Degenerative Cervical Myelopathy: Epidemiology, Genetics, and Pathogenesis.

SPINE Volume 40, Number 12, pp E675-E693 ©2015, Wolters Kluwer Health, Inc. All rights reserved.

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Degenerative Cervical Myelopathy Epidemiology, Genetics, and Pathogenesis Aria Nouri, MD,*†‡ Lindsay Tetreault, BSc,*†‡ Anoushka Singh, PhD,*† Spyridon K. Karadimas, MD, PhD,*†‡ and Michael G. Fehlings, MD, PhD, FRCSC, FACS*†‡

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 From the *Division of Neurosurgery and Spine Program, Toronto Western Hospital, Toronto, Ontario, Canada; †Toronto Western Research Institute and Krembil Neuroscience Center, University Health Network, Ontario, Canada; and ‡Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Acknowledgment date: December 22, 2014. Revision date: March 3, 2015. Acceptance date: March 24, 2015. The manuscript submitted does not contain information about medical device(s)/drug(s). Alexander S. Onassis Public Benefit Foundation funds were received to support this work. No relevant financial activities outside the submitted work. Address correspondence and reprint requests to Michael G. Fehlings, MD, PhD, FRCSC, FACS, Suite 4W449, Toronto Western Hospital, University of Toronto, 399 Bathurst St, Toronto, ON M5T 2S8, Canada; E-mail: Michael [email protected] DOI: 10.1097/BRS.0000000000000913 Spine

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. Key words: cervical spondylotic myelopathy (CSM), ossification of posterior longitudinal ligament (OPLL), degenerative disc disease (DDD), ossification of ligamentum flavum (OLF), spine, spondylosis, nontraumatic spinal cord injury, introduction. Level of Evidence: 5 Spine 2015;40:E675–E693

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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), ossification of the posterior longitudinal ligament (OPLL), ossification of the ligamentum flavum (OLF), and degenerative disc disease (DDD). Unfortunately, there is neither a specific term nor a specific diagnostic International Classification 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 www.spinejournal.com

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DEGENERATIVE CERVICAL MYELOPATHY Degeneration of tissue anywhere in the body occurs principally as a function of use intensity over time. Musculoskeletal structures that bear significant structural loads, however, may experience accelerated deterioration. In the cervical spine, these degenerative changes can be divided into spondylotic (or osteoarthritic) and nonosteoarthritic changes, with further subtype categorization (Figure 1). However, although these pathological changes have been segregated into separate clinical entities, there is a loose divergence between them in practical terms because they are highly interrelated and oftentimes manifest concomitantly. Ultimately, the principal unifying problem is the propensity of degenerative changes to cause spinal canal stenosis, lead to compression of the spinal cord, and, eventually, result in disability due to the development of myelopathy. Figure 2 illustrates the various progressive pathological changes that contribute to myelopathy in patients with DCM. Pathophysiologically, symptomatic DCMs can result from static compression of the spinal cord, spinal malalignment leading to altered cord tension and vascular supply, and repeated dynamic injury owing to segmental hypermobility. In terms of the latter, it has also been recognized that unstable

Degenerative Cervical Myelopathy • Nouri et al

spine segments may be responsible for chronic repetitive microtrauma upon the spinal cord not large enough to be recognized as traumatic spinal cord injury (SCI). In addition, patients with spinal stenosis who have experienced minor trauma to the neck may be at a substantial risk of developing myelopathy or experiencing deterioration of pre-existing myelopathy.2 Accordingly, some degree of trauma is likely to be contributory to the natural history of DCM development. In the following section, the pathology of CSM and DDD will be discussed together and separated from the discussion of the ossification, hypertrophy, and calcification of spinal ligaments. The current understanding of the pathobiology of spinal cord compression will then be discussed as a consequence of these. After this, degenerative spondylolisthesis (DSL) and evidence supporting dynamic injury mechanisms are briefly reviewed. Finally, emerging evidence to support cervical spine malalignment as a contributor to DCM pathogenesis will be discussed.

CSM and DDD Each intervertebral disc (IVD) comprises an outer layer, the annulus fibrosus, and an inner layer called the “nucleus pulposus.” The nucleus pulposus largely comprises proteoglycans, which, due to their hydrophilic nature, become encased in water molecules. The resulting viscoelastic nucleus pulposus converts axial load into hoop stress and is contained by the dense connective tissue of the annulus fibrosus, which serves to provide structural integrity to the IVD. This construction provides a unique capacity to withstand high

TABLE 1. International Classification of Diseases, Tenth Revision (ICD-10) List of Conditions That

May be Used to Describe Degenerative Cervical Conditions Resulting in Myelopathy

Classification Group M25: Other joint disorders, not elsewhere classified

Specific Category M25.3: Other instability of joint M25.7: Osteophyte M25.9: Joint disorder, unspecified

M43: Other deforming dorsopathies

M43.3: Recurrent atlantoaxial subluxation with myelopathy M43.4: Other recurrent atlantoaxial subluxation M43.5: Other recurrent vertebral subluxation

M47: Spondylosis (including arthrosis or osteoarthritis, spine degeneration of facet joints)

M47.1: Other spondylosis with myelopathy

M48: Other spondylopathies

M48.0: Spinal stenosis

M47.9: Spondylosis, unspecified M48.8: Other specified spondylopathies (including OPLL) M48.9: Spondylopathy, unspecified

M50: Cervical disc disorders (including cervical disc disorders with M50.0+: Cervical disc disorder with myelopathy cervicalgia cervicothoracic disc disorders) M50.2: Other cervical disc displacement M50.3: Other cervical disc degeneration M50.8: Other cervical disc disorders M50.9: Cervical disc disorder, unspecified OPLL indicates ossification of the posterior longitudinal ligament.

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Figure 1. A conceptual breakdown of the pathoetiological constituents of degenerative cervical myelopathy (DCM). Predominant features form the basis of diagnosis, but more than one of these pathologies frequently present concomitantly. In addition, congenital anomalies may predispose to accelerated manifestation of DCM. CSS indicates congenital spinal stenosis; KFS, Klippel-Feil syndrome; DS, Down syndrome; OPLL, ossification of posterior longitudinal ligament; OLF, ossification of ligamentum flavum.

compressive loads and transfer of these forces longitudinally onto the cartilage endplates of vertebral bodies and radially onto the surrounding annulus fibrosus.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 flattened, 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 significant 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 findings more consistent with CSM. A T2-weighted magnetic resonance image of a patient with CSM and DDD is presented in Figure 3A.

