Review

J Vet Intern Med 1999;13:399–407

Current Concepts in the Management of Acute Spinal Cord Injury

Natasha Olby

Acute injury to the spinal cord initiates a sequence of vascular, biochemical, and inflammatory events that result in the development
of secondary tissue damage. Experimental studies and clinical trials in humans have demonstrated that the extent of this secondary
tissue damage can be limited by pharmacologic intervention at appropriate intervals after injury. High doses of methylprednisolone
sodium succinate (MPSS) improve the outcome of acute spinal cord injury in humans if treatment is initiated within 8 hours of
injury. Starting therapy more than 8 hours after injury is detrimental to outcome. The clinical efficacy of methylprednisolone in
improving the outcome of canine spinal cord injuries has not yet been demonstrated and its use by veterinarians is controversial.
Many dogs are not seen by a veterinarian within the 8-hour window after injury, and these dogs frequently are treated with
nonsteroidal anti-inflammatory drugs or large doses of dexamethasone or prednisone before methylprednisolone treatment can be
initiated, thus increasing the risk of severe adverse effects. Other drugs that may provide safer and more effective alternatives to
methylprednisolone include thyrotropin-releasing hormone (TRH), the 21-aminosteroids, and kappa opioid agonists. Recent studies
suggest that modulation of the influx of inflammatory cells and activation of endogenous microglial cells may provide another
means of improving the outcome of acute spinal cord injuries. Many drugs being developed to treat acute spinal cord injury have
shown promising results when evaluated experimentally. However, any proposed therapeutic strategy should be evaluated in pro-
spective blinded clinical trials before being adopted in clinics.
Key words: Disk disease; Methylprednisolone; Secondary injury; Spinal cord trauma; Thyrotropin-releasing hormone.

A cute spinal cord injuries form an important part of the

case load of veterinarians in general and specialty
practice. Such injuries are most commonly the result of
explosive protrusion of an intervertebral disc causing both
concussion and compression of the spinal cord. Other caus-
es include fractures, dislocation, or subluxation of the ver-
tebral column potentially causing laceration, compression,
or concussion of the spinal cord; infarction (usually the
result of a fibrocartilagenous embolus); and gun shot
wounds causing laceration of the spinal cord. Although re-
covery from incomplete spinal cord injuries is good, with
the majority of animals regaining motor function,1,2 animals
with more severe injuries have a much poorer prognosis.3
Treatment of spinal cord injuries by veterinarians has in
the past been aimed at surgical decompression of the spinal
cord where indicated, stabilization of the vertebral column,
and strict rest.4 Corticosteroids have been used historically
with the aim of decreasing spinal cord swelling. More re-
cently, high doses of corticosteroids with free radical scav-
enging properties have been recommended after reports of
successful clinical trials in humans.5,6 However, the current
interest in treating central nervous system (CNS) injuries
has led to a large number of often contradictory drug trials
that have been published over the last 2 decades. As a re-
sult, considerable controversy exists over the most appro-
priate way to manage acute spinal cord injury. Much of this
controversy is a result of the difficulty of performing ex-
From the College of Veterinary Medicine, North Carolina State Uni-
versity, Raleigh, NC.
Reprint requests: Natasha Olby, Vet MB, PhD, Department of Com-
panion Animals and Special Species, College of Veterinary Medicine,
North Carolina State University, 4700 Hillsborough Street, Raleigh,
NC 27606; e-mail: natashapolby@csu.edu.
Received March 23, 1998; Revised September 1, 1998 and Decem-
ber 22, 1998; Accepted February 16, 1999.
