Reviews
Degenerative cervical myelopathy
— update and future directions
Jetan H. Badhiwala1, Christopher S. Ahuja1, Muhammad A. Akbar1,
Christopher D. Witiw 2, Farshad Nassiri1, Julio C. Furlan3, Armin Curt4,
Jefferson R. Wilson2 and Michael G. Fehlings 1*
Abstract | Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord
dysfunction in adults worldwide. DCM encompasses various acquired (age-​related) and
congenital pathologies related to degeneration of the cervical spinal column, including
hypertrophy and/or calcification of the ligaments, intervertebral discs and osseous tissues.
These pathologies narrow the spinal canal, leading to chronic spinal cord compression and
disability. Owing to the ageing population, rates of DCM are increasing. Expeditious diagnosis
and treatment of DCM are needed to avoid permanent disability. Over the past 10 years, advances
in basic science and in translational and clinical research have improved our understanding of
the pathophysiology of DCM and helped delineate evidence-​based practices for diagnosis and
treatment. Surgical decompression is recommended for moderate and severe DCM; the best
strategy for mild myelopathy remains unclear. Next-​generation quantitative microstructural
MRI and neurophysiological recordings promise to enable quantification of spinal cord tissue
damage and help predict clinical outcomes. Here, we provide a comprehensive, evidence-​based
review of DCM, including its definition, epidemiology, pathophysiology, clinical presentation,
diagnosis and differential diagnosis, and non-​operative and operative management. With this
Review, we aim to equip physicians across broad disciplines with the knowledge necessary to
make a timely diagnosis of DCM, recognize the clinical features that influence management and
identify when urgent surgical intervention is warranted.
1
Division of Neurosurgery,
Department of Surgery,
University of Toronto, Toronto
Western Hospital, Toronto,
Ontario, Canada.
2
Division of Neurosurgery,
Department of Surgery,
University of Toronto,
St Michael’s Hospital,
Toronto, Ontario, Canada.
3
Division of Physical Medicine
and Rehabilitation,
Department of Medicine,
University of Toronto,
Lyndhurst Centre, Toronto
Rehabilitation Institute,
Toronto, Ontario, Canada.
4
Spinal Cord Injury Center,
Balgrist University Hospital,
Zürich, Switzerland.
*e-​mail:
michael.fehlings@uhn.ca
https://doi.org/10.1038/
s41582-019-0303-0
Degenerative cervical myelopathy (DCM) is the most
common cause of spinal cord dysfunction1. This clinicopathological entity is characterized by acquired stenosis
of the cervical spinal canal (with or without superimposed congenital stenosis) secondary to osteoarthritic
degeneration (for example, cervical spondylosis) or ligamentous aberrations (for example, ossification of the
posterior longitudinal ligament (OPLL)) of the spinal
column. The condition can be likened to osteoarthritis of the knee or hip, but besides pain, DCM can lead
to progressive disability and paralysis owing to chronic
spinal cord compression and non-​traumatic spinal cord
injury2,3 (Fig. 1).
With the global ageing population, DCM is becoming increasingly prevalent worldwide; the proportion of
the US population that is aged ≥65 years is expected to
increase from 13% in 2010 to 22% in 2050 (ref.4), and the
trend is similar in many developed and developing countries, including the UK, Japan, China, Brazil and India5.
Over 70% of individuals aged ≥65 years exhibit pathological or radiological evidence of cervical degenerative
108 | February 2020 | volume 16
disease, and ~25% of these people develop symptoms
of spinal cord compression6–8. Consequently, the identification of optimal treatment strategies and clinical
care pathways for DCM have become key public health
priorities; in the USA, three of the top 100 national prior­
ities for comparative effectiveness research identified
by the Institute of Medicine relate to DCM9. This situation has led to an increase in high-​quality prospective studies10,11, systematic reviews12,13 and multicentre
randomized controlled trials14,15 in DCM. In addition,
emerging quantitative microstructural MRI techniques
have improved our ability to image the spinal cord and
quantify the degree of tissue injury16–23. Indeed, over
the past 10 years, insights from novel basic science
and translational and clinical research have advanced
the diagnosis and treatment of DCM, culminating
in the publication of evidence-​based clinical practice
guidelines in 2017 (refs24–26).
Given that DCM is an important and growing public health problem, and that the literature on DCM has
undergone rapid expansion, we aim to provide a detailed
www.nature.com/nrneurol
Reviews
Key points
• Degenerative cervical myelopathy (DCM) develops when age-​related osteoarthritic
or genetically based changes to the spinal column cause progressive compression of
the cervical spinal cord, resulting in functional impairment.
• DCM is the most common cause of spinal cord impairment, and the resultant burden
of disability on our society is expected to grow owing to the ageing global population.
• The pathophysiology of DCM involves static and dynamic factors that lead to chronic
spinal cord compression and resultant ischaemia, inflammation and apoptosis of
neurons and oligodendrocytes.
• Diagnosis of DCM requires a careful history and physical examination to identify signs
and symptoms of myelopathy and to rule out alternative diagnoses; clinical findings
should be correlated with MRI findings.
• The natural history of DCM can include a period of stable neurological status in some
patients; however, a substantial number of individuals experience progressive,
stepwise decline in function.
• Current clinical practice guidelines recommend surgical decompression for patients
with severe or moderate DCM and either surgery or a supervised trial of structured
rehabilitation in patients with mild DCM.
review of the epidemiology, pathophysiology, diagnosis,
clinical course and operative and non-​operative management of DCM based on the latest and highest quality
evidence.
Spondylosis
Arthritic changes related to
degeneration of the discs,
ligaments and/or joints of the
spinal column.
Facet joints
Synovial plane joints between
the articular processes of two
adjacent vertebrae; also known
as zygapophyseal joints.
Uncovertebral joints
Joints formed between the
uncinate processes of two
adjacent vertebrae.
Osteophyte
A bony outgrowth associated
with arthritic degeneration.
Degenerative subluxation
The displacement of one
vertebra relative to the
adjacent vertebra.
Epidemiology
DCM is widely considered to be the leading cause of
spinal cord dysfunction, but precise estimates of its
incidence and prevalence are lacking27. One challenge
in the study of DCM epidemiology is the traditional
classification, in which DCM is defined according to
the underlying degenerative pathology. As a result, cervical spondylotic myelopathy (CSM) and OPLL have
often been recognized and studied as separate clinical
entitites3,28. In addition, DCM itself is often included
under the broader umbrella of non-​traumatic spinal
cord injury, together with infectious, inflammatory,
neoplastic, vascular and congenital (for example,
neural tube) disorders29. Moreover, several studies of
non-​traumatic spinal cord injury have included only
patients with paraplegia or tetraplegia and would,
therefore, have excluded patients with less severe disability, who are likely to make up the majority with
DCM3.
A comprehensive review of the literature30 showed
that the estimated annual incidence of non-​traumatic
spinal cord injury is 76 per million per year in North
America, 26 per million per year in Australia, 20 per
million per year in Japan and 6 per million per year in
Europe, and other studies have indicated that degenerative conditions account for 54% of all non-​traumatic
spinal cord injury in North America 30, 18–26% in
Australia31,32, 59% in Japan33 and 16–39% in Europe34–40.
Very few studies of DCM prevalence have been conducted. In Canada, the prevalence of all non-​traumatic
spinal cord injury is ~1,120 per million29,41. On the basis
of these figures, the estimated incidence of DCM in
North America is 41 per million per year and the estimated prevalence is 605 per million3. However, these
estimates are limited by the poor quality of the data from
which they are derived, and the numbers are likely to
severely underestimate the burden of disease.
NaTure RevIewS | NeuROLOGy
In some studies, hospital admissions data have been
used to calculate epidemiological estimates for DCM.
The reported incidence of DCM-​related hospitalization is 4.04 per 100,000 persons per year in Taiwan42
and 7.88 per 100,000 persons per year in the USA43. On
the basis of surgical case volumes, the reported prevalence of operatively treated CSM in the Netherlands
was 1.6 per 100,000 persons, although whether this
group also included patients with OPLL was unclear27.
Each of these estimates excluded cases that did not lead
to hospital admission or surgical intervention, so are
also likely to have underestimated the true incidence
of DCM.
Pathophysiology
Spinal cord compression
The aetiopathogenesis of cervical spinal cord compression
in DCM includes static and dynamic factors44,45 (Fig. 1).
Static factors relate to spinal canal stenosis that is either
congenital or secondary to intervertebral disc degeneration and spondylosis. The intervertebral disc has
a tough, collagen-​rich outer ring called the annulus
fibrosus and a gelatinous inner layer called the nucleus
pulposus46. The nucleus pulposus is made up of proteo­
glycans, which are hydrophilic and consequently take
up and retain water, resulting in a turgid nucleus47. The
viscoelastic properties of this nucleus allow redistribu­
tion of axial load forces and maintenance of disc height48.
With ageing and/or repetitive stress, the proteoglycan
composition of the nucleus changes and, as a result,
hydrostatic pressure and disc height are reduced, and the
nucleus becomes less turgid, more fibrous and less efficient at redistributing vertical compressive loads to the
annulus49–51. Consequently, the annulus, facet joints and
uncovertebral joints bear greater load, which initiates a
cascade of degenerative changes that characterize cervical spondylosis; these changes include structural failure
of the disc (for example, annular tears, disc bulging or
herniation and/or further loss of disc height), osteophyte
formation, and ligament hypertrophy and calcification.
The precise pathophysiology of OPLL remains unclear,
but the underlying cause is thought to be multifactorial
and involve interplay between genetic and environmental factors (see Genetic risk factors below)52. Regardless,
the primary degenerative process in OPLL involves
ectopic calcification and ossification of the posterior longitudinal ligament. All of the above factors culminate in
reduction of the cross-​sectional area of the spinal canal
and compression of the spinal cord53.
Dynamic mechanisms of spinal cord compression involve worsening of compression with physio­
logical or pathological (for example, in the case of
degenerative subluxation ) movement of the cervical
spine44,53. In the extreme, dynamic factors that contribute to DCM can also result in acute traumatic spinal cord
injury (for example, central cord syndrome) superimposed onto pre-​existing myelopathy. Traumatic central cord syndrome typically results from a low-​energy
hyperextension neck injury (for example, secondary
to a fall forward) without spinal column disruption
in the setting of cervical degenerative disease, usually in
older patients54–56. Hyperextension is thought to cause
volume 16 | February 2020 | 109
Reviews
Dura
Dura
C2
Posterior longitudinal
ligament
Ligamentum flavum
Cerebrospinal fluid
Hypertrophy of ligamentum
flavum
Increased anterior–posterior
vertebral body length
C3
Spinal cord
Osteophyte
Spinal cord compression with
cavitation
Loss of vertebral body height
Loss of inververtebral disc
height with migration of
disc material into canal
C4
Dissociation of posterior
longitudinal ligament from
vertebrae
C5
Ossification of ligamentum
flavum
Hourglass reshaping
Hypertrophy of posterior
longitudinal ligament
C6
Ossification of posterior
longitudinal ligament
Hypermobility and listhesis
C7
Fig. 1 | Pathological changes that occur in the cervical spinal column and spinal cord in degenerative cervical
myelopathy. Redrawn from original figure courtesy of Diana Kryski, Kryski Biomedia (https://www.kryski.com).
the ligamentum flavum to buckle, resulting in sudden
impingement of the spinal cord in the anteroposterior
plane57 (Fig. 2). The cardinal feature of central cord syndrome is upper limb weakness that is disproportionately
greater than lower limb weakness57–60.
Hyalinization
Arterial wall thickening
characterized by a pink, glassy
appearance with haematoxylin
and eosin staining.
Pathobiology of neural injury
The long-​term mechanical forces applied to the cervical spinal cord as a result of the processes described
above cause direct injury to neuronal and glial cells
and trigger a cascade of pathobiological processes.
Characterization of the pathological processes that
occur within the spinal cord has been limited by the
lack of a reliable animal model of DCM2,61,62. However,
development of animal models that reproduce the slow,
progressive cervical spinal cord compression seen in
human DCM has provided novel insights into the
pathophysiological underpinnings of DCM, including
110 | February 2020 | volume 16
changes in microvascular architecture, neuroinflammation and apoptosis61–64 (Fig. 3). Nevertheless, the basic
scientific evidence pertaining to DCM is limited, so the
pathobiological mechanisms remain largely putative.
Ischaemia. Impaired spinal cord perfusion has long
been considered a central pathophysiological tenet of
DCM65. Chronic compression reduces regional spinal
cord blood flow, and local deformation leads to further
ischaemia66,67. The luminal diameter of extra-​spinal
blood vessels (such as the vertebral arteries, anterior
spinal artery and radicular arteries) is compromised
by extrinsic compression from spondylotic ridges and
other hypertrophic connective tissue68,69. These effects
are furthered by pathological changes to the vessels
themselves. Post-​mortem studies have shown that
wall thickening and hyalinization occur in the anterior
spinal artery and parenchymal arterioles, presumably
www.nature.com/nrneurol
Reviews
Hyperextension
C2
Dura
Cerebrospinal fluid
Spinal cord
C3
Increased anterior–posterior
vertebral body length
Posterior longitudinal
ligament
Ligamentum flavum
Osteophyte
Loss of vertebral body height
C4
Loss of intervertebral disc
height with migration of
disc material into canal
Buckling of ligamentum
flavum
Injury to spinal cord
C5
C6
C7
Fig. 2 | Aetiology of traumatic central cord syndrome. Traumatic central cord syndrome typically occurs in older
individuals with spinal canal stenosis secondary to cervical degenerative disease. During a hyperextension neck injury,
such as that sustained in a fall, buckling of the ligamentum flavum causes a sudden decrease in the cross-​sectional area of
the spinal canal and results in a compression injury to the spinal cord. Redrawn from original figure courtesy of Diana
Kryski, Kryski Biomedia (https://www.kryski.com).
Kyphosis
An outward curvature of the
spinal column, causing
hunching of the back.
in response to long-​term mechanical stresses65,70. As
a consequence, blood flow velocity within the major
feeding vessels might be reduced and regional perfusion impaired71. Consistent with this hypothesis, post-​
mortem histopathological studies have indicated that
demyelination in DCM predominantly occurs in the
grey matter and medial white matter tracts (centromedullary area)70, which suggests that malperfusion through
the anterior spinal artery and its terminal branches plays
a role. With regard to local perfusion, chronic spinal
cord compression causes stretching, flattening and
loss of penetrating branches of the lateral pial arterial
plexus62,68. This observation supports the hypothesis
that compromised blood flow to axonal pathways within
the spinal cord, particularly the lateral corticospinal
tract, has an important role in the onset and progression of myelopathy66. Cadaveric studies have indicated
that some degree of compensatory neovascularization
occurs, but perfusion is ultimately reduced overall72,73.
Kyphosis of the cervical spine also interrupts perfusion
within the spinal cord microvasculature, particularly
along the ventral aspect74.
