27
CH A P T E R
Spinal Cord Injury
David W. Cadotte, Michael G. Fehlings
CLINICAL PEARLS
● Spinal cord injury (SCI) is a problem in both the developed
and developing countries and is associated with significant
morbidity and long-term human and financial costs.
● Spinal cord injury is a medical emergency. Patients suffering
from this injury should be treated in specialized centers with
strict adherence to proper clinical examination, imaging,
and medical and surgical therapies.
● SCI is a result of primary damage to neural structures and
vasculature, followed by secondary damage from physi-
ological insults such as hypotension and hypoxia and resul-
tant cytotoxic swelling and death of neurons and glial cells.
● There have been a multitude of strategies of neuroprotec-
tion and repair in SCI and can be found in Box 27.2.
● Spinal shock is represented by depressed or absent spinal
reflexes below the injury site. Neurogenic shock after
trauma results from disruption of the sympathetic nervous
system usually at T6 or higher, which may lead to hypoten-
sion and may be difficult to distinguish from hypovolemic
shock. The optimal treatment of neurogenic shock is restor-
ing intravascular volume; if symptoms of neurogenic shock
persist, vasopressors such as dopamine may be useful.
Spinal cord injury (SCI) can result from a traumatic event, such
as a motor vehicle accident or penetrating assault, or a chronic
progressive disorder such as cervical spondylitic myelopathy.
In either case the neural elements of the spinal cord, includ-
ing both the gray and white matter of the spinal cord and the
exiting nerve roots, become damaged to the point of causing
neurological deficit in the patient. In this chapter we will focus
on traumatic SCI. We will highlight the pathophysiological
events that occur as a direct consequence of trauma and the
biological mechanisms that follow this event. We will then
provide an overview of some of the research that is being done
to understand the reasons why neurological deficit occurs fol-
lowing trauma, beyond the obvious destructive forces, and
discuss attempts at resolving these mechanisms in order to
restore neurological function. Lastly, we will discuss the clini-
cal management of the SCI patient with an emphasis on how
specialized treatment is geared at minimizing neurological
● Central cord syndrome is often the result of a traumatic spinal
cord contusion and affects the central part of the spinal cord.
This can cause loss of bilateral pain and temperature sensation
and loss of motor function at the level of the lesion and below.
● Early closed reduction of bilateral locked facets in an awake
patient, who can participate in a neurological examination,
may relieve spinal cord compression and restore normal
alignment.
● The use of methylprednisolone as a neuroprotective agent
in acute SCI shows moderate benefit in terms of neurologi-
cal outcome but the benefits of its administration should
be considered against the risks associated with medical
comorbid conditions in individual patients.
● There are several indications for surgical decompression in
SCI. The first is to treat spinal instability caused by fractures
and ligamentous injury that may cause further neurologi-
cal damage. There is some evidence, albeit controversial
or evolving, that surgical decompression within 24 hours
may improve neurological outcome in some patients with
isolated SCI, especially those with cervical SCI who are
deteriorating neurologically.
deficit. These specialized treatment options are the result of
extensive studies into the pathophysiological mechanisms
presented in the first portion of this chapter and represent
important advances in translational research—the notion that
understanding a disease process at its most fundamental level
can result in treatment strategies that will ultimately improve
the quality of life for patients and their families.
To frame the concepts of SCI—from pathophysiology to
translational research to clinical practice—it is important to
understand the reasons for undertaking such an endeavor. Spi-
nal cord injury has been studied at a population level in order
to understand the incidence, prevalence, and economic costs of
this devastating event. These studies tend to come from devel-
oped countries that have the financial resources to conduct
such research, but this problem certainly does not respect bor-
ders. In fact, the frequency of neurotrauma in the developing
world is estimated to be higher than in the developed world
445
446 PART 5 Spine
for reasons such as poor quality of roads, unsafe driving prac-
tices, old vehicles without seatbelts or airbags, and a greater
proportion of relatively inexpensive transportation such as
small motorcycles. Nonetheless, the estimated incidence in the
developed world is in the range of 11.5 to 53.4 people per 1
million population.1 This number must be interpreted with
caution as some authors point out that the actual incidence
may be on the higher side because an unknown number of
patients suffering SCI die at the scene of the accident without
ever being examined or treated in a hospital.2 Another study
estimated that approximately 48% to 79% of individuals die
either at the scene of the accident or on arrival to hospital.3
This study was performed in the mid-1970s and most surgeons
treating this disease would agree that the number of patients
who die is likely less today, mainly as a result of an improved
understanding of the cardiorespiratory complications that can
arise following injury and advanced intensive care units that
are well versed in managing these complications.
One way to comprehend the costs involved in treating
a person with SCI is to imagine that a 25-year-old sustains
an injury and becomes completely dependent on family and
the health care system from this point forward in life. One
study estimated that the total cost would be in the range of
$3 million (U.S. dollars),4 not to mention the impact of this
event on the person’s family and peers. The average age of
SCI patients is the late 20s and early 30s and tends to occur
more commonly in males. Going back to our example, this
event therefore affects people as they are starting their careers
and families. A lack of income combined with insurmountable
medical costs translates into financial and emotional hardship.
Depression and forms of psychological distress are common in
this patient group. In well-developed health care systems sup-
port networks exist to aid patients and families through the
life that they could not have imagined. In third world coun-
tries, patients and families are left to their own devices. From
either case comes a drive to understand the pathobiology of
this devastating condition and hopefully offer treatment strat-
egies. In the pages that follow, we will systematically discuss
the events that occur following a traumatic accident—from
the shear forces that destroy white matter tracts to the cel-
lular mechanisms that result. With this as a foundation we
will discuss different translational research programs that
are under way to minimize neurological deficit and hopefully
offer neuroregenerative strategies in the near future. Lastly we
discuss how a detailed understanding of the pathophysiology
of this condition has led to clinical treatment strategies. These
strategies are an essential knowledge base for any medical stu-
dent or resident interested in the treatment of this devastating
condition.
PATHOPHYSIOLOGY
Acute traumatic injury to the spinal cord can come in the form
of a blunt mechanism, such as an acrobat falling onto a hard
surface or a person thrown from a car during an automobile
collision, or a penetrating injury such as a stab or gunshot
wound. The forces involved in each of these events are trans-
mitted to the spinal column and if great enough result in dis-
ruption of the bony and ligamentous structures and in damage
to the neural elements. Damage to the spinal cord or the
Primary mechanical injury
Compression/contusion
Bone/disc displacement
Fracture/dislocation
Secondary injury
Hypoxia/ischemia
Ionic dysregulation
Excitotoxicity
Free radical and lipid peroxidation
Disruption of blood-brain barrier
Inflammatory response
Apoptosis/necrosis
FIGURE 27.1 Following a primary mechanical injury, numerous sec-
ondary mechanisms result in ongoing damage to the spinal cord
and minimize the chance for recovery.
exiting nerve roots can result in motor, sensory, or autonomic
dysfunction. In an attempt to delineate the precise cause of
neurological dysfunction researchers have divided the tempo-
ral sequence of destructive events into primary and second-
ary injury. Primary injury refers to the destructive forces that
directly damage the neural structures such as the shear force
tearing an axon or direct compressive force occluding a blood
vessel, resulting in ischemia. These destructive primary mecha-
nisms not only result in instantaneous damage to neurons and
blood vessels but also initiate a cascade of cellular mechanisms
that result in ongoing damage to the neural structures, termed
secondary injury. In fact, in cases of ongoing primary injury,
for example, in the setting of a fracture dislocation where the
bony spinal column is displaced and physically pushed up
against the spinal cord, these cellular mechanisms are thought
to be locked into the “on” position until such physical forces
are removed either by closed reduction or surgically. Second-
ary injury may persist from hours to weeks to years following
primary injury. A great deal of work has gone into the detailed
understanding of these cellular cascades and along with this
work has come an appreciation for the destructive effects
of the mechanisms and the role of potential therapeutics to
halt these cascades. In the remainder of this section we will
highlight the most important secondary mechanisms of injury
(Fig. 27.1) and in the section titled “Translational Research”
we will discuss some of the therapeutic targets that resulted
from these basic science discoveries.
Secondary injury stems from any aberrant physiological or
physical force and results in further tissue damage and potential
exacerbation of primary injury. Two of the easiest physiologi-
cal parameters to recognize are hypotension and hypoxia. Both
of these conditions are relatively common in trauma patients,
who often sustain concomitant injuries and blood loss. Both are
also amenable to medical management shortly after the patient
arrives at the hospital. Specific treatment options will be discussed
later; here we highlight the importance of these two causes of
secondary injury and the fact that they further exacerbate sec-
ondary cellular cascades. Both global hypotension and hypoxia
add to the overall effect of hypoperfusion to the damaged area