Copyright q 1999 by the American College of Veterinary Internal
Medicine
0891-6640/99/1305-0002/$3.00/0
perimental drug trials. A useful experimental model of spi-
nal cord injury should fulfill several criteria including pro-
duction of reproducible, quantifiable pathologic changes
comparable to clinical lesions and production of measurable
neurologic deficits. Models of spinal cord injury have been
developed to mimic concussion of the cord,7 compression
of the cord,8 and spinal cord ischemia.9 Most of these mod-
els fulfill 1 or more of the above criteria, but a common
problem is lack of lesion reproducibility.10 The resultant
decrease in the statistical power of the model necessitates
the use of large numbers of animals in experimental groups
to establish significant differences. Conflicting conclusions
drawn by different groups testing the same treatment par-
adigm often can be ascribed to inadequate group size as
well as to the use of different models and different methods
of assessing the effect of a treatment. When interpreting the
results of such an experiment, it is necessary to assess in-
tragroup variability, the parameters that have been mea-
sured, and the relevance of the model to the clinical situ-
ation in which its findings may be used.
With the exception of injuries that cause lacerations of
the spinal cord, the primary tissue damage that occurs at
the time of injury is minor when compared to the secondary
damage that develops over the next 48 hours. The period
after an injury can be divided into 3 different therapeutic
windows: biochemical and vascular events, starting at the
time of injury and continuing for up to 48 hours; the influ-
ence of inflammatory cells, starting within hours of injury
and peaking at 4 days after injury; and axonal regeneration
and lesion repair (CNS plasticity) from 1 week after injury.
This paper has 3 goals: first, to review the pathophysi-
ology of the development of secondary tissue damage fo-
cusing on vascular, biochemical, and inflammmatory
events; second, to review experimental and clinical thera-
peutic trials targeted at the developing lesion and the in-
flammatory response; and third, to highlight those treatment
strategies that have been shown to have a beneficial effect
clinically. Research developments in transplantation and the
400
use of growth factors aimed at promoting axonal regener-
ation and CNS plasticity have been reviewed elsewhere.11–14
Vascular and Biochemical Events During
Lesion Development: Pathophysiology and
Therapeutic Strategies
Vascular Abnormalities
Acute injury to the spinal cord causes both systemic and
local vascular abnormalities, which ultimately result in a
progressive decrease in perfusion and necrosis of the in-
jured section of the spinal cord.15–19 The development of
spinal cord ischemia has been proposed to be one of the
fundamental causes of secondary tissue damage.20 The de-
crease in spinal cord perfusion develops over several hours,
giving clinicians the opportunity for therapeutic interven-
tion. The abnormalities that occur have been reviewed in
detail,20 and can be summarized as follows
Initial Systemic Hypertension. Initial systemic hyperten-
sion is followed within 10 minutes by sympathetic paralysis
and hypotension that is maintained for several hours.21–25
These changes occur in the rat,25 cat,23 dog,21 and primate.22
The severity of the changes is dependent on the degree of
injury.
Progressive Decrease in Spinal Cord Blood Flow. This
change is the result of loss of autoregulation (see below),
destruction of microvasculature,20 thrombus formation,26,27
and vasospasm induced by increased intracellular calcium
concentrations28 and release of vasoactive chemicals such
as prostanoids.29 These events affect gray matter before
white matter and in severe injuries have been maintained
for up to 7 days after injury.30,31 In less severe injuries,
reactive hyperemia of the damaged cord may occur.30
Loss of Autoregulation. The spinal cord can normally
maintain constant blood flow in the face of changing sys-
temic blood pressure, but this property is lost after inju-
ry.23,32,33
Spinal cord blood flow and injury severity are inversely
related,28 and many treatments therefore are aimed at sup-
porting spinal cord blood flow. Decreasing systemic blood
pressure results in a decrease in spinal cord perfusion be-
cause of loss of autoregulation,34 and therefore supporting
systemic blood pressure has been proposed to support spi-
nal cord blood flow.20 Maintaining systemic blood pressure
with pressors, whole blood transfusions, or dextran will im-
prove spinal cord perfusion postinjury,35,36 but only 1 study
has demonstrated an improvement in spinal cord function.37
Moreover, hypertension does not result in an increase in
spinal cord blood flow, and indeed may increase chances
of hemorrhage and edema.38,39 The importance of maintain-
ing systemic blood pressure has become more apparent in
studies testing other drugs. For example the calcium chan-
nel blocker nimodipine has been demonstrated to improve
axonal function and spinal cord blood flow after injury
when used in combination with dextran to maintain system-
ic blood pressure.28 In view of the importance of systemic
blood pressure, the recommended procedure when manag-
ing acute spinal cord injury is to maintain normotension.20
This is important to bear in mind as many veterinary pa-
tients undergo prolonged general anesthesia for myelogra-
phy and surgery soon after severe spinal cord injuries. Al-
Olby
though 1 study has demonstrated a neuroprotective effect
of halothane anesthesia (postulated to be the result of a
direct vasodilatory effect),40 this effect was only apparent
when halothane anesthesia was administered at the time of
injury, a delay of even 10 minutes abolished any benefits.