NaTure RevIewS | NeuROLOGy
Blood–spinal cord barrier disruption. The blood–spinal
cord barrier (BSCB), which is a morphological and functional analogue of the blood–brain barrier, is disrupted
in acute traumatic spinal cord injury75,76. Compromise
of the BSCB is believed to also have a role in DCM,
although the evidence is less clear and consistent in this
condition77. Chronic cervical spinal cord compression is
thought to precipitate loss and dysfunction of endothelial cells, which are critical to the integrity of the BSCB;
hypoxic cell death in the spinal cord parenchyma as a
result of ischaemia could potentiate BSCB compromise61,62,78. In acute traumatic spinal cord injury, BSCB
integrity is restored after some time79,80, but data published in 2013 indicate that the BSCB remains chronically disrupted in patients with DCM62. This persistent
disruption might be mediated by matrix metalloproteinase 9, the expression of which remains increased in
chronic phases in experimental DCM81.
Breakdown of the BSCB has been seen in a rat model
of DCM that closely emulates the human condition82.
Despite the merits of this study, validation that the BSCB
is compromised in DCM is lacking. In studies in humans
volume 16 | February 2020 | 111
Reviews
with DCM in which gadolinium-​enhanced MRI was
used to investigate BSCB integrity, contrast enhancement was seen in only a subset of patients, raising the
question of whether BSCB disruption is a crucial and
uniform pathological occurrence83–85.
Limitations of existing studies therefore prevent
definitive conclusions from being drawn about the
role of BSCB disruption in DCM and the mechanisms
at play. Further experimental and human studies are
Static factors
Spondylosis, OPLL,
disc bulging, HLF and
congenital stenosis
Dynamic factors
Subluxation,
physiological
movement
Stenosis
Decreased spinal
canal cross-sectional
area
Chronic cervical
spinal cord
compression
Endothelial cell
dysfunction
Regional malperfusion
Decreased blood flow
velocity in feeding
vessels
Local deformation
Stretching, flattening
and loss of
perforating vessels
Ischaemia
Hypoxia
BSCB disruption
Microglia/macrophage
activation
Neuroinflammation
Apoptosis
Neuronal and
oligodendroglial cell
death
Fig. 3 | The pathophysiological process of degenerative cervical myelopathy.
Static factors (for example, spondylosis, ligament hypertrophy and calcification)
reduce the cross-​sectional area of the spinal canal. This effect is exacerbated by dynamic
factors during pathological movement (for example, degenerative subluxation) and
physiological movement. Consequent chronic spinal cord compression results in
ischaemia owing to regional malperfusion and local vessel deformation. Chronic
compression also disrupts the blood–spinal cord barrier (BSCB) via endothelial cell
dysfunction and hypoxic cell death as a result of ischaemia. BSCB disruption permits
entry of peripheral inflammatory cells into the spinal cord parenchyma. Activation of
microglia and recruitment of macrophages follows, and these processes might also be
triggered via the CX3CR1–CX3CL1 axis secondary to ischaemia. Both the ensuing
neuroinflammatory process and ischaemia activate apoptotic pathways, culminating in
neuronal and oligodendroglial cell death. HLF, hypertrophy of the ligamentum flavum;
OPLL, ossification of the posterior longitudinal ligament.
112 | February 2020 | volume 16
needed to assess the integrity of the BSCB in DCM by
use of a combination of imaging and cerebrospinal fluid
biomarkers.
Inflammation. Increased vascular permeability in DCM,
which might be accentuated by BSCB compromise as
discussed above, promotes oedema in the spinal cord
parenchyma and promotes the entry of inflammatory
cells from the peripheral circulation. The ensuing neuro­
inflammatory process is characterized by activation
of microglia and recruitment of macrophages at the
site of compression62,86,87. These cells are the primary
source of pro-​inflammatory cytokines within the spinal
cord after injury that are involved in the potentiation of
a broad spectrum of cellular responses88–90. Interaction
of fractalkine (CX3CL1) with its receptor (CX3CR1)
is thought to be a driver of microglial activation and
macrophage recruitment. CX3CL1 is expressed by neurons on their cell membranes and CX3CR1 is highly
expressed on microglia91. After neural injury, the ligand
can be released from the membrane, generating a solu­
ble chemokine92. In a post-​mortem study, expression
of CX3CR1 was found to be increased in the spinal cord of
patients with DCM93. Ischaemia can lead to CX3CR1–
CX3CL1-mediated microglial activation94, meaning that
the CX3CR1–CX3CL1 axis provides a possible mechanistic link between chronic hypoxia and inflammation in
the setting of DCM.
Inflammatory processes can be deleterious or protective. Classically activated macrophages (referred to as
having an M1 phenotype) highly express inflammatory
cytokines, whereas alternatively activated macrophages
(M2 phenotype) have phagocytic and anti-​inflammatory
properties95,96. In DCM, cytotoxic effects of the M1
pheno­type might mediate neuronal loss and demyelination, whereas the M2 phenotype might promote recovery after spinal cord injury through suppression of the
immune and inflammatory responses97–99. In experi­
mental DCM, an initial M2 response is observed; however, the prevalence of M1 microglia and macrophages
increases with greater severity of spinal cord compression87. On this basis, alternative activation of microglia
and/or macrophages is a potential therapeutic approach
for DCM.
Apoptosis. The chronic ischaemia and neuroinflammation described above converge on the activation of
apoptotic pathways, resulting in progressive neuronal
and oligodendroglial death and the clinical neurological deficits that characterize DCM62,100,101. This apoptosis
is mediated by signalling through the Fas86,100, tumour
necrosis factor (TNF)102 and mitogen-​activated protein
(MAP) kinase103 pathways.
Fas is a receptor that is a member of the TNF receptor superfamily. Binding of Fas ligand to Fas leads to
recruitment of Fas-​associated protein with death domain
(FADD), which drives caspase-​mediated apo­ptosis104.
This signalling pathway has been implicated in cell death
as a result of spinal cord injury105–107. Fas is expressed on
neurons and oligodendrocytes and can be upregulated
after injury107. In a murine model of DCM, blockade of
the Fas signalling pathway reduced cellular apoptosis,
www.nature.com/nrneurol
Reviews
attenuated inflammation, promoted axonal repair and
improved neurobehavioural function, suggesting this
approach could be a viable neuroprotective strategy86.
Another parallel in pathophysiology between DCM
and traumatic spinal cord injury relates to the role of glutamate excitotoxicity. A key cellular event after spinal cord
injury is constitutive activation of neuronal voltage-​gated
Na+ channels, which results in an influx of Na+, cytotoxic
oedema and an influx of Ca2+ via the Na+–Ca2+ exchange
pump108–110. The Ca2+ influx leads to glutamate release
and consequent excitotoxic local cell death111,112. Further,
in the setting of DCM, impaired intracellular energy
metabolism is thought to increase neuronal vulnerability to endogenous glutamate, leading to slow excito­toxic
neuronal death113; this pathway is also implicated in neuronal death in neurodegenerative disorders that follow a
chronic progressive disease course akin to that of DCM,
namely amyotrophic lateral sclerosis (ALS), Huntington
disease and spinal muscular atrophy114–117.
Pathology
Histopathological features of DCM include demyelination, gliosis, microcystic cavitation, central grey and
medial white matter degeneration, Wallerian degeneration of ascending and descending tracts, and dorsal
and ventral horn atrophy78,118,119. Post-​mortem studies
have indicated axonal loss within the lateral funiculi, which house the lateral corticospinal tracts, in the
early phases of DCM120,121. These histological changes
reflect the underlying pathophysiological mechanisms
at play in DCM, namely ischaemia, BSCB disruption,
inflammation and apoptosis, and account for the clinical
presentation with long tract signs, as discussed below.
Lhermitte phenomenon
The passing of an electric-​like
shock sensation radiating from
the neck down into the back,
trunk and limbs.
Hoffman sign
Flexion and adduction of the
thumb on flicking the fingernail
of the second digit downwards.
Trömner sign
Flexion of the thumb and index
finger on tapping the volar
surface of the distal phalanx
of the middle finger.
Genetic risk factors
Evidence indicates that individuals can have a genetic
susceptibility to the development of DCM122–125. The
evidence is generally of low quality owing to small
sample sizes, heterogeneity in the polymorphisms and
haplotypes considered, lack of replication, imprecision
in effect estimates and risks of bias and confounding122.
Nevertheless, single nucleotide polymorphisms and haplo­
types of several genes have been significantly associated
with OPLL and/or CSM; these include TGF-​β1 (ref.126),
NPPS127,128, BMP2 (ref. 129) , BMP4 (refs 130,131) , BMP9
(ref.132), BMPR1A133, RXRβ (ref.134), IL15RA135,136, RUNX2
(ref.137), RSPO2 (ref.138), COL6A1 (refs139,140), COL11A2
(refs141,142), VDR143, collagen IX144, APOE145,146 and OPN147
(Supplementary Table 1). The proteins that these genes
encode are generally structural components of connective tissue (for example, collagen) or are involved
in bone metabolism (for example, bone morpho­
genetic protein), and therefore are believed to influence
the development of DCM as a result of their effects on the
spinal column. A notable exception is APOE, which
encodes apolipoprotein E (ApoE) and therefore affects
the spinal cord. ApoE is the primary lipoprotein in the
CNS and contributes to repair and regeneration after
neural injury by transporting cholesterol to damaged
cells148,149. The APOE*ε4 allele has been associated with
the development of myelopathy in patients with chronic
cervical spinal cord compression145 and with a lack of
NaTure RevIewS | NeuROLOGy
neurological improvement after surgical decompression146. These findings are yet to be replicated but, considering the critical role of ApoE in other neurological
disorders, such as Alzheimer disease150 and traumatic
brain injury151,152, further study of ApoE as a candidate
biomarker in DCM is warranted.
Assessment and diagnosis
Diagnosis of DCM requires agreement between clinical and imaging findings (Fig. 4). Quantitative metrics
derived from advanced microstructural MRI can serve
as biomarkers of cervical spinal cord tissue injury and
predict neurological outcomes, although this remains an
area of active investigation16. Electrophysiological studies provide valuable additional information and can help
to rule out alternative diagnoses.
Clinical assessment
When DCM is suspected, a detailed history and physical examination should first be undertaken153. Common
presenting symptoms include: neck pain or stiffness;
pain, weakness or numbness (paraesthesias) in the upper
limbs; loss of manual dexterity (clumsiness); stiffness,
weakness or numbness of the lower limbs; gait imbalance or unsteadiness; falls; the Lhermitte phenomenon;
frequency and urgency of urination and/or defecation;
and urge incontinence62,154–156. Objective physical signs
of myelopathy include upper motor neuron signs in the
upper and/or lower limbs (for example, hyper-​reflexia,
clonus, a positive Hoffman sign, a positive Trömner sign,
an upgoing plantar response and lower limb spasticity),
corticospinal tract distribution motor deficits, atrophy
of intrinsic hand muscles, dermatomal sensory loss and
a broad-​based, unstable gait62,153–155.
Functional impairment in DCM can be graded with
the modified Japanese Orthopaedic Association (mJOA)
scale157 or the Nurick grading system1,158, both of which
are clinician-​administered, DCM-​specific indices. The
mJOA scale157 (Table 1) enables assessment of functional
abilities on an 18-point scale divided between sub­domains
of upper limb motor function, lower limb motor function, upper limb sensation and sphincter function. On
this scale, the severity of DCM can be classified as mild
(mJOA score 15–17), moderate (mJOA score 12–14) or
severe (mJOA score ≤11)26. Notably, the mJOA scale is
culture-​dependent159. The JOA was originally designed
for use in the Japanese population160. The modi­fied version (mJOA)157 is the most widely used version of the scale
among Western populations, but versions of the mJOA are
also available for Indian and other Asian populations161.
The Nurick grading system (Box 1) enables assessment of
functional status on a six-​point scale.
Additional measures that provide valuable information when assessing patients with possible DCM, either
in the clinical or research setting, include the Neck
Disability Index (NDI), the Myelopathy Disability Index,
the 30-Metre Walk Test, QuickDASH (a questionnaire
to assess disability of the arm, shoulder and hand), the
Berg Balance Scale, the Graded Redefined Assessment
of Strength Sensibility and Prehension Myelopathy
(GRASSP-​M), a grip dynamometer, and temporospatial
gait analysis (for example, GAITRite)21,162. The plethora
volume 16 | February 2020 | 113
Reviews
Patient with possible
degenerative cervical
myelopathy
History and physical
examination
Evoked potentials
(EMG, NCS, SSEPs,
MEPs)
Microstructural MRI
(DTI, MT, fMRI, MWF,
MRS, T2*WI)
Imaging
(MRI, CT, plain
radiography)
Advanced assesssment
techniques
(under active research)
Contact heat-evoked
potentials
Early detection
Cervical spinal cord
compression without
myelopathy
Degenerative
cervical
myelopathy
Severe myelopathy
mJOA score ≤11
Moderate
myelopathy
mJOA score 12–14
Clinical radiculopathy
with or without
electrophysiological
changes
Mild myelopathy
mJOA score 15–17
Surgery
Worsening
No signs or symptoms
of radiculopathy
Non-operative
treatment
Monitoring for myelopathic progression
Outcome
Outcome prediction
Fig. 4 | The diagnostic work-​up and treatment of degenerative cervical myelopathy. The diagnostic work-​up for
degenerative cervical myelopathy (DCM) begins with a detailed history and physical examination. Electrophysiological
studies can help rule out differential diagnoses. Different imaging techniques provide different information. MRI reveals
the presence, distribution and extent of spinal cord compression. CT is useful for visualizing bony anatomy and when
MRI is contraindicated. Plain radiography is useful for assessing cervical spinal alignment. Findings could indicate
a diagnosis of DCM or of cervical spinal cord compression without myelopathy. Contemporary clinical guidelines
recommend surgery for severe or moderate DCM. Surgery or non-​operative treatment are reasonable initial
strategies for mild DCM, but surgery is recommended upon neurological deterioration or if no improvement is seen
with non-operative treatment. Surgery and non-​operative management can be offered to patients with cervical spinal
cord compression and no myelopathy with clinical evidence of radiculopathy with or without electrophysiological
confirmation. Patients with cervical spinal cord compression and no myelopathy without evidence of radiculopathy
should be monitored clinically. Quantitative microstructural MRI and recording of contact heat-​evoked potentials
could provide a biomarker readout of cervical spinal cord tissue injury, thereby facilitating early detection of subclinical
tissue injury, monitoring of myelopathic progression, and prognostication. Dashed lines indicate pathways that
remain under investigation. DTI, diffusion tensor imaging; EMG, electromyography; fMRI, functional MRI; MEPs, motor
evoked potentials; mJOA, modified Japanese Orthopaedic Association scale; MRS, magnetic resonance spectroscopy;
MT, magnetization transfer; MWF, myelin water fraction; NCS, nerve conduction studies; SSEPs, somatosensory evoked
potentials; T2*WI, T2*-weighted imaging.
of available outcome assessments can be problematic:
a systematic review published in 2016 demonstrated
that variables and reported outcomes varied widely
between studies of DCM163. To address this issue and
enable more efficient and effective synthesis of research,
the RE-​CODE DCM initiative has been established to
114 | February 2020 | volume 16
define a core set of outcomes and data elements for
DCM research164.
The mJOA scale is currently the most widely accepted
outcome measure for assessing patients with DCM165.
