Degenerative Cervical Myelopathy: Epidemiology, Genetics, and Pathogenesis

Study Design. Review. Objective. To formally introduce “degenerative cervical myelopathy” (DCM) as the overarching term to describe the various degenerative conditions of the cervical spine that cause myelopathy. Herein, the epidemiology, pathogenesis, and genetics of conditions falling under this hypernym are carefully described. Summary of Background Data. Nontraumatic, degenerative forms of cervical myelopathy represent the commonest cause of spinal cord impairment in adults and include cervical spondylotic myelopathy, ossification of the posterior longitudinal ligament, ossification of the ligamentum flavum, and degenerative disc disease. Unfortunately, there is neither a specific term nor a specific diagnostic International Classification of Diseases, Tenth Revision code to describe this collection of clinical entities. This has resulted in the inconsistent use of diagnostic terms when referring to patients with myelopathy due to degenerative disease of the cervical spine. Methods. Narrative review. Results. The incidence and prevalence of myelopathy due to degeneration of the spine are estimated at a minimum of 41 and 605 per million in North America, respectively. Incidence of cervical spondylotic myelopathy–related hospitalizations has been estimated at 4.04/100,000 person-years, and surgical rates seem to be rising. Pathophysiologically, myelopathy results from static compression, spinal malalignment leading to altered cord tension and vascular supply, and dynamic injury mechanisms. Occupational hazards, including transportation of goods by weight bearing on top of the head, and other risk factors may accelerate DCM development. Potential genetic factors include those related to MMP-2 and collagen IX for degenerative disc disease, and collagen VI and XI for ossification of the posterior longitudinal ligament. In addition, congenital anomalies including spinal stenosis, Down syndrome, and Klippel-Feil syndrome may predispose to the development of DCM. Conclusion. Although DCMs can present as separate diagnostic entities, they are highly interrelated, frequently manifest concomitantly, present similarly from a clinical standpoint, and seem to be in part a response to compensate and improve stability due to progressive age and wear of the cervical spine. The use of the term “degenerative cervical myelopathy” is advocated. Level of Evidence: 5

N ontraumatic, degenerative forms of cervical myelopathy represent the commonest cause of spinal cord impairment in the elderly population. 1 This group of conditions largely comprises cervical spondylotic myelopathy (CSM), ossifi cation of the posterior longitudinal ligament (OPLL), ossifi cation of the ligamentum fl avum (OLF), and degenerative disc disease (DDD). Unfortunately, there is neither a specifi c term nor a specifi c diagnostic International Classifi cation of Diseases, Tenth Revision ( ICD-10 ) code to describe this collection of clinical entities ( Table 1 ). This has resulted in the inconsistent use of diagnostic terms when referring to patients with myelopathy due to degenerative disease of the cervical spine and, subsequently, has given rise to ambiguity in critically exploring diagnosis, interventions, and outcomes for this prevalent and disabling set of conditions. Ultimately, this has impacted knowledge dissemination and has resulted in an under-recognition of the collective importance of these disorders by primary care physicians, patients, and health care funders. In the present review, we introduce "degenerative cervical myelopathy" (DCM) as an overarching term to represent this set of clinical entities, while compressive loads and transfer of these forces longitudinally onto the cartilage endplates of vertebral bodies and radially onto the surrounding annulus fi brosus. 3 With repeated use of everyday living, periods of trauma and excessive use, and other nutritional and environmental factors, the IVDs begin to degenerate and the uncovertebral processes of the vertebrae become fl attened, altering the weight-bearing and loadtransferring functions of the intervertebral joint. 1 , 4 As a result, there is increased stress on the articular cartilage endplates and hypermobility in adjacent segments. 1 , 4 Uneven pressure forces exerted upon the vertebrae as a consequence of these structural changes are thought to encourage the formation of osteophytic spurs in an adaptive remodeling process meant to stabilize an unstable spine segment. 3 As DDD generally precedes the onset of osteophytosis, 5 severe cases of disc degeneration that result in signifi cant migration of disk elements into the canal can be solely implicated in the development of myelopathy. 6 However, more subtle forms of disc degeneration that are accompanied by progressive changes in the anatomical architecture of the entire cervical joint, as is frequently observed in the elderly, present with a constellation of fi ndings more consistent with CSM. A T2-weighted magnetic resonance image of a patient with CSM and DDD is presented in Figure 3A .

Ossifi cation, Hypertrophy, and Calcifi cation of Spinal Canal Ligaments
Age-related changes to spinal ligaments implicated in the development of cervical myelopathy involve the posterior longitudinal ligament (PLL) and the ligamentum fl avum (LF).
Although hypertrophy and ossifi cation of spinal ligaments may be infl uenced signifi cantly by underlying genetics, their manifestation in older age as well as presumed multifactorial pathogenesis suggests a progressive and degenerative cause for their development. [7][8][9][10][11][12] Stiffening and buckling of the LF has been suggested to occur as a consequence of natural cervical joint degenerative changes, including loss of IVD height. 1 , 4 Similarly, prolapse of the nucleus pulposus has been implicated as an initiating stimulus for hypertrophy of PLL. 8 Although this suggests that stiffening or hypertrophy may develop as a consequence of cervical joint degeneration, the recognition that the prevalence varies between spinal regions (OLF is more common in the thorax 13 ) and the frequent manifestation of these changes without signs of DDD or CSM supports additional pathomechanistic processes in their development. A T2-weighted magnetic resonance image of spinal cord compression due to hypertrophy of the LF is displayed in Figure 3B .
It remains unclear how a normal ligament transitions into an ossifi ed ligament, but it has been suggested that hypertrophy may be a precursor for ossifi cation. 8 Histologically, hypertrophy of PLL has been defi ned as "hyperplasia of nonfi brous cartilage with strong metaplasia in the PLL in more than two intervertebral spaces, with capillary hyperplasia and infi ltration of the connective tissue." 8 It has been hypothesized that hypertrophy of PLL may be replaced by lamellar bone to become ossifi ed when hypertrophy has potential systematic or genetic factors to induce secondary ossifi cation. 14 The role of genetic factors is reinforced by the frequent coexistence of cervical and thoracic OPLL and OLF disease (referred to as tandem ossifi cation) in which different segmental stresses still exhibit similar pathological changes in nearly one-third of patients. 15 This fi nding is also interesting as it suggests that although OPLL and OLF may have different natural histories, they share some form of pathological relationship. 8 , 16 , 17 Figure 3C displays a computed tomographic scan of a patient with OPLL.
It has been stated that calcifi cation of the ligamentum fl avum (CLF) is a common fi nding on computed tomographic scans 18 ; however, much remains unknown about this clinical entity. Given the limited amount of research on CLF, it has been challenging to defi nitively classify its common pathological features; however, reports have supported different histopathology from OLF. 19 , 20 CLF has been described as occuring in degenerated and thickened ligaments and that the calcifi cation has no continuity with the lamina. 19 Moreover, the superfi cial and deep layers of the LF are relatively preserved. 19 This is in contrast to OLF, which has been described as a metaplastic process in which endochondral ossifi cation leads to lamellar bone formation. 21 More specifi cally, Miyasaka et al 19 state that in OLF, cartilage forms an ossifi ed bridge that extends from the upper and lower edges of 2 adjacent laminae.
Reports indicate that CLF may be more common in females and that it may be a manifestation of pseudogout (calcium pyrophosphate dihydrate deposition disease) 18 , 19 , 22 ; however, a number of other potential associations have also been noted, including hypercalcemia, hyperparathyroidism, hemochromatosis, and renal failure. 23 Despite these reports, there remains a paucity of research on the subject and further investigation is necessary.

