CHAPTER 273 Diagnosis and Management of Diskogenic Lower Back Pain
Low back pain (LBP) is the most common health problem in men and women between the ages of 20 and 50 years; it results in approximately 13 million visits to physicians in the United States each year and costs $28 billion in annual loss of productivity.1–3 Although the exact origin of most LBP remains unknown, it is understood that degenerative damage to the intervertebral disk (IVD) plays a central role in the pathogenic mechanism leading to back pain.4 Despite advancements in our understanding of spinal biomechanics and technologic innovations in spinal instrumentation, the diagnosis and treatment of diskogenic LBP remain problematic. The development and implementation of effective treatment strategies for patients with diskogenic LBP require a thorough understanding of the structure and function of the normal IVD, as well as the cellular, biochemical, and biomechanical changes that occur with degeneration of the IVD. Once an understanding of IVD physiology and pathophysiology has been gained, current diagnostic tools and treatment strategies for patients with LBP secondary to degenerative disk disease (DDD) will be reviewed.
Physiology of Intervertebral Disks
Structure and Composition
The IVD forms an avascular fibrocartilaginous joint between adjacent vertebral bodies. It consists of three major components: the gelatinous nucleus pulposus (NP), the annulus fibrosus (AF), and the superior and inferior end plates (Fig. 273-1). The NP is centrally located and composed of type II collagen within a dense matrix of proteoglycans and water. The end plates and annular matrix serve as selective permeability barriers that restrict transport to and from the nucleus based on charge and molecular weight. A fixed negative charge associated with nucleus proteoglycans generates an osmotic pressure gradient that creates the normal swelling pressure and volume of NP needed to support spinal forces. The AF has between 15 and 25 distinct type I collagen layers, or lamellae, attached to the vertebral rim and surrounding the NP.5 It serves both as a ligament to guide intervertebral movement and as a barrier to contain nuclear swelling and thereby facilitate disk pressurization.
Cell and Matrix Biology
The IVD contains few cells relative to its abundant extracellular matrix (ECM).6 In the IVDs of young individuals, the NP contains both notochordal and chondrocytic cells. The notochordal cells are remnants of spinal development7,8 and are uniquely designed for maintaining production of proteoglycans, but they disappear via apoptosis well before early adulthood, probably because of pressure from an upright stance,9 thereby leaving only the chondrocyte-like cells.10,11 The presence of these chondrocytic cells in the inner AF and end plates has led some researchers to suggest that these cells may migrate into the NP as part of the aging process.12–14 Chondrocytes in the mature NP are generally round or oval, whereas annular fibroblasts tend to be more elongated.15 Long cell processes that may be involved in sensing mechanical strain have also been identified in all areas of the IVD.16 Cells at the transition between the NP and AF have the capacity to behave both as chondrocytes and fibroblasts, perhaps fluctuating in response to local environmental cues. For example, loss of nuclear volume as a result of notochordal cell apoptosis causes redistribution of stress and inner annular chondroplasia, with denaturation of lamellar collagen leading to chondrocyte proliferation into the nuclear space.13 This process results in the age-related loss of nuclear/annular distinction.
IVD cells secrete and maintain a dense and heterogeneous ECM. The major constituent of the NP is proteoglycans, mostly large aggrecan molecules, and they make up 50% of the dry weight in normal disks.17 The NP also contains randomly organized collagen fibers, predominantly type II, and elastic fibers, which are oriented vertically near the superior and inferior end plates.18–20 Type I collagen is the major extracellular component of the AF; it accounts for 67% of the dry weight of the AF, with decreasing amounts from the outer portion of the AF toward the NP.18 The collagen fibers are aligned and oriented at 60 degrees relative to the vertical axis and alternate in adjacent lamellae.21 Although elastin represents only 2% of the dry weight of the IVD,22 recent findings suggest that it is an important contributor to normal disk function.23,24 Inside the lamella, long elastin fibers are oriented in parallel with collagen fibers.24 Interlamellar elastin fibers bridge adjacent layers, where “kinks” have been observed histologically to exit collagen bundles.23,25
Nutrition
Because the IVD is the largest avascular tissue in the body, transport of essential nutrients (oxygen and glucose) and substrates for matrix production (amino acids) by NP cells is essential for disk homeostasis.26,27 The IVD loses direct communication with the vertebral blood supply after the second decade of life27,28 and thereafter is dependent on diffusion of nutrients from surrounding capillaries29 at the periphery of the annulus and at the vertebral end plates.30 The majority of transport to and from NP cells occurs via the vertebral end plates.31 The availability of nutrients at the vertebral end plates is in turn dependent on capillary supply through mesenchymal stem cells within the subchondral bone.
