Degenerative Cervical Myelopathy: A Spectrum of Related Disorders Affecting the Aging Spine.

Cervical spinal cord dysfunction can result from either traumatic or nontraumatic causes, including tumors, infections, and degenerative changes. In this article, we review the range of degenerative spinal disorders resulting in progressive cervical spinal cord compression and propose the adoption of a new term, degenerative cervical myelopathy (DCM). DCM comprises both osteoarthritic changes to the spine, including spondylosis, disk herniation, and facet arthropathy (collectively referred to as cervical spondylotic myelopathy), and ligamentous aberrations such as ossification of the posterior longitudinal ligament and hypertrophy of the ligamentum flavum. This review summarizes current knowledge of the pathophysiology of DCM and describes the cascade of events that occur after compression of the spinal cord, including ischemia, destruction of the blood-spinal cord barrier, demyelination, and neuronal apoptosis. Important features of the diagnosis of DCM are discussed in detail, and relevant clinical and imaging findings are highlighted. Furthermore, this review outlines valuable assessment tools for evaluating functional status and quality of life in these patients and summarizes the advantages and disadvantages of each. Other topics of this review include epidemiology, the prevalence of degenerative changes in the asymptomatic population, the natural history and rates of progression, risk factors of diagnosis (clinical, imaging and genetic), and management strategies.

S pinal cord injury (SCI) and neurological dysfunction result from an insult to the spinal cord parenchyma that manifests clinically as disturbances to sensory, motor, or autonomic pathways and that affects physical, emotional, and social well-being. 1 An SCI can be caused by a traumatic event such as a motor vehicle accident or a fall or can result from nontraumatic causes such as tumors, degenerative changes, loss of blood supply, or infection. Cervical spondylotic myelopathy (CSM) is a neurological disorder caused by the degeneration of the spinal axis and resultant spinal cord compression. This nontraumatic SCI may result in pro-gressive functional decline owing to severe neurological impairment and in reduced quality of life. 2 CSM is the commonest cause of spinal cord dysfunction in adults globally. In a recent review on the epidemiology of nontraumatic SCI, New et al 3 estimated that degenerative spine disease encompasses 59% of nontraumatic SCIs in Japan, 54% in the United States, 31% in Europe, 22% in Australia, and between 4% and 30% in Africa. Furthermore, the regional incidences of nontraumatic SCI in North America, Europe, and Australia are 76, 26, and 6 per million, respectively, and the prevalence in Canada is 1120 per million. From these numbers, Nouri et al 4 conservatively estimated the incidence and prevalence of myelopathy caused by degenerative pathology of the spine in North America to be 41 and 605 per million, respectively.
As identified in the 2013 AOSpine North America focus issue, there is a need to standardize nomenclature and to better define CSM. 5 In a recent review, Nouri et al 4 proposed the adoption of a new term, degenerative cervical myelopathy (DCM), that comprises osteoarthritic changes to the spine, including spondylosis, disk herniation, and facet arthropathy, as well as ligamentous hypertrophy, calcification, or ossification. The main counterargument to this unified terminology is that ossification of the posterior longitudinal ligament (OPLL) and disk degeneration or CSM are distinct diagnostic entities and vary with respect to common risk factors, diagnostic methodology, global prevalence, management strategies, and surgical prognosis. Although differences exist, both conditions are related to advancing age and result in progressive spinal cord compression and neurological dysfunction and thus can be categorized under the same umbrella term, DCM. The term DCM was also adopted in several recent studies, including the AOSpine CSM-International and North American studies. These studies used broader inclusion criteria and enrolled patients if they presented with myelopathy secondary to spondylosis, disk herniation, OPLL, or hypertrophy of the ligamentum flavum. 6 Interestingly, in these surgical cohorts, very few participants had isolated OPLL without other forms of degenerative changes. Furthermore, there were no significant differences in functional status or quality-of-life outcomes at 2 years postoperatively between patients with OPLL and those with other forms of DCM. However, a longer-term comparative study of surgical outcomes is required to further support this unified nomenclature because the natural history of OPLL appears to be different from that of CSM and because fusion may not be as effective at halting its progression.
This review summarizes current knowledge on the pathophysiology, epidemiology, natural history, diagnosis, assessment, and treatment strategies for patients with DCM.