Pathobiology of Spinal Cord Compression
In comparison with traumatic forms of SCI, the pathophysiological sequelae of spinal cord compression in DCM have been considerably less investigated. Having said this, recent studies on CSM rodent models 24 , 25 as well as on human spinal cords 26 of patients with CSM have uncovered a number of underlying phenomena related to chronic and progressive compression and have implicated chronic stretching in the development of important pathophysiological events. In particular, it has been demonstrated that chronic cervical spinal cord compression results in chronic reduction of the intraparenchymal spinal cord blood fl ow. 24 , 27 The resulting chronic ischemic injury, in conjunction with mechanical stretch, has been found to activate some key biological events and cause neural degeneration.
There is emerging evidence supporting the idea that chronic intraparenchymal ischemia generates a unique immune response. 28 , 29 Persistent activation of microglia and macrophage accumulation at the site of the compression are the main known components of this neuroinfl ammatory reaction. 5 , 26 , 30 However, the role of microglia/macrophage activation under the chronic compression of the cervical spinal cord has yet to be fully elucidated. Hirai et al 31 demonstrated that both the M1 and M2 microglia phenotype are activated in CSM, indicating that microglia may be involved in promoting neural damage and in the repairing process. Interestingly, Moon et al 30 demonstrated that riluzole attenuated the neuropathic pain in a rodent model of CSM that was associated with decreased levels of microglia activation. The neuroinfl ammatory story becomes more complex because it has recently been shown that chronic endothelial cell dysfunction and blood spinal cord barrier disruption are occurring even during the late stages of the compression, 24 phenomena that inevitably exaggerate the existing infl ammatory process being propagated by peripheral immune cell infi ltration.
This persistent hypoxic insult and the ongoing neuroinfl ammatory response during chronic spinal cord compression may be implicated in progressive neuronal and oligodendroglial cell death through activation of apoptotic pathways. 1,5,26,32,33 Indeed, the levels of neuronal and oligodendroglial injury have been well associated with neurobehavioral dysfunction. As previously indicated by histological studies on human and experimental CSM tissue, the compression-mediated activation of the pathophysiological cascades described previously can lead to development of gliosis, cavity formation, degeneration of the main corticospinal tracts, interneuronal loss, and atrophy of the anterior horns associated with motoneuronal loss, the constellation of which is consistent with the principal   Table 2 .

Dynamic Injury Mechanisms and DSL
In addition to stretching and static compression, it is also recognized that the spinal cord may be injured through dynamic injury mechanisms. [34][35][36][37] It has been proposed that dynamic injury may occur through instability, 38 increased range of motion, 34 , 37 and through minor trauma in the setting of preexisting DCM. 36 DSL results in regional instability of the spine that can manifest as an anterior or posterior subluxation of a vertebral segment and is due to a number of degenerative changes, including facet joint arthropathy, disc degeneration, and increased stretch of discs as well as ligaments. 38 , 39 DSL occurs most frequently between C3-C4 and C4-C5, representing 46% and 49% of observed occurrences, respectively. 38 It has been suggested that this region may be preferentially affected because of greater degenerative changes occurring in the lower cervical spine, which result in excessive compensatory mobility in the upper cervical segments. 40 Although there is no clear grading system for delineating severity, it is generally accepted that patients with 3-to 3.5-mm of horizontal translation have severe DSL. 40 , 41 When severe and unstable, DSL can result in narrowing of the spinal canal 38 and potentially recurrent compression of the spinal cord. Indeed, a recent systematic review has reported that myelopathy or myeloradiculopathy was present in 64% of patients with DSL referred for surgery. 38 However, static imaging can make it challenging to discover movement-dependent subluxation and, therefore, patients with suspected DSL may benefi t from kinematic magnetic resonance imaging (MRI) examination. Hayashi et al 35 recently reported that spinal cord compression in the cervical spine of symptomatic patients (neck pain with or without neurological signs) was observed in 5.3% in the neutral position, but that missed dynamic stenosis was discovered in 8.3% in extension and 1.6% in fl exion using kinematic MRI.
It has also been suggested that an increased range of motion in the cervical spine may result in dynamic injury to   the cord. Matsunaga et al 34 previously showed that patients with OPLL with critical stenosis ( < 6 mm) all had myelopathy and that no myelopathy was present in patients with canal diameters of 14 mm or greater. However, when spinal canal size was greater than 6 mm but less than 14 mm in diameter, myelopathy preferentially developed in those with increased range of motion. 34 Given these results, the authors suggest that static compression cannot be solely implicated in myelopathy development and hypothesize that dynamic injury mechanisms play a role. Recently, it has been shown that dynamic injury to the spinal cord may also occur in patients with CSM in the setting of minor trauma. Fengbin et al 36 have shown that patients with minor trauma, particularly in the setting of lower cervical instability, had a greater incidence of neurological deterioration and experienced less postoperative improvement than those without trauma.
It is clear, however, that further research on dynamic injury mechanisms in the setting of a degenerated cervical spine is warranted.