However, the scale has poor sensitivity and modest inter-​
rater and intra-​rater reliability; the minimum detectable
www.nature.com/nrneurol
Reviews
Fractional anisotropy
A value between 0 and 1,
describing the degree to which
diffusion of water is limited to
one axis.
Scoliosis
An abnormal coronal curvature
of the spinal column.
Cervical lordosis
An inward curvature of the
spinal column.
change is two points159,166. Similarly, the Nurick grading
system has low sensitivity and poor responsiveness, with
limited ability to detect change167. These limitations are
especially problematic in the context of mild DCM, in
which strong ceiling and floor effects in the current
scales prevent detection of subtle neurological changes
that inform surgical decision-​making168. Objective
assessment tools do now exist (for example, GAITRite
and GRASSP-​M) but their application requires specialized equipment and they are time-​consuming, factors
that limit their clinical utility169,170.
For these reasons, development of more sensitive
and objective outcome instruments that are relevant and
practical for the clinical and research settings is a critical
area for future work. This development could incor­
porate the use of smartphone and wearable technol­
ogies, which are becoming increasingly relevant across
neurology171,172.
Imaging assessment
Conventional MRI. Imaging is used in DCM to characterize the structural anatomical source and the severity
of compression of the cervical spinal cord. MRI is the
modality of choice because it enables high-​resolution
visualization of neural, osseous and ligamentous structures173. Conventional MRI can delineate the nature and
degree of degenerative changes (for example, spondylosis, OPLL, hypertrophy of the ligamentum flavum and
disc herniation), reveal decreases in the diameter of the
Table 1 | The modified Japanese Orthopaedic Association scale
Type of dysfunction Level of dysfunction
Score
Motor dysfunction,
upper extremity
Inability to move hands
0
Inability to eat with a spoon, but able to move hands
1
Inability to button shirt, but able to eat with a spoon
2
Able to button shirt with great difficulty
3
Able to button shirt with slight difficulty
4
Motor dysfunction,
lower extremity
Sensory dysfunction,
upper extremity
Sphincter
dysfunction
No dysfunction
5
Complete loss of motor and sensory function
0
Sensory preservation without ability to move legs
1
Able to move legs, but unable to walk
2
Able to walk on flat floor with a walking aid (cane or
crutch)
3
Able to walk up and/or down stairs with handrail
4
Moderate-​to-significant lack of stability, but able to
walk up and/or down stairs without handrail
5
Mild lack of stability, but walks with smooth
reciprocation unaided
6
No dysfunction
7
Complete loss of hand sensation
0
Severe sensory loss or pain
1
Mild sensory loss
2
No sensory loss
3
Inability to micturate voluntarily
0
Marked difficulty with micturition
1
Mild-​to-moderate difficulty with micturition
2
Normal micturition
3
Adapted from ref.157.
NaTure RevIewS | NeuROLOGy
spinal canal, identify compression of the spinal cord, and
detect signal intensity changes within the spinal cord
parenchyma174,175. Whereas intramedullary hyperintensity on T2-weighted images is associated with clinical
impairment, hypointensity on T1-weighted images is
associated with greater clinical impairment — signal
changes on T1-weighted images indicate more permanent injury17,176–178. Signal intensity changes, particularly
at multiple levels, suggest cavitation or necrosis in the
spinal cord and are associated with poorer surgical outcomes17,178–181. MRI can also differentiate DCM from
mimicking conditions or other causes of myelopathy (for
example, a tumour, demyelinating plaques or syringomyelia)153–155. If MRI is contraindicated, CT myelography
should be conducted instead182.
Quantitative microstructural MRI. Advanced spinal
MRI protocols with acquisition times of <35 min mean
that quantitative microstructural MRI sequences are
now feasible in the setting of DCM; these sequences
include diffusion tensor imaging (DTI), magnetization
transfer, functional MRI, myelin water fraction, MR
spectroscopy, and T2*-weighted imaging17–20. Metrics
that derive from these modalities — including cross-​
sectional area, T2* white matter to grey matter signal
intensity ratio, fractional anisotropy and magnetization
transfer ratio — are highly sensitive to progression of
myelopathy and can enable detection of subclinical tissue injury in patients with asymptomatic cervical spinal
cord compression19,21,22,183,184. In particular, the T2* white
matter to grey matter signal intensity ratio has shown
promise as a novel biomarker of white matter injury
in patients with DCM23 (Fig. 5). Moreover, measures of
spinal cord motion across spinal segments can reveal
dynamic strains exerted on the cervical cord beyond
static compression185–187.
CT and plain radiographs. CT is useful for studying
bony anatomy, for example, when spinal fusion is being
considered as part of the treatment. CT is also a valuable diagnostic tool when MRI is contraindicated (for
example, in a patient with a pacemaker). Plain radiographs can reveal degenerating discs and joints, narrowing of the spinal canal and vertebral fusion69,154,155. This
technique is particularly useful for assessing cervical
spinal alignment (for example, scoliosis, loss of normal
cervical lordosis, kyphosis and subluxation) in an upright
position under physiological load. The spine functions
as a global unit, so cervical alignment parameters influence, and are influenced by, alignment parameters in the
lower spine. Dynamic lateral films (that is, of flexion and
extension views) can be used to assess cervical spinal
instability.
Electrophysiological assessment
The value of electrophysiological studies in the assessment of DCM is threefold: first, it aids diagnosis and
enables longitudinal assessment; second, it enables the
coexistence of cervical radiculopathy to be ruled out;
and third, it enables neuromuscular diseases such as
ALS, peripheral neuropathy and motor neuron disease,
which can mimic DCM, to be ruled out188,189. Needle
volume 16 | February 2020 | 115
Reviews
Box 1 | The Nurick grading system
Grade 0
Signs or symptoms of root involvement, but without
evidence of spinal cord disease.
Grade I
Signs of spinal cord disease, but no difficulty in walking.
Grade II
Slight difficulty in walking that does not prevent full-​time
employment.
Grade III
Difficulty in walking that prevents full-​time employment
or the ability to do all housework, but that is not so severe
as to require someone else’s help to walk.
Grade IV
Able to walk only with someone else’s help or with the aid
of a frame.
Grade V
Chair-​bound or bedridden.
electromyography (EMG) is a highly sensitive technique
for the detection of damage to anterior horn cells, which
occurs in DCM as a result of compression and ischaemia190. This damage can manifest as long-​duration,
high-​amplitude and/or polyphasic potentials associated
with reduced recruitment of motor units154. Fibrillation
action potentials and positive sharp waves suggest an
active denervating process191.
Nerve conduction studies are useful to rule out
peripheral polyneuropathy, peripheral nerve entrapment (for example, carpal tunnel syndrome or cubital
tunnel syndrome) and brachial plexopathy154,192. These
studies can also indicate extensive damage to anterior
horn cells, which causes reductions in the amplitude
of compound motor action potentials, although sensory nerve conduction studies sometimes reveal no
abnormalities193,194.
Somatosensory evoked potentials (SSEPs) can be
used to evaluate the degree of central sensory conduction impairment in DCM, which manifests as latency
or low amplitude154. Similarly, motor evoked potentials (MEPs) can be used to detect a prolonged central
motor latency190,195. Some clinicians have advocated the
use of SSEPs and MEPs in the routine examination of
patients with DCM to maximize sensitivity and specificity in making the diagnosis190. SSEPs and MEPs can
also be helpful in the setting of asymptomatic (preclinical) degenerative cervical spinal cord compression, as
they can detect subclinical involvement of the spinal
cord or nerve roots, thereby identifying patients who
should be monitored vigilantly for development of
myelopathy196–199. SSEPs and MEPs are routinely used for
intraoperative neurophysiological monitoring200–203.
Some studies have demonstrated that neurophysio­
logical recording of spinothalamic pathways (contact
heat evoked potentials (CHEPs)) is a feasible and sensitive approach to the assessment of damage to central
sensory nerve fibres204–206. This damage usually occurs
at the segmental crossings of the spinothalamic pathways, as DCM has a high impact on centromedullary
areas of the spinal cord. In this context, CHEPs are more
116 | February 2020 | volume 16
sensitive to damage than SSEPs and enable assessment
of individual cervical segments by testing along defined
dermatomes207,208.
Differential diagnosis
Several conditions can present in a similar way to DCM.
An alternative diagnosis should be suspected if sensori­
motor findings do not correspond with the degree of
spondylosis and/or cervical spinal cord compression
seen with MRI. An absence of sensory symptoms indicates the possibility of motor neuron disease (for example, ALS), neuromuscular junction disease (for example,
myasthenia gravis) or myopathy (for example, inclusion
body myositis). Severe weakness, wasting of intrinsic
hand muscles, and fasciculations more commonly occur
in ALS than in DCM209,210. Peripheral nerve entrapments,
such as carpal tunnel syndrome or cubital tunnel syndrome, can mimic DCM; however, these conditions cause
sensory and motor symptoms only in the median and
ulnar distributions, respectively, whereas DCM usually
causes long tract signs, sensory symptoms in a dermatomal distribution, gait deficits, bladder dysfunction and/
or bowel dysfunction211.
Other differential diagnoses include demyelinating
diseases (for example, multiple sclerosis or neuromyelitis optica), other causes of spinal cord degeneration
(for example, subacute combined degeneration), neoplasms (for example, metastatic epidural spinal cord
compression or intradural tumour), spinal vascular
malformations (for example, arteriovenous malformation or cavernous malformation), infectious spinal
diseases (for example, epidural abscess), hereditary spinal diseases (for example, hereditary spastic paraplegia
or spinal cerebellar atrophy) and other CNS disorders
(for example, normal pressure hydrocephalus)212,213.
Natural history
Several historical and contemporary studies of DCM
have demonstrated that the disease course is highly vari­
able214–227. According to current understanding, some
patients experience a long period of quiescence marked
by stable neurological status, but a substantial number
of individuals experience a progressive, stepwise decline
in function228. A systematic review published in 2017
showed that 20–62% of patients with DCM had experienced neurological deterioration (defined as a decrease
in mJOA score of one point or more) after 3–6 years of
follow-​up2,13. Furthermore, the review identified low-​
level evidence that the presence of circumferential spinal cord compression is associated with a greater risk
of neurological deterioration than partial spinal cord
compression2,13. Therefore, circumferential compression might warrant more expeditious referral and more
careful consideration for intervention.
In the setting of cervical spinal cord compression
without clinical signs or symptoms of myelopathy, the
presence of clinical and/or electrophysiological evidence
of cervical radicular dysfunction or central conduction
deficit (for example, prolonged SSEPs and MEPs and/or
EMG signs of anterior horn denervation) are predictors of development of myelopathy197–199. In this
scenario, patients should be counselled on the risk of
www.nature.com/nrneurol
Reviews
developing myelopathy and the option of surgery; if non-​
operative management is chosen, frequent reassessment
is warranted24,199.
One concern in the case of untreated DCM is an
increased susceptibility to acute spinal cord injury, such
as central cord syndrome, after low-​energy trauma (for
example, fall-​related injury). Attempts to quantify this risk
on the basis of hospital admissions data have produced
an estimated annual incidence of hospitalization for
spinal cord injury of 2.4–13.9 per 1,000 among patients
with CSM42,229 and 4.1–4.8 per 1,000 among patients with
myelopathy secondary to OPLL229,230. By comparison,
the incidence of acute traumatic spinal cord injury in the
general population is 10–50 per million per year, depending on geographic location231. Patients should be counselled on this risk when discussing the benefits and risks
of treatment options13.
The data pertaining to the natural history of DCM
are, by and large, derived from poor-​quality retrospective studies2,228. The few prospective studies that do
exist were severely underpowered and had important
limitations that have been well described previously232.
Consequently, there remains a critical unmet need for a
large-​scale, prospective study of the natural history of
DCM — most importantly of patients with mild myelopathic symptoms — that includes comprehensive clinical, multiparametric quantitative MRI and advanced
electrophysiological assessments.
a
b
d
c
e
f
Fig. 5 | Cervical spine MRI. a | Midsagittal T2-weighted imaging in a healthy individual.
No spinal cord compression is seen. b | Axial T2*-weighted imaging at C4–C5. A clear
contrast is visible between the white matter (WM) and the grey matter (GM) (WM:GM
ratio 0.831). c | The same images as in part b with a probabilistic atlas of WM (red),
GM (green), lateral corticospinal tracts (yellow) and fasciculi gracilis (blue). d | Midsagittal
T2-weighted imaging in a patient with moderate degenerative cervical myelopathy.
Multilevel disc degeneration, spondylosis and spinal cord compression are visible.
e | Axial T2*-weighted imaging at C4–C5. Spinal cord compression from a disc herniation
is visible, with loss of contrast between the GM and WM (WM:GM ratio 0.904). f | The same
image as part e with the same probabilistic atlas overlaid as that in part c. The overlay
illustrates the distortion caused by the compression. Probabilistic atlas overlays were
generated with Spinal Cord Toolbox.
NaTure RevIewS | NeuROLOGy
Management
Clinical practice guideline recommendations for the
management of DCM were published in 2017 under
the auspices of AOSpine North America and the Cervical
Spine Research Society24–26. These recommendations were
developed by a multidisciplinary guidelines development
group according to the methodology proposed by the
Grading of Recommendations, Assessment, Development
and Evaluations (GRADE) Working Group233–235. The
results of comprehensive systematic reviews12,13 were
combined with clinical expertise to develop the clini­
cal practice guideline recommendations24 (Table 2).
In practice, management of DCM falls into two classes:
non-​operative and operative. The evidence and practical
considerations for each are discussed below.
Non-​operative management
Non-​operative management options for DCM include
cervical traction216,218,236, bracing214,218,237–239, analgesics,
therapeutic exercise218,240, manual therapy240, bedrest and
avoidance of risky activities (for example, contact sports)
and environments (for example, slippery floors)216.
However, the role of non-​operative treatment for DCM
is poorly defined owing to a paucity of evidence12,13,241.
Structured, non-​operative treatment is not associated
with any direct harms, but few data support its efficacy13.
Published studies involving cohorts of patients with
DCM who received non-​operative management have
demonstrated minimal responses — changes in mJOA
scores have mostly been 0–1 (refs12,242). In a comprehensive systematic review published in 2017 (refs12,242),
in only one of eight eligible studies219 did the observed
improvements in function exceed the reported minimum clinically important difference in mJOA score243.
However, this study included patients with myelopathy
secondary to soft disc herniations, a condition that is
likely to respond favourably to non-​operative treatment because soft disc herniations can spontaneously
regress over time244,245. The current literature indicates
that 23–54% of patients who initially receive non-​
operative management require surgical intervention
within a mean follow-​up of 29–74 months, suggesting
that structured, non-​operative care does not produce
durable eff­ects218,219,227,246,247. Given the poorly defined
role of non-​operative care, the nuanced decision-​making
required for clinical management and the potential for
neurological deterioration if therapy is delayed, a diagnosis of DCM warrants expeditious referral for surgical
assessment in addition to ongoing care and follow-​up,
even when electing for non-​operative treatment.