THE DEGENERATIVE PROCESS AND PATHOPHYSIOLOGY
DCM is a progressive disease caused by age-related degeneration of the facet joints, intervertebral disks, or vertebral bodies; hypertrophy of the ligamentum flavum; and, in some cases, OPLL or progressive cervical kyphosis. 2,7 As the spine ages, the disks begin to degenerate and can no longer fulfill their weight-bearing and load-transferring functions. 2,8 As a result, the uncovertebral processes experience increased load and become flattened, thus altering the load-bearing function of the intervertebral joint and increasing stress on the articular cartilage endplates. Osteophytes develop to stabilize the abnormal motion and to increase the weight-bearing surface of the endplates. 9 These bony spurs also protrude outward from the vertebral body to cover the bulging intervertebral disk. 10 In addition, the ligamentum flavum may stiffen and buckle as a result of loss of disk height and straightening of cervical lordosis, and other spinal ligaments may hypertrophy or ossify. 2,11 Table 1 lists the degenerative pathologies included under the umbrella term DCM. Figure 1 provides a magnetic resonance image (MRI) and x-ray of a patient with multiple forms of DCM, including spondylosis, disk herniation, OPLL, and subluxation of C4. Figure 2 displays other forms of ligamentous aberrations.
These age-related degenerative changes ultimately narrow the spinal canal and encroach on the spinal cord. In addition to static factors, nerve root and spinal cord compression can be aggravated by dynamic mechanisms. 12 During neck flexion, the spinal cord can be compressed by ventral osteophytes, and in extension, the cord can be pinched between the vertebral body and the lamina or ligamentum flavum. 10 Chronic mechanical compression of the cord causes flattening and widening of the spinal cord and results in a cascade of pathophysiological events, including ischemia, endothelial cell impairment, disruption of the blood-spinal cord barrier, neuroinflammation, and apoptosis. 12 Eventually, the spinal cord may experience axonal demyelination, gliosis, scarring, cavitation, degeneration of the corticospinal tracts, interneuronal loss, and atrophy of the anterior horn cells. 8 The macrovascular and microvascular architecture is also altered in DCM: (1) The anterior spinal artery and parenchymal arterioles experience wall thickening and hyalinization; (2) the diameter of the radicular arteries narrows as a result of stenosis of the intervertebral foramen; (3) blood flow velocity decreases in major feeding arteries; and (4) overall perfusion to the spinal cord is compromised. 13 All of these changes result in chronic hypoxic conditions, a decrease in the number of vessels, and reduced blood flow to axonal pathways, including the corticospinal tract. Interestingly, levels 5 to 7 of the cervical spine are the most susceptible to vascular injury and are the most common levels of myelopathy in DCM. 14,15 The mechanical stretch on the spinal cord also results in a decrease in the number of endothelial cells that are partly responsible for the integrity of the blood-spinal cord barrier. 16 Quantitative loss and dysfunction of these cells increase the permeability of the blood-spinal cord barrier, causing edema in the spinal parenchyma, infiltration of peripheral inflammatory cells, and entry of blood-borne toxins. Compression in DCM also results in microglial activation and macrophage recruitment to the site of compression; this neuroinflammation is exacerbated by the destruction of the blood-spinal cord barrier. 17 Furthermore, hypoxia combined with inflammation triggers oligodendrocyte and neuronal apoptosis and results in axonal degeneration in the main corticospinal tracts. 18 Disease pathophysiology varies slightly in the case of spinal deformity but ultimately results in neuronal apoptosis, decreased vascular supply, and demyelination. 19 In patients with progressive cervical kyphosis, the spinal cord is forced anteriorly against the vertebral bodies and is tethered by the dentate ligaments and cervical nerve roots. This longitudinal tension of the spinal cord results in increased intramedullary cord pressure, cord flattening, and progressive neurological dysfunction. 19,20 Figure 3 summarizes the pathophysiology of DCM.

THE ASYMPTOMATIC POPULATION AND PREVALENCE OF DEGENERATIVE CHANGES
The prevalence of degenerative changes in the asymptomatic population is not well documented. Boden et al 21 reported that 95% of men and 70% of women in a cohort of 200 asymptomatic patients 60 to 65 years of age exhibited evidence of degenerative changes on a lateral cervical spine radiograph. In a study by Ernst et al, 22 the prevalence of annular tears and bulging disks on MRI was 36.7% and 73%, respectively, in asymptomatic volunteers 19 to 69 years of age. Disk protrusions were also seen in 50%, and an extrusion was identified in 1 subject at the C5-C6 level. Severe degeneration of $1 disks was observed in 33% of volunteers, and 13.3% exhibited radiologic evidence of spinal cord compression. A second study of 1211 asymptomatic volunteers 20 to 79 years of age in Japan reported significant disk bulging in 87.6% of the sample and evidence of spinal cord compression in 5.3%. 23 Furthermore, 2.3% exhibited high-signal-intensity lesions on T2-weighted images, and 3.1% had flattening of the spinal cord. Finally, Matsumoto et al 24 evaluated the disks of 497 volunteers and identified grade 1 (dark or speckled) and grade 2 (almost black) disk degeneration in 86-89% of subjects .60 years of age. Approximately 8% of volunteers exhibited grade 2 posterior disk protrusion with spinal cord compression. All 3 studies reported an increase in the prevalence of degenerative changes with increasing age. [22][23][24] In addition, Kato et al 25 demonstrated a decrease in the diameter of the spinal cord, spinal canal, and dural tube and a decrease in the cross-sectional area of the dural tube and spinal cord with increasing age.