Degenerative Cervical Spine Deformity and Myelopathy
The cervical spine has a natural lordotic disposition, and agerelated degeneration may result in hyperlordosis, scoliosis, and most notably kyphosis. Indeed, the cervical alignment in patients with DCM must be taken into consideration during surgical planning, particularly to prevent the development or progression of kyphosis postoperatively. Interesting however, there is emerging evidence that cervical alignment also contributes to the pathogenesis and severity of cervical myelopathy. [42][43][44] Ames et al 42 hypothesize that the mechanism behind myelopathy development in patients with kyphosis can be attributed to the deformity forcing the spinal cord against the vertebral bodies. They further state that this results in anterior cord pathology as well as longitudinal cord tension due to the cord being tethered by the dentate ligaments and cervical nerve roots. 42 Ultimately, spinal cord tethering is thought to increase intramedullary pressure that results in neuronal loss, demyelination, and decreased blood supply due to the fl attening of small blood vessels. 42 These fi ndings indicate that spinal cord compression due to canal stenosis may not be the only pathoetiological factor contributing to myelopathy. Furthermore, this supports the idea that the absence of frank spinal cord compression on medical imaging cannot exclude a diagnosis of DCM.
Recent research on patients with kyphotic deformity using kinematic MRI has also indicated that subtypes of kyphosis affect cervical spine mobility differently and that kinematic MRI may be better than standard supine MRI in investigating both the degree of instability and the spinal cord compression. 45 The same authors also found that in patients with kyphosis, spinal cord compression was mostly located at C4-C6, the apex in C-type, and the transition zone of S-type and R-type kyphotic deformities; however, the apex of the focal kyphotic deformities was also noted as a high-risk area for spinal cord compression. 45

EPIDEMIOLOGY OF DCM
Although degenerative cervical conditions are generally regarded as the most common cause of spinal cord impairment in the elderly, their global epidemiological trends remain challenging to evaluate. There are 3 fundamental reasons for this: (1) the prevailing classifi cation of degenerative conditions into separate clinical entities has resulted in segregation of their previous epidemiological investigation; (2) there is a general paucity of literature on the topic; and (3) investigations that have been conducted have focused on particular geographical regions or populations. Current epidemiological trends of degenerative pathologies from around the world are summarized in Table 3 . In the following section, incidence, prevalence, progression, and surgical rates as well as survival will be further discussed.

Estimation of Incidence and Prevalence of DCM From Nontraumatic Spinal Cord Injury
One potential way of estimating the incidence and prevalence of DCM is by looking at the reported rates of SCIs, which are generally broken down into traumatic and nontraumatic forms. DCMs represent nontraumatic forms of spinal cord injury (ntSCI) and, therefore, are included in such estimates. This classifi cation, however, also includes motor neuron and infectious, infl ammatory, and neoplastic disease as well as various other conditions. 66 In a recent review on nontraumatic spinal cord injury epidemiology, New et al 67 indicated that degenerative diseases of the spine make up 59% of ntSCI in Japan, 54% in the United States, 31% in Europe, 22% in Australia, and between 4% and 30% in Africa. In this same review, it was estimated that the regional incidence of ntSCI in North America, Europe, and Australia was 76, 26, and 6 per million, respectively, and that the prevalence is 1,120 per million in Canada and 2,310 per million in the Kashmir region. From these numbers, it can be estimated that the incidence and prevalence of ntSCI related to DCM in the North American region is at a minimum of 41 and 605 per million, respectively. A number of important limitations of this estimate have to be considered, however. These include the general low level of quality of literature that was available to make these approximations, and the fact that patients recorded as having ntSCI injury in countries with higher quality data, such as Canada, 66 included only the fi ndings of those with paraplegia and quadriplegia and not those with less severe disability. The recognition that many myelopathic patients will have a milder clinical presentation indicates that the aforementioned fi gure is signifi cantly underestimated and likely represents only those at the severe end of the spectrum of disease. On the contrary, it should also be noted that not all cases of ntSCI are cervical in nature.

Epidemiological Trends and Patient Characteristics of the Various Forms of Degenerative Pathologies
Type of Degenerative Pathology Trends in Patient Characteristics

Regional Incidences
Spondylosis Male:female ratio is 3:2. 46 Males present with a greater incidence of canal stenosis, more vertebral levels, and more severe stenosis at the primary level of pathology. 48 , 49 The height and AP diameter of the vertebral body are larger in males. 48 , 49 Females present at a younger age and have a larger canal body ratio. 48 , 49 The incidence of osteophyte development in the cervical vertebra of skeletons was greater in Caucasians than in native Africans at all cervical levels studied in South Africa. Native Africans, however, had smaller midsagittal and transverse diameter at all cervical levels. 47 Disc degeneration Disc degeneration was the most frequent fi nding. Accompanied by either anterior (78%) or posterior (71%) protrusions (80% bulges, 20% prolapsed).
Ossifi cation of the ligamentum fl avum (OLF) Thoracic OLFs are more likely to present asymptomatically than cervical. 52 Southeast Asian : Thought to be commonly affl icted, particularly males between 40  ( Continued