of the spinal cord. Several other mechanisms add to hypoper-
fusion including disruption of the microvasculature, loss of
normal autoregulatory mechanisms, and increased interstitial
pressure.5-7 The effects of this ischemic insult are cytotoxic cell
swelling of both neurons and glial cells; as a downstream effect
of this, blockade of action potentials has been demonstrated as a
result of axonal swelling.8
Ionic dysregulation and excitotoxicity are closely linked
events that contribute to tissue damage. Calcium dysregula-
tion in particular has been widely linked to cell death through
a number of different processes including calpain activation,
mitochondrial dysfunction, and free radical production.9
Whether calcium dysregulation or disruption of other ionic
gradients occurs, loss of ionic homeostasis is central to both
necrotic and apoptotic cellular death. Excitotoxicity results
from activation of glutamate receptors via the influx of both
sodium and calcium ions. As cell death occurs, either through
the process of necrosis or apoptosis, extracellular glutamate
levels rise presumably due to the failure of energy-dependent
transporters such as the Na+/K+-ATPase membrane trans-
porter.10 In the next section we will discuss how antagonists
of NMDA (N-methyl-d-aspartic acid) receptors are potential
targets of translational research in order to minimize cellular
death.
Free radical–mediated secondary injury occurs through the
process of lipid peroxidation that ultimately results in disrup-
tion of axons and death of both neurons and glial cells. Con-
sidering the mechanism of free radical damage, peroxynitrite
and other reactive oxygen species act through a chain reac-
tion that ultimately destroys cellular membranes and leads to
cell lysis, organelle dysfunction. and calcium dysregulation. 11
This, in turn, adds to the ionic dysregulation described in the
preceding paragraph. Free radicals have been measured in the
damaged tissue of experimental models and are found to be
elevated for approximately 1 week following injury, return-
ing to preinjury baseline only after 4 to 5 weeks.12 Examples
of these free radicals include hydrogen peroxide, hydroxyl
radical, nitric oxide, and the superoxide radical. Specific
radicals, such as peroxynitrite, have been directly liked to the
activation of apoptotic cascades in rat SCI models.13 As with
NMDA receptors, free radical oxygen species become a poten-
tial target of translational research. If one is theoretically able
to mediate the level of these dangerous compounds, could one
not prevent the degree of secondary damage that occurs fol-
lowing SCI? This idea will be expanded on in the translational
research section below.
Tight junctions between endothelial cells act as an inter-
face between the systemic circulation and the central nervous
system. Known as the blood-brain barrier (BBB), it also func-
tions in the spinal cord and acts as a selective barrier that
allows passage of solutes such as glucose while maintaining
impermeability to macromolecules and infectious agents such
as bacteria. Endothelial cells and astrocytes are normally
bridged by tight junctions and are interspersed with very
selective transmembrane proteins to allow the passage of vital
molecules and ions. With the destructive forces that accom-
pany SCI comes the destruction of the BBB. This can result
either from direct mechanical destruction, such as damaged
blood vessels and spinal cord parenchyma, or from destruc-
tion at a cellular level. The latter is best understood as a result
of the effects of numerous inflammatory mediators on the
CHAPTER 27 Spinal Cord Injury 447
endothelial cells that disrupt the normally impermeable bar-
rier. One way researchers have studied this effect is through
the use of a compound called horseradish peroxidase. When
injected into the peripheral circulation of a normal animal,
this compound does not cross the fortress of the BBB and
remains in the systemic tissues. When injected into animal
models of SCI, the compound was found to permeate into the
CNS at a peak time of 24 hours following injury. Such perme-
ability was persistent for up to 2 weeks following injury.14
A number of compounds have been identified that are thought
to contribute to this ongoing permeability following injury,
each of which is related to the secondary mechanisms of
SCI. Inflammatory mediators affecting vascular permeability
include tumor necrosis factor-α (TNF-α) and interleukin 1β
(IL-1β) and both have been shown to be unregulated follow-
ing SCI.15,16 Other compounds that play a role include matrix
metalloproteinases, histamine, and reactive oxygen species
including nitric oxide. 12
The inflammatory reaction following SCI has received a
renewed interest in recent years largely because of what is
thought of as the dual nature of the immune response. On
the one hand inflammatory mediators seem to be respon-
sible for the ongoing destruction of tissue, and on the other
hand they seem to be clearing cellular debris and optimizing
the environment for regenerative growth. Several noncel-
lular mediators are involved in the cascade, the most promi-
nent of which are TNF-α, interferons, and interleukins. 17
Cellular mediators following SCI include both resident
microglia and peripheral inflammatory cells. A few of the well-
characterized examples, mainly from studies in the rodent
population, include astrocytes, T cells, neutrophils, and
invading monocytes. 18 A great example of this dual nature
of protection and destruction comes from studies involv-
ing TNF-α, which has been demonstrated to be significantly
unregulated following SCI. 19 Subsequent studies involved
the application of neutralizing antibodies to TNF-α follow-
ing experimental injury, resulting in improved neurologi-
cal function.20 However, TNF-α-deficient mice have been
shown to have higher numbers of apoptotic cells, increased
lesion size, and worse function following SCI when com-
pared to wild-type mice. 21 This demonstrates the complex-
ity of the inflammatory cascade in SCI and should point the
novice reader in the direction of thinking beyond the notion
of one type of molecule causing destruction; rather, one
must view the many players as acting in a complex pattern,
some of which may aid in optimizing function and others
that may result in ongoing destruction. The role of research
in this field is to tease out these details and provide specific
targets for translational research that aim to optimize the
potential for recovery.
Cellular death via the apoptotic pathway is thought to
play little role in the fate of neurons22 but a considerable role
in the fate of oligodendrocytes23 following SCI. Although it
may be difficult to demonstrate the apoptotic mechanism of
neuronal death in human SCI, there is some evidence for its