Ossification, Hypertrophy, and Calcification 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 flavum (LF). Spine

Although hypertrophy and ossification of spinal ligaments may be influenced significantly by underlying genetics, their manifestation in older age as well as presumed multifactorial pathogenesis suggests a progressive and degenerative cause for their development.7–12 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 thorax13) 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 ossified ligament, but it has been suggested that hypertrophy may be a precursor for ossification.8 Histologically, hypertrophy of PLL has been defined as “hyperplasia of nonfibrous cartilage with strong metaplasia in the PLL in more than two intervertebral spaces, with capillary hyperplasia and infiltration of the connective tissue.”8 It has been hypothesized that hypertrophy of PLL may be replaced by lamellar bone to become ossified when hypertrophy has potential systematic or genetic factors to induce secondary ossification.14 The role of genetic factors is reinforced by the frequent coexistence of cervical and thoracic OPLL and OLF disease www.spinejournal.com

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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

Figure 2. An artistic depiction of the multiple anatomical changes that may present in the cervical spine of patients with degenerative cervical myelopathy. Conceptual design by primary author, edits by senior author, and medical illustration by Diana Kryski (Kryski Biomedia). PLL indicates posterior longitudinal ligament; CSF, cerebrospinal fluid.

(referred to as tandem ossification) in which different segmental stresses still exhibit similar pathological changes in nearly one-third of patients.15 This finding 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 calcification of the ligamentum flavum (CLF) is a common finding on computed tomographic scans18; however, much remains unknown about this clinical entity. Given the limited amount of research on CLF, it has been challenging to definitively 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 calcification has no continuity with the lamina.19 Moreover, the superficial 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 ossification leads to lamellar bone formation.21 More specifically, Miyasaka et al19 state that in OLF, cartilage forms an ossified bridge that extends from the upper and lower edges of 2 adjacent laminae. E678

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 models24,25 as well as on human spinal cords26 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 flow.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 neuroinflammatory 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 al31 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 al30 demonstrated that riluzole attenuated the neuropathic pain in a rodent model of CSM that was associated with decreased levels of microglia activation. The neuroinflammatory 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 inflammatory process being propagated by peripheral immune cell infiltration. This persistent hypoxic insult and the ongoing neuroinflammatory 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


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Figure 3. A, A T2-weighted magnetic resonance (MR) image depicting general degenerative changes of the cervical spine in a patient with confirmed cervical spondylotic myelopathy. The cervical vertebra bodies, most prominently seen in cervical vertebra 4 (asterisk), have lost their height and have increased anterior to posterior length. Intervertebral disc elements have migrated in the spinal canal C3–C4 (thin arrow) as well as C4–C5 and are contributing to spinal cord compression. Hyperintensity signal change of the spinal cord is also clearly visible extending from C3 to C5. B, A T2-weighted MR image of a patient with significant spinal canal compromise and cord compression due to hypertrophy of the ligamentum flavum. C, A computer tomographic scan of a patient with extensive ossification of the posterior longitudinal ligament (arrows). D, A radiograph depicting congenital fusion of vertebrae 5 and 6 (arrow) consistent with Klippel-Feil syndrome.

neuroanatomical features of myelopathy.1 A summary of the key pathobiological changes is outlined in 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

TABLE 2. Key Pathobiological Changes

Occurring in the Setting of Spinal Cord Compression Secondary to Degenerative Changes in the Cervical Spine

Pathobiological Consequence of Progressive and Chronic Cervical Spinal Cord Compression24,26,27,30 Chronic reduction in spinal cord blood flow Disruption of the microvascular network: Endothelial cell dysfunction Disruption of the vascular basement membrane Loss of blood-spinal cord barrier integrity Glutamate excitotoxicity Microglia activation regulated by CX3CR1:CX3CL1 axis CD200:CD200R axis Neuronal and oligodendroglial apoptosis Demyelination Astrogliosis Axonal degeneration Spine

injury mechanisms.34–37 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 canal38 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 benefit from kinematic magnetic resonance imaging (MRI) examination. Hayashi et al35 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 flexion using kinematic MRI. It has also been suggested that an increased range of motion in the cervical spine may result in dynamic injury to www.spinejournal.com

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Japan: Case series of 3 females with CLF predominately in the cervical spine at Rare22 C5–C7.19 Predominantly reported in the Japanese.22 French West Indies: A case series on 6 patients identified 5 females and 1 male; average age, 71.7 yr.22

Spondylosis

Disc degeneration

Ossification of the ligamentum flavum (OLF)

Calcification of the ligamentum flavum

(Continued)

Kuwait: 18.6% of patients with low back pain had evidence of OLF52 South China (volunteers): 3.8%13

Asymptomatic volunteers50: Annular tears: 37% Bulging discs: 73% Protrusions: 50% Disc extrusions: Rare Radiological signs of medullary compression: 13.3% Japanese asymptomatic volunteers51: Disc degeneration was the most frequent finding. Accompanied by either anterior (78%) or posterior (71%) protrusions (80% bulges, 20% prolapsed). Grade 2* posterior disc protrusion was identified in 7.6%.

Regional Incidences

46

Trends in Patient Characteristics

Type of Degenerative Pathology

TABLE 3. Epidemiological Trends and Patient Characteristics of the Various Forms of Degenerative Pathologies

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Male predominant: At least 2 times more common in males than in females.54–61 May occur in 20%–25% of patients treated for cervical myelopathy in North America64 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

Trends in Patient Characteristics

AP indicates anterior-posterior; CLF, calcification of the ligamentum flavum.

*Protrusion beyond the vertebral body causing cord compression.

Note that regarding OPLL regional incidence, authors have frequently used prevalence and incidence interchangeably.

Ossification of the posterior longitudinal ligament (OPLL)

Type of Degenerative Pathology

TABLE 3. (Continued)

Japan: 1–4.3% United States: 0.1%–1.3%62 North America: 0.12%60 New York City: 0.7%60 Western Caucasians: 0.16%63 Non-Japanese Asians: 2%–4%63 Indian Caucasians: 1%–8%63 Korea: 0.6%–3.6%8,55,59,62 Taiwan: 2.1%–3.0%55,62 Singapore: 0.8%62 Hong Kong: 0.4%62 Philippines: 1.5%62 Mongolia: 1.5%65 Non-Asian: 0.16% vs. Asia: 2.4%54 West Germany: 0.1%60 Italy: 1.7%62

Regional Incidences 8,16,56,60,62,63

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CERVICAL SPINE 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 defined 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 Bartels71 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 al72 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 findings, 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 al72 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 al73 examined national trends in outcome for CSM in the United States and reported that annual admissions increased from 9623 patients in 1993 to 19,212 patients in 2002 (∼3.73 to 7.88 per 100,000) on the basis of the US national inpatient database. Moreover, the authors found that a near 7-fold increase in the number of spinal fusions for CSM took place between 1993 and 2002 in the United States, representing a jump from 0.6 to 4.1 per 100,000 people.73 It should be noted that increases in fusion rates might be a reflection 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 al74 assessed the survival of patients with ntSCI between 1962 and 2000. Although these Spine