) Type of Degenerative Pathology
Trends in Patient Characteristics

Regional Incidences
Ossifi cation of the posterior longitudinal ligament (OPLL) Male predominant: At least 2 times more common in males than in females. [54][55][56][57][58][59][60][61] May occur in 20%-25% of patients treated for cervical myelopathy in North America 64 OPLL symptomatology: 50% in Japanese, 14% in non-Japanese Asians, and 50.5% in Indian Caucasians. 63 Japan : Prevalence was 4.3% in males, 2.4% in females. 56 Prevalence was 2.6% for patients in their 50s and 4.5% for patients in their 60s. 56 Peak incidence in the 50-60 yr age group. 56-59 , 65 Japan: of spinal OA. One exception to this has been a report on the radiographical cervical spine OA progression rates by Wilder et al . 69 In their longitudinal study, the authors found that progression of OA (as defi ned by the Lawrence and Kellgren ordinal scale, an increased grade denotes worse degeneration) increased in males at all ages at a greater rate than in females. Furthermore, the authors report that the highest progression rate was present in males between 70 and 79 years of age at 12.5 cases per 100 patient-years and in females older than 80 years at 9.3 cases per 100 patient-years. Unfortunately, in terms of DCM, this estimate is limited by the fact that it indicates patients at risk of myelopathy rather than representing clinically myelopathic patients and would also likely exclude patients considered to have OPLL and OLF. Having said this, however, a recent systematic review indicates that patients with cervical canal stenosis and cord compression secondary to spondylosis, without clinical evidence of myelopathy, develop clinical evidence of myelopathy at approximately a rate of 8% at 1-year follow-up and 23% at a median of 44-month follow-up. 70

Estimation by Hospital Admission Rates
Recently, 2 studies have emerged that estimated epidemiological trends for CSM on the basis of hospital admission data. Boogaarts and Bartels 71 estimated a prevalence of CSM in 1.6 per 100,000 inhabitants on the basis of surgical cases at their hospital in the Netherlands. Wu et al 72 retrospectively assessed a 12-year nationwide database and estimated an overall incidence of CSM-related hospitalization of 4.04 per 100,000 person-years. When interpreting these fi ndings, a number of limitations have to be taken into consideration, including the geographical basis (referral area), as well as the fact that patients undergoing surgery most likely represented those at the severe end of the spectrum of disease; therefore, it is likely that these estimations undervalue actual epidemiological trends. Furthermore, although Wu et al 72 included OPLL and disc pathologies as part of their CSM rate estimations, it is unclear whether this was the case with the study by Boogaarts and Bartels. 71 In addition to these studies, it has been proposed that the rate of surgical treatment of CSM is rising. Lad et al 73 73 It should be noted that increases in fusion rates might be a refl ection of the transition in the understanding of the pathophysiology of DCM from one simply based on static compression of the cord to one recognizing malalignment and dynamic injury as part of the disease process.

Survival
A study from Israel by Ronen et al 74 assessed the survival of patients with ntSCI between 1962 and 2000. Although these data included all forms of ntSCI, information regarding the location and type of etiology for ntSCI was provided. The authors found that of 1066 patients with ntSCI, 32% were cervical in nature and that 62% of those with spinal stenosis were cervical. Patients with ntSCI of the cervical spine of any etiology had a median survival of 22.7 years and patients with spinal stenosis at any site had a survival of 17.6 years. Patients with ntSCI due to a herniated disk had a survival of 29 years; however, most of these were lumbar in nature.

HEREDITY AND GENETIC CAUSES
A number of studies in the literature discuss the genetic basis of degenerative spinal disease. Much of this academic enquiry, however, has focused on OPLL and DDD, with relatively little research being conducted on CSM. Moreover, most studies seeking to elucidate an underlying genetic predisposition have been conducted in Asia, limiting global generalizability. It is evident from the literature, however, that OPLL, OLF, DDD, and CSM all may entail some form of genetic or hereditary etiological component, albeit, the degree of evidence varies between the types. Some of the strongest potential genetic factors implicated include those related to MMP-2 and collagen IX for DDD, 75 and collagen VI and XI for OPLL. 76 In addition, some of the candidate genetic variants have been shown to cause predisposition to the development of more than one of these conditions, for example, genetic studies on the vitamin D receptor (VDR) have shown it to be associated with both DDD and CSM. 75 , 77 Likewise, it has been found that the collagen VI gene is potentially linked to both OPLL and OLF. 78 These fi ndings indicate the possibility of some pathomechanical alignment between these conditions. Table 4 summarizes current genes/genetic products that have been studied.

CSM and DDD
Early reports suggesting a genetic susceptibility for the development of CSM were published by Bull et al 88 and Palmer et al . 89 In their research, both groups assessed and compared cervical radiographs of twin siblings. Although Bull et al 88 found that there was a marked resemblance in the degenerative process between twins on imaging, Palmer et al 89 observed the opposite, concluding instead that, although anatomical similarities in twins may predispose them to similar degeneration over time, the incongruence of pathological fi ndings among their subjects indicate that numerous other factors are likely at play and thus preclude a simple genetic causation. One potential reason for the discrepancy in their fi ndings may be related to epigenetic factors, specifi cally, the transcriptional alterations in cells over time related to nonhereditary infl uences such as the environment.
More recently, Setzer et al , 79 Wang et al , 77 and Wang et al 80 have sought for particular genetic determinants of CSM susceptibility, implicating the potential polymorphism of apolipoprotein E, VDR , and collagen IX genes, respectively. Wilson et al 76 in their systematic review on the topic caution that although these studies did fi nd signifi cant genetic associations between single nucleotide polymorphisms and CSM, none of the fi ndings have been validated in separate studies. To date, the strongest indication for a genetic etiological component has been published by Patel et al , 90 who assessed a genealogical database of more than 2 million Utah residents for excessive familial clustering, reporting the presence of signifi cant ( P < 0.001) relatedness of those with CSM. Most notably, they determined that there was a very signifi cant relative risk of 5.21 ( P < 0.001) for the development of CSM among fi rst-degree relatives.
In discussing genetic susceptibilities for CSM, it is also important to account for genes that have been associated with the development of DDD because it has been recognized that the pathogenesis of CSM is preceded by disc degeneration. 5 Erwin and Fehlings 75 recently summarized a number of such genes, including those related to metalloproteinases (MMP), collagen IX, VDR, and interleukins (ILs). Interestingly, genes related to VDR and collagen IX have been associated with both CSM and DDD, suggesting that these may be of particular importance in the natural course of CSM development. The recognition that multiple genes may be involved in the occurrence of these conditions indicates that there may substantial heterogeneity between patients, their clinical manifestation, and the natural course of their progression.