Ossification of the Posterior Longitudinal Ligament
The prevalence of OPLL has been better classified in Japanese individuals compared with other Asian or non-Asian populations. By studying 1879 volunteers $50 years of age, Ohtsuka et al 26 estimated the prevalence of cervical OPLL to be 4.3% in men, 2.4% in women, and 3.2% for the total Japanese population. With respect to age, the incidence of OPLL was 2.6% for subjects in their sixth decade of life and rose to 4.5% for individuals 60 to 69 years of age. In an earlier epidemiologic study by Nakanishi et al, 27 radiographic evidence of OPLL was present in 25 of 698 asymptomatic Japanese subjects (3.6%) and showed the highest prevalence in subjects 60 to 70 years of age. In the most recent update, Nakashima et al 23 reported that only 5 of 1211 volunteers (0.4%) displayed evidence of OPLL. Most studies have observed a higher prevalence in the general Japanese population than in other Asian or non-Asian countries and have reported frequencies between 1.0% and 4.3%. 11,26,[28][29][30][31] The prevalence of OPLL in the North American population is higher than what is generally appreciated. 32,33 In 1994, Resnick 34 estimated that 0.12% of whites from North America have OPLL; this percentage is likely higher today as a result of increased awareness of this disease among surgeons. Other studies have reported disease prevalence among outpatients with cervical spine  disorders across American states and cities, including New York City (0.7%), Hawaii (0.6%), Minnesota (0.1%), and Utah (1.3%). 28,29,31 In European countries and regions, the prevalence of OPLL in a similar sample was estimated to be 0.1% in West Germany and 1.7% in Italy. 29 Several studies have quantified the prevalence of OPLL across non-Japanese regions. Jayakumar et al 28 compared degenerative changes in the Japanese, non-Japanese Asians, Western whites, and Indian whites. The prevalence of OPLL in the general population was estimated at 2% to 4% in non-Japanese Asians, 1% to 8% in Indian whites, and 0.16% in Western whites. In a study by Lee et al, 35 the prevalence of OPLL was determined to be 0.83% in a sample consisting of 36 Chinese, 5 Malays, 1 Pakistani, and 1 Borneo aborigine. In the Korean population, the reported incidence ranges from 0.6% to 3.6% but has always been identified as lower than in Japanese cohorts. 11,29,36,37 Other estimated incidences across Asian populations include 2.1% to 3.0% in Taiwan, 0.8% in Singapore, 0.4% in Hong Kong, 1.5% in the Philippines, and 1.5% in Mongolia. 11,29,37,38 CURRENT APPROACHES TO DIAGNOSIS