Several different classes of drugs have been demonstrat-
ed to improve spinal cord blood flow after injury as a result
of local effects on the vasculature. These include calcium
channel antagonists,28,29 nonsteroidal anti-inflammatory
agents,29 free radical scavengers,29 and opioid antagonists
such as naloxone.41,42 These drugs will be discussed further
in the appropriate sections below.
Biochemical Events
The complex sequence of biochemical events initiated by
trauma to the spinal cord has been reviewed elsewhere.15–19
Separate events are summarized below.
Increases in Intracellular Calcium. After acute trau-
matic spinal cord injury, a rapid increase in intracellular
calcium concentrations occurs.43,44 The routes of calcium
entry include direct membrane damage, voltage-gated cal-
cium channels triggered by membrane depolarization, and
activation of N-methyl D-aspartate (NMDA) receptors by
the excitatory neurotransmitter glutamate. The increase in
calcium results in activation of intracellular proteases and
phospholipase A2, impairment of mitochondrial function,
spasm of vascular smooth muscle, and binding of phos-
phates by calcium, thus depleting the cell of energy sourc-
es.45
The calcium channel antagonist nimodipine has been
shown to improve posttraumatic spinal cord blood flow and
axonal function in the rat when used at a dosage of 0.02
mg/kg for 1 hour in combination with dextran to support
systemic blood pressure.28 Nimodipine also supported spi-
nal cord blood flow when used in baboons with compres-
sive spinal cord lesions at a dosage of 0.02 mg/kg/hour for
2 hours and then 0.04 mg/kg/hour for 1 week.46 Neither of
these studies evaluated functional recovery. Other groups,
using similar injury models and comparable drug regimes,
have been unable to demonstrate a beneficial effect of ni-
modipine in spinal cord injury, bringing the efficacy of ni-
modipine into question.47–49 Other calcium channel blockers
also have been evaluated. Pretreatment with diltiazem (150
mg/kg given as a bolus IV 30 minutes before injury fol-
lowed by 5 mg/kg/minute as a constant-rate IV infusion for
4 hours) and nifedipine (10 mg/kg given as a bolus IV 30
minutes before injury followed by 1 mg/kg/minute as a con-
stant rate IV infusion for 4 hours) in a weight drop model
of spinal cord injury in the cat resulted in an improvement
in spinal cord blood flow.29 Verapamil did not produce this
effect. In the same study, animals treated with calcium
channel antagonists did not improve to the same extent as
those treated with the antioxidants vitamin E and selenium.
Flunarizine has been evaluated in a model of acute spinal
cord injury in the cat, and proved more effective than meth-
ylprednisolone. Unfortunately, this study only demonstrated
a greater restoration of somatosensory evoked potential am-
plitudes at 4 hours after injury. Flunarizine had no effect
on spinal cord blood flow, and a full functional study was
not performed.45 Drug treatment in these studies was insti-
 Acute Spinal Cord Injury
tuted either before or immediately after injury, and the ef-
fects of delaying treatment were not examined.
Calcium channel antagonists in combination with a pres-
sor may provide a useful clinical treatment for spinal cord
injury in the future.50 However, experimental studies eval-
uated indirect markers of recovery, with few studies eval-
uating functional recovery. This class of drug has not been
tested in clinical trials on spinal cord injury, and the clinical
efficacy of calcium channel blockers remains unclear at
present.