Ossifi cation of the PLL
The search for an underlying genetic basis for OPLL has been carried out by a number of investigators. Suspicion for a genetic etiological component is supported by the fi nding that OPLL presents signifi cantly more frequently in Asian populations than it does in Caucasians. 8,16,54,55,62,63 Indeed, a nationwide survey in Japan revealed that 24% of 2nd-degree or closer blood relatives and 30% of siblings of patients with OPLL had radiographically detectable OPLL. 62 At the present time, a number of candidate genes including those related to collagen VI and XI, BMP 2 and 4, tumor necrosis factor α , tumor necrosis factor β 1 and 3, nucleotide pyrophosphatase (NPPS), retinoic X receptor, VDR, parathyroid hormone, IL-1B and IL-15, RUNX2, promyelocytic leukemia zinc fi nger, connective tissue growth factor, prostaglandin I2, endothelin-1, leptin receptor, estrogen receptor 1, and interferonγ have been investigated. 8,11,78,81,86 However, despite the numerous investigations, a recent systematic review on the topic by Wilson et al 76   Investigation of OPLL as a single disease may be hindering attempts to attribute specifi c genetic factors with its development. Based on its pathological distribution, OPLL has been classifi ed into 4 subtypes: localized (bridged or circumscribed); segmental; continuous; and mixed, with segmental considered as the most common type. 9 , 91 Recently, Kudo et al 11 looked at the genetic differences among these subtypes and proposed 2 categories for OPLL: continuous (include continuous and mixed) and segmental (include segmental and circumscribed). They concluded that cells of the OPLL continuous group had higher osteogenic differentiation potency than segmental group cells, and that a different genetic background between the groups also exists. 11 This fi nding is supported by previous research that has found that patients with continuous and mixed OPLL types frequently experience progression of their ossifi cation postoperatively, and that contrarily, progression is rare in patients with segmental OPLL. 92 , 93 This is worthy of note since Kawaguchi et al 93 indicated that 3 of their 45 patients developed neurological deterioration because of OPLL progression at 10-year follow-up. Thus, the recognition of potential etiological differences between OPLL types may have signifi cant clinical ramifi cations.
A general limitation of the interpretation of the genetic studies, as is the case with OLF, is that studies assessing candidate genes have been conducted in Asia and, therefore, may not be etiologically translatable to other populations.

Ossifi cation of the LF
At the present time, there is insuffi cient evidence available to support a genetic basis for the development of OLF in isolation. Having said this, a greater frequency of the disease in some regions, such as Asia, has given support to the idea for a genetic and/or environmental susceptibility. 16 Additional support for an isolated genetic connection has also been demonstrated recently using a mouse model with homozygous mutation in the NPPS gene, which has been specifi cally linked with the development of OLF at C2-C3. 32 However, few studies have looked at OLF in humans and have frequently studied OPLL in parallel. For example, Kong et al 78 found that intron 33 ( + 20) as well as promoter ( − 572) single nucleotide polymorphisms of COL6A1 were associated with both OPLL and OLF in the Chinese Han population, although they also found that haplotype 4 was associated with OLF but not with OPLL, and that haplotype 1 was associated with OPLL but not with OLF. Other work by Liu et al 86 has given support to a previously described genetic association related to the RUNX2 gene in patients with OPLL 87 and has also found a similar association with patients with OLF, concluding that genetic variants in the gene may be responsible for ectopic bone formation in spinal ligaments.
It is clear that further research needs to be conducted to establish whether a genetic susceptibility exists and if such susceptibility is genetically separate from OPLL as well as conditions with generalized spinal ligament ossifi cation such as diffuse idiopathic skeletal hyperostosis.

Congenital Disorders Associated With DCM
Although congenital disorders do not generally cause DCM directly, they can indirectly accelerate the pathological process or result in earlier clinical manifestation. This may occur through various gross as well as microstructural anatomical aberrations of the cervical spine, including congenitally fused vertebral segments, 94 congenital spinal stenosis, 95 or structural abnormalities leading to hypermobility syndromes. 96

Down Syndrome
Patients with trisomy 21 or Down syndrome (DS) have been recognized to be at a predisposition for developing degenerative cervical disease. [97][98][99] This can occur because of a litany of congenital factors including atlantoaxial instability, odontoid abnormalities, atlanto-occipital abnormalities, and hypoplasia of the posterior arch of C1. 97 Atlantoaxial instability has been estimated to occur in 10% to 20% of patients with DS, of whom 1% to 2% present with symptomatic spinal cord compression. 99 Unfortunately, however, although it has been recognized that spondylosis is common in patients with DS, specifi c epidemiological data do not currently exist. The signifi cance of this knowledge gap from a clinical perspective is evinced by the approximately 5400 children with DS born in the United States per year and their increasing lifespan, which has increased from a median age of death from 25 years in 1983 to 49 years in 1997. 100 As the occurrence of degenerative changes in the cervical spine is naturally progressive and seems to manifest at a younger age in patients with DS, 97 , 99 this trend suggests that an increase in DCM arising from this population can be anticipated over the years.

Klippel-Feil Syndrome
Patients with Kilppel-Feil syndrome (KFS) are diagnosed by the "hallmark" fi nding of congenital fusion of cervical vertebrae and have been described by a clinical triad encompassing a short neck, low posterior hairline, and restriction of neck motion 101 , 102 ( Figure 3D ). Most occurrences of KFS are thought to occur sporadically, but autosomal dominant, autosomal recessive and X-linked forms have also been described. 102 Recently, Rosti 103  Patients with KFS may be at increased predisposition for the development of cervical joint degeneration. 94 , 105 Although the mechanism for such a relationship has not been fully elucidated, the postulation that patients who undergo surgical fusion of cervical vertebrae may be at risk for the development of adjacent segment pathology 106-108 supports the supposition that increased biomechanical stress on nonfused segments may be contributory. 105 In a recent prospective and multicenter study on a surgical cohort of patients treated for CSM, it was discovered that the prevalence of KFS among surgical patients was nearly 4%, and that MRI features in patients with KFS were generally worse than those in patients with CSM without KFS. 105 Given that the prevalence of KFS E686 www.spinejournal.com June 2015 in the general population has been estimated at 0.71%, 109 this suggests that patients with KFS may be at a substantial predisposition for DCM. Further research will be necessary to fully uncover the relationship between these conditions and whether the clinical approach to their management should differ from the general population.

