Natural History of the Degenerative Cascade

The degenerative process encompasses every element of the spine: the ligamentous structures, facet joints, intervertebral discs, endplates, and vertebral bodies. Changes occur in a sequential fashion on a multitude of levels, including the gross visual level, the radiographic level, the biomechanical level, and the biochemical level. Unfortunately, the changes seen in the normal aging spine are very similar to the changes seen in the pathologic and symptomatic spine. Hence, it becomes extremely difficult to differentiate the symptomatic conditions from the manifestations of a normal aging spine. It is only after understanding the normal changes associated with aging that we may be able to identify some of the pathologic changes.

The natural history of degenerative disc disease has been studied for many years. Lees and Turner, in 1963, followed 51 patients with cervical radiculopathy for 19 years and found that 25% had worsening of the symptoms, 45% had no recurrence, and 30% had what they classified as mild symptoms.¹ Nurick studied the nonsurgical treatment of 36 patients with cervical myelopathy over 20 years.² Sixty-six percent of the patients who presented with early symptoms did not progress, and approximately 66% of patients with moderate to severe symptoms did not progress either. The patients who progressed tended to be the younger patients.

Anatomy and General Mechanisms of Pain

In order to understand the degenerative cascade of the spine, it is of paramount importance to understand the normal function of the different structures and how they interrelate with each other. The facet joints are designed to bear approximately 10% to 30% of the load in the lumbar spine, depending on the patient’s position. The articular cartilage that bears such loads is supported by the subchondral bone. The subchondral bone also serves to provide nutrition to the articular cartilage. The facet joints are diarthrodial synovial joints that have a capsule. The capsules together with the ligaments constrain joint motion. The medial and anterior capsule is formed by a lateral extension of the ligamentum flavum. The capsules and ligaments are innervated by primary articular branches from larger peripheral nerves and accessory articular nerves. Such nerves consist of both proprioceptive and nociceptive fibers. They are monitored by the central nervous system, and may perceive excessive joint motion (potentially due to instability or an injury) as a noxious stimulus and mediate a muscular reflex to counteract such excursions. Nociceptive free nerve endings and mechanoreceptors have been isolated in the human facet capsules and synovium. Such nerve endings may perceive chemical stimuli or mechanical stimuli such as instability, trauma, or capsular distention as noxious stimuli. Joint effusions, commonly seen on MRIs, may prevent such reflexes due to capsular distention, similar to a distended knee joint and absent patellar reflex. Substance P, a pain-related neuropeptide, has been identified in synovium. Higher concentrations have been found in arthritic joints. Additionally, capsular free nerve endings have been found to become sensitized in arthritic joints. This has caused otherwise dormant nerve endings to become reactive to motion that was perceived as normal in nonarthritic conditions.

The intervertebral disc is another significant component of the degenerative cascade. The sinuvertebral nerve innervates the posterior and posterolateral aspect of the intervertebral disc, as well as the posterior longitudinal ligament (PLL) and the ventral aspect of the thecal sac. The lateral and anterior aspect of the disc is innervated by the gray ramus communicans. These free nerve endings have been found primarily in the outer one third of the annulus, and have been found to be immunoreactive for painful neuropeptides. Some complex endings have been identified within the annulus as well. The considerable overlap of the descending and ascending nerve endings with branches of the sinuvertebral nerves of the adjacent one to two discs makes identifying the exact pain generator even more difficult when performing clinical diagnostic tests. Leakage of such neuropeptides out of the disc in the presence of annular tears, onto the nearby dorsal root ganglion (DRG), can cause irritation of the DRG and become another source of pain. The PLL fibers are closely intertwined with the posterior annulus. The PLL has been identified to contain a variety of free nerve endings. Hence any irritation of the posterior annulus and disc can cause irritation of these nerve endings. Such irritation can be mechanical secondary to pressure from a herniated disc, abnormal motion from instability, or mechanical incompetence of the annulus. Irritants can also be chemical such as low pH fluids, cytokines, or neuropeptides that can leak out from the disc via annular tears.

Cortical bone, bone marrow, and periosteum have been found to be innervated by nerves containing nociceptive neuropeptides such as calcitonin, gene-related peptides, and substance P. Periosteal elevation, such as in cases of infection, tumor, or hematoma, can be painful. Periosteal tears in cases such as fractures, inflammation, or subsidence (e.g., in osteoarthritic conditions) can cause pain. Vascular congestion from bone infarcts or sickle cell can cause the intramedullary nerve fibers to initiate a painful response. Nociceptive nerve fibers have been identified in varying concentrations within the fibrous tissue of spondylolytic pars defects as well.