Clinical Assessment
Patients with evidence of cervical degeneration may be completely asymptomatic or simply have localized neck pain. 10 If these degenerative changes result in nerve root or spinal cord compression, patients may experience radicular pain into the upper extremities or exhibit motor dysfunction in the upper and lower limbs, sensory loss, or sphincter disturbance. 10 The diagnosis of DCM begins with a detailed patient history and comprehensive neurological examination. 39 Common self-reported symptoms include hand numbness, loss of manual dexterity, bilateral arm paresthesias, impaired gait, lower-extremity weakness, Lhermitte phenomenon, urge incontinence, and urgency of urination and defecation. 8,10 Objective signs of myelopathy are hyperreflexia, clonus, a positive Hoffman sign, up-going plantar responses, lower-limb spasticity, corticospinal distribution motor deficits, atrophy of intrinsic hand muscles, broad-based unstable gait, and sensory loss. 8,10 Imaging Assessment Plain radiographs are typically the initial imaging modality for the assessment of DCM. Lateral views are often used in conjunction with other forms of cross-sectional imaging, including MRI and computed tomography scans to depict spinal canal narrowing and OPLL. 10 In addition, lateral images can identify subluxation, disk degeneration, and kyphosis. Dynamic lateral radiographs in the form of flexion and extension views may also be used to detect cervical instability. Specific measurements of spinal alignment should be assessed, including cervical lordosis, sagittal plane translation, and horizontal gaze. Cervical lordosis from either C1-C7 or C2-C7 is commonly evaluated by calculating the Cobb angle ( Figure 4, derived from Ames et al 19 ). Sagittal plane translation is assessed through the cervical sagittal vertical axis: (1) C2 and C7 cervical sagittal vertical axes are good measurements of global sagittal alignment and are determined by the distance between the C2 or C7 plumb line and the posterior superior corner of sacrum, and (2) a plumb line dropped from the centroid of C2 to the posterior superior aspect of C7 can be used to measure regional cervical sagittal vertical axis. Finally, horizontal gaze can be assessed by the chin-brow vertical angle, which is the angle between a vertical line drawn from the forehead and a line drawn between the chin and eyebrow. Other measurements included in Figure 4 are the T1 slope (angle between horizontal plane at T1 endplate), pelvic incidence, sacral slope, and pelvic tilt. The spine functions as a global unit, and as a result, parameters in the lower spine may influence alignment in the cervical region.
MRI can visualize neural, osseous, and soft-tissue structures with high-resolution and is routinely used to confirm the diagnosis of DCM. 40 MRI can clearly delineate the degree of degeneration and canal stenosis, identify compression of the spinal cord, and detect intramedullary signal changes. 41 It is also one of the most valuable tools to differentiate between DCM and other causes of neurological dysfunction because it can detect anatomic changes of the spinal axis and parenchymal abnormalities, including neoplasms, demyelinating plaques, and syringomyelia. 39 Unfortunately, MRI is contraindicated in the setting of ocular metallic foreign bodies, aneurysm clips, embedded wires, stimulators or batteries, nitroglycerin patches, pacemakers, or severe claustrophobia. Computed tomography scans with or without myelography are alternative diagnostic modalities for patients who are unable to undergo MRI scanning. 42 This form of imaging can also be used to visualize bony abnormalities and to detect ossification of ligamentous structures.
MRI findings of relevance include the anteroposterior diameter, compression ratio and transverse area of the spinal cord, T1 signal hypointensity, T2 signal hyperintensity, segmentation of T2 signal change, effacement of cerebrospinal fluid (CSF), and deformation of where Di is the anteroposterior canal diameter at the level of maximum compression, Da and Db are the anteroposterior diameters of noncompressed levels from above and below, di is the anteroposterior spinal cord diameter at the level of maximum compression, and da and db are the anteroposterior diameters of noncompressed levels from above and below ( Figure 5C). Several studies have evaluated the association between clinical presentation and MRI findings. As outlined previously, individuals may have imaging evidence of degeneration or spinal cord FIGURE 4. Assessment of cervical alignment. Left, measurement of sagittal plane translation through the cervical sagittal vertical axis (SVA; distance between the C2 or C7 plumb line and the posterior superior corner of the sacrum). Top right, assessment of regional cervical SVA angle by measurement of the Cobb angle (drawing 2 lines parallel to the inferior plate of C2 and C7 and measuring the angle between them), T1 slope (angle between the horizontal plane and T1 endplate), and horizontal gaze evaluated by chin-brow angle. Bottom right, parameters in lower regions of the spine that may affect cervical alignment. CL, cervical lordosis; COG, center of gravity; FS, femoral shaft; PI, pelvic incidence, PT, pelvic tilt; SS, sacral slope. Derived with permission from Ames et al. 19 compression without presenting with signs and symptoms of myelopathy. For example, in a study by Schmidt et al, 45a impingement of the spinal cord was visible on the MRI in 16% and 26% of asymptomatic patients ,64 and .64 years of age, respectively. On the other hand, in a study by Harrop et al, 39 myelopathy, defined as the presence of .1 long-tract sign localized to the cervical spinal cord, was highly correlated with the presence of hyperintensity on a T2-weighted image and spinal cord compression (indentation of the spinal cord parenchyma changing the contour of the spinal cord perimeter). In fact, all patients with myelopathy (defined as the presence of .1 longtract finding) had evidence of spinal cord compression in this series. The presence of long-tract signs was also significantly correlated with the transverse area of the spinal cord in a study by Karpova et al. 45 Furthermore, smaller transverse area was related to a higher number of myelopathic signs (r = 0.34, P = .01), hyperreflexia (r = 0.19, P = .02), a positive Hoffman sign (r = 0.30, P , .001), up-going plantar responses (r = 0.26, P = .003), numbness of the hands (r = 0.18, P = .04), and a lower preoperative modified Japanese Orthopaedic Association (mJOA) score (r = 0.24, P , .001). There was also a significant association between JOA and preoperative cumulative MRI score (0 = normal image, 5 = spinal cord deformity observed both anteriorly and posteriorly). 46 The study by Karpova et al 45 demonstrated significant correlations between signal change (normal T2/normal T1; high T2/normal T1; high T2/low T1) and the presence of up-going plantar responses (r = 20.2, P = .02) and numb hands (r = 20.2, P = .02). Leg spasticity, hyperreflexia, and atrophy of the intrinsic hand muscles were also more common in patients with either high T2/normal T1 or high T2/low T1 signal changes than in patients with a normal MRI. 47 The overall prevalence of myelopathic signs was highest in patients with hyperintensity on a T2-weighted MRI. There were no significant differences in preoperative JOA or mJOA score between the 3 T2/T1 signal intensity groups. However, other studies have reported correlations between T2 hyperintensity and preoperative walking test time and Nurick score and between T1 hypointensity and baseline mJOA, 30-m walking test time and cadence, grip strength, Nurick, and Berg Balance Scale. 48 T2 signal grade has also been associated with preoperative myelopathy severity. In a study by Shin et al, 49 the baseline JOA was higher in patients with no intramedullary signal change (11.6 6 2.3) than in patients with grade 1 (10.8 6 2.3, predominantly faint and indistinct borders) or grade 2 (9.2 6 3.6, predominantly intense and well-defined borders) signal change. Finally, segmentation of T2 hyperintensity was significantly associated with walking test time and cadence and Berg Balance Score. 48 MRI also plays a role in surgical decision making and may be useful in predicting postoperative outcomes. On the basis of a systematic review by Tetreault et al, 50 T2 signal hyperintensity is a significant predictor of outcome when used in combination with T1 signal hypointensity, as a ratio comparing compressed and noncompressed segments, or as a ratio of T2 vs T1. In addition, multilevel signal change is also associated with a poor surgical prognosis. Both a high signal change ratio and T1 signal change reflect advanced histological damage such as necrosis, myelomalacia, and cavitation that may be irreversible despite spinal cord decompression. Because T2-weighted signal change can be associated with a broad spectrum of compressive pathologies and highly variable recuperative potential, it is relatively nonspecific and is unable to effectively predict surgical outcomes when used in isolation. [51][52][53][54][55] The predictive value of MRI has also been demonstrated recently with data from the AOSpine CSM-North America study. This analysis indicated that the presence of T1 signal hypointensity and an increased maximum canal compromise are associated with a lower probability of achieving a mJOA score $ 16 at 6 months after surgery. 44 Diffusion tensor imaging is an emerging neuroimaging technique that may be useful in detecting early stages of myelopathy, predicting disease progression, and evaluating surgical prognosis. Two important parameters measured by diffusion tensor imaging are apparent diffusion coefficient and fractional anisotropy. Both of these measurements may provide insight into the structural integrity of the spinal cord: Typically, lower fractional anisotropy and higher apparent diffusion coefficient values are present in patients with myelopathy. [56][57][58][59] Several studies have also demonstrated that diffusion tensor imaging is more sensitive and specific than MRI and, as a result, may have superior diagnostic ability and improved correlation with baseline severity scores. In particular, diffusion tensor imaging can detect damage to the white matter tracts before a signal change is identified on a T2-weighted MRI. 58,60 Electrodiagnosis Electrodiagnosis is less commonly used to diagnose DCM but can help differentiate between patients with degenerative spinal cord compression and those with mimicking diagnoses. 10 Common forms of electrodiagnosis include electromyography, electroneurography, and nerve conduction studies and evoked potentials.
Electromyography assesses the activity of muscle cells by repeatedly stimulating receptors of the sensory nervous system and measuring the resultant cortical activity. 61 At rest, insertion activity may be absent in various neuromuscular disorders, reduced in metabolic diseases, and prolonged in denervated muscle. Both rhythmic fibrillation potentials and positive sharp waves are indicators of denervation. Fasciculation potentials reflect chronic partial denervation and are observed in amyotrophic lateral sclerosis. 62 Alterations in motor unit potentials may indicate physiological changes and can confirm the diagnosis. Double discharges at the beginning of voluntary contractions can indicate disorders of the anterior horn cells, roots, or peripheral nerves; myokymic discharges can reflect radiation myelopathy, multiple sclerosis, chronic radiculopathy, entrapment neuropathy, or syringomyelia; and neuromyotonic discharges can be present in patients with peripheral axonal or demyelinated neuropathy. 62 Electroneurography or nerve conduction studies can quantify the motor and sensory conduction velocities of peripheral nerves. This is done by placing 2 electrodes at different points along a peripheral nerve. The time interval between the stimulus and recorded response is measured and divided by the distance between the 2 electrodes. 61,62 Nerve conduction studies are less useful for detecting CSM and pure sensory radiculopathies 10 but are essential to rule out alternative diagnoses, including peripheral axonal and demyelinating neuropathy and peripheral nerve entrapment such as carpal tunnel syndrome. 10,63 Evoked potentials are important tools for determining the integrity of various functional systems, including the visual, auditory, somatosensory, and motor systems. In the case of somatosensory evoked potentials, an electric stimulus applied to the skin will travel through the peripheral nerve, nerve root, posterior columns, spinothalamic tract, medial lemniscus, and thalamocortical connections. 61,62 Any decrease in velocity may reflect injury along any of these pathways and can help assess the degree of sensory conduction impairment. Although these potentials may be useful in the diagnosis of DCM, they are not commonly used in clinical practice except for electrophysiological monitoring during surgery. 10