Congenital Cervical Spine Stenosis
Congenital cervical spinal stenosis has been widely recognized as a signifi cant predisposing factor for the development of DCM 95 , 110 , 111 and has been defi ned as a sagittal canal diameter of less than 13 mm 112 or a ratio of less than 0.82 using the Torg-Pavlov 113 measure (canal diameter/ vertebral body diameter). It is thought that a reduction of the spinal canal size will render the spinal cord vulnerable to compression even from minor encroachment of tissue into the canal. 110 It has also been suggested that a narrow canal reduces the effect size of cerebrospinal fl uid and will impair cushioning of kinetic energy in the setting of minor trauma 114 and presumably other dynamic injury mechanisms. However, variability in the transverse area of the spinal cord between individuals 115 indicates that cervical canal size should be related to the size of the spinal cord when evaluating risk of injury.
It has been estimated that spinal canal stenosis is present in approximately 250,000 to 500,000 people in the United States, of which 20% to 25% are cervical. 112 Moreover, the prevalence in the United States is expected to increase substantially over the next decade. 112 These patients, and, in particular, those with conditions that are known to present with a predilection for the occurrence of cervical spinal stenosis, such as achondroplasia, 116 should be monitored regularly for the early onset of myelopathic symptoms.

Other Congenital Associations
It is important to recognize that a number of other congenital conditions resulting in gross structural malformations of the spine may be of importance in DCM development. Giampietro et al 102 have published an extensive list of conditions related to congenital vertebral malformations that may be highly relevant. In addition, more generalized congenital aberrations such as those related to collagen structure may be of importance in DCM development as well. A particularly noteworthy group includes patients with signifi cant generalized hypermobility. Patients with Ehlers-Danlos syndrome, for example, experience a substantial amount of joint instability secondary to widespread ligament as well as tendon laxity, and resulting joint pain and orthopedic complications are common. 117 Furthermore, it has been suggested that chronic subluxation in these patients renders them susceptible to OA. 117 Although limited, there is some evidence linking Ehlers-Danlos syndrome with atlantoaxial instability, in particular. 118 Given these fi ndings, it seems reasonable to assume that patients with Ehlers-Danlos syndrome may have a substantial risk for both accelerated spine degeneration and spinal cord trauma. In terms of surgical treatment, this emphasizes that stabilization of the spine to correct hypermobility should be a key objective if myelopathy is suspected. However, discussion of the impact of hypermobility syndromes on DCM and spinal cord trauma in general requires substantially more investigation.

OCCUPATIONAL, PERSONAL, AND OTHER ASSOCIATIONS
The development of DCM has been related to a number of personal and occupational risk factors as well as comorbidities. These factors may contribute to accelerate degeneration of the spine through mechanical stress, both dynamic and static, but may also involve pathobiological processes. Also, the association between individual risk factors has been shown to vary between DCM types, potentially providing insight into differences in their pathomechanics.

Physical Transportation of Goods
Porters and coolies in less developed countries transport substantial amounts of goods by bearing weight on their heads and backs. A number of researchers have investigated the potential for this mode of transportation to accelerate cervical spondylosis. [119][120][121][122] However, as the types of load bearing and techniques may differ among the various populations, it is diffi cult to extract a collective conclusion on the precise biomechanical factors that may be at play. There is a general consensus among these studies that degenerative changes of the cervical spine in weight bearers are signifi cantly more pronounced than what is observed in the general population, and that the C5-C6 region is particularly affected. [119][120][121][122] In addition, weight bearers more commonly complained of neck stiffness and pain. 120 Bista and Roka 123 hypothesized that Nepalese porters using a "Namlo" (a particular type of carriage in Nepal where weight bearing occurs principally on backs) would promote cervical spondylosis as well. However, it was found that the prevalence of spondylosis was actually lower than that of controls (nonporters). The authors suggest that using this method, the orientation of the cervical spine requires isometric fl exion of the neck and, therefore, may signifi cantly reduce the risk of spondylosis compared with nonporters.
Given these fi ndings, it seems that the method of transportation of goods can signifi cantly impact the rate of spondylosis, and this recognition may be useful in reducing this occupational hazard.

Cervical Spine Degeneration in High-Performance Aviators and Astronauts
The potential of an increased susceptibility for degenerative changes in fi ghter pilots emerged after reports of acute neck injuries during fl ight and the recognition that Gz (G-force) places substantial axial force on the cervical spine. 124 Upon neck movement during fl ight maneuvering, the ability of the cervical spine to withstand high compressive forces is substantially reduced and the IVDs are predominately affected because they are the chief components of the spine that adapt stress and have viscoelastic properties. 124 , 125 Investigations on fi ghter pilots have mostly supported the suggestion that accelerated DDD and osteophytosis takes place. [125][126][127][128][129] Spine www.spinejournal.com E687 One of the more comprehensive studies on the subject was conducted by Petrén-Mallmin and Linder. 126 , 127 These authors studied an asymptomatic group of fi ghter pilots against controls (nonfi ghter pilots) for evidence of spinal degeneration and then assessed them again at a 5-year follow-up. During their initial analysis of asymptomatic subjects, it was evident that signifi cant acceleration in degeneration occurred in older fi ghter pilots compared with younger fi ghter pilots as well as age-matched controls without exposure to Gz; specifi cally, experienced pilots had signifi cantly increased degeneration in the form of osteophytes, disk protrusions/herniations, cord compression, and foraminal stenosis. Upon follow-up at 5 years, the authors noted that the difference between the groups diminished signifi cantly, and they concluded that high-performance fl ying results in cervical spine degeneration at a younger age compared with controls; however, with increasing age, the difference between pilots and controls diminishes. 126 Astronauts frequently complain of back pain in microgravity 130 and have been recognized to be at risk for degenerative disease of the cervical spine. 131 It has been proposed that this may be attributable to the physiological changes as a result of weightlessness, including spine elongation and loss of thoracic and lordotic curvatures. 131 Recently, it was reported that astronauts have a signifi cantly higher incidence rate ratio of nucleus pulposus herniations than controls. 131 The incidence of herniation was reported to be highest within the fi rst year after return from a space mission, a striking 35.9 times the risk compared with matched (age, sex, body mass index) controls. 131 It was also particularly interesting to note that the incidence of cervical herniation was 21.4 times higher in astronauts. 131 The authors postulate that prolonged abnormal posture during space missions, exposure to both low and high Gz environments, predisposition to injury due to postfl ight dysfunction of the neurovestibular system, and changes within the disc structures may be responsible for these fi ndings. 131

