature is affected by both aging [115,190] and injury [115]. Blood and nutrient supply to the disk may be affected in several ways. Diseases that may block blood flow through the vasculature, such as atherosclerosis [118,120] and thrombotic disorders [113,117], have been associated with degenerative disk disease. Other factors observed in people such as smoking [50] and chronic exposure to vibration [59] (such as long-haul trucking) may impair the vasculature by affecting muscarinic receptors [191] and are shown to have an association with higher incidence of disk degeneration. In addition, the thickness of the vertebral endplate diminishes with age and becomes calcified [25,27,94,192,193]. Sclerosis of the subchondral bone and vertebral endplate calcification alters the permeability of the endplate and has been associated with degenerative disk disease [73,192]. It is not known, however, if these endplate changes precede or are a part of the degenerative process [17]. As the intervertebral disk becomes dessicated, the relative content of proteoglycan increases and the movement of solutes becomes even more restricted, setting up a vicious cycle of loss of nutrition [17].

Degenerative Disk Disease of the Dog

In the dog, morphologic and physiologic changes in the intervertebral disk have been divided into two categories: Hansen's type I and type II. Hansen's type I disk degeneration is associated with chondroid metaplasia, which is characterized by extracellular matrix degeneration, peripheral and central mineralization of the nucleus pulposus, and cellular death [11]. These changes are biochemically associated with a 40 to 50% decrease of proteoglycan and reversal of the chondroitin sulfate: keratan sulfate ratio. Decreased GAG content results in decreased water imbibition by the disk and loss of properties of "shock absorption" and deformability [2,22,46,194,195]. The annulus is then subject to increased loading by axial pressures. Failure of the mechanical properties of the nucleus pulposus results in dysfunction of the annulus fibrosus, causing fissures and displacement of the nucleus pulposus [2]. Alternatively, it is possible that the changes in the annulus pulposus are primary rather than secondary. It is theorized that an increased proteolysis of type I collagen and elastin leads to the weakening of the annulus pulposus [2]. Hansen's type I disk degeneration is associated frequently with massive extrusion of nucleus pulposus material and dorsal annulus pulposus (Fig. 46-6). Hansen's type I disk material consistency ranges from soft and cheesy to firm with a granular appearance (mineralization). Historically, the period of time over which the disk extrusion occurs in the clinical setting varies from acute to slowly progressive.

Figure 46.6. A. Computed tomographic image (uncontrasted) of a normal vertebral canal and spinal cord; B. massive Type I disk extrusion (large arrow) has severely compressed the spinal cord to about 20% of its normal diameter to the left of the disk (small arrow).

Hansen type I intervertebral disk disease is primarily seen in chondrodystrophic breeds of dogs [2]. The breed most commonly affected with this form of disk degeneration by far is the dachshund, with a relative risk [12] six times greater than any other breed [196]. Other affected breeds include the Shih tzu, Lhasa apso, Pomeranian, beagle, poodle, Basset hound, Cocker spaniel, and the Welsh corgi. However, other less commonly considered breeds appear to have similar changes. For example, the author has seen many Dalmatians with this form of disk pathology, particularly in the cervical discs. In these breeds, the aging pattern of the intervertebral disk is different from that found in Hansen's type II disk degeneration. Degeneration of the disk may start as early as four months of age and is usually complete by 12 to 18 months [2]. Mechanical properties of the disk are usually decreased by two to three years of age, about the time when clinical signs first occur [2]. Although disk degeneration is seen in dachshunds as old as 13 to 15 years of age, most animals are between two and eight years of age when clinical signs first occur. Although the older dog probably has disk degeneration, the change in the disk may reach a stage where the intradiscal pressure is so low that the annulus is no longer affected [2]. Genetics have been shown to play a role in the disease in the beagle and dachshund [2]. In dachshunds, intervertebral disk disease is thought to be governed by polygenetic, nondominant, factors that are not sex-linked [197]. Environmental factors such as life-style and nutrition probably play a role.

Hansen's type II IVDDz is most commonly seen in nonchondrodystrophic dogs and is an aging change that results in fibroid metaplasia of the intervertebral disk, particularly the nucleus pulposus [2]. This type of degeneration is more similar to the aging and degenerative changes in the intervertebral disk commonly observed in people. The disease is usually seen in middle-aged-to-older large breed dogs but any nonchondrodystrophic breed is susceptible to type II disk disease [2]. Even chondrodystrophic breeds may develop this type of disk degeneration with advancing age. As the intervertebral disk ages, the nucleus pulposus is gradually replaced by more mature fibrocartilage (fibroid metaplasia), and eventually the difference between the nucleus pulposus and the annulus fibrosus is difficult to determine grossly. The disk eventually changes in its biochemistry to possess lower GAG levels [2,47,124]. Mineralization of the disk is uncommon in this type of degeneration. Typically, type II disk disease is associated with a partial rupture (fissures) in the dorsal annulus. This is observed as a herniation (or bulging) of the dorsal annulus [2]. Although massive ejection of the nucleus pulposus is not considered to be part of the disease process, acute rupture with concussive spinal cord injury is possible. Typically, when this occurs and surgery is performed, the material removed from the spinal canal is more ligamentous and similar to the annulus fibrosus in appearance.