role in animal models.24 In contrast, the apoptotic mechanism
of oligodendrocyte death has been convincingly demonstrated
and its mechanism at least partially elucidated. Following
SCI, microglia are activated within the first 2 to 48 hours and
express the Fas ligand.25 This ligand has a receptor largely
expressed on the oligodendrocyte, and communication occurs
448 PART 5 Spine
via the p75 neurotrophin receptor.26 The interaction of the
Fas ligand and its receptor initiate apoptosis by way of the
caspase cascade that ultimately results in proteolysis, DNA
cleavage, and cellular death. This pathway has been the target
of translational research strategies and will be expanded on in
the next section.
In contrast, cellular death via the necrotic pathway has
been demonstrated in both the neuronal and non-neuronal cell
populations. Several of the secondary mechanisms of injury
previously discussed, such as hypoperfusion and excitotoxic-
ity, culminate in the necrotic death of neurons. Oligodendro-
cytes are also susceptible to this death pathway and the loss
of this cell type has the consequence of axonal demyelination.
This demyelination, in combination with other insults on the
neuronal processes such as lipid peroxidation and ischemic
swelling, results in death of the associated neuronal cell bod-
ies. 27 Animal studies have provided evidence that preserved
axons represent a critical therapeutic target in order to regain
neurological function.28 In stark contrast to this, postmortem
human studies have failed to identify demyelinated axons 29
and may represent an important disconnect between animal
and human pathology following SCI.
Primary and secondary injuries are conceptual frame-
works that divide the temporal sequence of events following
SCI. This framework provides a basis for research into the
complex pathways that are activated in response to trauma,
some of which may result in optimizing the local environment
for neurological recovery and others that have deleterious side
effects. The pathological processes that occur at the cellular
level include ischemia, vasospasm, ion-mediated cellular dam-
age, excitotoxicity, oxidative cellular damage, neuroinflam-
mation, and cellular death. Each of these processes involves
complex cascades of events. As research continues into each
of these cascades different targets for intervention are discov-
ered. In the paragraphs to follow we will highlight some of
these targets and explain how they may eventually prove to be
beneficial in treating persons that suffer an SCI.
TRANSLATIONAL RESEARCH
As previously stated, an in-depth understanding of second-
ary mechanisms of SCI has led to identification of numerous
possible targets for prevention of this secondary damage and
possible regeneration of partially damaged neural circuits.
Here we will review a number of agents that are currently
under investigation. Broad categories include neuroprotective
agents (minocycline and riluzole), myelin-associated inhibi-
tors of neural regeneration (ATI355 and Cethrin), and cellular
transplantation strategies (activated autologous macrophages,
bone marrow stromal cells, and human embryonic stem cells).
This list is by no means exhaustive. Numerous other strate-
gies have been attempted in the past and many lessons have
been learned—both positive and negative. Readers interested
in a recent history of translational research in the field of SCI
are referred to a recently published open source review.30
Alongside developments in neurobiology have come advances
in clinical management and operative strategies. In a similar
fashion to the scrutiny of drug delivery trials, these clinical
and surgical options have also been the focus of clinical tri-
als and extensive review to determine if their effects provide
BOX 27.1 Selected Neuroprotective Approaches, in Early
Phase Clinical Trials, with a Potential Role
for Improving Outcomes in Spinal Cord Injury
Riluzole
Minocycline
Polyethylene glycol/magnesium
Hypothermia
better outcomes for patients. Research that has gone into
blood pressure management, methylprednisolone therapy,
closed reduction of bilateral locked facets, and early surgical
decompression will be discussed in the following section on
clinical management.
Neuroprotective Agents
Several promising neuroprotective strategies are under inves-
tigation (Box 27.1); two of these are reviewed in greater detail
here. Minocycline is a tetracycline derivative that has been of
interest to neuroscience for quite some time. It has been shown
to have neuroprotective properties in a diversity of animal
models, including those that aim to study stroke, Parkinson’s
disease, Huntington disease, amyotrophic lateral sclerosis
(ALS), and multiple sclerosis.31 As a result of its promise in
these conditions, its potential application was carried over to
the realm of SCI. Initially studied in animal models, its benefit
became apparent in improved neurological outcomes32 and its
mechanism of action was thought to be a result of decreased
microglia activation and antiapoptotic pathways mediated by
the inhibition of cytochrome c release. Because of its extensive
use in other neurological conditions, and promise in animal
models of SCI, at least two clinical trials are under way to test
the efficacy of minocycline in human SCI.
Riluzole is a benzothiazole anticonvulsant that has been
in clinical use for greater than a decade. Used primarily in
patients with ALS, it has been shown to prolong the lives of
persons by 2 to 3 months.33 Relevant to our earlier discus-
sion of ionic dysregulation as a secondary means of injury,
riluzole is thought to act by blocking voltage-sensitive sodium
channels, whose overactivity after trauma has been associated
with neural tissue destruction. In addition, riluzole has been
shown to block presynaptic calcium-dependent glutamate
release, whose deleterious effects have been discussed. Multi-
center clinical trials are under way to study this agent. Its dos-
ing will be similar to that for ALS patients and the duration
will be 10 days. This duration was decided as a direct effect
of studies into secondary injury cascades, where results indi-
cate that sodium- and glutamate-mediated damage persists for
that time period—an excellent example of how translational
research is the direct result of thorough and comprehensive
basic science research.
A nonpharmacological means of neuroprotection cur-
rently under study in the SCI population is hypothermia.
Cooling the human body to slow metabolism and enzymatic
processes is certainly not new in clinical medicine. However,
its application for SCI has received recent attention likely due
to new methods that allow for easy and faster cooling via a
femoral sheath catheter. A recent retrospectively designed
study34 demonstrated the safety of this method and gathered