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 findings 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 al88 and Palmer et al.89 In their research, both groups assessed and compared cervical radiographs of twin siblings. Although Bull et al88 found that there was a marked resemblance in the degenerative process between twins on imaging, Palmer et al89 observed the opposite, concluding instead that, although anatomical similarities in twins may predispose them to similar degeneration over time, the incongruence of pathological findings 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 findings may be related to epigenetic factors, specifically, the transcriptional alterations in cells over time related to nonhereditary influences such as the environment. More recently, Setzer et al,79 Wang et al,77 and Wang et al80 have sought for particular genetic determinants of CSM susceptibility, implicating the potential polymorphism of apolipoprotein E, VDR, and collagen IX genes, respectively. Wilson et al76 in their systematic review on the topic caution that although these studies did find significant genetic associations between single nucleotide polymorphisms and CSM, none of the findings have been validated in separate studies. www.spinejournal.com

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TABLE 4. Summary of Genetic Research Conducted on Cervical Spondylotic Myelopathy,

Degenerative Disc Disease, Ossification of Posterior Longitudinal Ligament, and Ossification of Ligamentum Flavum

DCM Type

Studied Genes/Gene Products

Cervical spondylotic myelopathy77,79,80

Structural: Collagen IX Hormonal: VDR Other: Apolipoprotein E

Degenerative disc disease

75

Structural: Collagen IX Enzymes: MMP-2, MMP-3, MMP-9, ADAMTS Hormonal: VDR Immunological: IL-β, IL-1 receptor

Ossification of posterior longitudinal ligament7,8,11,76,81–85

Structural: Collagen VI and XI Hormonal: Retinoic X receptor, VDR, parathyroid hormone, leptin receptor, estrogen receptor Immunological: TSG-6, TNF-β1, IL-1 α and β, IL-15, interferon-γ Transcription factors: RUNX2, Promyelotic Leukemia Zinc Finger, Msx2 Growth factors: Insulin-like growth factor, connective tissue growth factor, BMP 2 and 4, growth hormone–binding protein, platelet-derived growth factor Other: Nucleotide pyrophosphatase, endothelin-1, prostaglandin I2

Ossification of ligamentum flavum78,86,87

Structural: Collagen VI Hormonal: VDR Growth factors: BMP-2 Transcription factors: RUNX2

DCM indicates degenerative cervical myelopathy; VDR, vitamin D receptor; MMP, matrix metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; IL, interleukin; TSG-6, tumor necrosis factor-alpha-stimulated gene 6; TNF, tumor necrosis factor; BMP, bone morphogenetic proteins.

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 significant (P < 0.001) relatedness of those with CSM. Most notably, they determined that there was a very significant relative risk of 5.21 (P < 0.001) for the development of CSM among first-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 Fehlings75 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. E684

Ossification 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 finding that OPLL presents significantly 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 finger, connective tissue growth factor, prostaglandin I2, endothelin-1, leptin receptor, estrogen receptor 1, and interferon-γ have been investigated.8,11,78,81,86 However, despite the numerous investigations, a recent systematic review on the topic by Wilson et al76 determined an overall low strength of evidence in support for a genetic association for OPLL development.


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CERVICAL SPINE Investigation of OPLL as a single disease may be hindering attempts to attribute specific genetic factors with its development. Based on its pathological distribution, OPLL has been classified into 4 subtypes: localized (bridged or circumscribed); segmental; continuous; and mixed, with segmental considered as the most common type.9,91 Recently, Kudo et al11 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 finding is supported by previous research that has found that patients with continuous and mixed OPLL types frequently experience progression of their ossification postoperatively, and that contrarily, progression is rare in patients with segmental OPLL.92,93 This is worthy of note since Kawaguchi et al93 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 significant clinical ramifications. 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.

Ossification of the LF At the present time, there is insufficient 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 specifically 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 al78 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 al86 has given support to a previously described genetic association related to the RUNX2 gene in patients with OPLL87 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 ossification such as diffuse idiopathic skeletal hyperostosis. Spine


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.97–99 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, specific epidemiological data do not currently exist. The significance 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” finding 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 motion101,102 (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, Rosti103 implicated mutations in the MEOX1 gene as the culprit behind autosomal recessive forms of KFS and Tassabehji et al104 implicated a GDF6 gene locus in familial and sporadic cases of KFS. 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 pathology106–108 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 www.spinejournal.com

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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.

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.

Congenital Cervical Spine Stenosis

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.

Congenital cervical spinal stenosis has been widely recognized as a significant predisposing factor for the development of DCM95,110,111 and has been defined as a sagittal canal diameter of less than 13 mm112 or a ratio of less than 0.82 using the Torg-Pavlov113 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 fluid and will impair cushioning of kinetic energy in the setting of minor trauma114 and presumably other dynamic injury mechanisms. However, variability in the transverse area of the spinal cord between individuals115 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 al102 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 significant 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 findings, 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 E686

OCCUPATIONAL, PERSONAL, AND OTHER ASSOCIATIONS

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.119–122 However, as the types of load bearing and techniques may differ among the various populations, it is difficult 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 significantly more pronounced than what is observed in the general population, and that the C5–C6 region is particularly affected.119–122 In addition, weight bearers more commonly complained of neck stiffness and pain.120 Bista and Roka123 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 flexion of the neck and, therefore, may significantly reduce the risk of spondylosis compared with nonporters. Given these findings, it seems that the method of transportation of goods can significantly 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 fighter pilots emerged after reports of acute neck injuries during flight and the recognition that Gz (G-force) places substantial axial force on the cervical spine.124 Upon neck movement during flight 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 fighter pilots have mostly supported the suggestion that accelerated DDD and osteophytosis takes place.125–129


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CERVICAL SPINE 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 fighter pilots against controls (nonfighter 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 significant acceleration in degeneration occurred in older fighter pilots compared with younger fighter pilots as well as age-matched controls without exposure to Gz; specifically, experienced pilots had significantly 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 significantly, and they concluded that high-performance flying 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 microgravity130 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 significantly higher incidence rate ratio of nucleus pulposus herniations than controls.131 The incidence of herniation was reported to be highest within the first 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 postflight dysfunction of the neurovestibular system, and changes within the disc structures may be responsible for these findings.131

Cervical Spine Degeneration in Athletes Athletes engaging in significant 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. Scher133 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 al132 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 Spine


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 al80 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 influenced 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 fibrosis 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 Tsuyama65 and Takeuchi et al.142 More recently, Kobashi et al143 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 ossification 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 influence the development OPLL, if at all, remains to be investigated.144 Recently, 2 reports have described deficiency of vitamin B12 as a potential contributor to the pathology in patients with CSM.145,146 Indeed, vitamin B12 deficiency 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 finding does suggest that when MRI findings are equivocal, an assessment of vitamin B12 deficiency should be considered. www.spinejournal.com

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Motor Vehicle Accident Injury and DCM

PERSPECTIVES

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 al153 in their 10-year prospective follow-up on whiplash patients and controls found that although some evidence of disc degeneration was significantly more common in patients with whiplash injury, no patients developed myelopathy or required surgery.

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 specific 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 influenced by distinct genetic or environmental factors.8 This, as a result, may have significant 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 age46,51,69 and the finding 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 specific morphological characteristics play a significant 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 efficient clinical management for these patients.160 In particular, identification 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 identified and reported in literature, but there are a number of other conditions that have been associated with cervical anatomical anomalies such as skeletal dysplasias,

Other Associations There are a number of less defined associations with DCM. In a study of 30 patients with schizophrenia, Matsunaga et al154 reported a finding 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 findings 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 benefited 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 al156 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 significant 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 E688


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CERVICAL SPINE connective tissue disorders, metabolic syndromes, and inflammatory 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 findings 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.