EVALUATING FUNCTIONAL STATUS AND QUALITY OF LIFE
Quantitative tools are valuable in the clinical setting because they can be used to objectively describe disease severity at baseline, to assess the effectiveness of interventions, to predict outcome, and to provide decision support to clinicians. 64,65 Singh et al 66 reported the results of a survey in which clinicians agreed on the importance of quantifying functional disability in patients with DCM. However, respondents also believed that specific assessment tools are underused or not ideal. In the field of DCM, there is no gold standard for assessing disease severity, predicting outcome, or evaluating a patient's improvement after intervention. 67 Clinicians are therefore unable to establish standard quantitative guidelines for DCM management.
Several tools are designed to evaluate neurological impairment, functional status, and health-related quality of life in patients with DCM (Table 2). [67][68][69] (5) Clinician administered The four categories are not equally weighted Lower-extremity function (7) DCM-specific index Reliability has not been established Sensory function (3) Valid Bladder function (3) Responsive to change The lower the score, the greater the disability SF-36v2 General health disability (

RISK FACTORS OF DIAGNOSIS
Asymptomatic patients with evidence of cervical canal stenosis and cord compression caused by spondylosis are at risk of developing signs and symptoms of myelopathy. 70 According to a systematic review by Wilson et al, 70 approximately 8% of these patients will deteriorate and exhibit clinical evidence of DCM at 1 year, and 23% will demonstrate objective findings at a median of 44 months.

Clinical Risk Factors
Several studies have examined the association between age, sex, and DCM diagnosis. Age was identified as a significant risk factor for DCM by 2 studies. 71,72 Yue et al 71 compared age between DCM patients and control subjects with neck pain but no evidence of spondylosis. Patients in the myelopathy group had a mean age of 56.7 years and were significantly older than subjects in the control group (mean age, 43.3 years). In a study by Takamiya et al, 72 increased age was also a significant risk factor for cervical myelopathy (odds ratio, 1.07; confidence interval, 1.01-1.14). In contrast, a single study reported no significant relationship between age and DCM diagnosis 73 (Table 3). Two studies indicated that sex is not a risk factor of diagnosis. 71,72