BOX 27.2 Selected Molecular/Pharmaceutical Strategies
with a Potential Role for Improving Outcomes in
Spinal Cord Injury by Influencing Regeneration
or Plasticity
Nogo-A monoclonal antibody (ATI335)
Cethrin
Rolipram
Lithium carbonate
Chondroitinase ABC
BOX 27.3 Selected Cellular and Bioengineered Strategies
with a Potential Role for Improving Outcomes in
Spinal Cord Injury
Cellular strategies either in phase I clinical trials or destined
for phase I clinical trials
Neural stem cells
Oligodendroglial precursor cells
Schwann cells
Olfactory ensheathing cells
Bioengineered strategies in late stage preclinical trials or early
phase I studies
Cethrin
Transcriptional factors to up regulate vascular endothelial
growth factor (ZFP-VEGF)
preliminary data with regard to cooling temperature, time
to target temperature, duration of cooling, and any adverse
events. The long-term follow-up of these patients compared
to control subjects will be necessary to demonstrate any func-
tional benefit.
Myelin-Associated Inhibitors of Neural
Regeneration
Many regenerative strategies for the treatment of SCI are
under investigation; the most prominent molecular and phar-
maceutical strategies are listed in Box 27.2 and selected cel-
lular and bioengineered strategies are listed in Box 27.3. Here,
we further discuss the evolution of this field along with two
therapeutic agents. The notion that the central nervous system
cannot regenerate axons after injury was convincingly dis-
proved in the 1980s 35 and with numerous other studies after
this. Axons, however, do not typically regrow after injury
for the many reasons discussed in the secondary injury cas-
cade. Of the innate mechanisms that stunt this growth are the
myelin-associated proteins whose activity has been directly
linked to a lack of regenerative capacity. Many inhibitors of
myelin-associated proteins have been researched in cell culture
and animal models and two have been the focus of investiga-
tion in clinical trials: ATI335 and Cethrin.
ATI335 has a rich history ranging from basic laboratory
science through animal models and into the realm of trans-
lational research. CNS myelin, at this time known to be an
inhibitor of axonal growth, was biochemically separated into
component proteins.36 Antibodies to these proteins were then
developed and applied to in vitro models that demonstrated
their ability to diminish the inhibitory effects of myelin.
CHAPTER 27 Spinal Cord Injury 449
Subsequent animal models demonstrated improved neurologi-
cal outcomes with administration of these antibodies.37 After
a flurry of excitement in the animal world, Nogo was charac-
terized as the target antigen and human antibodies were sub-
sequently developed. These antibodies were demonstrated to
promote axonal growth and functional recovery in primate
models of SCI. Clinical trials began shortly thereafter and are
currently under way in both Europe and Canada.
Myelin inhibitors of axonal growth are known to signal
through the Rho cascade. Briefly, Rho is a guanosine triphos-
phatase that, when activated, binds to Rho kinase (ROCK).
ROCK, in turn, is a key regulator of axonal growth cone
dynamics and cellular apoptosis. Disruption of this cascade
has been shown to facilitate axon growth and functional
recovery in mice.38 Initial studies made use of a toxin pro-
duced by Clostridium botulinum termed C3 transferase, a spe-
cific inhibitor of Rho. Eventually, a recombinant protein was
created, commercialized, and brought to clinical trial. Cethrin
is a combination of this recombinant protein and fibrin glue—
the mixture is applied directly to the dura at the time of surgi-
cal decompression of SCI. Initial results of a multicenter phase
I/IIa trial are becoming available and appear promising in terms
of neurological recovery. A phase II study is being planned.
CELLULAR TRANSPLANTATION
STRATEGIES
Up to this point we have discussed how secondary mechanisms
following SCI result in a hostile environment that prevents
recovery of neural function and may lead to damage beyond
the original injury. We then discussed how a detailed under-
standing of these secondary mechanisms has led to various
research strategies aimed at combating these cascades in hopes
of optimizing spinal cord recovery. In the next few paragraphs
we will discuss the idea behind cellular transplantation, a con-
cept that transcends the notions of optimizing the spinal cord
for natural recovery and introduces cell types with the goal
of integrating these cells within spinal circuits and allowing
for neurological recovery. Many different cell types have been
studied. Here we will focus on three: activated autologous
macrophages, bone marrow stromal cells, and human embry-
onic stem cells. Although the theory surrounding transplan-
tation strategies sounds promising, the experimental results
have been humble. Nonetheless, it is hoped that careful atten-
tion to the barriers will lead to a successful treatment strategy
in the near future.
Activated Autologous Macrophages
It has been realized for about 2 decades that macrophages play
a vital role in the regeneration of peripheral nervous func-
tion and that this role does not exist in the central nervous
system. Following injury to a nerve in the peripheral nervous
system, macrophages are recruited to the site of injury and are
responsible for clearing myelin debris and optimizing the local
environment for regeneration. In order to capitalize on this
finding in the central nervous system, researchers attempted
to take autologous macrophages from SCI patients, activate
them with peripheral myelin, and inject them into the dam-
aged area of the spinal cord shortly after injury. The initial
450 PART 5 Spine
results were promising, although only a small number of indi-
viduals received treatment. Owing to financial circumstances,
the trial was never expanded beyond the initial study. This
strategy once again highlights a bridge between understanding
the secondary mechanisms of damage, in this case how central
myelin acts to inhibit neural regeneration and repair, and the