Innervation
Despite being almost entirely avascular, the normal adult IVD is innervated. The posterior part of the AF and the posterior longitudinal ligament are innervated by the sinuvertebral nerve, which is thought to be capable of nociception, whereas the anterior and lateral portions of the AF are supplied by branches of the autonomic nervous system.32 Nociceptors are normally found in the outer layers of the AF and, as recent evidence indicates, in the central portion of the vertebral end plates as well.33,34 These observations have been confirmed by pain provocation studies in human participants.35
Biomechanics
The IVD is the only joint that can deform along 6 degrees of freedom (three orthogonal translations and three rotations). Its main function is to support spinal compression and provide flexibility, and along with the facet joints, it defines the range of motion of the spine. The structural unit consisting of the IVD, adjacent vertebra, and facet joints experiences a wide range of loading modalities in vivo, including axial compression, shear, flexion and extension, lateral bending, and axial rotation. During activities of daily living, forces are shared between the disk, vertebra, and facets in a posture-dependent manner. Typically, the vertebral end plate is the vulnerable tissue during supraphysiologic compression, whereas the facets are vulnerable during supraphysiologic shear and the facets/annulus during supraphysiologic rotations.36,37
Degeneration of the Intervertebral Disk
Pathologic Features
Morphologic changes in the IVD commence with loss of the notochordal nucleus before the second decade of life and progress continuously with age.38 With this age-related remodeling, the normal lamellar architecture of the AF becomes progressively disorganized and the NP becomes less hydrated and more fibrotic (see Fig. 273-1).39 At the same time, the border between the AF and NP becomes less distinct.40 Structural disorganization of the end plate, including cracks and microfractures in the subchondral bone, are also evident.38 Macroscopically, three types of lesions can be distinguished in a degenerate AF: (1) circumferential tears, or delaminations, which are formed by mechanical separation of the layers along the circumference of the disk; (2) radial fissures, which progress outward from the NP and cut through layers; and (3) rim lesions, which are peripheral radial tears that occur near the end plates (see Fig. 273-3).41,42 These tears are accompanied by vascularized granulation tissue and growth of new nerves and blood vessels not present in the normal IVD.43,44 Microscopically, cellular proliferation occurs with the formation of cell clusters, especially in the NP.45 These observations are concurrent with necrotic and apoptotic changes at the cellular level.7 It is also believed that the inflammatory process is an important characteristic of DDD,46 and elevated levels of cytokines, matrix metalloproteinases (MMPs), and growth factors have been identified in the degenerate disk.47–49
Cell and Matrix Biology
The earliest biochemical change involves loss of proteoglycan in the NP, which results in decreased hydration and swelling pressure.39 Although absolute amounts of collagen in the disk change relatively little, the type and distribution of collagen are altered. For example, with degeneration, type II collagen is increasingly denatured.50 A recent study demonstrated that the total elastin content increases with degeneration as well.51 Degenerate disks have elevated levels of proteolytic and degradative enzymes, including collagenase, lysozyme, elastase, and several MMPs.52–54 In addition, reduced levels of enzyme inhibitors have been observed in the degenerate IVD.54,55 IVD cells continue to synthesize new ECM during the early stages of degeneration,56,57 yet this anabolic behavior becomes outpaced by catabolism in more degenerate disks. Incomplete breakdown of disk macromolecules leads to the accumulation of degenerative debris in the ECM,58 which can form a catabolic stimulus for disk cells.