Cervical Spine Degeneration in Athletes
Athletes engaging in signifi cant physical contact have been shown to present with accelerated cervical degeneration. This has been demonstrated in rugby players who have been studied by Berge et al , 132 Scher, 133 and Silver. 134 There is a general consensus that accelerated cervical degeneration in this group is likely attributable to the exorbitant amount of force placed upon the cervical spine, particularly in rugby forwards. Scher 133 postulates that the forces in the rugby scrum that can generate up to 1.5 tons upon the cervical spine, coupled with rapid changes in direction and intensity of thrust, likely result in repeated minor trauma. In addition to this, in a series of 47 rugby players and 40 age-matched controls, Berge et al 132 noted increased rates of disc herniation, disc degeneration, and reduction of spinal canal diameter among rugby players. Much like rugby players, American football players are also exposed to potentially injurious energy inputs directed at the cervical spine. 135 Although protective equipment such as helmets may diminish some of these forces, it would be reasonable to assume that players in sports in which great force is repeatedly exerted on the cervical spine will likely experience accelerated degeneration.
Cervical spine pain is also a common complaint across other high performance athletes including cyclist and triathlon participants. 136 Chronic neck pain ( ≥ 3 mo) was reported in 15.4% of triathlon respondents in a recent study, and it has been suggested that this is possibly due to discogenic injury and overuse. 136 Although it would seem intuitive to think that such athletes may be predisposed to accelerated degenerative disease of the spine, research on weightlifters and participants of various other sports has shown that these activities are not harmful. 137 Indeed, it has been postulated that participation in most sports may exert a protective effect against IVD herniations. 137

Personal Factors
Personal factors have been implicated in the development of both CSM and OPLL. Wang et al 80 assessed the impact of smoking status on disease development in their study of 172 Chinese subjects. They found that patients who smoked were at increased risk of CSM development, and that the risk increased in patients who carried tryptophan alleles of collagen IX. In addition, a recent clinical prediction model on surgical outcome in patients with CSM included smoking as one of the predictive variables, 138 indicating that smoking status may also impact treatment outcome of patients with CSM. Indeed, it has been well reported that smoking impacts bone metabolism, decreases bone mineral density, and increases fracture risk. 139 Furthermore, the effect on bones has been shown to be infl uenced by dose and duration of smoking as well as body weight. 139 Animal studies have shown that smoking has a considerable effect on collagen structure, increases chondrocyte degeneration, and is related to cell necrosis and fi brosis in the nucleus pulposus. 140 However, given that other research has indicated that cigarette smoking may actually reduce the occurrence of OA, 140 , 141 further research is necessary to substantiate a potential relationship.
Early reports indicating that there is a high incidence of diabetes in patients with OPLL were discussed by Tsuyama 65 and Takeuchi et al . 142 More recently, Kobashi et al 143 in their sex-and age-matched study in Japanese subjects found that excessive weight gain between 20 and 40 years of age and diabetes were independent risk factors for the development of OPLL. It has also been reported that general ossifi cation of spinal ligaments is associated with non-insulin-dependent diabetes mellitus. 143 Although it has been suggested that insulin has implications on bone formation, the precise mechanism by which diabetes and weight infl uence the development OPLL, if at all, remains to be investigated. 144 Recently, 2 reports have described defi ciency of vitamin B 12 as a potential contributor to the pathology in patients with CSM. 145 , 146 Indeed, vitamin B 12 defi ciency by itself can result in subacute combined degeneration of the spinal cord, which can present with an inverse V-shaped T2-weighted MRI hyperintensity on axial view. 146 Although it is likely to be a rare phenomenon, this fi nding does suggest that when MRI fi ndings are equivocal, an assessment of vitamin B 12 defi ciency should be considered.

Motor Vehicle Accident Injury and DCM
Motor vehicle accidents represent one of the most frequent causes of traumatic SCI worldwide, 147 and it has been suggested that spinal canal stenosis and DDD render individuals more susceptible to neck injury and reduce injury thresholds. 148 , 149 However, the long-term effects of soft tissue injury surrounding the cervical spine including neck strains (muscletendon overloading) and sprains (ligamentous and capsular damage) in the absence of acute damage to neural elements remain less clear. 149 , 150 The biomechanical effects on the cervical spine during motor vehicle accidents are complex and depend on the type of accident ( e.g. , rear-end, side impact), and, therefore, multiple injury mechanisms are likely relevant. In terms of whiplash injuries, it has been reported that disc pathology may be responsible for persistent symptoms that may lead to neurological impairment later on. 151 , 152 However, Matsumoto et al 153 in their 10-year prospective follow-up on whiplash patients and controls found that although some evidence of disc degeneration was signifi cantly more common in patients with whiplash injury, no patients developed myelopathy or required surgery.

Other Associations
There are a number of less defi ned associations with DCM. In a study of 30 patients with schizophrenia, Matsunaga et al 154 reported a fi nding of OPLL in 20% of these patients, noting that this represents nearly 5 times the reported incidence in the general Japanese population. However, it is unclear how these patients were selected and thus these fi ndings may be subject to bias. The authors suggest a potential connection between the conditions via calcineurin, which has been linked with susceptibility for schizophrenia development and has been shown to partake in osteogenesis by osteoblast activation. 154 Although this would suggest a biochemical etiology, it is unclear whether perhaps aberrant kinetics such as dystonias or other movement abnormalities, which may appear in some schizophrenics because of neuroleptic use, may be contributory. Indeed, other aberrant kinetics, as are seen in patients with Parkinson disease, for example, may contribute to accelerated degeneration as well. Patients with Parkinson disease who have chronic dystonia and who have not benefi ted from medical or botulinum toxin treatment should be reassessed for complex cervical dystonia with tonic posture and phasic movements. 155 These patients can rapidly develop progressive myelopathy secondary to their dyskinesias and dystonia with generalized movement. 155 Additional noteworthy conditions with associated movement abnormalities that have implicated with accelerated cervical spondylosis were described by Wong et al 156 and include cerebral palsy, torticollis, and Tourette syndrome. In particular, patients with cerebral palsy who exhibit severe involuntary movements of the head and neck have shown a propensity to develop signifi cant degenerative changes in the cervical spine at an earlier age. 157 Additional potential population groups associated with OPLL development include patients with hypoparathyroidism, polyhypophosphatemic rickets, and short sleeping hours. 8