development of potential therapy. Hopefully this promising
strategy will be revitalized and studied in a larger population.
Bone Marrow Stromal Cells
The use of bone marrow stromal cells aims to take advan-
tage of a relatively accessible multipotent stem cell that has
the potential to differentiate and integrate into existing spi-
nal circuits and result in neural recovery. A number of groups
around the world are reporting the use of these cells includ-
ing scientists from Korea, China, Russia, the Czech Republic,
and Brazil. To date, the trials have been small and are often
not blinded, prompting cautious interpretation of the results.
Nonetheless, researchers report significant neurological recov-
ery after direct injection of this cell type in the damaged area
of the spinal cord. Researchers in Prague, Czech Republic, did
have blind assessors evaluate patients at follow-up in terms of
both the ASIA (American Spinal Injury Association) scale and
electrophysiologically. Significant improvement was noted in
patients who received therapy within 3 to 4 weeks of injury
but not in those who were in the chronic stages of injury.39
Human Embryonic Stem Cells
Although human embryonic stem cells are theorized as one of
the more promising strategies in cell replacement in the spinal
cord, there are a number of hurdles that must be overcome.
This cell type is first cultured in vitro and the purity of these
cultures is paramount and somewhat challenging. In addition,
viral contamination via delivery vectors and the acquisition
of membrane polysaccharides that may react with the host
immune system are all concerns that are being addressed. Sig-
nificant advances have been made in this field, mainly out of the
University of California at Irvine,40,41 and are currently being
evaluated by the Food and Drug Administration (FDA) in the
United States. The goal of this therapy is to achieve differentia-
tion of these stem cells into oligodendrocytes that would aid in
remyelination of spared but demyelinated axons. This repre-
sents a promising avenue of research in the decades to come.
Each of these translational research concepts is extremely
important in the overall undertaking to prevent neurological
decline and optimize a hostile environment for recovery, and
several translational ideas have already made their way into
mainstream clinical practice. These practices include mainte-
nance of blood pressure, methylprednisolone therapy, early
closed reduction of bilateral locked facets, and early surgical
decompression. Each of these topics will be briefly reviewed in
the next section on clinical management.
CLINICAL MANAGEMENT
A patient who sustains an SCI has often sustained concomitant
injuries and may be medically unstable; in fact, the treating
physician may not recognize the presence of SCI immediately.
Adherence to Advanced Trauma Life Support (ATLS) pro-
tocol is essential. Airway, breathing, and circulation (ABCs)
are of paramount importance, followed by the treatment of
any immediate life-threatening condition. If there is concern
that any one of these domains is unstable, it should be revis-
ited before moving on. Hypotension, in particular, must be
observed for an ongoing secondary SCI can result. Follow-
ing stabilization of the patient, the treating physician should
then proceed with the neurological examination. This comes
in the form of testing for motor power, sensory impairment,
and reflexes including rectal tone. This examination should
be documented on the standard ASIA forms.42 Following a
detailed examination, and assuming the finding of a deficit,
imaging of the spinal column with computed tomography
(CT) scan and imaging of the spinal cord with magnetic reso-
nance imaging (MRI) should follow in short order. To frame
the concepts of SCI, refer to Figure 27.2, which displays the
MRI of an 18-year-old male subject who sustained an SCI.
Also shown in this figure is the method for calculating the
maximal spinal canal compromise and the maximal cord
compression—two measurements that are useful for quantify-
ing the degree of injury.43 In the remainder of this chapter we
will review the following important concepts that are essential
to understand in order to properly care for the SCI patient:
spinal shock, neurogenic shock, spinal cord syndromes, evi-
dence for early closed reduction of bilateral locked facets, evi-
dence for methylprednisolone therapy, and evidence for early
surgical decompression.
Spinal Shock
Spinal shock is a term used to describe depressed spinal
reflexes caudal to the injury site following SCI. This is an
important concept to understand because the initial neuro-
logical examination may not be an accurate reflection of dis-
rupted neuronal circuits, including those that control motor
and sensory pathways. Normally, these reflex pathways
receive continuous input from the brain. When this tonic
input is disrupted, the normal reflex pattern is disrupted and
can vary from areflexic through to hyperreflexic depending
on the time since the original injury. Clinically, this translates
into the potential for a misleading representation of deficits
if spinal reflexes are absent following injury. It is therefore
recommended that patients be examined not only on presen-
tation to the treating physician but also at the 72-hour mark
following injury.
Neurogenic Shock
Neurogenic shock is a potentially life-threatening condition
and must be managed as such. Without a clear understand-
ing of this condition inappropriate management of a trauma
patient, who often suffers concomitant hemodynamic instabil-
ity, could be fatal. Neurogenic shock is defined as disruption
of the sympathetic nervous system with preserved parasym-
pathetic activity. This typically occurs with patients suffering
a severe SCI at the level of T6 or higher. Disruption of the
sympathetic division of the autonomic nervous system affects
three areas of the cardiovascular system: coronary blood flow,
cardiac contractility, and heart rate. With preserved parasym-
pathetic activity this translates clinically into bradycardia
 CHAPTER 27 Spinal Cord Injury 451