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 specific 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.

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 findings 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 specific 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.

➢ 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 ossification of the posterior longitudinal ligament and ligamentum flavum. 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 Spine

Acknowledgments The authors acknowledge the input of Juan J. Zamorano, MD, as well as Kristian Dalzell, MBChB, and the careful review of Mohammed F. Shamji, MD, MSc, PhD, FRCSC.

References

1. Kalsi-Ryan S, Karadimas S, Fehlings M. Cervical spondylotic myelopathy: the clinical phenomenon and the current pathobiology of an increasingly prevalent and devastating disorder. Neuroscientist 2013;19:409–21. 2. Yoo DS, Lee SB, Huh PW, et al. Spinal cord injury in cervical spinal stenosis by minor trauma. World Neurosurg 2010;73:50–2; discussion e4. 3. Galbusera F, van Rijsbergen M, Ito K, et al. Ageing and degenerative changes of the intervertebral disc and their impact on spinal flexibility [published online ahead of print January 31, 2014]. Eur Spine J 2014;23(suppl):S324–32. doi: 10.1007/s00586-014-3203-4. 4. Baptiste D, Fehlings M. Pathophysiology of cervical myelopathy. Spine J 2006;6(suppl):190S–7S. 5. Karadimas S, Erwin W, Ely C, et al. Pathophysiology and natural history of cervical spondylotic myelopathy. Spine 2013;38(suppl 1):36. 6. Jacobs W, Willems PC, van Limbeek J, et al. Single or double-level anterior interbody fusion techniques for cervical degenerative disc disease. Cochrane Database Syst Rev 2011:CD004958. 7. Ogata N, Koshizuka Y, Miura T, et al. Association of bone metabolism regulatory factor gene polymorphisms with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity. Spine (Phila Pa 1976) 2002;27:1765–71. 8. Inamasu J, Guiot B, Sachs D. Ossification of the posterior longitudinal ligament: an update on its biology, epidemiology, and natural history. Neurosurgery 2006;58:1027. 9. Stapleton C, Pham M, Attenello F, et al. Ossification of the posterior longitudinal ligament: genetics and pathophysiology. Neurosurg Focus 2011; 30:E6. doi: 10.3171/2010.12.FOCUS10271. 10. Stetler W, La Marca F, Park P. The genetics of ossification of the posterior longitudinal ligament. Neurosurg Focus 2011;30:E7. doi: 10.3171/2010.12.FOCUS10275. 11. Kudo H, Furukawa K-I, Yokoyama T, et al. Genetic differences in the osteogenic differentiation potency according to the classification www.spinejournal.com

E689


21/05/15 1:03 PM

CERVICAL SPINE

12. 13.

14. 15.

16. 17.

18. 19. 20.

21. 22. 23. 24. 25. 26.

27.

28.

29. 30. 31.

32.

of ossification of the posterior longitudinal ligament of the cervical spine. Spine 2011;36:951–7. Hayashi K, Ishidou Y, Yonemori K, et al. Expression and localization of bone morphogenetic proteins (BMPs) and BMP receptors in ossification of the ligamentum flavum. Bone 1997;21:23–30. Guo J, Luk K, Karppinen J, et al. Prevalence, distribution, and morphology of ossification of the ligamentum flavum: a population study of one thousand seven hundred thirty-six magnetic resonance imaging scans. Spine 2010;35:51–6. Mizuno J, Nakagawa H, Hashizume Y. Analysis of hypertrophy of the posterior longitudinal ligament of the cervical spine, on the basis of clinical and experimental studies. Neurosurgery 2001;49:1091. Park JY, Chin DK, Kim KS, et al. Thoracic ligament ossification in patients with cervical ossification of the posterior longitudinal ligaments: tandem ossification in the cervical and thoracic spine. Spine (Phila Pa 1976) 2008;33:E407–10. Ono K, Yonenobu K, Miyamoto S, et al. Pathology of ossification of the posterior longitudinal ligament and ligamentum flavum. Clin Orthop Relat Res 1999;359:18–26. Yoshida M, Shima K, Taniguchi Y, et al. Hypertrophied ligamentum flavum in lumbar spinal canal stenosis: pathogenesis and morphologic and immunohistochemical observation. Spine 1992;17:1353–60. Meyer C, Vagal A, Seaman D. Put your back into it: pathologic conditions of the spine at chest CT. Radiographics 2011;31:1425–41. Miyasaka K, Kaneda K, Sato S, et al. Myelopathy due to ossification or calcification of the ligamentum flavum: radiologic and histologic evaluations. AJNR Am J Neuroradiol 1983;4:629–32. Inoue H, Seichi A, Kimura A, et al. Multiple-level ossification of the ligamentum flavum in the cervical spine combined with calcification of the cervical ligamentum flavum and posterior atlanto-axial membrane. Eur Spine J 2013;22(suppl 3):S416–20. Ben Hamouda K, Jemel H, Haouet S, et al. Thoracic myelopathy caused by ossification of the ligamentum flavum: a report of 18 cases. J Neurosurg 2003;99(suppl):157–61. Cabre P, Pascal-Moussellard H, Kaidomar S, et al. Six cases of cervical ligamentum flavum calcification in Blacks in the French West Indies. Joint Bone Spine 2001;68:158–65. Ruiz Santiago F, Alcázar Romero PP, López Machado E, et al. Calcification of lumbar ligamentum flavum and facet joints capsule. Spine 1997;22:1730. Karadimas S, Moon E, Yu W-R, et al. A novel experimental model of cervical spondylotic myelopathy (CSM) to facilitate translational research. Neurobiol Dis 2013;54:43–58. Klironomos G, Karadimas S, Mavrakis A, et al. New experimental rabbit animal model for cervical spondylotic myelopathy. Spinal Cord 2011;49:1097–102. Yu W, Liu T, Kiehl T-R, et al. Human neuropathological and animal model evidence supporting a role for Fas-mediated apoptosis and inflammation in cervical spondylotic myelopathy. Brain 2011;134(pt 5):1277–92. Karadimas SK, Gatzounis G, Fehlings MG. Pathobiology of cervical spondylotic myelopathy [published online ahead of print March 14, 2014]. Eur Spine J 2015;24(suppl 2):132–8. doi: 10.1007/ s00586-014-3264-4. Karadimas S, Klironomos G, Papachristou D, et al. Immunohistochemical profile of NF-κB/p50, NF-κB/p65, MMP-9, MMP-2, and u-PA in experimental cervical spondylotic myelopathy. Spine 2013;38:4–10. Beattie M, Manley G. Tight squeeze, slow burn: inflammation and the aetiology of cervical myelopathy. Brain 2011;134(pt 5):1259–61. Moon E, Karadimas S, Yu W-R, et al. Riluzole attenuates neuropathic pain and enhances functional recovery in a rodent model of cervical spondylotic myelopathy. Neurobiol Dis 2014;62:394–406. Hirai T, Uchida K, Nakajima H, et al. The prevalence and phenotype of activated microglia/macrophages within the spinal cord of the hyperostotic mouse (twy/twy) changes in response to chronic progressive spinal cord compression: implications for human cervical compressive myelopathy. PloS One 2013;8:e64528. Yu W-R, Baptiste D, Liu T, et al. Molecular mechanisms of spinal cord dysfunction and cell death in the spinal hyperostotic mouse:

E690


33.