Imaging Risk Factors
Five studies explored the relationship between DCM diagnosis and various imaging findings (Table 4). 71,[73][74][75][76] In a study by Hukuda et al, 74 several computed tomography measurements were compared between patients with DCM and a control group of patients with other spinal pathologies (eg, metastatic thoracic tumor, rheumatoid spondylitis, traumatic subluxation). In the myelopathy group, patients had vertebral bodies with significantly larger cross-sectional areas (C3-C6), transverse diameters (C3, C5-C7), and sagittal diameters (C3-C7). The transverse diameter and sagittal diameter of the spinal canal were significantly smaller in the DCM group at all vertebral levels. In addition, at C3 and C7, the cross-sectional area of the spinal canal was significantly smaller in the myelopathy group compared with the control group. DCM patients also had a smaller sagittal diameter of the spinal cord at all levels and a smaller transverse diameter at C4, C6, and C7. The space available for the spinal cord in the sagittal (C5-C7) and transverse planes (C3 and C5) was significantly smaller in the myelopathy group than in the control group. There was no significant difference in the crosssectional space available for the spinal cord between the 2 groups. Finally, the ratios of vertebral body to spinal canal and spinal canal to spinal cord (sagittal, C3-C4; transverse, C5-C7; cross sectional, C3-C7) were significantly larger in DCM patients.
Using MRIs, Okada et al 75 compared the transverse area of the spinal canal and dural tube and the occupying ratio of the spinal cord between patients with DCM (n = 28) and control subjects without neurological symptoms (n = 96). The canal-occupying ratio was computed by dividing the area of the spinal cord by the area of the spinal canal. Although these measurements were made at C3 where no compression was present, patients with DCM still had a significantly smaller transverse area and a higher canaloccupying ratio of the spinal cord at C3 than the control subjects. There was no correlation between transverse area of the dural tube and DCM diagnosis.
Chen et al 73 compared the sagittal diameter of the vertebral bodies and spinal canal in 100 patients undergoing surgery for DCM and 100 asymptomatic volunteers. In the myelopathic group, the sagittal diameter of the vertebral bodies was significantly larger and that of the spinal canal significantly smaller than in the control group. The Torg-Pavlov ratio, defined as the ratio between the sagittal diameter of the cervical canal and the cervical vertebra at the same level, was significantly lower in DCM patients than in the volunteers. This finding was subsequently confirmed by Yue et al. 71 Finally, Golash et al 76 compared MRI features across 3 groups: healthy volunteers, asymptomatic patients with radiologic evidence of cervical spondylosis, and patients with symptomatic myelopathy and MRI evidence of spondylosis. The crosssectional areas of the spinal canal, cord, and CSF space were  significantly smaller in the DCM groups than in the asymptomatic and healthy control groups. However, cross-sectional area of the CSF space was the only independent predictor of DCM diagnosis. Specifically, patients had a 90% risk of clinical myelopathy if the area of their CSF space was ,0.7 cm 2 .

Genetic Risk Factors
In 2013, Wilson et al 77 conducted a systematic review to determine whether individuals with affected relatives are at an increased risk of CSM or OPLL and to summarize specific genetic polymorphisms associated with these diseases. The authors identified 3 studies supporting a heritable predisposition for CSM and OPLL. In a study by Patel et al, 78 first-degree relatives of patients with CSM were 5.1 times (95% confidence interval, 2.07-13.1) more likely to develop the disease. The risk ratio of second-degree relatives was nonsignificant (P = .07). However, third-degree relatives were at twice the risk of disease development (95% confidence interval, 1.04-3.7). Similar results were reported in 2 OPLL studies: The risk of OPLL was 5.19 to 7.1 times higher in first-degree relatives with OPLL than in control subjects. 79,80 According to Wilson et al, 77 several studies identified specific single-nucleotide polymorphisms, haplotypes, and gene alleles associated with OPLL and CSM (Table 5). Specific candidate genes include TGF-b, IL-15 receptor a, NPPS, BMP-2 and BMP-4, RUNX2, VDR, RXRb, Leptin receptor, APOE, COL6A1, and COL11A2. There is low-level evidence suggesting that singlenucleotide polymorphisms on the COLA1 (intron 32 [229], C/T) and the COL11A2 (intron 6 [24], A/T) genes are associated with an increased risk of OPLL development. 77 Other single-nucleotide polymorphisms and haplotypes were examined only by single studies and cannot yet be deemed significant genetic risk factors. In CSM, disease development was significantly associated with single-nucleotide polymorphisms in the rs7975232 and rs731236 locations of the VDR gene, the e4 allele of APOE, and the Trp2 allele of Collagen IX. 77 However, these findings have yet to be reproduced, so we cannot label these genetic variants as significant risk factors for CSM. Additionally, Nouri et al 4 identified a number of genetic conditions that increase the risk of spinal degeneration and myelopathy, including Klippel-Feil syndrome, Down syndrome, and congenital spinal stenosis.

THE SYMPTOMATIC POPULATION AND DISEASE NATURAL HISTORY
The pattern of progression in DCM is highly variable and not well defined. Some patients with radiologic spondylosis will remain clinically stable over time, whereas others, once symptomatic, will progress rapidly to advanced clinical myelopathy. In a study by Clarke and Robinson 81 of 120 DCM patients, 75% of patients deteriorated episodically, 20% experienced steady neurological decline, and 5% had a rapid onset of symptoms followed by stability. Lees and Turner 82 indicated that "long periods of non-progressive disability are the rule, and a progressively deteriorating course is exceptional." In 1972, Nurick 83 defined DCM as a "benign" disorder and confirmed that patients with DCM are often stable for long periods of time after symptom onset. Matz et al 84 conducted a systematic review of the literature and presented Class III evidence that the natural history of DCM is highly variable: Patients may experience a slow, stepwise decline, long periods of stability, or improvements.
Several studies have observed DCM patients after initial diagnosis or have followed them throughout a course of conservative treatment. In a study by Oshima et al, 85 (4) 13.3% deteriorated at least 1 grade on the Nurick score. 90 Conversion to surgery occurred in 16.1% to 31.9% of patients and in the majority of patients who progressed neurologically. In a systematic review by Karadimas et al, 12 moderate evidence suggested that 20% to 62% of patients deteriorate by at least 1 point on the JOA 3 to 6 years after initial assessment. This conclusion was based on both longitudinal nonsurgical cohorts and studies comparing operative and nonoperative management.