The pathogenesis of spinal cord injury with intervertebral disk extrusion is associated with both concussive and compressive forces. Although compression secondary to extrusion is associated with some degree of concussion, concussive injury does not always result in compression of the spinal cord. In the author's experience, concussive disk extrusions without significant compression are seen most commonly in poodles and Cocker spaniels. Paucity or complete absence of disk material has been observed by many surgeons during surgical intervention.

The velocity and force of the intervertebral disk extrusion is the single most important factor responsible for irreversible paraplegia. In experimental spinal cord injury, it is the magnitude of the force of the injury (=/> 400 g/cm) that produces irreversible changes [198]. The sequelae of the concussive event are hemorrhage, ischemia, and vascular spasm [198]. This results in release of potent inflammatory mediators, as well as iron and propagation of ischemia with a final common pathway to the production of oxygen free radicals [198]. These biochemical events induce an inherent, progressive autodestruction of the spinal cord [198]. These autodestructive processes may continue for 24 to 48 hours [198] and are probably responsible for those animals that are presented for surgery within a few hours of onset with good deep-pain response and wake from anesthesia without a deep-pain response. When these autodestructive processes are not limited to a focal area of injury, they may continue in both directions from the injury and result in ascending/descending myelomalacia. Impacts of lesser magnitude and rate often produce more transient dysfunction and are associated with reversible changes [198]. Improvement in these cases is probably secondary to resolution of edema, hemorrhage, demyelination, and ischemia.

Compression of the spinal cord may result in a grossly swollen, indented, flattened, or atrophied spinal cord, depending on the duration of the compression. Adherence of disk material to the dura is sometimes observed with chronic lesions. Extensive epidural and/or subdural hemorrhage may be present with highly concussive disk extrusions. The disk material may migrate over one to two vertebral bodies. Microscopic changes in the spinal cord depend on the force of disk extrusion and duration of compression. Severe concussion of the cord will result in edema, inflammation, and focal and multifocal hemorrhage and malacia in the gray and white matter [199-221]. Astrocytosis and skeletonized trabeculae of blood vessels are observed in old malacic lesions [200,206-227]. Chronic compression is associated with demyelination, remyelination, Wallerian degeneration, and focal areas of ischemia [200,206-227]. The pathomechanisms of spinal cord compression are discussed in depth in Chapter 42.

Clinical Signs of Intervertebral Disk Disease

Clinical signs associated with intervertebral disk disease depend on both the location (lesion localization) and the degree and severity of disk extrusion. One of the earliest clinical signs of intervertebral disk disease is pain. The origins of pain associated with disk disease are presented in the following section. Neurologic abnormalities occur either concurrently or may follow pain when intervertebral disk extrusion results in compression and concussion of the spinal cord. Determining the localization of a neurologic lesion is important for choosing the appropriate clinical diagnostic tests, list of differential diagnoses, and occasionally, prognosis. Lesion localization can be divided into four anatomic spinal cord syndromes: C1-C5 (cervical), C6-T2 (cervicothoracic), T3-L3 (thoracolumbar), and L4-S3 (lumbosacral). Clinical signs of spinal cord disease can be divided into anatomic syndromes because, in general, the clinical signs are similar for lesions inclusive in these spinal cord segments. This is because of the location of the lower motor neurons supplying the thoracic (C6-T2) and pelvic limbs (L4-S3). Not all of the clinical signs (neurologic deficits) will be present in each case. The signs associated with each syndrome can be found in Table 46.1, Table 46.2, Table 46.3 and Table 46.4.

No evidence exists that trauma plays a role in the pathogenesis of intervertebral disk extrusion; however, clinical signs may be precipitated by a seemingly minor trauma or normal activity. Many dogs that become acutely paralyzed with Hansen's type I thoracolumbar intervertebral disk extrusions have a recent history of jumping off a piece of furniture. Trauma is not necessary, however, for clinical signs to occur. Significant trauma is usually required to cause extrusion (rupture) of a healthy disk. This has been most commonly observed by the author in animals that have been hit by motor vehicles or have run head first into a solid immovable object (i.e., tree or wall).