34. 35. 36. 37.

38. 39.

40. 41. 42.

43.

44.

45.

46. 47. 48. 49. 50. 51. 52. 53.

implications for the pathophysiology of human cervical spondylotic myelopathy. Neurobiol Dis 2009;33:149–63. Karadimas S, Gialeli C, Klironomos G, et al. The role of oligodendrocytes in the molecular pathobiology and potential molecular treatment of cervical spondylotic myelopathy. Curr Med Chem 2010;17:1048–58. Matsunaga S, Kukita M, Hayashi K, et al. Pathogenesis of myelopathy in patients with ossification of the posterior longitudinal ligament. J Neurosurg 2002;96(suppl):168–72. Hayashi T, Wang JC, Suzuki A, et al. Risk factors for missed dynamic canal stenosis in the cervical spine. Spine (Phila Pa 1976) 2014;39:812–9. Fengbin Y, Deyu C, Xinwei W, et al. Trauma-induced spinal cord injury in cervical spondylotic myelopathy with or without lower cervical instability. J Clin Neurosci 2013;20:419–22. Fujiyoshi T, Yamazaki M, Okawa A, et al. Static versus dynamic factors for the development of myelopathy in patients with cervical ossification of the posterior longitudinal ligament. J Clin Neurosci 2010;17:320–4. Jiang SD, Jiang LS, Dai LY. Degenerative cervical spondylolisthesis: a systematic review. Int Orthop 2011;35:869–75. Chaput CD, Allred JJ, Pandorf JJ, et al. The significance of facet joint cross-sectional area on magnetic resonance imaging in relationship to cervical degenerative spondylolisthesis. Spine J 2013;13:856–61. Kawasaki M, Tani T, Ushida T, et al. Anterolisthesis and retrolisthesis of the cervical spine in cervical spondylotic myelopathy in the elderly. J Orthop Sci 2007;12:207–13. Suzuki A, Daubs MD, Inoue H, et al. Prevalence and motion characteristics of degenerative cervical spondylolisthesis in the symptomatic adult. Spine (Phila Pa 1976) 2013;38:E1115–20. Ames CP, Blondel B, Scheer JK, et al. Cervical radiographical alignment: comprehensive assessment techniques and potential importance in cervical myelopathy. Spine (Phila Pa 1976) 2013;38(suppl 1):S149–60. Mohanty C, Massicotte EM, Fehlings MG, et al. The association of preoperative cervical spine alignment with spinal cord magnetic resonance imaging hyperintensity and myelopathy severity: analysis of a series of 124 cases. Spine (Phila Pa 1976) 2015;40:11–6. doi: 10.1097/BRS.0000000000000670. Smith JS, Lafage V, Ryan DJ, et al. Association of myelopathy scores with cervical sagittal balance and normalized spinal cord volume: analysis of 56 preoperative cases from the AOSpine North America Myelopathy study. Spine (Phila Pa 1976) 2013;38(suppl 1): S161–70. Ruangchainikom M, Daubs MD, Suzuki A, et al. Effect of cervical kyphotic deformity type on the motion characteristics and dynamic spinal cord compression. Spine (Phila Pa 1976) 2014;39:932–8. Tracy JA, Bartleson JD. Cervical spondylotic myelopathy. Neurologist 2010;16:176–87. Taitz C. Osteophytosis of the cervical spine in South African blacks and whites. Clin Anatomy 1999;12:103–9. Hukuda S, Kojima Y. Sex discrepancy in the canal/body ratio of the cervical spine implicating the prevalence of cervical myelopathy in men. Spine 2002;27:250–3. Northover JR, Wild JB, Braybrooke J, et al. The epidemiology of cervical spondylotic myelopathy. Skeletal Radiol 2012;41: 1543–6. Ernst CW, Stadnik TW, Peeters E, et al. Prevalence of annular tears and disc herniations on MR images of the cervical spine in symptom free volunteers. Eur J Radiol 2005;55:409–14. Matsumoto M, Fujimura Y, Suzuki N, et al. MRI of cervical intervertebral discs in asymptomatic subjects. J bone Joint Surg Br 1998;80:19–24. Al-Jarallah K, Al-Saeed O, Shehab D, et al. Ossification of ligamentum flavum in Middle East Arabs: a hospital-based study. Med Princ Pract 2012;21:529–33. Wani AA, Laherwal M, Ramzan AU, et al. Compressive myelopathy due to ossified ligamentum flavum. Neurosurg Quart 2012;22:119–22 doi: 10.1097/WNQ.0b013e31823cc336.