Free Radical Production. Demopoulos et al.51 suggested
that free radical-induced lipid peroxidative damage to mem-
branes was a major factor causing secondary tissue destruc-
tion after spinal cord injury. Increased intracellular calcium
concentrations, ischemic conditions, reperfusion, and the
presence of iron and copper complexes in petechial hem-
orrhages all contribute to the production of free radicals.52,53
When the intrinsic protective free radical scavenging sys-
tems are overwhelmed, free radicals start to react with cell
enzymes and unsaturated fatty acids in cell membranes,
causing lipid peroxidation. The result is direct lipid per-
oxidative damage of neuronal and glial cell membranes. In
addition, peroxidation of endothelial cell membranes trig-
gers platelet aggregation, which results in intensification
and extension of the area of posttraumatic spinal cord is-
chemia.28,51,53
Pretreatment of cats for 5 days with a combination of the
free radical scavengers vitamin E (1,000 IU/day) and se-
lenium (50 mg/day) has been shown to preserve spinal cord
perfusion28 and improve neurologic outcome after spinal
cord injury.54 The length of time required for these anti-
oxidants to reach therapeutic concentrations in the CNS
precludes their use after acute spinal cord injury, and de-
velopment of other drugs for this purpose has been neces-
sary. The most notable of these drugs is methylprednisolone
sodium succinate (MPSS). MPSS is a glucocorticoid that
has free radical scavenging properties when used at very
high dosages.52,53 Many experimental studies using models
of both acute spinal cord concussion and compression have
demonstrated that MPSS has a neuroprotective effect when
given at the time of or within minutes after spinal cord
injury.55–59 Despite variation in reported dosage regimes, the
common aim is to maintain therapeutic concentrations of
MPSS in the spinal cord during the 24–48 hours of lesion
development.
Multicenter clinical trials have tested the use of MPSS
in humans after acute spinal cord injury and have demon-
strated a positive outcome when MPSS is given within 8
hours of injury.5,6 Patients received an initial IV bolus of
30 mg/kg of MPSS followed by an IV infusion of 5.4 mg/
kg/hour of MPSS for 24 hours. The clinically detectable
benefits are small but significant and involve both long tract
and segmental function.60 These trials also demonstrated
that initiation of MPSS treatment in those patients with in-
complete injuries more than 8 hours after injury resulted in
a worse outcome.6,60 The proposed mechanism for this find-
ing is that glucocorticoids interfere with normal regenera-
tion61,62 and will enhance neurodegeneration by inhibiting
neuronal glucose uptake in the face of ischemia and glu-
tamate-induced damage.63,64 MPSS should therefore be giv-
en within 8 hours after spinal cord injury, when consider-
401
able free radical-induced damage is occurring. A more re-
cent clinical trial in humans demonstrated that if treatment
with MPSS is initiated within 3 hours of injury, a regime
that continues a maintenance infusion of the drug for 24
hours should be used.65 If treatment is initiated between 3
and 8 hours after injury, the infusion should be continued
for 48 hours.65 The same study demonstrated increased oc-
currence of severe pneumonia and sepsis when MPSS treat-
ment was continued for 48 hours, but this finding was not
associated with increased mortality. In another clinical
study, high doses of MPSS in acute spinal cord injury were
associated with prolonged hospitalization as a result of ste-
roid-related adverse effects. This study questioned the ben-
efits of MPSS use.66 Despite the positive reports on the use
of MPSS in spinal cord injury, use of this drug remains
controversial.