Operative treatment
According to existing clinical guidelines24, surgery is
strongly recommended for moderate (mJOA score 12–14)
and severe (mJOA score ≤11) DCM. For mild myelopathy (mJOA score 15–17), the guidelines suggest either
surgery or a supervised trial of structured rehabilitation
as initial management strategies. However, mounting
evidence suggests that even DCM classified as mild can
be associated with substantial reductions in quality of
life that patients consider unacceptable and that surgery
can be effective in this population168,248. High-​quality
volume 16 | February 2020 | 117
Reviews
Table 2 | AOSpine clinical practice guidelines for the management of DCM24
Severity of DCM
Recommendation
Strength Quality of evidence
Severe DCM
(mJOA score ≤11)
“We recommend surgical intervention for patients with
severe DCM”
Strong
Moderate
Moderate DCM
“We recommend surgical intervention for patients with
(mJOA score 12–14) moderate DCM”
Strong
Moderate
Mild DCM
“We suggest offering surgical intervention or a supervised
(mJOA score 15–17) trial of structured rehabilitation for patients with mild
DCM. If initial nonoperative management is pursued, we
recommend operative intervention if there is neurological
deterioration and suggest operative intervention if the
patient fails to improve”
Weak
Very low to low
Cervical spinal
cord compression
without symptoms
of myelopathy
“We suggest not offering prophylactic surgery for
nonmyelopathic patients with evidence of cervical cord
compression without signs or symptoms of radiculopathy.
We suggest that these patients be counselled as to potential
risks of progression, educated about relevant signs and
symptoms of myelopathy, and be followed clinically”
Weak
No identified
evidence; based on
clinical expert opinion
“Nonmyelopathic patients with cord compression and
clinical evidence of radiculopathy with or without electrophysiological confirmation are at a higher risk of
developing myelopathy and should be counselled about
this risk. We suggest offering either surgical intervention or
nonoperative treatment consisting of close serial follow-​up
or a supervised trial of structured rehabilitation. In the
event of myelopathic development, the patient should be
managed according to the recommendations above”
Weak
Low
DCM, degenerative cervical myelopathy ; mJOA , modified Japanese Orthopaedic Association scale.
prospective comparisons of outcomes after operative and non-​operative management of mild DCM are
needed to definitively address this question. When
non-​operative measures are adopted, progressive neuro­
logical deterioration is an important indication for
decompressive surgery.
The central tenet of operative intervention for DCM is
to alleviate mechanical compression on the cervical spinal cord. In addition, surgery can involve fusion to reconstruct and stabilize the spinal column and restore cervical
alignment. Spinal column instability can be iatro­genic as
a result of resection of bony and ligamentous elements
for decompression or can be pre-​existing as a result of
the overall degenerative disease process (for example,
spondylolisthesis, subluxation or kyphosis). Anterior,
posterior or combined anterior and posterior surgical
approaches might be used to achieve the goals of surgery.
Anterior surgical procedures include anterior cervical
discectomy and fusion, anterior cervical corpectomy and
fusion, and combined (hybrid) discectomy–corpectomy
constructs249,250. Posterior surgical procedures are most
commonly laminectomy with instrumented fusion and
laminoplasty251–254.
Factors that guide the choice of surgical approach
have been reviewed in detail elsewhere255. Briefly, posterior approaches are often preferred for multilevel
compression from predominantly dorsal pathology
or in the setting of OPLL with preserved cervical lordosis. Anterior approaches are considered suitable for
restoring lordosis or addressing predominantly ventral compressive pathology over a limited number of
segments (for example, single-​level disc herniations).
In some scenarios, the choice of approach is not clear
— a randomized controlled trial to compare anterior
118 | February 2020 | volume 16
and posterior surgery in these situations is currently
underway15,256.
Efficacy of surgery
Traditionally, the main goal of operative intervention
for DCM was to maintain current neurological status
and prevent further deterioration. However, evidence
from the past decade suggests that surgical decompression can improve neurological function. To date,
the AOSpine CSM North America (CSM-​NA)10 and
AOSpine CSM International (CSM-​I)11 studies are the
largest prospective investigations of clinical outcomes
after decompressive surgery for DCM. Both studies
demonstrated that surgery significantly improves long-​
term (>1 year) neurological function (assessed with the
mJOA scale and the Nurick grading system), disability
(assessed with the NDI) and health-​related quality of
life (assessed with the Short Form (36 question) Health
Survey). The greatest improvements were seen in
patients with moderate or severe DCM at presentation.
The cumulative incidence of complications was low in
both studies, and surgery was well tolerated. These findings have been validated in large systematic reviews of
the literature and led to publication of clinical practice
guidelines13,24–26. In addition, health economic analyses
have shown that surgery is cost-​effective, with an incremental cost–utility ratio of about Canadian $11,000 per
quality-​adjusted life year257.
Predictors of outcome
Multiple studies have been conducted to identify clinical predictors of outcome after surgical decompression
for DCM258–265, and the findings have been extensively
reviewed elsewhere266. Factors that have been associated
www.nature.com/nrneurol
Reviews
with worse clinical outcomes are a longer duration of
symptoms, a higher severity of preoperative myelopathy
and, less consistently, older age155,267. The first two factors
in particular underscore the critical importance of early
diagnosis of DCM, before irreversible spinal cord tissue
destruction has occurred. This early diagnosis hinges
upon the ability of primary care physicians to recognize
the signs and symptoms of DCM and to differentiate
these from other mimicking diagnoses2,61,78,118,119,268–270.
The need for early diagnosis is also reflected in studies
of rodent models of DCM, in which delayed decompression has been associated with prolonged elevation of
inflammatory cytokines, greater astrogliosis and poorer
neurological recovery271. The effect of age is thought
to reflect the lesser ability of older patients to translate
neurological recovery into functional gains than that of
younger individuals266.
Other clinical predictors of outcome that have been
identified include smoking 264,272–274, comorbid status259,264,273,275,276, diabetes mellitus262,277,278, psychiatric
disease (depression or bipolar disorder)274,279,280, specific signs and symptoms (for example, upgoing plantar
responses, lower limb spasticity, unstable gait, hyper-​
reflexia and hand muscle atrophy)264,273,274,276,281,282 and
BMI283. However, the prognostic utility of any of these
factors is controversial. Furthermore, the biological
mechanisms by which these factors influence outcomes
are not known.
Certain MRI features may also be predictive of outcomes284. Specifically, a greater number of high signal
intensity segments on T2-weighted images285,286, a low
signal intensity on T1-weighted images287, a combination of T1 and T2 signal intensity changes278,288–290 and
a higher signal intensity ratio (T2-weighted images:
T1-weighted images or compressed:non-​compressed
on T2-weighted images)281,291–293 have all been associated
with poorer neurological outcomes after surgery192. These
features probably reflect irreversible neural tissue injury.
Use of DTI has shown that higher fractional anisotropy
is associated with improved outcomes after surgery in
DCM294–296; use of other quantitative microstructural
MRI techniques remains an active area of investigation
and could produce other predictive markers.
Perioperative neuroprotection
In most patients, surgical decompression effectively
prevents progression of neurological deficits and, in
many, improves functional outcomes in DCM. However,
a minority of patients have considerable residual postoperative disability10,11 — in several studies, neuro­logical
deterioration has occurred in 7–11% of patients after
surgery268,297,298. This risk might be determined by the
molecular and cellular changes that occur after surgical decompression, but few studies have investigated
these changes. One study has demonstrated that axonal
sprouting and restoration of functional synapses takes
place after surgical decompression for DCM, suggesting
that axonal plasticity underpins functional recovery299.
Other evidence suggests that ischaemia–reperfusion
injury after decompressive surgery leads to neurological worsening268. On the basis of these findings, there
has been interest in combining surgical decompression
NaTure RevIewS | NeuROLOGy
with pharmacological agents that promote axonal plasticity or provide neuroprotection; the latter is an area of
active investigation.
One agent that has been studied in this context is
riluzole, a benzothiazole anticonvulsant drug. Riluzole
alters excitatory neurotransmission by blocking sodium
and glutamate signalling. In patients with ALS, riluzole
treatment improves survival300. Results of animal studies suggest that riluzole is neuroprotective and promotes
functional recovery after brain and spinal cord ischaemic
and traumatic injury301–304. Furthermore, in animal models of spinal cord injury, riluzole attenuated secondary
injury cascades, increased preservation of neural tissue
and improved neurobehavioural outcomes in comparison with placebo and other sodium channel-​blocking
medications112,303,305,306. Studies of experimental DCM
have suggested that riluzole can mitigate perioperative
ischaemia–reperfusion injury and improve outcomes
after decompression268. Some data from animal studies
suggest that riluzole can also mitigate neuropathic pain
in DCM307. A multicentre randomized controlled trial
of riluzole and surgery compared with placebo and surgery has been completed and is currently in the analysis
phase14,308.
Conclusions and future prospects
DCM is characterized by progressive neurological disability owing to age-​related degeneration of the spinal
column and resultant spinal cord compression. As a
result of the ageing population, the physical and socio­
economic burden of disability from DCM is expected
to grow steadily. The natural history of DCM is highly
variable, but generally entails progressive decline or, at
best, no worsening of neurological function. Surgical
decompression halts the progression of clinical deficits
and improves long-​term neurological function, disability and health-​related quality of life. Severe permanent
disability is therefore preventable by early detection and
intervention, before irreversible histological injury to the
spinal cord has occurred. An important social responsibility therefore rests on the shoulders of neurologists
and primary care physicians, who must be able to recog­
nize the signs and symptoms of DCM, differentiate these
from mimics and initiate appropriate clinical care.
Investigation is warranted in several areas to address
critical gaps in our knowledge of DCM. First, multi­
centre randomized controlled trials will shed light
on the optimal choice of surgical approach for DCM
and the role of perioperative neuroprotection with riluzole. Second, although surgery has become the standard
of care for patients with moderate or severe myelopathy,
the optimal treatment strategy for patients with mild
DCM remains to be defined. The development of more
sensitive outcome instruments to detect and monitor the
progression of myelopathy could facilitate realization
of this goal. Similarly, advances in quantitative microstructural MRI techniques, development of serological
biomarkers and improved genetic analyses could transform diagnosis, monitoring and prognostic assessment,
paving the way to personalized medicine for DCM.
Published online 23 January 2020
volume 16 | February 2020 | 119
Reviews
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Nurick, S. The pathogenesis of the spinal cord
disorder associated with cervical spondylosis.
Brain 95, 87–100 (1972).
Karadimas, S. K., Erwin, W. M., Ely, C. G., Dettori, J. R.
& Fehlings, M. G. Pathophysiology and natural history
of cervical spondylotic myelopathy. Spine 38,
S21–S36 (2013).
Nouri, A., Tetreault, L., Singh, A., Karadimas, S. K.
& Fehlings, M. G. Degenerative cervical myelopathy:
epidemiology, genetics, and pathogenesis. Spine 40,
E675–E693 (2015).
The World Bank. DataBank: Population estimates
and Projections. http://databank.worldbank.org/data/
reports.aspx?source=health-​nutrition-and-​populationstatistics:-population-​estimates-and-​projections#
(2019).
World Health Organization. World Report on Ageing
and Health (WHO, 2015).
Hughes, J. T. & Brownell, B. Necropsy observations on
the spinal cord in cervical spondylosis. Riv. Patol.
Nerv. Ment. 86, 196–204 (1965).
Gore, D. R., Sepic, S. B. & Gardner, G. M.
Roentgenographic findings of the cervical spine in
asymptomatic people. Spine 11, 521–524 (1986).
Irvine, D. H., Foster, J. B., Newell, D. J. & Klukvin, B. N.
Prevalence of cervical spondylosis in a general
practice. Lancet 1, 1089–1092 (1965).
Institute of Medicine. Initial National Priorities for
Comparative Effectiveness Research https://
www.nationalacademies.org/hmd/Reports/2009/
ComparativeEffectivenessResearchPriorities.aspx
(2009).
Fehlings, M. G. et al. Efficacy and safety of surgical
decompression in patients with cervical spondylotic
myelopathy: results of the AOSpine North America
prospective multi-​center study. J. Bone Joint Surg.
Am. 95, 1651–1658 (2013).
Fehlings, M. G. et al. A global perspective on the
outcomes of surgical decompression in patients with
cervical spondylotic myelopathy: results from the
prospective multicenter AOSpine international study
on 479 patients. Spine 40, 1322–1328 (2015).
Tetreault, L. A. et al. Change in function, pain, and
quality of life following structured nonoperative
treatment in patients with degenerative cervical
myelopathy: a systematic review. Glob. Spine J. 7,
42S–52S (2017).
Rhee, J. et al. Nonoperative versus operative
management for the treatment degenerative cervical
myelopathy: an updated systematic review. Glob.
Spine J. 7, 35S–41S (2017).
Fehlings, M. G., Wilson, J. R., Karadimas, S. K.,
Arnold, P. M. & Kopjar, B. Clinical evaluation of a
neuroprotective drug in patients with cervical
spondylotic myelopathy undergoing surgical
treatment: design and rationale for the CSM-​Protect
trial. Spine 38, S68–S75 (2013).
Ghogawala, Z. et al. Cervical spondylotic myelopathy
surgical trial: randomized, controlled trial design and
rationale. Neurosurgery 75, 334–346 (2014).
Martin, A. R. et al. Imaging evaluation of degenerative
cervical myelopathy: current state of the art and
future directions. Neurosurg. Clin. N. Am. 29, 33–45
(2018).
Nouri, A. et al. The relationship between MRI signal
intensity changes, clinical presentation, and surgical
outcome in degenerative cervical myelopathy:
analysis of a global cohort. Spine 42, 1851–1858
(2017).
Martin, A. R. et al. Translating state-​of-the-​art spinal
cord MRI techniques to clinical use: a systematic
review of clinical studies utilizing DTI, MT, MWF, MRS,
and fMRI. Neuroimage Clin. 10, 192–238 (2016).
Martin, A. R. et al. Can microstructural MRI detect
subclinical tissue injury in subjects with asymptomatic
cervical spinal cord compression? A prospective
cohort study. BMJ Open. 8, e019809 (2018).
Martin, A. R. et al. Clinically feasible microstructural
MRI to quantify cervical spinal cord tissue injury using
DTI, MT, and T2*-weighted imaging: assessment of
normative data and reliability. AJNR Am. J.
Neuroradiol. 38, 1257–1265 (2017).
Martin, A. R. et al. Monitoring for myelopathic
progression with multiparametric quantitative MRI.
PLoS One 13, e0195733 (2018).
Yoo, W. K. et al. Correlation of magnetic resonance
diffusion tensor imaging and clinical findings of
cervical myelopathy. Spine J. 13, 867–876 (2013).
Martin, A. R. et al. A novel MRI biomarker of spinal
cord white matter injury: T2*-weighted white matter
to gray matter signal intensity ratio. AJNR Am.
J. Neuroradiol. 38, 1266–1273 (2017).
120 | February 2020 | volume 16
24. Fehlings, M. G., Kwon, B. K. & Tetreault, L. A.
Guidelines for the management of degenerative
cervical myelopathy and spinal cord injury: an
introduction to a focus issue. Glob. Spine J. 7, 6S–7S
(2017).
25. Tetreault, L. A. et al. Guidelines for the management
of degenerative cervical myelopathy and acute spinal
cord injury: development process and methodology.