June 2015


21/05/15 1:03 PM

CERVICAL SPINE 54. Saetia K, Cho D, Lee S, et al. Ossification of the posterior longitudinal ligament: a review. Neurosurg Focus 2011;30:E1. doi: 10.3171/2010.11.FOCUS10276. 55. Smith Z, Buchanan C, Raphael D, et al. Ossification of the posterior longitudinal ligament: pathogenesis, management, and current surgical approaches. A review. Neurosurg Focus 2011;30:E10. doi: 10.3171/2011.1.FOCUS10256. 56. Ohtsuka K, Terayama K, Yanagihara M, et al. A radiological population study on the ossification of the posterior longitudinal ligament in the spine. Arch Orthop Trauma Surg 1987; 106:89–93. 57. Harsh GRT, Sypert GW, Weinstein PR, et al. Cervical spine stenosis secondary to ossification of the posterior longitudinal ligament. J Neurosurg 1987;67:349–57. 58. Jeon T-S, Chang H, Choi B-W. Analysis of demographics, clinical, and radiographical findings of ossification of posterior longitudinal ligament of the cervical spine in 146 Korean patients. Spine 2012;37:E1498–503. 59. Kim T-J, Bae K-W, Uhm W-S, et al. Prevalence of ossification of the posterior longitudinal ligament of the cervical spine. Joint Bone Spine 2008;75:471–4. 60. Trojan DA, Pouchot J, Pokrupa R, et al. Diagnosis and treatment of ossification of the posterior longitudinal ligament of the spine: report of eight cases and literature review. Am J Med 1992;92: 296–306. 61. Wu J-C, Liu L, Chen Y-C, et al. Ossification of the posterior longitudinal ligament in the cervical spine: an 11-year comprehensive national epidemiology study. Neurosurg Focus 2011;30:E5. 62. Matsunaga S, Sakou T. Ossification of the posterior longitudinal ligament of the cervical spine: etiology and natural history. Spine 2012;37:14. 63. Jayakumar P, Kolluri V, Vasudev M, et al. Ossification of the posterior longitudinal ligament of the cervical spine in Asian Indians—a multiracial comparison. Clin Neurol Neurosurg 1996;98: 142–8. 64. Epstein NE. The surgical management of ossification of the posterior longitudinal ligament in 43 North Americans. Spine (Phila Pa 1976) 1994;19:664–72. 65. Tsuyama N. Ossification of the posterior longitudinal ligament of the spine. Clin Orthop Relat Res 1984;(184):71–84. 66. Farry A, Baxter D. The incidence and prevalence of spinal cord injury in Canada: overview and estimates based on current evidence: Rick Hansen Institute and Urban Futures, 2010. http://fecst .inesss.qc.ca/fileadmin/documents/photos/Lincidenceetlaprevalence destraumamedullaireauCanada.pdf. Accessed May 11, 2015. 67. New P, Cripps R, Bonne Lee B. Global maps of non-traumatic spinal cord injury epidemiology: towards a living data repository. Spinal Cord 2014;52:97–109. 68. Arden N, Nevitt M. Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatology 2006;20:3–25. 69. Wilder F, Fahlman L, Donnelly R. Radiographic cervical spine osteoarthritis progression rates: a longitudinal assessment. Rheumatol Int 2011;31:45–8. 70. Wilson JR, Barry S, Fischer DJ, et al. Frequency, timing, and predictors of neurological dysfunction in the nonmyelopathic patient with cervical spinal cord compression, canal stenosis, and/or ossification of the posterior longitudinal ligament. Spine (Phila Pa 1976) 2013;38(suppl 1):S37–54. 71. Boogaarts H, Bartels R. Prevalence of cervical spondylotic myelopathy [published online ahead of print April 25, 2013]. Eur Spine J 2015;24(suppl 2):139–41. doi: 10.1007/s00586-013-2781-x. 72. Wu JC, Ko CC, Yen YS, et al. Epidemiology of cervical spondylotic myelopathy and its risk of causing spinal cord injury: a national cohort study. Neurosurg Focus 2013;35:E10. 73. Lad S, Patil C, Berta S, et al. National trends in spinal fusion for cervical spondylotic myelopathy. Surg Neurol 2009;71:66. 74. Ronen J, Goldin D, Bluvshtein V, et al. Survival after nontraumatic spinal cord lesions in Israel. Arch Phys Med Rehabil 2004;85: 1499–502. 75. Erwin W, Fehlings M. Intervertebral disc degeneration: genes hold the key. World Neurosurg 2013;80:3. Spine


76. Wilson J, Patel A, Brodt E, et al. Genetics and heritability of cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament: results of a systematic review. Spine 2013;38(suppl 1):46. 77. Wang Z, Chen X, Wang DW, et al. The genetic association of vitamin D receptor polymorphisms and cervical spondylotic myelopathy in Chinese subjects. Clin Chim Acta 2010;411:794–7. 78. Kong Q, Ma X, Li F, et al. COL6A1 polymorphisms associated with ossification of the ligamentum flavum and ossification of the posterior longitudinal ligament. Spine 2007;32:2834–8. 79. Setzer M, Hermann E, Seifert V, et al. Apolipoprotein E gene polymorphism and the risk of cervical myelopathy in patients with chronic spinal cord compression. Spine 2008;33:497–502. 80. Wang Z, Shi J, Chen X, et al. The role of smoking status and collagen IX polymorphisms in the susceptibility to cervical spondylotic myelopathy. GMR 2012;11:1238–44. 81. Kim K, Kim D, Chung J-Y, et al. Association of interferon gamma polymorphism with ossification of the posterior longitudinal ligament in the Korean population. Immunol Invest 2012;41:876–87. 82. Ikeda R, Yoshida K, Tsukahara S, et al. The promyelotic leukemia zinc finger promotes osteoblastic differentiation of human mesenchymal stem cells as an upstream regulator of CBFA1. J Biol Chem 2005;280:8523–30. 83. Yoshizawa T, Takizawa F, Iizawa F, et al. Homeobox protein Msx2 acts as a molecular defense mechanism for preventing ossification in ligament fibroblasts. Mol Cell Biol 2004;24:3460–72. 84. Iwasawa T, Iwasaki K, Sawada T, et al. Pathophysiological role of endothelin in ectopic ossification of human spinal ligaments induced by mechanical stress. Calcif Tissue Int 2006;79:422–30. 85. Ohishi H, Furukawa K-I, Iwasaki K, et al. Role of prostaglandin I2 in the gene expression induced by mechanical stress in spinal ligament cells derived from patients with ossification of the posterior longitudinal ligament. J Pharmacol Exp Therap 2003;305:818–24. 86. Liu Y, Zhao Y, Chen Y, et al. RUNX2 polymorphisms associated with OPLL and OLF in the Han population. Clin Orthop Relat Res 2010;468:3333–41. 87. Kishiya M, Sawada T, Kanemaru K, et al. A functional RNAi screen for Runx2-regulated genes associated with ectopic bone formation in human spinal ligaments. J Pharmacol Sci 2008;106:404–14. 88. Bull J, el Gammal T, Popham M. A possible genetic factor in cervical spondylosis. Br J Radiol 1969;42:9–16. 89. Palmer P, Stadalnick R, Arnon S. The genetic factor in cervical spondylosis. Skeletal Radiol 1984;11:178–82. 90. Patel A, Spiker W, Daubs M, et al. Evidence of an inherited predisposition for cervical spondylotic myelopathy. Spine 2012;37: 26–9. 91. Mizuno J, Nakagawa H. Ossified posterior longitudinal ligament: management strategies and outcomes. Spine J 2006;6(suppl): 282S–8S. 92. Hori T, Kawaguchi Y, Kimura T. How does the ossification area of the posterior longitudinal ligament progress after cervical laminoplasty? Spine (Phila Pa 1976) 2006;31:2807–12. 93. Kawaguchi Y, Kanamori M, Ishihara H, et al. Progression of ossification of the posterior longitudinal ligament following en bloc cervical laminoplasty. J Bone Joint Surg Am 2001;83-A:1798–802. 94. Pizzutillo PD, Woods M, Nicholson L, MacEwen GD. Risk factors in Klippel-Feil syndrome. Spine 1994;9:2110–6. 95. Singh A, Tetreault L, Fehlings M, et al. Risk factors for development of cervical spondylotic myelopathy: results of a systematic review. Evid Based Spine Care J 2012;3:35–42. 96. McKay SD, Al-Omari A, Tomlinson LA, et al. Review of cervical spine anomalies in genetic syndromes. Spine (Phila Pa 1976) 2012;37:E269–77. 97. Bosma G, van Buchem M, Voormolen J, et al. Cervical spondylarthrotic myelopathy with early onset in Down’s syndrome: five cases and a review of the literature. J Intellect Disabil Res 1999;43(pt 4):283–8. 98. Olive P, Whitecloud T, Bennett J. Lower cervical spondylosis and myelopathy in adults with Down’s syndrome. Spine 1988;13: 781–4. www.spinejournal.com