Da da

Di di

Db db

A1 A2 B C

Maximum canal compromise Maximum cord compression

Di di
(1 − ) × 100% (1 − ) × 100%
(D a + Db)/2 (d a + db)/2
FIGURE 27.2 Preoperative T2-weighted (A1 and A2) and postoperative T1-weighted (B) and T2-weighted (C) MRI studies of an 18-year-old
man who sustained a spinal cord injury after being involved in a motor vehicle accident. A1 illustrates how to calculate maximal canal
compromise (MCC): Di is the anteroposterior canal diameter at the level of maximum injury, Da is the anteroposterior canal diameter at the
nearest normal level above the level of injury, and Db is the anteroposterior canal diameter at the nearest normal level below the level of
injury. A2 illustrates how to calculate the maximum spinal cord compression (MSCC): di is the anteroposterior cord diameter at the level of
maximum injury, da is the anteroposterior cord diameter at the nearest normal level above the level of injury, and db is the anteroposterior
cord diameter at the nearest normal level below the level of injury. B and C illustrate the effect of decompressive surgery on relieving spinal
cord compression and restoring normal alignment.

(and possibly other cardiac arrhythmias) in the setting of pro-
found hypotension. A prudent clinician must look for these
characteristics in combination, as many trauma patients are
hypotensive as a result of blood loss or intravascular hypo-
volemia but will mount an appropriate tachycardic response.
The treatment of neurogenic shock is therefore quite diffi-
cult. Although it is theoretically possible to distinguish between
hypovolemic and neurogenic shock, clinically this distinction
is not so clear. In fact, acute trauma patients sustaining a high
cervical SCI may suffer from both conditions. It has therefore
been recommended by the Consortium for Spinal Cord Medi-
cine to rule out other causes of shock before assuming a diag-
nosis of neurogenic shock. The practical treatment of these
patients rests on initially restoring intravascular volume and if
symptoms of neurogenic shock persist, vasopressors (such as
dopamine) should be used. The goal of treatment in the first
week after sustaining an SCI is to maintain a mean arterial
blood pressure of 85 mm Hg.
Spinal Cord Syndromes
One should be aware of the terminology used to describe defi-
cits and identify different spinal cord syndromes in order to
localize the lesion to a particular area of the spinal cord and
a particular level.
Paresis is a term used to describe weakness or partial
paralysis. For example, hemiparesis describes weakness on
one side of the body. In contrast, both paralysis and the
suffix -plegia refer to no movement. For example, hemiplegia
refers to no movement on one side of the body. Keeping these
terms in mind, we turn our attention to spinal cord syndromes
that occur when a select region of the spinal cord is damaged,
resulting in a predictable pattern of neurological deficit. These
syndromes are expanded on in the paragraphs that follow and
are depicted in Figure 27.3, along with a description of the
ASIA impairment scale.
Transverse spinal cord lesions disrupt all motor and sen-
sory pathways at and below the level of the lesion. There is a
sensory level that corresponds to the level of the lesion.
Hemisection of the spinal cord, commonly referred to as
Brown-Sequard syndrome, is characterized by damage to one
half of the spinal cord and all motor and sensory pathways at
that level and neurological deficits at and below that level. This
results in ipsilateral upper motor neuron weakness and ipsilat-
eral loss of vibration and position sense at and below the level
of lesion. There is contralateral loss of pain and temperature
sensation below the level of the lesion. There may also be ipsi-
lateral loss of pain and temperature sensation at the level of the
lesion for one or two spinal segments if the lesion has damaged
posterior horn cells before fibers have crossed to the other side.
452 PART 5 Spine

ASIA IMPAIRMENT SCALE

ASIA Grade Complete or
incomplete
A Complete
B Incomplete
C Incomplete
D Incomplete
E Incomplete
Description
No motor or sensory function is preserved in the sacral
segments S4-S5
Sensory but not motor function is preserved below the
neurological level and includes the sacral segments S4-S5
Motor function is preserved below the neurological level, and
more than half of the key muscles below the neurological level
have a muscle grade less than 3
Motor function is preserved below the neurological level, and
at least half of key muscles below the neurological level have
a muscle grade of 3 or more
Motor and sensory function are normal