Glob. Spine J. 7, 8S–20S (2017).
26. Tetreault, L. et al. The modified Japanese Orthopaedic
Association scale: establishing criteria for mild,
moderate and severe impairment in patients with
degenerative cervical myelopathy. Eur. Spine J. 26,
78–84 (2017).
27. Boogaarts, H. D. & Bartels, R. H. Prevalence of
cervical spondylotic myelopathy. Eur. Spine J. 24,
139–141 (2015).
28. Goel, A. Ossification of posterior longitudinal ligament
and cervical spondylosis: same cause - same
treatment. J. Craniovertebr. Junction Spine 9, 1–2
(2018).
29. New, P. W., Cripps, R. A. & Bonne Lee, B. Global maps
of non-​traumatic spinal cord injury epidemiology:
towards a living data repository. Spinal Cord 52,
97–109 (2014).
30. McKinley, W. O., Seel, R. T. & Hardman, J. T.
Nontraumatic spinal cord injury: incidence,
epidemiology, and functional outcome. Arch. Phys.
Med. Rehabil. 80, 619–623 (1999).
31. New, P. W., Rawicki, H. B. & Bailey, M. J.
Nontraumatic spinal cord injury: demographic
characteristics and complications. Arch. Phys. Med.
Rehabil. 83, 996–1001 (2002).
32. New, P. W. Functional outcomes and disability after
nontraumatic spinal cord injury rehabilitation: results
from a retrospective study. Arch. Phys. Med. Rehabil.
86, 250–261 (2005).
33. Ide, M., Ogata, H., Tokuhiro, A. & Takechi, H.
Spinal cord injuries in Okayama Prefecture: an
epidemiological study ‘88-’89. J. UOEH 15, 209–215
(1993).
34. Biering-​Sorensen, E., Pedersen, V. & Clausen, S.
Epidemiology of spinal cord lesions in Denmark.
Paraplegia 28, 105–118 (1990).
35. Ronen, J. et al. Survival after nontraumatic spinal cord
lesions in Israel. Arch. Phys. Med. Rehabil. 85,
1499–1502 (2004).
36. Catz, A. et al. Recovery of neurologic function
following nontraumatic spinal cord lesions in Israel.
Spine 29, 2278–2282; discussion 2283 (2004).
37. Citterio, A. et al. Nontraumatic spinal cord injury:
an Italian survey. Arch. Phys. Med. Rehabil. 85,
1483–1487 (2004).
38. Scivoletto, G., Farchi, S., Laurenza, L. & Molinari, M.
Traumatic and non-​traumatic spinal cord lesions: an
Italian comparison of neurological and functional
outcomes. Spinal Cord 49, 391–396 (2011).
39. Schonherr, M. C., Groothoff, J. W., Mulder, G. A.
& Eisma, W. H. Rehabilitation of patients with spinal
cord lesions in the Netherlands: an epidemiological
study. Spinal Cord 34, 679–683 (1996).
40. Buchan, A. C. et al. A preliminary survey of the
incidence and aetiology of spinal paralysis. Paraplegia
10, 23–28 (1972).
41. Noonan, V. K. et al. Incidence and prevalence of spinal
cord injury in Canada: a national perspective.
Neuroepidemiology 38, 219–226 (2012).
42. Wu, J. C. et al. Epidemiology of cervical spondylotic
myelopathy and its risk of causing spinal cord injury:
a national cohort study. Neurosurg. Focus. 35, E10
(2013).
43. Lad, S. P. et al. National trends in spinal fusion for
cervical spondylotic myelopathy. Surg. Neurol. 71,
66–69 (2009).
44. White, A. A. 3rd & Panjabi, M. M. Biomechanical
considerations in the surgical management of
cervical spondylotic myelopathy. Spine 13, 856–860
(1988).
45. Baptiste, D. C. & Fehlings, M. G. Pathophysiology
of cervical myelopathy. Spine J. 6, 190S–197S
(2006).
46. Humzah, M. D. & Soames, R. W. Human intervertebral
disc: structure and function. Anat. Rec. 220,
337–356 (1988).
47. Schultz, D. S., Rodriguez, A. G., Hansma, P. K.
& Lotz, J. C. Mechanical profiling of intervertebral
discs. J. Biomech. 42, 1154–1157 (2009).
48. Roberts, S., Evans, H., Trivedi, J. & Menage, J.
Histology and pathology of the human intervertebral
disc. J. Bone Joint Surg. Am. 88, 10–14 (2006).
49. Nixon, J. Intervertebral disc mechanics: a review.
J. R. Soc. Med. 79, 100–104 (1986).
50. Palepu, V., Kodigudla, M. & Goel, V. K. Biomechanics
of disc degeneration. Adv. Orthop. 2012, 726210
(2012).
51. Ferguson, S. J. & Steffen, T. Biomechanics of the aging
spine. Eur. Spine J. 12, S97–S103 (2003).
52. Stapleton, C. J., Pham, M. H., Attenello, F. J.
& Hsieh, P. C. Ossification of the posterior longitudinal
ligament: genetics and pathophysiology. Neurosurg.
Focus. 30, E6 (2011).
53. Shedid, D. & Benzel, E. C. Cervical spondylosis
anatomy: pathophysiology and biomechanics.
Neurosurgery 60, S7–S13 (2007).
54. Aarabi, B. et al. Predictors of outcome in acute
traumatic central cord syndrome due to spinal
stenosis. J. Neurosurg. Spine 14, 122–130 (2011).
55. Lenehan, B. et al. The urgency of surgical
decompression in acute central cord injuries with
spondylosis and without instability. Spine 35,
S180–S186 (2010).
56. Aarabi, B. et al. Management of acute traumatic
central cord syndrome (ATCCS). Neurosurgery 72,
195–204 (2013).
57. Schneider, R. C., Cherry, G. & Pantek, H. The
syndrome of acute central cervical spinal cord injury;
with special reference to the mechanisms involved in
hyperextension injuries of cervical spine. J. Neurosurg.
11, 546–577 (1954).
58. Pouw, M. H. et al. Diagnostic criteria of traumatic
central cord syndrome. Part 1: a systematic review of
clinical descriptors and scores. Spinal Cord 48,
652–656 (2010).
59. van Middendorp, J. J. et al. Diagnostic criteria of
traumatic central cord syndrome. Part 2: a
questionnaire survey among spine specialists.
Spinal Cord 48, 657–663 (2010).
60. Pouw, M. H. et al. Diagnostic criteria of traumatic
central cord syndrome. Part 3: descriptive analyses of
neurological and functional outcomes in a prospective
cohort of traumatic motor incomplete tetraplegics.
Spinal Cord 49, 614–622 (2011).
61. Karadimas, S. K., Gatzounis, G. & Fehlings, M. G.
Pathobiology of cervical spondylotic myelopathy.
Eur. Spine J. 24, 132–138 (2015).
62. Kalsi-​Ryan, S., Karadimas, S. K. & Fehlings, M. G.
Cervical spondylotic myelopathy: the clinical
phenomenon and the current pathobiology of an
increasingly prevalent and devastating disorder.
Neuroscientist 19, 409–421 (2013).
63. Klironomos, G. et al. New experimental rabbit animal
model for cervical spondylotic myelopathy. Spinal Cord
49, 1097–1102 (2011).
64. Akter, F. & Kotter, M. Pathobiology of degenerative
cervical myelopathy. Neurosurg. Clin. N. Am. 29,
13–19 (2018).
65. Brain, W. R., Knight, G. C. & Bull, J. W. Discussion
of rupture of the intervertebral disc in the cervical
region. Proc. R. Soc. Med. 41, 509–516 (1948).
66. Gooding, M. R., Wilson, C. B. & Hoff, J. T.
Experimental cervical myelopathy. Effects of ischemia
and compression of the canine cervical spinal cord.
J. Neurosurg. 43, 9–17 (1975).
67. Gooding, M. R., Wilson, C. B. & Hoff, J. T.
Experimental cervical myelopathy: autoradiographic
studies of spinal cord blood flow patterns.
Surg. Neurol. 5, 233–239 (1976).
68. Breig, A., Turnbull, I. & Hassler, O. Effects of
mechanical stresses on the spinal cord in cervical
spondylosis. A study on fresh cadaver material.
J. Neurosurg. 25, 45–56 (1966).
69. Taylor, A. R. Mechanism and treatment of spinal-​cord
disorders associated with cervical spondylosis.
Lancet 1, 717–720 (1953).
70. Mair, W. G. & Druckman, R. The pathology of spinal
cord lesions and their relation to the clinical features
in protrusion of cervical intervertebral discs; a report
of four cases. Brain 76, 70–91 (1953).
71. Strek, P., Reron, E., Maga, P., Modrzejewski, M. &
Szybist, N. A possible correlation between vertebral
artery insufficiency and degenerative changes in the
cervical spine. Eur. Arch. Otorhinolaryngol. 255,
437–440 (1998).
72. Murakami, N., Muroga, T. & Sobue, I. Cervical
myelopathy due to ossification of the posterior
longitudinal ligament: a clinicopathologic study.
Arch. Neurol. 35, 33–36 (1978).
73. Shingu, H. et al. Microangiographic study of spinal
cord injury and myelopathy. Paraplegia 27, 182–189
(1989).
74. Shimizu, K. et al. Spinal kyphosis causes demyelination
and neuronal loss in the spinal cord: a new model of
kyphotic deformity using juvenile Japanese small game
fowls. Spine 30, 2388–2392 (2005).
www.nature.com/nrneurol
Reviews
75. Whetstone, W. D., Hsu, J. Y., Eisenberg, M., Werb, Z. &
Noble-​Haeusslein, L. J. Blood-​spinal cord barrier after
spinal cord injury: relation to revascularization and
wound healing. J. Neurosci. Res. 74, 227–239 (2003).
76. Figley, S. A., Khosravi, R., Legasto, J. M., Tseng, Y. F. &
Fehlings, M. G. Characterization of vascular disruption
and blood-​spinal cord barrier permeability following
traumatic spinal cord injury. J. Neurotrauma 31,
541–552 (2014).
77. Beattie, M. S. & Manley, G. T. Tight squeeze, slow
burn: inflammation and the aetiology of cervical
myelopathy. Brain 134, 1259–1261 (2011).
78. Bohlman, H. H. & Emery, S. E. The pathophysiology
of cervical spondylosis and myelopathy. Spine 13,
843–846 (1988).
79. Noble, L. J. & Wrathall, J. R. Distribution and time
course of protein extravasation in the rat spinal cord
after contusive injury. Brain Res. 482, 57–66 (1989).
80. Loy, D. N. et al. Temporal progression of angiogenesis
and basal lamina deposition after contusive spinal
cord injury in the adult rat. J. Comp. Neurol. 445,
308–324 (2002).
81. Karadimas, S. K. et al. Immunohistochemical profile of
NF-​κB/p50, NF-​κB/p65, MMP-9, MMP-2, and u-​PA in
experimental cervical spondylotic myelopathy.
Spine 38, 4–10 (2013).
82. Karadimas, S. K. et al. A novel experimental model
of cervical spondylotic myelopathy (CSM) to facilitate
translational research. Neurobiol. Dis. 54, 43–58
(2013).
83. Flanagan, E. P. et al. Specific pattern of gadolinium
enhancement in spondylotic myelopathy. Ann. Neurol.
76, 54–65 (2014).
84. Ozawa, H. et al. Clinical significance of intramedullary
Gd-​DTPA enhancement in cervical myelopathy.
Spinal Cord 48, 415–422 (2010).
85. Lee, J. et al. Spinal cord edema: unusual magnetic
resonance imaging findings in cervical spondylosis.
J. Neurosurg. 99, 8–13 (2003).
86. Yu, W. R., Liu, T., Kiehl, T. R. & Fehlings, M. G.
Human neuropathological and animal model evidence
supporting a role for Fas-​mediated apoptosis and
inflammation in cervical spondylotic myelopathy.
Brain 134, 1277–1292 (2011).
87. Hirai, T. 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 8, e64528 (2013).
88. Hausmann, O. N. Post-​traumatic inflammation following
spinal cord injury. Spinal Cord 41, 369–378 (2003).
89. Popovich, P. G., Wei, P. & Stokes, B. T. Cellular
inflammatory response after spinal cord injury in
Sprague-​Dawley and Lewis rats. J. Comp. Neurol. 377,
443–464 (1997).
90. Popovich, P. G. et al. The neuropathological and
behavioral consequences of intraspinal microglial/
macrophage activation. J. Neuropathol. Exp. Neurol.
61, 623–633 (2002).
91. Harrison, J. K. et al. Role for neuronally derived
fractalkine in mediating interactions between neurons
and CX3CR1-expressing microglia. Proc. Natl Acad.
Sci. USA 95, 10896–10901 (1998).
92. Chapman, G. A. et al. Fractalkine cleavage from
neuronal membranes represents an acute event in the
inflammatory response to excitotoxic brain damage.
J. Neurosci. 20, RC87 (2000).
93. Yu, W. R., Karadimas, S. & Fehlings, M. G. The role of
CX3CR1 in promoting inflammation and neural
degeneration in cervical spondylotic myelopathy
[Abstract 722.01]. Presented at the Annual SfN
Meeting https://www.abstractsonline.com/Plan/
ViewAbstract.aspx?sKey=07bddef1-57b5-4f49-998b216024824dc6&cKey=a1fbe26d-6aa6-47e9-bc9c143c28c3e6ca&mKey=%7b70007181-01C9-4DE9A0A2-EEBFA14CD9F1%7d (2012).
94. Fumagalli, S., Perego, C., Ortolano, F.
& De Simoni, M. G. CX3CR1 deficiency induces an
early protective inflammatory environment in ischemic
mice. Glia 61, 827–842 (2013).
95. David, S. & Kroner, A. Repertoire of microglial and
macrophage responses after spinal cord injury.
Nat. Rev. Neurosci. 12, 388–399 (2011).
96. Mantovani, A., Sozzani, S., Locati, M., Allavena, P. &
Sica, A. Macrophage polarization: tumor-​associated
macrophages as a paradigm for polarized M2
mononuclear phagocytes. Trends Immunol. 23,
549–555 (2002).
97. Laskin, D. L. Macrophages and inflammatory
mediators in chemical toxicity: a battle of forces.
Chem. Res. Toxicol. 22, 1376–1385 (2009).
NaTure RevIewS | NeuROLOGy
98. Schwartz, M. “Tissue-​repairing” blood-​derived
macrophages are essential for healing of the injured
spinal cord: from skin-​activated macrophages to
infiltrating blood-​derived cells? Brain Behav. Immun.
24, 1054–1057 (2010).
99. Busch, S. A. et al. Multipotent adult progenitor cells
prevent macrophage-​mediated axonal dieback and
promote regrowth after spinal cord injury. J. Neurosci.
31, 944–953 (2011).
100. Yu, W. R. et al. Molecular mechanisms of spinal cord
dysfunction and cell death in the spinal hyperostotic
mouse: implications for the pathophysiology of human
cervical spondylotic myelopathy. Neurobiol. Dis. 33,
149–163 (2009).
101. Karadimas, S. K. et al. The role of oligodendrocytes in
the molecular pathobiology and potential molecular
treatment of cervical spondylotic myelopathy.