Approximately 70% of intervertebral disk extrusions are between T11-12 and L2-3. C2-3 is reported to be the most common location of cervical intervertebral disk extrusions [2], but extrusion is seen commonly in all cervical discs up to C6-7. C7-T1 extrusions do occur but are rare. Dogs are less likely to be neurologically affected with cervical disk extrusions compared with thoracolumbar intervertebral disk extrusions unless they are severe and/or acute. Advanced imaging, such as computed tomography or magnetic resonance imaging, has helped to identify severe compression of the spinal cord (e.g., disk material filling 75% of the canal) when the only clinical sign the dog displays is unremitting cervical pain (Fig. 46-6). Dogs with thoracolumbar disk extrusions are more likely to show neurologic deficits than are those with cervical disk extrusion, but dogs may have significant compression of the spinal cord and show only spinal pain clinically [228]. Cervical and lumbar disk extrusions in the intervertebral foramen can result in radiculopathy and nerve root signature as the only clinical sign.

Figure 46.6. A. Computed tomographic image (uncontrasted) of a normal vertebral canal and spinal cord; B. massive Type I disk extrusion (large arrow) has severely compressed the spinal cord to about 20% of its normal diameter to the left of the disk (small arrow).

Pathogenesis of Pain Associated with Intervertebral Disk Disease

Animals with acute intervertebral disk extrusion are almost always in pain. This differentiates disk extrusion from fibrocartilagenous emboli, which are almost never associated with persistent pain. Pain associated with disk disease in the thoracolumbar region is usually manifested by a kyphotic posture. A dog with pain from cervical disk disease will often keep its neck flexed with the nose pointed to the ground and roll the eyes upward when spoken to or encouraged to move. Because of the low head carriage, these animals may also appear to have a kyphotic posture. Pain may be elicited by palpation of the neck and cervical spine manipulation, such as lifting the head or turning the neck laterally. Pain often decreases in intensity over time and with the use of analgesics or anti-inflammatory medications. Animals with Hansen's type II disk extrusions are often not in overt pain or may not be experience pain on spinal palpation if the lesion is chronic.

The spinal cord itself does not possess pain receptors. Pain associated with intervertebral disk degeneration has been shown to be secondary to both biochemical mediators and nervous tissue impingement. The ligaments, joint capsule and bone of the spinal column are highly innervated [7]. The external periosteum, articular facet joint capsule, and longitudinal ligaments receive sensory innervation by way of the medial branches of the dorsal rami of the spinal nerves. These rami form the recurrent sinuvertebral nerve [12]. The dorsal longitudinal ligament and the ventral meningeal surface are highly innervated by complex encapsulated nerve endings as well as poorly myelinated free nerve endings [12]. These fibers also innervate the outer lamellae of the dorsal annulus fibrosus [12,136,229]. and direct stimulation of the intervertebral disk has been shown to induce pain [7]. Although the innervation to these structures is diverse and includes postganglionic efferent fibers from the thoracolumbar autonomic ganglia (which mediate smooth muscle function of the vasculature of the spinal canal) and proprioceptive fibers (which modulate postural reactions), the majority of these fibers are nociceptive in function [12,136]. In fact, it has been shown experimentally that stimulation of tissues innervated by the sinuvertebral nerve elicits back pain [12]. In the clinical setting, mechanical impingement of the nerve roots (radiculopathy) and meninges by extruded disk material and hypertrophy of supporting structures play a role in generation of pain [36,230]. For example, as the intervertebral disk space narrows, concomitant settling of the facet joint and narrowing of the cross-sectional area of the intervertebral foramen occur, which may result in nerve root compression [231,232]. The production of osteophytes may also play a role by contributing to pre-existing narrowing of the intervertebral foramen [231]. In addition, arthritic changes often occur in the facet joint synovium and joint capsule.

Disruption of the intervertebral disk and its ligaments and compression of nervous tissue lead to production of neuropeptides. Algesic molecules can activate nociceptors in the dorsal longitudinal ligament and dorsal annulus [40,230]. The somata of the dorsal root ganglia make various algesic neuropeptides that are transported to central and peripheral terminals [230]. Implicated neurogenically derived cytokines include substance P and calcitonin gene-related protein (CRGP). Substance P has been shown be a part of the inflammatory cascade and of the generation of pain in radiculopathy. CGRP found in primary sensory neurons has been shown to mediate nociception and mechanoreception [230]. Non-neurogenic-derived chemicals released during tissue damage (e.g., bradykinin, serotonin, histamine, and Pgs) also sensitize pain fibers [230]. Extruded intervertebral disk material itself has been implicated as a source of biochemical mediators in the pathophysiology of radicular pain [157,233-235]. In an in vitro study of human herniated disk material removed during decompressive surgery, nitric oxide, prostaglandin E2a, and interleukin 6 concentrations were elevated compared with non herniated control disks from patients undergoing spinal surgery for other reasons (e.g., scoliosis correction) [151]. Nitric oxide is a novel mediator of inflammation and immune regulation [235]. This biochemical has been shown to have both proinflammatory and anti-inflammatory functions. As a proinflammatory agent, it exerts strong vasodilatory effects, promoting vascular leakiness resulting in edema. As an anti-inflammatory agent, it has been shown to inhibit production of IL-6, PgE2, and thromboxane. The exact function of nitric oxide in the disk and disk degeneration is not known at this time, however.