E691


21/05/15 1:03 PM

CERVICAL SPINE 99. Ali FE, Al-Bustan MA, Al-Busairi WA, et al. Cervical spine abnormalities associated with Down syndrome [published online ahead of print March 7, 2006]. Int Orthop 2006;30:284–9. 100. Shin M, Besser L, Kucik J, et al. Prevalence of Down syndrome among children and adolescents in 10 regions of the United States. Pediatrics 2009;124:1565–71. 101. Samartzis D, Herman J, Lubicky J, et al. Classification of congenitally fused cervical patterns in Klippel-Feil patients: epidemiology and role in the development of cervical spine-related symptoms. Spine 2006;31:804. 102. Giampietro P, Raggio C, Blank R, et al. Clinical, genetic and environmental factors associated with congenital vertebral malformations. Mol Syndromol 2013;4:94–105. 103. Rosti RO. Of mice, men, and King Tut: autosomal recessive Klippel-Feil syndrome is caused by mutations in MEOX1. Clin Genet 2013;84:19. 104. Tassabehji M, Fang ZM, Hilton EN, et al. Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome. Hum Mutat 2008;29:1017–27. 105. Nouri A, Tetreault L, Zamorano J, et al. Prevalence of Klippel-Feil syndrome in a surgical series of patients with cervical spondylotic myelopathy: analysis of the prospective, multicentre AO spine North America study [published online ahead of print March 5, 2015]. Global Spine J. doi: 10.1055/s-0035-1546817. 106. Bartolomei J, Theodore N, Sonntag V. Adjacent level degeneration after anterior cervical fusion: a clinical review. Neurosurg Clin North Am 2005;16:575. 107. Ishihara H, Kanamori M, Kawaguchi Y, et al. Adjacent segment disease after anterior cervical interbody fusion. Spine J 2004;4:624–8. 108. Lawrence B, Hilibrand A, Brodt E, et al. Predicting the risk of adjacent segment pathology in the cervical spine: a systematic review. Spine 2012;37(suppl):64. 109. Brown MW, Templeton AW, Hodges FJ III. The incidence of acquired and congenital fusions in the cervical spine. Am J Roentgenol Radium Ther Nucl Med 1964;92:1255–9. 110. Countee R, Vijayanathan T. Congenital stenosis of the cervical spine: diagnosis and management. J Nat Med Assoc 1979;71: 257–64. 111. Bernhardt M, Hynes R, Blume H, et al. Cervical spondylotic myelopathy. J Bone Joint Surg Am 1993;75:119–28. 112. Bajwa N, Toy J, Young E, et al. Establishment of parameters for congenital stenosis of the cervical spine: an anatomic descriptive analysis of 1,066 cadaveric specimens. Eur Spine J 2012;21: 2467–74. 113. Pavlov H, Torg JS, Robie B, et al. Cervical spinal stenosis: determination with vertebral body ratio method. Radiology 1987;164: 771–5. 114. Del Bigio MR, Johnson GE. Clinical presentation of spinal cord concussion. Spine (Phila Pa 1976) 1989;14:37–40. 115. Kameyama T, Hashizume Y, Ando T, et al. Morphometry of the normal cadaveric cervical spinal cord. Spine (Phila Pa 1976) 1994;19:2077–81. 116. King JA, Vachhrajani S, Drake JM, et al. Neurosurgical implications of achondroplasia. J Neurosurg Pediatr 2009;4:297–306. 117. Raff ML, Byers PH. Joint hypermobility syndromes. Curr Opin Rheumatol 1996;8:459–66. 118. Halko GJ, Cobb R, Abeles M. Patients with type IV Ehlers-Danlos syndrome may be predisposed to atlantoaxial subluxation. J Rheumatol 1995;22:2152–5. 119. Jumah K, Nyame P. Relationship between load carrying on the head and cervical spondylosis in Ghanaians. West Afr J Med 1994;13:181–2. 120. Echarri J, Forriol F. Influence of the type of load on the cervical spine: a study on Congolese bearers. Spine J 2005;5:291–6. 121. Jäger H, Gordon-Harris L, Mehring U, et al. Degenerative change in the cervical spine and load-carrying on the head. Skeletal Radiol 1997;26:475–81. 122. Joosab M, Torode M, Rao PV. Preliminary findings on the effect of load-carrying to the structural integrity of the cervical spine. Surg Radiol Anat 1994;16:393–8.

E692


123. Bista P, Roka Y. Cervical spondylosis in Nepalese porters. JNMA J Nepal Med Assoc 2008;47:220–3. 124. Schall D. Non-ejection cervical spine injuries due to +Gz in high performance aircraft. Aviat Space Environ Med 1989;60: 445–56. 125. Hämäläinen O, Vanharanta H, Kuusela T. Degeneration of cervical intervertebral disks in fighter pilots frequently exposed to high +Gz forces. Aviat Space Environ Med 1993;64:692–6. 126. Petrén-Mallmin M, Linder J. Cervical spine degeneration in fighter pilots and controls: a 5-yr follow-up study. Aviat Space Environ Med 2001;72:443–6. 127. Petrén-Mallmin M, Linder J. MRI cervical spine findings in asymptomatic fighter pilots. Aviat Space Environ Med 1999;70:1183–8. 128. Hendriksen I, Holewijn M. Degenerative changes of the spine of fighter pilots of the Royal Netherlands Air Force (RNLAF). Aviat Space Environ Med 1999;70:1057–63. 129. Landau D-A, Chapnick L, Yoffe N, et al. Cervical and lumbar MRI findings in aviators as a function of aircraft type. Aviat Space Environ Med 2006;77:1158–61. 130. Sayson JV, Hargens AR. Pathophysiology of low back pain during exposure to microgravity. Aviat Space Environ Med 2008;79:365– 73. 131. Johnston SL, Campbell MR, Scheuring R, et al. Risk of herniated nucleus pulposus among U.S. astronauts. Aviat Space Environ Med 2010;81:566–74. 132. Berge J, Marque B, Vital J, et al. Age-related changes in the cervical spines of front-line rugby players. Am J Sports Med 1999;27:422–9. 133. Scher A. Premature onset of degenerative disease of the cervical spine in rugby players. S Afr Med J 1990;77:557–8. 134. Silver J. The impact of the 21st century on rugby injuries. Spinal Cord 2002;40:552–9. 135. Nyland J, Johnson D. Collegiate football players display more active cervical spine mobility than high school football players. J Athl Train 2004;39:146–50. 136. Villavicencio AT, Hernandez TD, Burneikiene S, et al. Neck pain in multisport athletes. J Neurosurg Spine 2007;7:408–13. 137. Mundt DJ, Kelsey JL, Golden AL, et al. An epidemiologic study of sports and weight lifting as possible risk factors for herniated lumbar and cervical discs. The Northeast Collaborative Group on Low Back Pain. Am J Sports Med 1993;21:854–60. 138. Tetreault L, Kopjar B, Vaccaro A, et al. A clinical prediction model to determine outcomes in patients with cervical spondylotic myelopathy undergoing surgical treatment: data from the prospective, multi-center AOSpine North America study. J Bone Joint Surg Am 2013;95:1659–66. 139. Yoon V, Maalouf N, Sakhaee K. The effects of smoking on bone metabolism. Osteoporos Int 2012;23:2081–92. 140. Abate M, Vanni D, Pantalone A, et al. Cigarette smoking and musculoskeletal disorders. Muscles Ligaments Tendons J 2013;3:63–9. 141. Felson D, Zhang Y, Hannan M, et al. Risk factors for incident radiographic knee osteoarthritis in the elderly: the Framingham Study. Arthritis Rheum 1997;40:728–33. 142. Takeuchi Y, Matsumoto T, Takuwa Y, et al. High incidence of obesity and elevated serum immunoreactive insulin level in patients with paravertebral ligamentous ossification: a relationship to the development of ectopic ossification. J Bone Miner Metab 1989;7:17–21. 143. Kobashi G, Washio M, Okamoto K, et al. High body mass index after age 20 and diabetes mellitus are independent risk factors for ossification of the posterior longitudinal ligament of the spine in Japanese subjects: a case-control study in multiple hospitals. Spine 2004;29:1006–10. 144. Karasugi T, Nakajima M, Ikari K, et al. A genome-wide sib-pair linkage analysis of ossification of the posterior longitudinal ligament of the spine. J Bone Miner Metab 2013;31:136–43. 145. Xu Y, Chen W, Jiang J. Cervical spondylotic myelopathy with vitamin B deficiency: two case reports. Exp Ther Med 2013;6: 943–6. 146. Miyazaki T, Sudo H, Hiratsuka S, et al. Cervical spondylotic myelopathy with subacute combined degeneration. Spine J 2014;14:381–2.