Curr. Med. Chem. 17, 1048–1058 (2010).
102. Inukai, T. et al. Tumor necrosis factor-​alpha and its
receptors contribute to apoptosis of oligodendrocytes
in the spinal cord of spinal hyperostotic mouse
(twy/twy) sustaining chronic mechanical compression.
Spine 34, 2848–2857 (2009).
103. Takenouchi, T., Setoguchi, T., Yone, K. & Komiya, S.
Expression of apoptosis signal-​regulating kinase 1
in mouse spinal cord under chronic mechanical
compression: possible involvement of the stress-​
activated mitogen-​activated protein kinase pathways
in spinal cord cell apoptosis. Spine 33, 1943–1950
(2008).
104. Letellier, E. et al. CD95-ligand on peripheral myeloid
cells activates Syk kinase to trigger their recruitment
to the inflammatory site. Immunity 32, 240–252
(2010).
105. Demjen, D. et al. Neutralization of CD95 ligand
promotes regeneration and functional recovery after
spinal cord injury. Nat. Med. 10, 389–395 (2004).
106. Casha, S., Yu, W. R. & Fehlings, M. G. FAS deficiency
reduces apoptosis, spares axons and improves
function after spinal cord injury. Exp. Neurol. 196,
390–400 (2005).
107. Ackery, A., Robins, S. & Fehlings, M. G. Inhibition of
Fas-​mediated apoptosis through administration of
soluble Fas receptor improves functional outcome and
reduces posttraumatic axonal degeneration after
acute spinal cord injury. J. Neurotrauma 23,
604–616 (2006).
108. Agrawal, S. K. & Fehlings, M. G. Mechanisms of
secondary injury to spinal cord axons in vitro: role of
Na+, Na(+)-K(+)-ATPase, the Na(+)-H+ exchanger, and
the Na(+)-Ca2+ exchanger. J. Neurosci. 16, 545–552
(1996).
109. Haigney, M. C., Miyata, H., Lakatta, E. G., Stern, M. D.
& Silverman, H. S. Dependence of hypoxic cellular
calcium loading on Na(+)-Ca2+ exchange. Circ. Res.
71, 547–557 (1992).
110. Haigney, M. C., Lakatta, E. G., Stern, M. D. &
Silverman, H. S. Sodium channel blockade reduces
hypoxic sodium loading and sodium-​dependent
calcium loading. Circulation 90, 391–399 (1994).
111. Regan, R. F. & Choi, D. W. Glutamate neurotoxicity in
spinal cord cell culture. Neuroscience 43, 585–591
(1991).
112. Schwartz, G. & Fehlings, M. G. Secondary injury
mechanisms of spinal cord trauma: a novel therapeutic
approach for the management of secondary
pathophysiology with the sodium channel blocker
riluzole. Prog. Brain Res. 137, 177–190 (2002).
113. Choi, D. W. Excitotoxic cell death. J. Neurobiol. 23,
1261–1276 (1992).
114. Wadman, R. I. et al. Drug treatment for spinal
muscular atrophy type I. Cochrane Database Syst. Rev
4, CD006281 (2011).
115. Mestre, T., Ferreira, J., Coelho, M. M., Rosa, M.
& Sampaio, C. Therapeutic interventions for
symptomatic treatment in Huntington’s disease.
Cochrane Database Syst. Rev 3, CD006456 (2009).
116. Lacomblez, L., Bensimon, G., Leigh, P. N., Guillet, P.
& Meininger, V. Dose-​ranging study of riluzole in
amyotrophic lateral sclerosis. Amyotrophic Lateral
Sclerosis/Riluzole Study Group II. Lancet 347,
1425–1431 (1996).
117. Beal, M. F. Does impairment of energy metabolism
result in excitotoxic neuronal death in
neurodegenerative illnesses? Ann. Neurol. 31,
119–130 (1992).
118. Swagerty, D. L. Jr. Cervical spondylotic myelopathy:
a cause of gait disturbance and falls in the elderly.
Kans. Med. 95, 226–227, 229 (1994).
119. Fehlings, M. G. & Skaf, G. A review of the
pathophysiology of cervical spondylotic myelopathy
with insights for potential novel mechanisms drawn
from traumatic spinal cord injury. Spine 23,
2730–2737 (1998).
120. Ito, T., Oyanagi, K., Takahashi, H., Takahashi, H. E.
& Ikuta, F. Cervical spondylotic myelopathy.
Clinicopathologic study on the progression pattern
and thin myelinated fibers of the lesions of seven
patients examined during complete autopsy. Spine 21,
827–833 (1996).
121. Payne, E. E. & Spillane, J. D. The cervical spine; an
anatomico-​pathological study of 70 specimens (using
a special technique) with particular reference to the
problem of cervical spondylosis. Brain 80, 571–596
(1957).
122. Wilson, J. R. et al. Genetics and heritability of cervical
spondylotic myelopathy and ossification of the
posterior longitudinal ligament: results of a systematic
review. Spine 38, S123–S146 (2013).
123. Patel, A. A., Spiker, W. R., Daubs, M., Brodke, D. S.
& Cannon-​Albright, L. A. Evidence of an inherited
predisposition for cervical spondylotic myelopathy.
Spine 37, 26–29 (2012).
124. Tanikawa, E., Furuya, K. & Nakajima, H. Genetic study
on ossification of posterior longitudinal ligament.
Bull. Tokyo Med. Dent. Univ. 33, 117–128 (1986).
125. Terayama, K. Genetic studies on ossification of the
posterior longitudinal ligament of the spine. Spine 14,
1184–1191 (1989).
126. Kamiya, M., Harada, A., Mizuno, M., Iwata, H. &
Yamada, Y. Association between a polymorphism of
the transforming growth factor-​β1 gene and genetic
susceptibility to ossification of the posterior
longitudinal ligament in Japanese patients. Spine 26,
1264–1266 (2001).
127. Koshizuka, Y. et al. Nucleotide pyrophosphatase gene
polymorphism associated with ossification of the
posterior longitudinal ligament of the spine. J. Bone
Miner. Res. 17, 138–144 (2002).
128. Nakamura, I. et al. Association of the human NPPS
gene with ossification of the posterior longitudinal
ligament of the spine (OPLL). Hum. Genet. 104,
492–497 (1999).
129. Wang, H. et al. Association of bone morphogenetic
protein-2 gene polymorphisms with susceptibility
to ossification of the posterior longitudinal ligament
of the spine and its severity in Chinese patients.
Eur. Spine J. 17, 956–964 (2008).
130. Ren, Y. et al. A new haplotype in BMP4 implicated in
ossification of the posterior longitudinal ligament
(OPLL) in a Chinese population. J. Orthop. Res. 30,
748–756 (2012).
131. Wang, D. et al. BMP-4 polymorphisms in the
susceptibility of cervical spondylotic myelopathy and
its outcome after anterior cervical corpectomy
and fusion. Cell Physiol. Biochem. 32, 210–217
(2013).
132. Ren, Y. et al. Association of a BMP9 haplotype with
ossification of the posterior longitudinal ligament
(OPLL) in a Chinese population. PLoS One 7, e40587
(2012).
133. Wang, H., Jin, W. & Li, H. Genetic polymorphisms in
bone morphogenetic protein receptor type IA gene
predisposes individuals to ossification of the posterior
longitudinal ligament of the cervical spine via the
smad signaling pathway. BMC Musculoskelet. Disord.
19, 61 (2018).
134. Numasawa, T. et al. Human retinoic X receptor beta:
complete genomic sequence and mutation search for
ossification of posterior longitudinal ligament of the
spine. J. Bone Miner. Res. 14, 500–508 (1999).
135. Kim, D. H. et al. Association between interleukin 15
receptor, alpha (IL15RA) polymorphism and Korean
patients with ossification of the posterior longitudinal
ligament. Cytokine 55, 343–346 (2011).
136. Guo, Q., Lv, S. Z., Wu, S. W., Tian, X. & Li, Z. Y.
Association between single nucleotide polymorphism
of IL15RA gene with susceptibility to ossification of
the posterior longitudinal ligament of the spine.
J. Orthop. Surg. Res. 9, 103 (2014).
137. Chang, F. et al. Role of Runx2 polymorphisms in risk
and prognosis of ossification of posterior longitudinal
ligament. J. Clin. Lab. Anal. 31, e22068 (2017).
138. Nakajima, M., Kou, I. & Ohashi, H., Genetic Study
Group of the Investigation Committee on the
Ossification of Spinal Ligaments & Ikegawa, S.
Identification and functional characterization of
RSPO2 as a susceptibility gene for ossification of the
posterior longitudinal ligament of the spine. Am. J.
Hum. Genet. 99, 202–207 (2016).
139. Kong, Q. et al. COL6A1 polymorphisms associated
with ossification of the ligamentum flavum and
ossification of the posterior longitudinal ligament.
Spine 32, 2834–2838 (2007).
volume 16 | February 2020 | 121
Reviews
140. Tanaka, T. et al. Genomewide linkage and linkage
disequilibrium analyses identify COL6A1, on
chromosome 21, as the locus for ossification of the
posterior longitudinal ligament of the spine. Am. J.
Hum. Genet. 73, 812–822 (2003).
141. Koga, H. et al. Genetic mapping of ossification of the
posterior longitudinal ligament of the spine. Am. J.
Hum. Genet. 62, 1460–1467 (1998).
142. Maeda, S. et al. Functional impact of human collagen
α2(XI) gene polymorphism in pathogenesis of
ossification of the posterior longitudinal ligament of
the spine. J. Bone Miner. Res. 16, 948–957 (2001).
143. Wang, Z. C. et al. The genetic association of vitamin D
receptor polymorphisms and cervical spondylotic
myelopathy in Chinese subjects. Clin. Chim. Acta 411,
794–797 (2010).
144. Wang, Z. C. et al. The role of smoking status and
collagen IX polymorphisms in the susceptibility to
cervical spondylotic myelopathy. Genet. Mol. Res. 11,
1238–1244 (2012).
145. Setzer, M., Hermann, E., Seifert, V. & Marquardt, G.
Apolipoprotein E gene polymorphism and the risk of
cervical myelopathy in patients with chronic spinal
cord compression. Spine 33, 497–502 (2008).
146. Setzer, M., Vrionis, F. D., Hermann, E. J., Seifert, V. &
Marquardt, G. Effect of apolipoprotein E genotype on
the outcome after anterior cervical decompression
and fusion in patients with cervical spondylotic
myelopathy. J. Neurosurg. Spine 11, 659–666
(2009).
147. Wu, J., Wu, D., Guo, K., Yuan, F. & Ran, B. OPN
polymorphism is associated with the susceptibility to
cervical spondylotic myelopathy and its outcome after
anterior cervical corpectomy and fusion. Cell Physiol.
Biochem. 34, 565–574 (2014).
148. Maysinger, D. et al. Ceramide is responsible for the
failure of compensatory nerve sprouting in
apolipoprotein E knock-​out mice. J. Neurosci. 28,
7891–7899 (2008).
149. Shea, T. B., Rogers, E., Ashline, D., Ortiz, D.
& Sheu, M. S. Apolipoprotein E deficiency promotes
increased oxidative stress and compensatory
increases in antioxidants in brain tissue. Free. Radic.
Biol. Med. 33, 1115–1120 (2002).
150. Verghese, P. B., Castellano, J. M. & Holtzman, D. M.
Apolipoprotein E in Alzheimer’s disease and other
neurological disorders. Lancet Neurol. 10, 241–252
(2011).
151. Alexander, S. et al. Apolipoprotein E4 allele presence
and functional outcome after severe traumatic brain
injury. J. Neurotrauma 24, 790–797 (2007).
152. Houlden, H. & Greenwood, R. Apolipoprotein E4 and
traumatic brain injury. J. Neurol. Neurosurg.
Psychiatry 77, 1106–1107 (2006).
153. Harrop, J. S. et al. Cervical myelopathy: a clinical and
radiographic evaluation and correlation to cervical
spondylotic myelopathy. Spine 35, 620–624 (2010).
154. Tracy, J. A. & Bartleson, J. D. Cervical spondylotic
myelopathy. Neurologist 16, 176–187 (2010).
155. Tetreault, L. et al. Degenerative cervical myelopathy:
a spectrum of related disorders affecting the aging
spine. Neurosurgery 77, S51–S67 (2015).
156. Davies, B. M., Mowforth, O. D., Smith, E. K.
& Kotter, M. R. Degenerative cervical myelopathy.
Br. Med. J. 360, k186 (2018).
157. Benzel, E. C., Lancon, J., Kesterson, L. & Hadden, T.
Cervical laminectomy and dentate ligament section for
cervical spondylotic myelopathy. J. Spinal Disord. 4,
286–295 (1991).
158. Nurick, S. The natural history and the results of
surgical treatment of the spinal cord disorder
associated with cervical spondylosis. Brain 95,
101–108 (1972).
159. Furlan, J. C. & Catharine Craven, B. Psychometric
analysis and critical appraisal of the original, revised,
and modified versions of the Japanese Orthopaedic
Association score in the assessment of patients with
cervical spondylotic myelopathy. Neurosurg. Focus.
40, E6 (2016).
160. Yonenobu, K., Abumi, K., Nagata, K., Taketomi, E. &
Ueyama, K. Interobserver and intraobserver reliability
of the Japanese Orthopaedic Association scoring
system for evaluation of cervical compression
myelopathy. Spine 26, 1890–1894 (2001).
161. Revanappa, K. K., Moorthy, R. K., Jeyaseelan, V. &
Rajshekhar, V. Modification of Nurick scale and
Japanese Orthopedic Association score for Indian
population with cervical spondylotic myelopathy.
Neurol. India 63, 24–29 (2015).
162. Kalsi-​Ryan, S. et al. Ancillary outcome measures for
assessment of individuals with cervical spondylotic
myelopathy. Spine 38, S111–S122 (2013).
122 | February 2020 | volume 16
163. Davies, B. M. et al. Reported outcome measures in
degenerative cervical myelopathy: a systematic review.
PLoS One 11, e0157263 (2016).
164. Davies, B. M. et al. RE-​CODE DCM (REsearch
Objectives and Common Data Elements for
Degenerative Cervical Myelopathy): a consensus
process to improve research efficiency in DCM,
through establishment of a standardized dataset for
clinical research and the definition of the research
priorities. Glob. Spine J. 9, 65S–76S (2019).
165. Kopjar, B., Tetreault, L., Kalsi-​Ryan, S. & Fehlings, M.
Psychometric properties of the modified Japanese
Orthopaedic Association scale in patients with cervical
spondylotic myelopathy. Spine 40, E23–E28 (2015).
166. Zhou, F. et al. Assessment of the minimum clinically
important difference in neurological function and
quality of life after surgery in cervical spondylotic
myelopathy patients: a prospective cohort study.
Eur. Spine J. 24, 2918–2923 (2015).
167. Singh, A. & Crockard, H. A. Comparison of seven
different scales used to quantify severity of cervical
spondylotic myelopathy and post-​operative
improvement. J. Outcome Meas. 5, 798–818 (2001).
168. Badhiwala, J. H. et al. Efficacy and safety of surgery
for mild degenerative cervical myelopathy: results of
the AOSpine North America and international
prospective multicenter studies. Neurosurgery 84,
890–897 (2019).