Biomechanics
Altered biomechanics secondary to changes in the ECM are characteristic of the progression of disk degeneration. Loss of proteoglycan in the NP leads to a reduction in water content, swelling pressure, and subsequent disk height.59,60 Loss of nuclear volume and disk height causes relaxation of stress in ligamentous structures surrounding the disk and leads to spinal hypermobility. With progressive nuclear fibrosis and collagenous cross-linking, the IVD stiffens, which results in the reduced flexibility associated with late-stage degeneration. The degenerate NP no longer behaves hydrostatically; it loses fluid rapidly under load, and the resultant changes in viscoelasticity suggest a shift from a “fluid-like” NP to a more “solid-like” material with degeneration.61,62 This also reflects a shift in the load-bearing mechanism: from hydration and pressurization in the NP to greater elastic deformation and peak stress incurred in the AF.63,64 Loss of normal nuclear function and increased stress in the AF predispose the disk to annular tears and end plate damage, as well as to mechanical delamination.65
Etiology of Degeneration
Nutrition
Although many factors are involved in the pathogenesis of disk degeneration, reduction of disk cell nutrition is probably a contributor. Cell culture studies demonstrate that synthesis of matrix is drastically reduced when the oxygen concentration falls below 5% or the pH is below 6.8, but active MMPs are continually being produced regardless of the conditions.66,67 Cells do not survive in this type of environment for long; exposure to an environment with a pH below 6.3, observed in some symptomatic disks, will result in cell death.26,62,68 Further evidence for loss of nutrition in the degenerate disk comes from findings of increased lactate levels in patients reporting diskogenic pain.69 The mechanism leading to loss of disk nutrition is still unknown, although several areas are being investigated.62 Atherosclerosis, which would affect the blood supply to the vertebrae, is associated with significant increases in degeneration.70,71 Long-term lack of exercise may also have a negative impact on transport of nutrients into the disk, although a potential mechanism is still unclear.72 Smoking is a risk factor for LBP in humans, and studies in rats have shown a direct link between smoking and disk degeneration.73,74 Finally, calcification of the cartilaginous end plate, as occurs with aging, impedes delivery of nutrients to the disk.28,75 Because of its avascularity, the IVD depends on a strict pathway for delivery of nutrients. Regardless of the inciting stimulus, disruption of this nutrient pathway will lead to harmful cellular changes and alterations in the ECM that contribute to the pathogenesis of DDD.
Catabolic Activity
Matrix degradation appears to be a key factor in the progression of disk degeneration. In its simplest form, disk degeneration is caused by an imbalance between anabolic and catabolic factors.76 Increased levels of MMPs, lysozyme, elastase, and inflammatory mediators such as macrophages, mast cells, interleukin-6 (IL-6), IL-8, prostaglandin E2 (PGE2), and tumor necrosis factor-α have been identified in human degenerate IVDs.49,52–54,77–79 Animal models have implicated nitric oxide and IL-1 as mediators in the pathologic process as well, but studies of human disks have not confirmed this finding yet.46 The exact mechanism by which an elevated catabolic process occurs and how it results in degeneration are unclear; however, it is possible that an acute injury leads to the synthesis of inflammatory mediators by disk cells in an attempt to heal themselves. Degradation of matrix by these molecules can enhance hypermobility and induce further injury to the disk. Furthermore, degraded macromolecules trapped in the disk ECM may independently signal additional degenerative changes.58
Mechanical Injury