In veterinary neurology, a similar controversy exists con-
cerning the beneficial effects of MPSS on the injured spinal
cord. A study by Coates et al67 failed to demonstrate a pro-
tective effect of MPSS in a model of spinal cord injury in
dogs. However, only 4 animals were used to test MPSS and
such a small number would only demonstrate a difference
if the model were extremely reproducible. In contrast, an-
other study found a beneficial effect of MPSS in dogs un-
dergoing spinal surgery, but no controls were included, and
the relevance of these findings was unclear.68 As a result, it
is still uncertain whether the use of MPSS is helpful in dogs
with spinal cord injury. Most experimental and clinical ev-
idence in other species indicates that MPSS is beneficial,
but only when given within a certain time period after in-
jury and following a particular dosage regimen. The regi-
men recommended for cats is to start with an initial dosage
of 30 mg/kg IV, followed at 2 and 6 hours with dosages of
15 mg/kg and then to continue with an IV infusion of 2.5
mg/kg/hour for 42 hours.53 The regimen adopted by Sie-
mering and Vomering68 for dogs before performing spinal
surgery was to give an initial IV bolus of 30 mg/kg fol-
lowed by a 24-hour continuous IV infusion of 5.4 mg/kg/
hour as in the clinical trials in humans. However, little in-
formation is available on the optimal dosage regimen in
dogs.
High doses of MPSS are associated with several prob-
lems in veterinary patients. A recent study of dogs under-
going spinal surgery that received a single bolus of 30 mg/
kg of MPSS followed by a second half to full dose 2–4
hours later reported that 90% of the dogs developed occult
gastrointestinal hemorrhage.69 Unfortunately, many patients
with spinal cord injuries that are seen at referral institutions
already have been treated with large doses of prednisone,
dexamethasone, or a nonsteroidal anti-inflammatory agent.
How such treatment would influence the effect of subse-
quent treatment with MPSS is not known, but such com-
binations of drugs may predispose the patient to the adverse
effects of high doses of MPSS. Another important consid-
eration is the time interval after injury. In referred patients,
this interval is often greater than 8 hours, and experience
in clinical trials involving humans suggests that the use of
MPSS is contraindicated in such patients.60 As a result of
the potential adverse effects of MPSS use and the limited
efficacy of this drug, care should be exercised before using
it. MPSS should be reserved for patients with severe spinal
402
cord injuries that have occurred within 8 hours of presen-
tation and that have not been pretreated with other steroids.
Some veterinary institutions pretreat dogs with MPSS
when performing potentially traumatic procedures such as
myelography and spinal surgery. Although seemingly log-
ical, the benefits of such MPSS use are unclear. The main
concern is that the animal has already suffered an acute
spinal cord injury more than 8 hours previously, and further
doses of MPSS may be detrimental. Five days of pretreat-
ment with vitamin E and selenium may be considered
whenever an elective procedure that may result in trauma
to the spinal cord is to be performed. This approach has
the advantage of affording a similar degree of neuroprotec-
tion as MPSS without the potential detrimental effects.28
The adverse effects associated with high doses of MPSS
have led to controversy over their use66 and have resulted
in development of the 21-aminosteroids. These drugs are
similar in structure to MPSS but lack the glucocorticoid
receptor-mediated effects. These drugs have been effective
in experimental studies in cats70,71 and rats57,72 but not in
dogs.67 One of these drugs (tirilazad mesylate or U74006F)
recently was assessed in clinical trials in humans (NASCIS
3)65 in which a 48-hour dosage regimen was shown to have
efficacy similar to that of MPSS if initiated within 3 hours
of injury. However, tirilazad was shown to be inferior to
MPSS when treatment was initiated more than 3 hours after
injury.65 A drawback of this study was that all patients re-
cieved an initial bolus of 30 mg/kg of MPSS (as a result
of the demonstrated benefits of MPSS) and objective eval-
uation of the true efficacy of tirilazad is difficult. In addi-
tion, an optimal dosage regimen for tirilazad has yet to be
determined. Further clinical trials on the use of tirilazad to
treat acute spinal cord injury are planned.
The use of large doses of dexamethasone by veterinarians
with the aim of reducing posttraumatic spinal cord swelling
is widespread. However, experimental trials examining the
efficacy of dexamethasone have failed to show a beneficial
effect.73,74 Moreover, evidence exists that glucocorticoids
can be detrimental61–64 and the use of high doses of dexa-
methasone in the treatment of acute spinal cord injuries
should be avoided. Anti-inflammatory doses of prednisone
commonly are used for dogs with thoracolumbar and cer-
vical spinal pain. However, such dogs are at increased risk
of gastrointestinal hemorrhage, and care should be taken to
ensure that the animal is adequately confined while on pred-
nisone.