169. Bilney, B., Morris, M. & Webster, K. Concurrent
related validity of the GAITRite walkway system for
quantification of the spatial and temporal parameters
of gait. Gait Posture 17, 68–74 (2003).
170. Kalsi-​Ryan, S. et al. The Graded Redefined Assessment
of Strength Sensibility and Prehension: reliability and
validity. J. Neurotrauma 29, 905–914 (2012).
171. Mowforth, O. D., Davies, B. M. & Kotter, M. R.
The use of smart technology in an online community
of patients with degenerative cervical myelopathy.
JMIR Form. Res. 3, e11364 (2019).
172. Zhan, A. et al. Using smartphones and machine
learning to quantify Parkinson disease severity: the
mobile Parkinson disease score. JAMA Neurol. 75,
876–880 (2018).
173. Nouri, A., Martin, A. R., Mikulis, D. & Fehlings, M. G.
Magnetic resonance imaging assessment of
degenerative cervical myelopathy: a review of
structural changes and measurement techniques.
Neurosurg. Focus. 40, E5 (2016).
174. Nagata, K. et al. Clinical value of magnetic resonance
imaging for cervical myelopathy. Spine 15,
1088–1096 (1990).
175. Sun, Q. et al. Do intramedullary spinal cord changes in
signal intensity on MRI affect surgical opportunity and
approach for cervical myelopathy due to ossification of
the posterior longitudinal ligament? Eur. Spine J. 20,
1466–1473 (2011).
176. Yukawa, Y., Kato, F., Yoshihara, H., Yanase, M. & Ito, K.
MR T2 image classification in cervical compression
myelopathy: predictor of surgical outcomes. Spine 32,
1675–1678 (2007).
177. Yagi, M., Ninomiya, K., Kihara, M. & Horiuchi, Y.
Long-​term surgical outcome and risk factors in
patients with cervical myelopathy and a change in
signal intensity of intramedullary spinal cord on
magnetic resonance imaging. J. Neurosurg. Spine 12,
59–65 (2010).
178. Mastronardi, L. et al. Prognostic relevance of the
postoperative evolution of intramedullary spinal cord
changes in signal intensity on magnetic resonance
imaging after anterior decompression for cervical
spondylotic myelopathy. J. Neurosurg. Spine 7,
615–622 (2007).
179. Fernandez de Rota, J. J., Meschian, S., Fernandez de
Rota, A., Urbano, V. & Baron, M. Cervical spondylotic
myelopathy due to chronic compression: the role of
signal intensity changes in magnetic resonance
images. J. Neurosurg. Spine 6, 17–22 (2007).
180. Papadopoulos, C. A., Katonis, P., Papagelopoulos, P. J.,
Karampekios, S. & Hadjipavlou, A. G. Surgical
decompression for cervical spondylotic myelopathy:
correlation between operative outcomes and MRI of
the spinal cord. Orthopedics 27, 1087–1091 (2004).
181. Uchida, K. et al. Prognostic value of changes in spinal
cord signal intensity on magnetic resonance imaging
in patients with cervical compressive myelopathy.
Spine J. 14, 1601–1610 (2014).
182. Houser, O. W., Onofrio, B. M., Miller, G. M., Folger, W. N.
& Smith, P. L. Cervical spondylotic stenosis and
myelopathy: evaluation with computed tomographic
myelography. Mayo Clin. Proc. 69, 557–563 (1994).
183. Grabher, P., Mohammadi, S., David, G. & Freund, P.
Neurodegeneration in the spinal ventral horn prior to
motor impairment in cervical spondylotic myelopathy.
J. Neurotrauma 34, 2329–2334 (2017).
184. Grabher, P. et al. Voxel-​based analysis of grey and
white matter degeneration in cervical spondylotic
myelopathy. Sci. Rep. 6, 24636 (2016).
185. Wolf, K. et al. In cervical spondylotic myelopathy spinal
cord motion is focally increased at the level of stenosis:
a controlled cross-​sectional study. Spinal Cord 56,
769–776 (2018).
186. Vavasour, I. M. et al. Increased spinal cord movements
in cervical spondylotic myelopathy. Spine J. 14,
2344–2354 (2014).
187. Chang, H. S., Nejo, T., Yoshida, S., Oya, S. & Matsui, T.
Increased flow signal in compressed segments of the
spinal cord in patients with cervical spondylotic
myelopathy. Spine 39, 2136–2142 (2014).
188. Tsiptsios, I., Fotiou, F., Sitzoglou, K. & Fountoulakis, K. N.
Neurophysiological investigation of cervical
spondylosis. Electromyogr. Clin. Neurophysiol. 41,
305–313 (2001).
189. Liu, H. et al. Assessing structure and function of
myelin in cervical spondylotic myelopathy: evidence
of demyelination. Neurology 89, 602–610 (2017).
190. Dvorak, J., Sutter, M. & Herdmann, J. Cervical
myelopathy: clinical and neurophysiological
evaluation. Eur. Spine J. 12, S181–S187 (2003).
191. Kimura, J. Electrodiagnosis in Diseases of Nerve and
Muscle: Principles and Practice (Oxford Univ. Press,
2001).
192. Kim, H. J. et al. Differential diagnosis for cervical
spondylotic myelopathy: literature review. Spine 38,
S78–S88 (2013).
193. Curt, A. & Dietz, V. Neurographic assessment of
intramedullary motoneurone lesions in cervical spinal
cord injury: consequences for hand function. Spinal
Cord 34, 326–332 (1996).
194. Petersen, J. A. et al. Upper limb recovery in spinal
cord injury: involvement of central and peripheral
motor pathways. Neurorehabil. Neural Repair 31,
432–441 (2017).
195. Bischoff, C., Meyer, B. U., Machetanz, J. & Conrad, B.
The value of magnetic stimulation in the diagnosis of
radiculopathies. Muscle Nerve 16, 154–161 (1993).
196. Bednarik, J. et al. The value of somatosensory and
motor evoked evoked potentials in pre-​clinical
spondylotic cervical cord compression. Eur. Spine J. 7,
493–500 (1998).
197. Bednarik, J. et al. Presymptomatic spondylotic cervical
myelopathy: an updated predictive model. Eur. Spine J.
17, 421–431 (2008).
198. Bednarik, J. et al. Are subjects with spondylotic
cervical cord encroachment at increased risk of cervical
spinal cord injury after minor trauma? J. Neurol.
Neurosurg. Psychiatry 82, 779–781 (2011).
199. Wilson, J. R. 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 38, S37–S54 (2013).
200. Hadley, M. N., Shank, C. D., Rozzelle, C. J.
& Walters, B. C. Guidelines for the use of
electrophysiological monitoring for surgery of the
human spinal column and spinal cord. Neurosurgery
81, 713–732 (2017).
201. Clark, A. J. et al. Intraoperative neuromonitoring with
MEPs and prediction of postoperative neurological
deficits in patients undergoing surgery for cervical and
cervicothoracic myelopathy. Neurosurg. Focus. 35, E7
(2013).
202. Takeda, M., Yamaguchi, S., Mitsuhara, T., Abiko, M. &
Kurisu, K. Intraoperative neurophysiologic monitoring
for degenerative cervical myelopathy. Neurosurg. Clin.
N. Am. 29, 159–167 (2018).
203. Devlin, V. J., Anderson, P. A., Schwartz, D. M. &
Vaughan, R. Intraoperative neurophysiologic
monitoring: focus on cervical myelopathy and related
issues. Spine J. 6, 212S–224S (2006).
204. Kramer, J. L. et al. Test-​retest reliability of contact
heat-​evoked potentials from cervical dermatomes.
J. Clin. Neurophysiol. 29, 70–75 (2012).
205. Haefeli, J. S., Blum, J., Steeves, J. D., Kramer, J. L.
& Curt, A. E. Differences in spinothalamic function of
cervical and thoracic dermatomes: insights using
contact heat evoked potentials. J. Clin. Neurophysiol.
30, 291–298 (2013).
206. Kramer, J. L., Haefeli, J., Jutzeler, C. R., Steeves, J. D.
& Curt, A. Improving the acquisition of nociceptive
evoked potentials without causing more pain.
Pain 154, 235–241 (2013).
207. Jutzeler, C. R. et al. Improved diagnosis of cervical
spondylotic myelopathy with contact heat evoked
potentials. J. Neurotrauma 34, 2045–2053 (2017).
www.nature.com/nrneurol
Reviews
208. Jutzeler, C. R., Rosner, J., Rinert, J., Kramer, J. L. &
Curt, A. Normative data for the segmental acquisition
of contact heat evoked potentials in cervical
dermatomes. Sci. Rep. 6, 34660 (2016).
209. Rowland, L. P. Diagnosis of amyotrophic lateral
sclerosis. J. Neurol. Sci. 160, S6–S24 (1998).
210. Kiernan, M. C. et al. Amyotrophic lateral sclerosis.
Lancet 377, 942–955 (2011).
211. Chow, C. S. et al. Is symptomatology useful in
distinguishing between carpal tunnel syndrome and
cervical spondylosis? Hand Surg. 10, 1–5 (2005).
212. Baron, E. M. & Young, W. F. Cervical spondylotic
myelopathy: a brief review of its pathophysiology,
clinical course, and diagnosis. Neurosurgery 60,
S35–S41 (2007).
213. Young, W. F. Cervical spondylotic myelopathy:
a common cause of spinal cord dysfunction in older
persons. Am. Fam. Physician 62, 1064–1070, 1073
(2000).
214. Clarke, E. & Robinson, P. K. Cervical myelopathy:
a complication of cervical spondylosis. Brain 79,
483–510 (1956).
215. Oshima, Y. et al. Natural course and prognostic factors
in patients with mild cervical spondylotic myelopathy
with increased signal intensity on T2-weighted
magnetic resonance imaging. Spine 37, 1909–1913
(2012).
216. Shimomura, T. et al. Prognostic factors for
deterioration of patients with cervical spondylotic
myelopathy after nonsurgical treatment. Spine 32,
2474–2479 (2007).
217. Sumi, M. et al. Prospective cohort study of mild
cervical spondylotic myelopathy without surgical
treatment. J. Neurosurg. Spine 16, 8–14 (2012).
218. Yoshimatsu, H. et al. Conservative treatment for
cervical spondylotic myelopathy. prediction of
treatment effects by multivariate analysis. Spine J. 1,
269–273 (2001).
219. Matsumoto, M. et al. Relationships between outcomes
of conservative treatment and magnetic resonance
imaging findings in patients with mild cervical
myelopathy caused by soft disc herniations. Spine 26,
1592–1598 (2001).
220. Sampath, P., Bendebba, M., Davis, J. D. & Ducker, T. B.
Outcome of patients treated for cervical myelopathy.
A prospective, multicenter study with independent
clinical review. Spine 25, 670–676 (2000).
221. Matsumoto, M. et al. Increased signal intensity of the
spinal cord on magnetic resonance images in cervical
compressive myelopathy. Does it predict the outcome
of conservative treatment? Spine 25, 677–682
(2000).
222. Kadanka, Z. et al. Conservative treatment versus
surgery in spondylotic cervical myelopathy: a
prospective randomised study. Eur. Spine J. 9,
538–544 (2000).
223. Kadanka, Z. et al. Approaches to spondylotic cervical
myelopathy: conservative versus surgical results in a
3-year follow-​up study. Spine 27, 2205–2210 (2002).
224. Kadanka, Z. et al. Predictive factors for mild forms of
spondylotic cervical myelopathy treated conservatively
or surgically. Eur. J. Neurol. 12, 16–24 (2005).
225. Kadanka, Z., Bednarik, J., Novotny, O., Urbanek, I.
& Dusek, L. Cervical spondylotic myelopathy:
conservative versus surgical treatment after 10 years.
Eur. Spine J. 20, 1533–1538 (2011).
226. Bednarik, J. et al. The value of somatosensory- and
motor-​evoked potentials in predicting and monitoring
the effect of therapy in spondylotic cervical
myelopathy. Prospective randomized study. Spine 24,
1593–1598 (1999).
227. Nakamura, K. et al. Conservative treatment for
cervical spondylotic myelopathy: achievement and
sustainability of a level of “no disability”. J. Spinal
Disord. 11, 175–179 (1998).
228. Badhiwala, J. H. & Wilson, J. R. The natural history
of degenerative cervical myelopathy. Neurosurg. Clin.
N. Am. 29, 21–32 (2018).
229. Chen, L. F. et al. Risk of spinal cord injury in patients
with cervical spondylotic myelopathy and ossification
of posterior longitudinal ligament: a national cohort
study. Neurosurg. Focus 40, E4 (2016).
230. Wu, J. C. et al. Conservatively treated ossification of
the posterior longitudinal ligament increases the risk
of spinal cord injury: a nationwide cohort study.
J. Neurotrauma 29, 462–468 (2012).
231. Singh, A., Tetreault, L., Kalsi-​Ryan, S., Nouri, A. &
Fehlings, M. G. Global prevalence and incidence of
traumatic spinal cord injury. Clin. Epidemiol. 6,
309–331 (2014).
232. Ghogawala, Z., Benzel, E. C., Riew, K. D., Bisson, E. F.
& Heary, R. F. Surgery vs conservative care for cervical
NaTure RevIewS | NeuROLOGy
spondylotic myelopathy: surgery is appropriate for
progressive myelopathy. Neurosurgery 62, 56–61
(2015).
233. Guyatt, G. H. et al. GRADE: an emerging consensus
on rating quality of evidence and strength of
recommendations. Br. Med. J. 336, 924–926 (2008).
234. Guyatt, G. H. et al. What is “quality of evidence” and
why is it important to clinicians? Br. Med. J. 336,
995–998 (2008).
235. Guyatt, G. H. et al. Going from evidence to
recommendations. Br. Med. J. 336, 1049–1051
(2008).
236. Borden, J. N. Good Samaritan cervical traction.
Clin. Orthop. Relat. Res. 113, 162–163 (1975).
237. Campbell, A. M. & Phillips, D. G. Cervical disk lesions
with neurological disorder. Differential diagnosis,
treatment, and prognosis. Br. Med. J. 2, 481–485
(1960).
238. Lees, F. & Turner, J. W. Natural history and prognosis
of cervical spondylosis. Br. Med. J. 2, 1607–1610
(1963).
239. LaRocca, H. Cervical spondylotic myelopathy: natural
history. Spine 13, 854–855 (1988).
240. Almeida, G. P., Carneiro, K. K. & Marques, A. P. Manual
therapy and therapeutic exercise in patient with
symptomatic cervical spondylotic myelopathy: a case
report. J. Bodyw. Mov. Ther. 17, 504–509 (2013).
241. Rhee, J. M. et al. Nonoperative management of
cervical myelopathy: a systematic review. Spine 38,
S55–S67 (2013).
242. Tetreault, L. A. et al. The natural history of
degenerative cervical myelopathy and the rate of
hospitalization following spinal cord injury: an updated
systematic review. Glob. Spine J. 7, 28S–34S (2017).