The spine is covered with muscles and tendons in which the main nociceptive nerve endings are unencapsulated. Pain may be mediated by chemical or mechanical conditions or both. The mechanonociceptive units may respond to disruption, stretch, or pressure. Direct injury can cause damage to the intrafascicular nerve fibers or cause a hematoma and edema, which can lead to a chemically mediated pathway. Such a pathway can begin by release of nociceptive sensitizing chemicals such as histamine, potassium, and bradykinin from the damaged tissues. This, in turn, can lead to altered vascular permeability and an influx of the inflammatory cells. It is through such neuropeptides that sensitization of the receptors occurs and, in combination with interstitial edema, this can cause primary muscular pain. At times, the mechanical effect of spasm of a major muscle group in and of itself can cause further trauma to the muscle, and potentiate the pain cascade.

Pathogenesis of Lumbar Degeneration

During childhood and the first two decades of life, the spinal motion segments generally function in a physiologic manner and the disc maintains its hydrostatic properties. Hence, the disc maintains its height and its normal relationship with the facets, allowing the facets to experience normal loads and physiologic motion. The canal and the foramen are usually patent and the ligamentum flavum is only a few millimeters thick. Invagination of the disc into the endplates (Schmorl nodes) and some facet asymmetry may be seen, but are generally not symptomatic. In the next 20 years, however, degeneration does occur and annular tears occur that lead to disc bulging and protrusion, which can then cause loss of disc space height and loss of hydrostatic properties. This, in turn, will cause increased loads on the facets and initiate facet hypertrophy and neural encroachment. Such hypertrophy, when present in combination with loss of disc height, potentiates foraminal compromise. Ligamentum flavum hypertrophy occurs as well, which together with facet hypertrophy potentiates central canal compromise. Loss of disc height can certainly cause loss of stature in the elderly population.

Biochemical Changes

Numerous biochemical changes occur in the disc as a result of aging. The gelatinous nature of the disc degenerates into a more fibrotic state due to loss of water content. It is important to understand that a normal disc is composed of 80% water and 20% collagen and proteoglycans. The negatively charged glycosaminoglycans are what allows the nucleus to retain its water content and osmotic pressure. The actual cascade of nucleus degeneration occurs in the following order. First, there is loss of distinction between the nuclear and annular fibers and an increase in the collagen content of the disc, followed by the loss of the negative charges mentioned earlier and loss of water content, greatly reducing the proteoglycan aggregates. In fact, during the breakdown of the glycosaminoglycans, there is also a significant loss of chondroitin sulfate in comparison to keratin sulfate. The annulus degenerates by a decrease in cellularity and metabolic activity. The annulus is the only portion of the disc that in its healthy state has vascularity. This vascularity decreases with degeneration, which may hinder the healing process. Proteoglycan content decreases and large collagen fibrils appear. The large fibrils when present in a biomechanically vulnerable portion of the annulus may increase the likelihood of annular tears. Such tears generally occur due to a rotational force and occur in the posterolateral annulus. With annular disruption, changes take place within the disc itself. Vascularized granulation tissue forms along the margins of the annular ruptures and may pass as far as into the nucleus.³ Unlike discs from asymptomatic subjects, among discs taken from back pain patients, nerve endings extended deep into the annulus and in some cases into the nucleus. Such nerves produced substance P.⁴ These changes within the disc likely play a role in discogenic pain. Also, such changes may challenge disc regeneration as a pain-relieving intervention.

The cartilaginous endplate serves as a nutrition gradient for the healthy disc. Degeneration of the disc has been associated with a decrease in the diffusion capability across the endplate and sclerosis of the endplate, which in turn negatively affects the nutrition of the disc.⁵ This is thought to at least have a negative impact on the biochemical medium within the disc, if it is not the actual cause. These types of degenerative and nutritional changes within the disc will likely pose a significant challenge to disc regenerative therapies.

Kirkaldy-Willis et al. inspected 50 lumbar cadaveric specimens and also analyzed morphologic changes in 161 patients’ lumbar spines intraoperatively.⁶ It is such observations that have provided links between the different aspects of the degenerative cascade, leading to a better understanding of the transformation of a healthy level in the spine to a stenotic level with spondylolisthesis and instability.