PERSPECTIVES
At the present time, there are a number of different ICD-10 codes that describe pathological features of DCM subtypes. Indeed, it is clear that the natural history, individual characteristics, as well as risk factors will not be the same between patients, and, therefore, it remains imperative to identify the specifi c pathologies that are most relevant to each patient. The observation that OPLL occurs more frequently in certain regions and at younger age, for example, indicates that some of these conditions may be greatly infl uenced by distinct genetic or environmental factors. 8 This, as a result, may have signifi cant implications on the natural progression of the condition, operative treatment, as well as outcomes. However, it is also quite apparent that DCMs are highly interrelated and frequently contribute to the development of myelopathy in unison. Moreover, degeneration remains a central etiological component for DCM development and this is supported by the gradual loss of anatomical function and progression with increasing age 46 , 51 , 69 and the fi nding that mechanical stress accelerates this process. 158 In this review, it has also become apparent that there are conditions other than congenital spinal stenosis, such as DS and KFS, which may predispose patients to DCM development but have received much less attention. Indeed, investigating the natural history of these patients may provide unique insight into the pathogenesis of DCM and may support the suggestion that specifi c morphological characteristics play a signifi cant role in the extent of degeneration over time.
In the case of genetic susceptibility, it is noteworthy that such genes may have been naturally selected for their conferment of some other type of survival advantage. Such a relationship was alluded to by Furushima et al , 159 who found that osteoporosis was present in a lower frequency in patients with OPLL than in subjects of similar ages, suggesting perhaps that susceptibility genes for OPLL might be involved in a protective effect for osteoporosis.
In terms of an epidemiological perspective, the type of changes that occur in the spine has been shown to vary between populations. OPLL is perhaps the most studied DCM and represents a frequent cause of myelopathy in Asian populations. However, it is studied less in western countries, perhaps due to the perception of a relatively low prevalence in comparison. Conversely, there is a much greater emphasis on the study of CSM in western countries. These factors, along with a general dearth of investigation on the incidence and prevalence of DCM around the globe, have made it challenging to present a complete epidemiological picture on the topic. However, understanding the rates of DCM is of particular importance from a public health point of view. The rise in the ageing population as well as increasing life spans is reinforcing the need to evaluate how to provide more effective and effi cient clinical management for these patients. 160 In particular, identifi cation of risk factors may be fundamental in reducing the incidence and morbidity associated with DCM.
As is evident in this review, many at-risk population groups have been identifi ed and reported in literature, but there are a number of other conditions that have been associated with cervical anatomical anomalies such as skeletal dysplasias, Spine www.spinejournal.com E689

➢ Key Points
Degenerative cervical myelopathy (DCM) is an overarching term used to describe the various degenerative conditions of the cervical spine that result in myelopathy, including cervical spondylotic myelopathy, degenerative disc disease, and ossifi cation of the posterior longitudinal ligament and ligamentum fl avum. The incidence and prevalence for degenerative causes of myelopathy of the spine are estimated at a minimum of 41 and 605 per million in North America. Overall incidence of CSM-related hospitalizations has been estimated at 4.04 per 100,000 person-years, and surgical rates seem to be rising. Pathophysiologically, symptomatic DCMs result from static compression of the spinal cord, spinal malalignment leading to altered cord tension and vascular supply, as well as dynamic injury mechanisms. Potential genetic factors include those related to MMP-2 and collagen IX for DDD, and collagen VI and XI for OPLL. In addition, congenital factors including congenital spinal stenosis, Down syndrome, and Klippel-Feil syndrome may predispose to the development of DCM as well. It is advocated that researchers as well as clinicians embrace this new terminology to clearly delineate when discussion is reserved for specifi c pathological entities such as CSM or OPLL or the collection of these conditions under DCM. This adoption will provide a clearer platform for investigation and will allow for improved communication in the health care community.
connective tissue disorders, metabolic syndromes, and infl ammatory disorders whose relationship to DCM remains to be investigated. 161 Moreover, movement disorders arising from neurodegenerative disease of cortical or basal ganglia neurons, or psychogenic causes, may also play a role in accelerated wear and tear because of pathological kinetics. The relationship between these disorders and DCM as well as guidance with regard to how they should be approached is worthy of further investigation.
In terms of surgical treatment, approaches for DCM may vary depending on the constellation of fi ndings present in each patient. Factors that should be taken into consideration were recently described in a consensus statement on the surgical management for DCM and include sagittal alignment, anatomical location of the compressive pathology, number of compressed levels, presence/absence of instability or subluxation, the type of compressive pathology ( e.g. , spondylosis vs . OPLL), neck anatomy, bone quality, and surgical experience as well as preference. 162 Ultimately, however, although surgical approaches may differ, the objective remains the same: decompression of the spinal cord and stabilization of the cervical spine.

CONCLUSION
Degeneration of the cervical spine over time encompasses a complex set of anatomical changes that can result in the reduction of the spinal canal, instability of the cervical spine, changes in the sagittal alignment, and consequently, myelopathy. Because of the wide-ranging pathologies contributing to DCM development, the constellation of fi ndings in any given patient may vary considerably. It is clear, however, that although DDD, CSM, OPLL, and OLF can present as separate diagnostic entities, they are highly interrelated, frequently manifest concomitantly, present similarly from a clinical standpoint, and appear to be in part a response to compensate and improve stability due to progressive age and wear of the cervical spine. Accordingly, we propose that henceforth, the term "degenerative cervical myelopathy" be used as the overarching term to describe this collection of conditions, while preserving specifi c diagnostic terms such as CSM or OPLL to delineate between predominant pathologies. This adoption will provide a clearer platform for investigation and will allow for improved communication in the health care community.