243. Tetreault, L., Nouri, A., Kopjar, B., Cote, P.
& Fehlings, M. G. The minimum clinically important
difference of the modified Japanese Orthopaedic
Association scale in patients with degenerative
cervical myelopathy. Spine (Phila. Pa. 1976) 40,
1653–1659 (2015).
244. Maigne, J. Y. & Deligne, L. Computed tomographic
follow-​up study of 21 cases of nonoperatively treated
cervical intervertebral soft disc herniation. Spine 19,
189–191 (1994).
245. Mochida, K. et al. Regression of cervical disc
herniation observed on magnetic resonance images.
Spine 23, 990–997 (1998).
246. Fukui, K., Kataoka, O., Sho, T. & Sumi, M.
Pathomechanism, pathogenesis, and results of
treatment in cervical spondylotic myelopathy caused
by dynamic canal stenosis. Spine 15, 1148–1152
(1990).
247. Kong, L. D. et al. Evaluation of conservative treatment
and timing of surgical intervention for mild forms of
cervical spondylotic myelopathy. Exp. Ther. Med. 6,
852–856 (2013).
248. Badhiwala, J. H. et al. Predicting outcomes after
surgical decompression for mild degenerative cervical
myelopathy: moving beyond the mJOA to identify
surgical candidates. Neurosurgery https://doi.org/
10.1093/neuros/nyz160 (2019).
249. Shamji, M. F. et al. Comparison of anterior surgical
options for the treatment of multilevel cervical
spondylotic myelopathy: a systematic review. Spine
38, S195–S209 (2013).
250. Ghogawala, Z. Anterior cervical option to manage
degenerative cervical myelopathy. Neurosurg. Clin.
N. Am. 29, 83–89 (2018).
251. Yoon, S. T. et al. Outcomes after laminoplasty
compared with laminectomy and fusion in patients
with cervical myelopathy: a systematic review. Spine
38, S183–S194 (2013).
252. Manzano, G. R., Casella, G., Wang, M. Y., Vanni, S. &
Levi, A. D. A prospective, randomized trial comparing
expansile cervical laminoplasty and cervical
laminectomy and fusion for multilevel cervical
myelopathy. Neurosurgery 70, 264–277 (2012).
253. Lee, C. H. et al. Laminoplasty versus laminectomy and
fusion for multilevel cervical myelopathy: a meta-​
analysis of clinical and radiological outcomes.
J. Neurosurg. Spine 22, 589–595 (2015).
254. Fehlings, M. G. et al. Laminectomy and fusion versus
laminoplasty for the treatment of degenerative
cervical myelopathy: results from the AOSpine North
America and international prospective multicenter
studies. Spine J. 17, 102–108 (2017).
255. Wilson, J. R. et al. State of the art in degenerative
cervical myelopathy: an update on current clinical
evidence. Neurosurgery 80, S33–S45 (2017).
256. US National Library of Medicine. ClinicalTrials.Gov
https://clinicaltrials.gov/ct2/show/NCT02076113
(2019).
257. Witiw, C. D. et al. Surgery for degenerative cervical
myelopathy: a patient-​centered quality of life and
health economic evaluation. Spine J. 17, 15–25
(2017).
258. Chen, G. D. et al. Effect and prognostic factors of
laminoplasty for cervical myelopathy with an
occupying ratio greater than 50%. Spine 41,
378–383 (2016).
259. Furlan, J. C., Kalsi-​Ryan, S., Kailaya-​Vasan, A.,
Massicotte, E. M. & Fehlings, M. G. Functional and
clinical outcomes following surgical treatment in
patients with cervical spondylotic myelopathy:
a prospective study of 81 cases. J. Neurosurg. Spine
14, 348–355 (2011).
260. Hoffman, H. et al. Use of multivariate linear regression
and support vector regression to predict functional
outcome after surgery for cervical spondylotic
myelopathy. J. Clin. Neurosci. 22, 1444–1449
(2015).
261. Karpova, A. et al. Predictors of surgical outcome in
cervical spondylotic myelopathy. Spine 38, 392–400
(2013).
262. Machino, M. et al. Risk factors for poor outcome of
cervical laminoplasty for cervical spondylotic
myelopathy in patients with diabetes. J. Bone Joint
Surg. Am. 96, 2049–2055 (2014).
263. Nakashima, H. et al. Prediction of lower limb
functional recovery after laminoplasty for cervical
myelopathy: focusing on the 10-s step test. Eur. Spine
J. 21, 1389–1395 (2012).
264. Tetreault, L., Kopjar, B., Cote, P., Arnold, P.
& Fehlings, M. G. A clinical prediction rule for
functional outcomes in patients undergoing surgery
for degenerative cervical myelopathy: analysis of an
international prospective multicenter data set of 757
subjects. J. Bone Joint Surg. Am. 97, 2038–2046
(2015).
265. Tetreault, L. A. et al. A clinical prediction model to
assess surgical outcome in patients with cervical
spondylotic myelopathy: internal and external
validations using the prospective multicenter AOSpine
North American and international datasets of 743
patients. Spine J. 15, 388–397 (2015).
266. Tetreault, L. A., Karpova, A. & Fehlings, M. G.
Predictors of outcome in patients with degenerative
cervical spondylotic myelopathy undergoing surgical
treatment: results of a systematic review. Eur. Spine J.
24, 236–251 (2015).
267. Tetreault, L. et al. Significant predictors of outcome
following surgery for the treatment of degenerative
cervical myelopathy: a systematic review of the
literature. Neurosurg. Clin. N. Am. 29, 115–127
(2018).
268. Karadimas, S. K. et al. Riluzole blocks perioperative
ischemia-​reperfusion injury and enhances
postdecompression outcomes in cervical spondylotic
myelopathy. Sci. Transl Med. 7, 316ra194 (2015).
269. Hilton, B., Tempest-​Mitchell, J., Davies, B. & Kotter, M.
Route to diagnosis of degenerative cervical
myelopathy in a UK healthcare system: a retrospective
cohort study. BMJ Open. 9, e027000 (2019).
270. Hilton, B., Tempest-​Mitchell, J., Davies, B. & Kotter, M.
Assessment of degenerative cervical myelopathy
differs between specialists and may influence time to
diagnosis and clinical outcomes. PLoS One 13,
e0207709 (2018).
271. Vidal, P. M. et al. Delayed decompression exacerbates
ischemia-​reperfusion injury in cervical compressive
myelopathy. JCI Insight 2, e92512 (2017).
272. Kusin, D. J., Li, S. Q., Ahn, U. M. & Ahn, N. U.
Does tobacco use attenuate benefits of early
decompression in patients with cervical myelopathy?
Spine 41, 1565–1569 (2016).
273. Tetreault, L. et al. Predicting the minimum clinically
important difference in patients undergoing surgery
for the treatment of degenerative cervical myelopathy.
Neurosurg. Focus 40, E14 (2016).
274. Tetreault, L. 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.
95, 1659–1666 (2013).
275. Oichi, T., Oshima, Y., Takeshita, K., Chikuda, H. &
Tanaka, S. Evaluation of comorbidity indices for a
study of patient outcomes following cervical
decompression surgery: a retrospective cohort study.
Spine 40, 1941–1947 (2015).
276. Badhiwala, J. H. et al. Patient phenotypes associated
with outcome following surgery for mild degenerative
cervical myelopathy: a principal component regression
analysis. Spine J. 18, 2220–2231 (2018).
volume 16 | February 2020 | 123
Reviews
277. Kusin, D. J., Ahn, U. M. & Ahn, N. U. The influence of
diabetes on surgical outcomes in cervical myelopathy.
Spine 41, 1436–1440 (2016).
278. Kim, H. J. et al. Diabetes and smoking as prognostic
factors after cervical laminoplasty. J. Bone Joint Surg.
Br. 90, 1468–1472 (2008).
279. Zong, Y. et al. Depression contributed an
unsatisfactory surgery outcome among the posterior
decompression of the cervical spondylotic myelopathy
patients: a prospective clinical study. Neurol. Sci. 35,
1373–1379 (2014).
280. Tetreault, L. et al. Impact of depression and bipolar
disorders on functional and quality of life outcomes in
patients undergoing surgery for degenerative cervical
myelopathy: analysis of a combined prospective
dataset. Spine 42, 372–378 (2017).
281. Zhang, Y. Z. et al. Magnetic resonance T2 image signal
intensity ratio and clinical manifestation predict
prognosis after surgical intervention for cervical
spondylotic myelopathy. Spine 35, E396–E399
(2010).
282. Chiles, B. W. 3rd, Leonard, M. A., Choudhri, H. F.
& Cooper, P. R. Cervical spondylotic myelopathy:
patterns of neurological deficit and recovery after
anterior cervical decompression. Neurosurgery 44,
762–770 (1999).
283. Wilson, J. R. et al. Impact of elevated body mass index
and obesity on long-​term surgical outcomes for
patients with degenerative cervical myelopathy:
analysis of a combined prospective dataset. Spine 42,
195–201 (2017).
284. Tetreault, L. A. et al. Systematic review of magnetic
resonance imaging characteristics that affect
treatment decision making and predict clinical
outcome in patients with cervical spondylotic
myelopathy. Spine 38, S89–S110 (2013).
285. Park, Y. S. et al. Predictors of outcome of surgery for
cervical compressive myelopathy: retrospective
analysis and prospective study. Neurol. Med. Chir. 46,
231–239 (2006).
286. Wada, E., Yonenobu, K., Suzuki, S., Kanazawa, A. &
Ochi, T. Can intramedullary signal change on magnetic
resonance imaging predict surgical outcome in
cervical spondylotic myelopathy? Spine 24, 455–462
(1999).
287. Chibbaro, S. et al. Anterior cervical corpectomy for
cervical spondylotic myelopathy: experience and
surgical results in a series of 70 consecutive patients.
J. Clin. Neurosci. 13, 233–238 (2006).
288. Vedantam, A., Jonathan, A. & Rajshekhar, V.
Association of magnetic resonance imaging signal
changes and outcome prediction after surgery for
cervical spondylotic myelopathy. J. Neurosurg. Spine
15, 660–666 (2011).
289. Suda, K. et al. Local kyphosis reduces surgical
outcomes of expansive open-​door laminoplasty for
cervical spondylotic myelopathy. Spine 28,
1258–1262 (2003).
124 | February 2020 | volume 16
290. Suri, A., Chabbra, R. P., Mehta, V. S., Gaikwad, S. &
Pandey, R. M. Effect of intramedullary signal changes
on the surgical outcome of patients with cervical
spondylotic myelopathy. Spine J. 3, 33–45 (2003).
291. Okada, Y., Ikata, T., Yamada, H., Sakamoto, R. &
Katoh, S. Magnetic resonance imaging study on the
results of surgery for cervical compression myelopathy.
Spine 18, 2024–2029 (1993).
292. Wang, L. F. et al. Using the T2-weighted magnetic
resonance imaging signal intensity ratio and clinical
manifestations to assess the prognosis of patients with
cervical ossification of the posterior longitudinal
ligament. J. Neurosurg. Spine 13, 319–323 (2010).
293. Zhang, L. et al. Preoperative evaluation of the cervical
spondylotic myelopathy with flexion-​extension
magnetic resonance imaging: about a prospective
study of fifty patients. Spine 36, E1134–E1139
(2011).
294. Jones, J. G., Cen, S. Y., Lebel, R. M., Hsieh, P. C. &
Law, M. Diffusion tensor imaging correlates with the
clinical assessment of disease severity in cervical
spondylotic myelopathy and predicts outcome
following surgery. AJNR Am. J. Neuroradiol. 34,
471–478 (2013).
295. Nakamura, M. et al. Clinical significance of diffusion
tensor tractography as a predictor of functional
recovery after laminoplasty in patients with cervical
compressive myelopathy. J. Neurosurg. Spine 17,
147–152 (2012).
296. Wen, C. Y. et al. Is diffusion anisotropy a biomarker for
disease severity and surgical prognosis of cervical
spondylotic myelopathy? Radiology 270, 197–204
(2014).
297. Halvorsen, C. M. et al. Surgical mortality and
complications leading to reoperation in 318
consecutive posterior decompressions for cervical
spondylotic myelopathy. Acta Neurol. Scand. 123,
358–365 (2011).
298. Pumberger, M. et al. Clinical predictors of surgical
outcome in cervical spondylotic myelopathy:
an analysis of 248 patients. Bone Joint J. 95-B,
966–971 (2013).
299. Dhillon, R. S. et al. Axonal plasticity underpins the
functional recovery following surgical decompression
in a rat model of cervical spondylotic myelopathy.
Acta Neuropathol. Commun. 4, 89 (2016).
300. Miller, R. G., Mitchell, J. D. & Moore, D. H. Riluzole
for amyotrophic lateral sclerosis (ALS)/motor neuron
disease (MND). Cochrane Database Syst. Rev. 3,
CD001447 (2012).
301. Ates, O. et al. Comparative neuroprotective effect of
sodium channel blockers after experimental spinal
cord injury. J. Clin. Neurosci. 14, 658–665 (2007).
302. Lang-​Lazdunski, L., Heurteaux, C., Vaillant, N.,
Widmann, C. & Lazdunski, M. Riluzole prevents
ischemic spinal cord injury caused by aortic
crossclamping. J. Thorac. Cardiovasc. Surg. 117,
881–889 (1999).
303. Schwartz, G. & Fehlings, M. G. Evaluation of the
neuroprotective effects of sodium channel blockers
after spinal cord injury: improved behavioral and
neuroanatomical recovery with riluzole. J. Neurosurg.
94, 245–256 (2001).
304. Wu, Y., Satkunendrarajah, K. & Fehlings, M. G.
Riluzole improves outcome following ischemia-​
reperfusion injury to the spinal cord by preventing
delayed paraplegia. Neuroscience 265, 302–312
(2014).
305. Wu, Y. et al. Delayed post-​injury administration of
riluzole is neuroprotective in a preclinical rodent
model of cervical spinal cord injury. J. Neurotrauma
30, 441–452 (2013).
306. Wu, Y., Satkundrarajah, K., Teng, Y., Chow, D. S. &
Fehlings, M. G. Evaluation of the sodium-​glutamate
blocker riluzole in a preclinical model of ervical spinal
cord injury. Evid. Based Spine Care J. 1, 71–72
(2010).
307. Moon, E. S., Karadimas, S. K., Yu, W. R., Austin, J. W.
& Fehlings, M. G. Riluzole attenuates neuropathic pain
and enhances functional recovery in a rodent model of
cervical spondylotic myelopathy. Neurobiol. Dis. 62,
394–406 (2014).
308. US National Library of Medicine. ClinicalTrials.Gov
https://clinicaltrials.gov/ct2/show/NCT01257828
(2018).
Acknowledgements
M.G.F. acknowledges support from the Gerry and Tootsie
Halbert Chair in Neural Repair and Regeneration and the
DeZwirek Family Foundation.
Author contributions
The authors contributed equally to all aspects of the article.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Neurology thanks M. Koda, M. Kotter and
V. Traynelis for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Supplementary information
Supplementary information is available for this paper at
https://doi.org/10.1038/s41582-019-0303-0.
Related links
spinal Cord Toolbox: https://sourceforge.net/projects/
spinalcordtoolbox/
© Springer Nature Limited 2020
www.nature.com/nrneurol