The ability of the free radical scavenger dimethyl sulf-
oxide (DMSO) to decrease the severity of spinal cord injury
has been investigated in rats,75 cats,73 and dogs.76,77 How-
ever, results have been conflicting, varying from providing
good neuroprotection81 to no apparent effect.73,76 The stud-
ies used similar dosage regimens for DMSO, and why such
discrepancy exists in the results is not clear. However, all
of these studies were performed at least 15 years ago, when
physiologic parameters such as systemic blood pressure and
end tidal carbon dioxide concentrations were not controlled.
A study of the effect of DMSO on the circulation of the
dog showed that a dosage of 2 g/kg (ie, the standard initial
bolus used in the treatment of experimental spinal cord
trauma) caused significant hemolysis with a decrease in he-
matocrit and a significant decrease in spinal cord blood
Olby
flow.78 Concern also exists about other toxic effects such
as fever and renal toxicity.18,50
Increases in Excitatory Amino Acids. Extracellular con-
centrations of the excitatory amino acids (EAAs) glutamate
and aspartate are increased after trauma because of depo-
larization-induced release, release from damaged neurons,
and decreased uptake by ischemic astrocytes.79 These amino
acids interact with NMDA and non-NMDA receptors caus-
ing a rapid increase in intracellular sodium concentration
and cellular swelling, and a slower increase in intracellular
calcium concentration.79 The toxicity of excess EAAs has
been demonstrated conclusively both in vitro and in
vivo.79,80 Moreover, after acute thoracolumbar intervertebral
disc herniation in dogs, the concentration of glutamate in
lumbar cerebrospinal fluid is increased in proportion to the
severity of the injury.81 NMDA and non-NMDA receptor
antagonists such as MK801, thienylphencyclidine, and
NBQX have been tested in ischemic, concussive, and com-
pressive models of spinal cord injury in the rat.82–85 These
studies all demonstrated improvement in functional recov-
ery, but unfortunately these drugs can cause adverse effects
including sedation and ataxia, motor stimulation, cardio-
vascular changes, and vacuolation of certain neuronal pop-
ulations.86 Therefore, the search for drugs that counteract
the toxic effects of EAAs with minimal adverse effects is
continuing.
Endorphin-Associated Ischemia. The importance of en-
dorphins in mediating local ischemia in the injured spinal
cord is well recognized.42,87 Naloxone, a nonspecific opioid
antagonist, supports systemic blood pressure and spinal
cord blood flow in models of spinal cord injury in the rat
and cat, resulting in an improvement in functional out-
come.42,74,87,88 A clinical trial of the efficacy of naloxone in
humans, using a 5.4 mg/kg IV bolus, followed by 4 mg/
kg/hour constant-rate infusion for 23 hours, revealed im-
provement in descending motor function in patients with
incomplete spinal cord injuries if administered within 8
hours of injury.60 Because naloxone is both more expensive
and less effective than MPSS it is not used routinely.60
Research associated with manipulation of the endoge-
nous opioids is concentrated on k-opioid agonists (eg, U-
50488H) and antagonists (eg, nalmefene). Paradoxically,
both of these drugs improve the functional outcome of
acute spinal cord injury in rats.89–91 A good explanation for
these results has not been provided, but it is believed to be
due either to nonopioid actions of the drugs, or to action at
distinct k-receptor subtypes.90 The k-opioid agonist CI-977
exerts a neuroprotective effect on experimental models of
cerebral ischemia by its ability to decrease glutamate re-
lease.92 However, in a model of spinal cord ischemia, CI-
977 had a detrimental effect believed to be the result of a
decrease in systemic blood pressure.93 The development of
both k-opioid agonists and antagonists is continuing, but as
yet no drug has emerged that is superior to MPSS.