Predictors of Disease Development or Progression
Several studies have aimed to determine significant clinical predictors of disease development or progression in asymptomatic patients or those treated conservatively for myelopathy. Bednarik et al 91 evaluated key predictors of early symptomatic DCM in patients with MRI signs of spondylosis or disc compression of the cervical spinal cord with or without signal changes on T1-or T2-weighted MRIs, axial pain or clinical signs or symptoms of radiculopathy that could be managed conservatively, and no clinical signs and symptoms of myelopathy. Twenty-three percent of patients displayed clinical evidence and presented with symptoms of myelopathy within the 2-year follow-up period. In univariate analysis, patients with an abnormal electromyography, defined as motor axonal neuropathy in at least 2 myotomes, were 2.87 times more likely to progress to symptomatic DCM. In addition, disease development was predicted by clinically symptomatic radiculopathy (odds ratio, 4.69; P = .004) and abnormal motor (odds ratio, 2.94; P = .046) and sensory (odds ratio, 3.97; P = .01) evoked potentials. All of these clinical variables were included in the final multivariate model except for abnormal electromyography because it was highly correlated with clinical radiculopathy. Sex and age were not significant predictors of disease development, progression, or failed conservative treatment. 88,91 In a study by Barnes and Saunders,90 however, more women in the myelopathic group exhibited deterioration after conservative treatment than in the group who remained stable.
The objective of other studies was to assess various imaging predictors of disease development, progression, or failed conservative treatment. In the study by Bednarik et al, 91 there was no significant univariate association between development of early (,12 months) symptomatic DCM and the nature of the spinal cord compression (osteophytes vs other), number of stenotic levels (1 vs $1), MRI T2 hyperintensity, Torg-Pavlov ratio, compression ratio, or cross-sectional area of the spinal cord. In multivariate analysis, however, the presence of MRI T2 hyperintensity decreased the risk of early manifestation of myelopathy.
In a study by Oshima et al, 85 patients who converted to surgery had a significantly smaller segmental lordotic angle (21.7 6 4.4 degrees vs 2.3 6 2.8 degrees) and a greater percentage of local vertebral slip (37.5% vs 5.40%) than those who did not. There were no significant differences in C2-C7 alignment or range of motion, spinal cord diameter (ratio at the narrowest part of the canal to the C1 level), developmental canal stenosis, or segmental range of motion.
Increased signal intensity on a T2-weighted MRI was not predictive of failed conservative treatment or neurological deterioration. [87][88][89] Furthermore, there were no significant differences in posttreatment JOA, gain in JOA, or "percent satisfactory outcome" (gain in 1 point or maintenance of JOA in patients with a preoperative score $15) between patients with multisegmental, focal, or no increased T2-signal intensity. 92 Failed conservative treatment could not be predicted by compression ratio, partial cord compression on axial MRI, cross-sectional area of the spinal cord at the level of maximum compression, number of prolapsed intervertebral disks, canal size, presence or absence of subluxation, posterior osteophytosis, lordosis in extension, or kyphosis in flexion. [87][88][89][90] In a study by Shimomura et al, 88 circumferential compression on an axial MRI was a significant predictor of failed conservative management. Patients with circumferential compression were at a 26.62 (95% confidence interval, 1.68-421.54; P = .02) higher risk of deterioration on the JOA. Thirty percent of patients (30.3%) with this type of cord compression deteriorated, and 90% converted to surgery.
Sumi et al 87 defined the spinal cords of patients as ovoid (round and convex corner at both sides) or acute edge (acute angled or lateral corner at 1 or both sides), depending on the deformity at its lateral side. Deterioration was observed in 36% of cases with angular-edged spinal cords during conservative treatment, whereas only 5.3% of cases with ovoid deformity progressed (P = .006). Finally, in a study by Barnes and Saunders,90 patients were classified into 3 groups based on whether they improved by at least 1 functional grade after conservative treatment, stayed the same, or deteriorated. Patients who worsened had a greater range of preoperative neck and head movement as evaluated radiographically than patients who stayed the same.