Recently, Adams and Roughley proposed a simplified definition of disk degeneration to be “an aberrant cell-mediated response to progressive structural failure” and suggested that excessive mechanical loading in a vulnerable disk precipitates degeneration.41 Direct mechanical damage, whether through cyclic fatigue loading, hypermobility, or increased shear stress, can be associated with degenerative progression and clinically significant LBP.80 This hypothesis is supported by experimental animal models13,81,82 and epidemiologic data linking heavy lifting, intense physical work, and obesity with increased rates of mechanical LBP.83–85 Supraphysiologic combinations of bending, rotation, and compression can cause the major structural defects that are associated with degeneration, such as annular tears.37 Recent studies have also shown that loads of higher magnitude induce a catabolic response in the IVD characterized by increased protease gene and protein expression and activity.12 There is some evidence that high mechanical loads can also induce apoptosis in end plate cells.86 Furthermore, vertebral end plate damage can initiate degenerative changes by decompressing the NP and thus placing greater loads on the AF.87–89 The increased axial loading of the AF causes radial bulging both outwardly and inwardtoward the NP.41,90 The resultant shear stresses in the AF, which also occur as a result of preexisting annular tears, may lead to further degeneration.65,91 Additional support for a mechanical cause of DDD comes from evidence that altered mechanics in both the lumbar and cervical spine after surgical fusion leads to pathologic changes in adjacent segments.92
Genetics
Inherited traits are reported to account for up to 74% of the variability in disk degeneration.41,93 In a classic series of twin studies, Battie and coworkers demonstrated similar degeneration patterns in monozygotic twins who were not concordant for environmental risk factors such as smoking and heavy physical work.94 These studies are consistent with others noting that risk for back pain runs in families. Several genetic markers have been linked to disk degeneration, including alleles for collagen type IX, aggrecan, MMP-3, and the vitamin D receptor.95–98 Most of these markers have been identified through a candidate gene approach. Given that these genes encode proteins associated with physical properties of the ECM, it may be that inherited traits modulate the balance between damage accumulation and healing by tipping the scales toward accumulation of damage in at-risk patients. Better understanding of the genetic determinants and signaling pathways involved in disk degeneration may be achieved only through alternative approaches, such as genetic mapping.62 Research in this area may aid the development of improved risk stratification, diagnostic criteria, and prevention strategies.
Diskogenic Low Back Pain
With degeneration there is growth of new nerves fibers, with some extending into the inner AF and NP in patients with chronic LBP.43,99 Most of the newly formed nerve fibers in persons with LBP accompany granulation tissue and are associated with the nociceptive neurotransmitters substance P and vasoactive intestinal peptide.43 Additionally, increases in sensory nerves associated with substance P and calcitonin gene–related peptide (CGRP) were found in the vertebral bodies and end plates in patients with DDD.100 Substance P and CGRP are nociceptive neurotransmitters associated with nerve growth factor (NGF)-dependent neurons that bind to the NGF receptor tyrosine kinase A (TrKA). A recent study involving rat disks demonstrated that inflammatory-mediated pain was associated with significant growth of NGF-dependent neurons.101 It has been hypothesized that NGF may lower the IVD’s threshold for pain and that elevated TrKA expression is associated with the advent and maintenance of chronic pain.46
It has been widely held that symptomatic disk degeneration is associated with structural damage to the disk, as is the case with annular tears.41 Recent work has led to better understanding of the potential mechanisms that may lead to LBP. In analyzing IVDs from patients with diskogenic pain, researchers found vascularized granulation tissue forming alongside annular tears in the inner AF and NP.43 Growth factors such as basic fibroblast growth factor (bFGF) and transforming growth factor-β (TGF-β) were found to be localized to this region of the disk only in painful IVDs; these growth factors promote cellular proliferation and differentiation, ECM synthesis, and fibrosis.49 The cytokines IL-6, IL-8, and PGE2 are released from the granulation tissue and may sensitize the nociceptors to a lower threshold for pain.78 NGF is also increased in painful degenerate disks and leads to a lowered pain threshold.46 Thus, together with neoinnervation and nociceptor sensitization secondary to the inflammatory process, hypermobile mechanics as a result of altered matrix composition and tissue fibrosis may lead to diskogenic pain.