June 2015


21/05/15 1:03 PM

CERVICAL SPINE 147. Singh A, Tetreault L, Kalsi-Ryan S, et al. Global prevalence and incidence of traumatic spinal cord injury. Clin Epidemiol 2014;6: 309–31. 148. Pettersson K, Karrholm J, Toolanen G, et al. Decreased width of the spinal canal in patients with chronic symptoms after whiplash injury. Spine (Phila Pa 1976) 1995;20:1664–7. 149. Zhou S-W, Guo L-X, Zhang S-Q, et al. Study on cervical spine injuries in vehicle side impact. Open Mech Eng J 2010;4:29–35. 150. Otremski I, Marsh JL, Wilde BR, et al. Soft tissue cervical spinal injuries in motor vehicle accidents. Injury 1989;20:349–51. 151. Jonsson H Jr, Cesarini K, Sahlstedt B, et al. Findings and outcome in whiplash-type neck distortions. Spine (Phila Pa 1976) 1994;19:2733–43. 152. Pettersson K, Hildingsson C, Toolanen G, et al. Disc pathology after whiplash injury. A prospective magnetic resonance imaging and clinical investigation. Spine (Phila Pa 1976) 1997;22:283–7; discussion 8. 153. Matsumoto M, Okada E, Ichihara D, et al. Prospective ten-year follow-up study comparing patients with whiplash-associated disorders and asymptomatic subjects using magnetic resonance imaging. Spine (Phila Pa 1976) 2010;35:1684–90. 154. Matsunaga S, Koga H, Kawabata N, et al. Ossification of the posterior longitudinal ligament in dizygotic twins with schizophrenia: a case report. Mod Rheumatol 2008;18:277–80. 155. Krauss JK, Loher TJ, Pohle T, et al. Pallidal deep brain stimulation in patients with cervical dystonia and severe cervical dyskinesias

Spine


with cervical myelopathy. J Neurol Neurosurg Psychiatry 2002;72: 249–56. 156. Wong AS, Massicotte EM, Fehlings MG. Surgical treatment of cervical myeloradiculopathy associated with movement disorders: indications, technique, and clinical outcome. J Spinal Disord Tech 2005;18(suppl):S107–14. 157. Kim K, Ahn P, Ryu M, et al. Long-term surgical outcomes of cervical myelopathy with athetoid cerebral palsy [published online ahead of print December 15, 2013]. Eur Spine J 2014;23:1464–71. doi: 10.1007/s00586-013-3119-4. 158. Matsunaga S, Sakou T, Taketomi E, et al. Effects of strain distribution in the intervertebral discs on the progression of ossification of the posterior longitudinal ligaments. Spine (Phila Pa 1976) 1996;21:184–9. 159. Furushima K, Shimo-Onoda K, Maeda S, et al. Large-scale screening for candidate genes of ossification of the posterior longitudinal ligament of the spine. J Bone Miner Res 2002;17: 128–37. 160. Cunningham M, Hershman S, Bendo J. Systematic review of cohort studies comparing surgical treatments for cervical spondylotic myelopathy. Spine 2010;35:537–43. 161. Kim H. Cervical spine anomalies in children and adolescents. Curr Opin Pediatr 2013;25:72–7. 162. Lawrence BD, Shamji MF, Traynelis VC, et al. Surgical management of degenerative cervical myelopathy: a consensus statement. Spine (Phila Pa 1976) 2013;38(suppl 1): S171–2.


E693


21/05/15 1:03 PM

Degenerative cervical myelopathy.

Letter: Pathogenesis of myelopathy in cervical spondylosis.

Reported Outcome Measures in Degenerative Cervical Myelopathy: A Systematic Review.

Degenerative myelopathy.

Predictors of symptomatic myelopathy in degenerative cervical spinal cord compression.

Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update.

The reporting of study and population characteristics in degenerative cervical myelopathy: A systematic review.

Pathomechanism, pathogenesis, and results of treatment in cervical spondylotic myelopathy caused by dynamic canal stenosis.

Laminoplasty for cervical myelopathy.

Myelopathy due to degenerative and structural spine diseases.

The degenerative cervical spine.

Upper cervical myelopathy in achondroplasia.

Cervical myelopathy after metrizamide myelography.

Pathobiology of cervical spondylotic myelopathy.

Mechanical and cellular processes driving cervical myelopathy.

Diagnostic and therapeutic challenges of cervical myelopathy.

Is it necessary to resect osteophytes in degenerative spondylotic myelopathy?

Degenerative myelopathy in a SOD1 compound heterozygous Bernese mountain dog.

The Practical Application of Clinical Prediction Rules: A Commentary Using Case Examples in Surgical Patients with Degenerative Cervical Myelopathy.

Preoperative Computed Tomography Myelography Parameters as Predictors of Outcome in Patients With Degenerative Cervical Myelopathy: Results of a Systematic Review.

Pathogenesis and epidemiology of schizophrenia.

Pathogenesis and epidemiology of schizophrenia.

Diffuse idiopathic skeletal hyperostosis with cervical myelopathy.

Cervical extension magnetic resonance imaging in evaluating cervical spondylotic myelopathy.