MANAGEMENT AND TREATMENT STRATEGIES Nonoperative
Nonoperative treatments for DCM include physical therapy, medications (steroids, nonsteroidal anti-inflammatory drugs, gabapentin/pregabalin), spinal injections, cervical orthoses, and cervical traction. 10,93 Four studies compared the relative effectiveness of conservative management and surgical decompression for the treatment of DCM. In 1972, Nurick 83 demonstrated no difference in rates of disease deterioration between patients treated conservatively and those treated surgically. Of patients with a preoperative Nurick grade of 1 or 2, 64.28% treated conservatively remained at a grade 1 or 2, whereas 85.71% of surgical patients exhibited stability. This study was likely underpowered, given that these differences were not statistically significant.
Kadanka et al 94,95 conducted a randomized controlled trial to evaluate differences in outcomes between patients with mild (mJOA score $12) DCM treated conservatively with intermittent bedrest, collar immobilization, anti-inflammatory medication, and discouragement of high-risk activities and those treated surgically. The main conclusions from this study were the following: (1) There was no statistical difference between the nonoperative and operative groups at any time point with respect to the mJOA scores; (2) the timed 10-m walk time was significantly faster in the nonoperative group; (3) activities of daily living were similar in both groups 12 to 36 months after treatment initiation; and (4) the number of patients with declining scores increased in the conservative treatment group during follow-up. This trial was underpowered (n = 35 in the conservative group, n = 33 in the surgical group), and the improvements observed in the operative cohort were much smaller than in other published surgical series. These results also raise the question of whether the patients truly had myelopathy or simply radiographic evidence of degeneration and cord compression.
A fourth study by Matsumoto et al 96 compared the outcome of patients undergoing conservative treatment (n = 17) and those who ultimately were treated surgically (n = 10). The JOA scores at 3 months were significantly lower in the surgical group; however, at the final follow-up, there were no significant differences between treatment groups. Ninety percent of patients were satisfied with their treatment at the final follow-up, whereas only 77% of those treated conservatively were satisfied with treatment.
One prospective and 1 retrospective cohort study also examined treatment outcomes in surgical vs nonsurgical treatment groups. 89,97 Sampath et al 97 reported significant improvements in overall pain and functional status in patients treated surgically and a significant reduction in number of symptoms. This study also determined that patients undergoing nonoperative intervention (pharmacological therapy with either narcotic or nonsteroidal drugs, steroids, bedrest, home exercise, cervical traction, neck bracing, or spinal injections) experienced a significant worsening in their ability to perform activities of daily living, an increased number of neurological symptoms, and nonsignificant improvements in functional status. In a second study by Yoshimatsu et al, 89 78% of surgical patients improved according to their JOA score, whereas only 23% of the nonoperative group (cervical continuous traction, immobilization with a cervical orthosis, drug therapy, exercise, thermal therapy) demonstrated gains in functional status. Although neither study directly compared outcomes between treatment groups, the recorded differences in improvements suggest that surgery may be more effective for managing these patients. 93 In a systematic review of the literature, Rhee et al 93 investigated the safety and efficacy of nonoperative treatment for DCM. This review identified 4 studies examining the comparative effectiveness of conservative treatment and surgical intervention. On the basis of evidence synthesized from these studies, Rhee et al 93 developed the following clinical recommendation: "because myelopathy is known to be a typically progressive disorder and there is little evidence that non-operative treatment halts or reverses its progression, we recommend not routinely prescribing non-operative treatment as the primary modality in patients with moderate to severe myelopathy."

Surgery
Traditionally, surgery was used to halt disease progression and to prevent further neurological deterioration. However, recent results from the prospective AOSpine CSM-North America study indicate that cervical decompression not only arrests progression but also improves neurological outcomes, functional status, and quality of life in patients regardless of disease severity. 6 Surgery is therefore increasingly recommended as the standard treatment for DCM; thus, we can expect rates of surgical intervention to rise with the aging of the population. In fact, Lad et al 98  Surgery for DCM can be performed anteriorly or posteriorly. However, the main objective of both approaches is to remove compressive forces, to decompress the cord, and to provide adequate space for the spinal cord. 99 Common anterior surgeries include diskectomy and/or corpectomy and fusion with posterior techniques including laminectomy with or without fusion and common posterior techniques include laminectomy. Table 6 summarizes the indications and contraindications for these various surgical approaches. Circumferential procedures may be required to adequately accomplish surgical goals in patients with more complex pathology.
According to Fehlings et al, 100 patients treated anteriorly have more focal pathology, are younger, and have less severe myelopathy than those treated posteriorly. After adjustment for these differences in baseline characteristics, there were no significant differences in functional and quality-of-life outcomes between patients treated with an anterior approach and those treated with a posterior surgical approach. In a systematic review of studies comparing anterior and posterior surgeries for DCM, Lawrence et al 101 reported that the posterior approach results in a greater increase in sagittal spinal canal diameter, that rates of dysphagia are lower in posterior surgery than in anterior surgery, and that axial pain rates are lower after anterior operations. There was insufficient evidence in the literature to determine the association between approach and postoperative JOA scores or rates of pseudoarthrosis, C5 palsy, or infection.
Several studies have also compared the relative effectiveness of laminectomy and fusion and laminoplasty. Although the goal for both procedures is to decompress the spinal cord, the indications for each technique differ. Laminoplasty preserves motion and avoids complications related to fusion, but is contraindicated in patients with .13°of kyphosis and severe neck pain. 102 Increased preoperative kyphosis is also a contraindication to laminectomy and fusion. On the basis of data from the prospective AOSpine CSM-North America study, there are no significant differences in postoperative functional status and quality of life between patients treated by laminectomy and fusion and those treated by laminoplasty, thus confirming the results of 2 previous retrospective studies. 103 In a systematic review of the literature, Yoon et al 104 reported higher rates of reoperation, nonunion, and infection after laminectomy and fusion. However, there was insufficient evidence to draw conclusions about rates of perioperative neurological complications.

CONCLUSION
The aging spine undergoes natural degenerative changes that are unique to each individual; consequently, the precise anatomic changes that contribute to myelopathy development can vary. However, it is clear that there are many unifying qualities among specific diagnostic entities and that the pathological process remains fundamentally based on static and dynamic factors. Through discussion of the current knowledge on the pathophysiology, epidemiology, natural history, risk factors, and management strategies for DCM, this review has provided further rationale and support for describing the spectrum of degenerative spine conditions under the overarching term degenerative cervical myelopathy.

Disclosures
Dr Harrop reports being a consultant for DePuy. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.