Transverse cord Hemi-cord lesion Central cord lesion Posterior cord lesion Anterior cord lesion
lesion

Loss of vibration and position sense Loss of pain and temperature sense Loss of motor power
FIGURE 27.3 The ASIA impairment scale is outlined (top) along with spinal cord syndromes (bottom). Central cord syndrome is representa-
tive of a small lesion. If the central cord lesion were large, one would expect involvement of the motor and vibration/position sense sys-
tems (see text for further explanation). Motor power is graded according to the following scale: 0 = total paralysis, 1 = palpable or visible
contraction, 2 = active movement, full range of motion, gravity eliminated, 3 = active movement, full range of motion, against gravity, 4 =
active movement, full range of motion, against gravity, and provides some resistance, 5 = active movement, full range of motion, against
gravity, and provides normal resistance, NT = not testable because the patient is unable to reliably exert effort or the muscle is unavailable
for testing due to factors such as immobilization, pain on effort, or contracture. Sensory testing is graded according to the following scale:
0 = absent, 1 = impaired, 2 = normal, and NT = not testable.

Central cord syndrome is commonly caused by a trau-
matic spinal cord contusion, posttraumatic syringomyelia, or
a medullary spinal tumor. This lesion tends to affect pathways
that are in the immediate vicinity of the central portion of
the spinal cord, and the symptoms differ depending on the
size of the lesion. Small lesions affect spinothalamic fibers that
cross in the ventral commissure and cause bilateral regions of
suspended sensory loss to pain and temperature. If the lesion
is larger, anterior horn cells, corticospinal tracts, and poste-
rior columns may be affected. Loss of these pathways respec-
tively results in lower motor neuron deficits at the level of the
lesion, upper motor neuron signs below the level of the lesion,
and loss of vibration and position sense below the level of
the lesion. In addition to suspended pain and temperature loss
with small lesions, larger lesions can result in complete loss of
pain and temperature sensation below the level of the lesion
if the anterolateral pathways are compressed from a medial
aspect. Given the spinal cord laminations, sacral sparing is
observed.
Posterior cord syndrome involves bilateral loss of vibra-
tion and position sense below the level of the lesion as a result
of disruption of the posterior columns. If the lesion is large
enough, one may observe upper motor neuron signs below the
level of the lesion, indicating involvement of the lateral cor-
ticospinal tracts. In addition to traumatic injury, vitamin B12
deficiency or tertiary syphilis can cause isolated involvement
of the posterior columns.
Anterior cord syndrome results in loss of pain and tem-
perature sensation below the level of the lesion (spinothalamic
pathways), lower motor neuron signs at the level of the lesion
(anterior horn cell damage), and upper motor neuron signs
below the level of the lesion (lateral corticospinal tracts). In
addition, urinary incontinence is common because of the ven-
tral location of the descending pathways controlling sphincter

function. Common causes of this syndrome include trauma
and anterior spinal artery infarct.
Evidence for Early Closed Reduction
of Bilateral Locked Facets
As mentioned earlier, imaging of the spinal column with CT
scan and the spinal cord and soft tissues with MRI should
follow clinical examination. These imaging modalities pro-
vide essential information that determines subsequent steps in
management. In the setting of severe flexion injuries, disrup-
tion of the anterior, middle, and posterior columns along with
the ligamentous joint capsules can occur. This is an extreme
example on the spectrum of flexion injuries and usually results
in quadriplegia. CT imaging reveals the inferior articular fac-
ets from one vertebral body to be dislocated anteriorly with
respect to the superior facets of the adjacent vertebra. MRI is
necessary to investigate the degree of neural element involve-
ment and the degree of ligamentous compromise.
Treatment of this injury usually begins with closed reduc-
tion of the facet dislocation; whether or not one investigates
the cervical spine with MRI prior to this maneuver is a contro-
versial issue. An important qualifying factor in this situation
is that the patient must be awake, alert, and able to partici-
pate in repeated neurological examinations. This notion rests
in the dictum of “do no harm to your patients.” Early closed
reduction of bilateral locked facets aims to relieve severe spi-
nal cord compression in the setting of significant ligamentous
damage by restoring normal bony alignment. The technique
should be performed in a monitored setting and involves
applying either Gardner-Wells tongs or a halo crown as
a rigid fixation device to the skull and applying a traction
force. Increasing weight is added over time while neurologi-
cal status is monitored for stability and lateral radiographs
are used to follow the bony anatomy. The goal is to obtain
reduction of the cervical facets. A postreduction MRI should
be obtained to rule out disk herniation. This maneuver should
only be performed in specialty centers with surgeons experi-
enced in its application. Under no circumstances should this
maneuver delay operative management. The evidence for this
technique was recently reviewed and consisted of a number
of class II and III studies, with retrospective and prospective
designs.44 The results of these studies varied from neurologi-
cal deterioration to no neurological change to neurological
improvement. In order to further distill the controversy, sev-
eral authors reported that the method is safe and that neuro-
logical decline is often transient and improves with removal
of added weight. Furthermore, a number of studies report
neurological improvement that led to the recommendation of
early closed reduction as a clinical guideline in patients with
bilateral locked facets and an incomplete tetraplegia or in
those with deteriorating neurological status.
Evidence for Methylprednisolone Therapy
The use of methylprednisolone as a neuroprotective agent
to mitigate the deleterious effects of secondary injury is still
controversial. It has been shown to offer modest benefit in
terms of neurological outcome following SCI.45 The National
Acute Spinal Cord Injury Study (NASCIS) aimed to investi-
gate the question of whether or not patients would benefit
CHAPTER 27 Spinal Cord Injury 453
from its administration. In the paragraphs that follow we
will review the results of this study along with the method
and dose by which physicians administered the drug in each
trial.
NASCIS was designed as a multicenter trial and was com-
pleted as three separate trials: NASCIS I, NASCIS II, and
NASCIS III. The first study compared low- and high-dose
methylprednisolone (no placebo), the second trial was ran-
domized and controlled with a placebo, and the third trial
compared the effects of 24- versus 48-hour treatment. NASCIS
I randomized SCI patients into two cohorts: the first group
received a 100-mg loading dose of methylprednisolone fol-
lowed by 25 mg every 6 hours for 10 days, and the second
group received a 1000-mg loading dose of methylpredniso-
lone followed by 250 mg every 6 hours for 10 days.46 There
were no differences in neurological outcome between the
two groups at 1 year after injury. NASCIS II investigated a
30-mg/kg bolus of methylprednisolone over 1 hour followed
by 5.4 mg/kg/hour over the following 23 hours and included a
placebo group and naloxone administration group. The reason
for the higher doses (in comparison to NASCIS I) involved
the analysis of animal research that suggested a therapeu-
tic benefit only above a certain threshold. Results from the
overall group showed no significant differences in neurologi-
cal outcome at 6 months; a subgroup analysis demonstrated
improved motor and sensory outcomes in patients receiving
methylprednisolone within 8 hours of injury.47 NASCIS III
examined outcomes in acute SCI patients receiving a 30-mg/kg
bolus of methypredniosolone followed by 5.4 mg/kg/hour for
either 23 hours or 47 hours. Patients treated with methyl-
prednisolone for 48 hours had better neurological outcomes
in comparison to the other treatment groups if therapy was
initiated within 3 to 8 hours of injury; however, the 48-hour
regimen was associated with increased risk of sepsis and
pneumonia.48 Following the completion of each of these
studies, Bracken conducted a reviewed along with two other
independent trials and concluded that high-dose therapy was
safe and afforded a modest benefit in terms of neurological
outcome.49
Clearly the results were not overwhelmingly in favor of
methylprednisolone administration and there is still consid-
erable debate as to whether or not it should be used. Fur-
thermore, if a practicing physician decides to use this therapy,
there is debate as to which administration protocol should be
used. The senior author of this chapter has published his pro-
tocol for administering methylprednisolone following acute
SCI based on the timing of administration.45 Patients with
acute nonpenetrating SCI should receive methylprednisolone
as per the NASCIS II protocol if started less than 3 hours after
injury. If started between 3 and 8 hours after injury, then the
NASCIS III 48-hour protocol should be applied. If therapy
cannot be administered within 8 hours of injury, or there is
a penetrating SCI, then methylprednisolone should not be
administered for neuroprotection. The decision to administer
methylprednisolone must account for patient medical comor-
bid conditions. For example, the risks of administration may
outweigh the benefits in a patient with diabetes mellitus and
a complete thoracic SCI injury. Blood glucose levels must be
carefully monitored during the course of methylprednisolone
therapy, and hyperglycemia aggressively managed with an
insulin infusion.
454 PART 5 Spine
Evidence for Early Surgical Decompression
The concept of surgical decompression for SCI has received a
great deal of attention in the past 2 decades largely because of
the research questions posed around the concepts of second-
ary injury. It is important to consider the fact that there may
be several indications for surgery following traumatic SCI—
first and foremost is spinal instability caused by torn ligaments
and bony fracture. There is little controversy over the need
for surgical stabilization in this setting. The other, and the
focus of this section, is surgical decompression that aims to
improve neurological outcome without a strong indication for
the treatment of spinal column instability. As mentioned ear-
lier, physical compression of the spinal cord is responsible for
triggering an ongoing series of deleterious cascades, and surgi-
cal decompression aims to relieve this compression. Evidence
is mounting for improved outcomes in this setting and we will
review these concepts here.
One of the parameters to consider when studying the
effect of surgical decompression after SCI is the timing of
this decompression. There is no definition of this timing
although most authors and spinal surgeons would agree that
early surgery is that which is performed within 24 hours of
initial injury. A great deal of the preclinical animal literature
focuses on timing of surgical decompression at much ear-
lier times following injury, in the range of 8 to 24 hours.
These animal studies consistently report improved neurologi-
cal outcomes with early decompression. There have been a
number of recent systematic literature reviews that address
previous preclinical and clinical research.44,50,51 Perhaps the
main force behind these reviews is not only to get a firm grasp
on what has been accomplished to date but to form a clear
rationale for proceeding with clinical trials in the future. Pre-
liminary results from the Surgical Treatment of Acute Spinal
Cord Injuries Trial (STASCIS) indicate that decompression
within 24 hours of injury may actually improve outcome
in patients with isolated SCI.52 Based on both animal stud-
ies and recent clinical investigations guidelines have been
formed that recommend surgical decompression within 24
hours for cervical SCI. Very early decompression, within 12
hours of injury, should be strongly considered for patients
suffering incomplete cervical SCI or those who are deteriorat-
ing neurologically.
CONCLUSIONS
Throughout the course of this chapter we have discussed how
rigorous study of SCI has led to a detailed understanding of the
pathophysiological mechanisms that follow a traumatic event.
The paradigm of secondary injury has opened the door for many
research projects ranging from apoptosis to neuroprotection.
Each of these research avenues has, in turn, resulted in trans-
lational research initiatives aimed at preserving and restoring
neurological function. Lastly, many of these translational ideas
have resulted in clinical practices that result in better outcomes
for patients that suffer an SCI. We have therefore presented a
spectrum of thought, ranging from the molecular level to cel-
lular interactions to the neurological movement and sensation
that is transmitted through the spinal cord. It is through these
research programs and their clinical application that we are able
to advance science and our understanding of how to repair the
spinal cord or prevent further neurological damage after SCI.
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Fehlings MG, Perrin RG. The timing of surgical intervention in
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Please go to expertconsult.com to view the complete list of
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