The Role of Thyrotropin-Releasing Hormone
(TRH)
TRH has a wide variety of physiologic actions in addi-
tion to its well-known effect on production and release of
thyroxine. These include the ability to block the autonomic
 Acute Spinal Cord Injury
effects of opioids41 and antagonism of the effects of both
vasoactive agents94,95 and EAAs.96 Treatment with TRH (0.2
mg/kg/hour IV) after experimental spinal cord injury in the
cat improves functional outcome,74,97 even when adminis-
tration is delayed for up to 1 week after injury.98 This per-
haps is a result of TRH’s neurotrophic effects, influences
on plasticity, and facilitation of motor neuron firing.57 Sub-
sequent studies in cats and rats also have demonstrated that
the use of TRH and its analog in spinal cord injury is ben-
eficial and superior to naloxone, MPSS, U-50488H, and
nalmefene.74,75,90 Only 1 study failed to demonstrate a pos-
itive effect from the use of TRH in cats, but this study
suffered from having only 4 animals per treatment group.99
TRH has passed the 1st phase of clinical trials in humans
(at a dosage of 0.2 mg/kg initial IV bolus followed by a 6-
hour IV infusion of 0.2 mg/kg/hour initiated within 12
hours of injury).100 TRH has disadvantages, including its
analeptic, endocrine, and autonomic effects, but a new gen-
eration of TRH analogs has been developed that have the
protective effects of TRH without its adverse effects.101
These drugs could be of use to veterinarians both because
of their beneficial effect even when given at intervals of up
to 1 week after injury, and also because of their apparent
superiority to other drugs.
The Inflammatory Response: Pathophysiology
and Therapeutic Strategies
The inflammatory response to CNS damage results in the
production of a variety of cytotoxic and protective
agents.102–106 Therefore, it is not surprising that the role
played by the inflammatory response in the development of
secondary spinal cord damage is controversial. Recruitment
of inflammatory cells into spinal cord lesions lags behind
the development of acute secondary cell death,107 but co-
incides with demyelination of surviving axons and chronic
neuronal death.108–110 Several studies have reported that in-
hibiting the infiltration of mononuclear cells after spinal
cord injury is beneficial.111–114 The delayed pathologic effect
of macrophages infiltrating the damaged spinal cord of the
guinea pig is thought to be a consequence of their produc-
tion of the NMDA agonist quinolinic acid. This hypothesis
is supported by the observation that antagonists to quino-
linate reduce the severity of delayed injury.106 However, not
all species produce significant amounts of quinolinic acid
and the clinical importance of this finding remains to be
assessed in the dog and cat.
The situation is further complicated when the microglial
cell is considered. Microglial cells are the endogenous
phagocytic cells of the CNS, and can release potentially
cytotoxic chemicals such as hydrogen peroxide, nitric ox-
ide, proteinases, and the cytokines interleukin-1 (IL-1) and
tumour necrosis factor-a within minutes of injury.102,104 Ad-
ministration of an IL-1 receptor antagonist at 30 minutes
before and 10 minutes after inducing cerebral ischemia in
the rat significantly decreased infarct volume and this effect
was thought to be due to antagonism of IL-1 produced by
microglial cells.115 The presence of such cytokines in the
injured spinal cord has been described,116 but their role in
the production of secondary tissue damage has yet to be
investigated in detail. One study demonstrated marked neu-
403
roprotection in rats after spinal cord injury by administering
lipopolysaccharide to increase the release of growth-pro-
moting cytokines, in combination with a nonsteroidal anti-
inflammatory agent and steroid, to suppress the effects of
cytotoxic cytokines.117 However, this finding has not been
reproduced by other groups.
The neuroprotective effect of MPSS may be due in part
to glucocorticoid receptor-mediated inhibition of phospho-
lipase A2.58 However, MPSS has no effect on postinjury
concentrations of the products of phospholipase A2 activa-
tion, supporting the hypothesis that MPSS’s neuroprotective
action is mediated by free radical scavenging rather than
anti-inflammatory actions.59
Miscellaneous Therapeutic Strategies
Gangliosides
Gangliosides are lipid components of the outer bilayer of
plasma membranes that play vital roles in the normal func-
tion of the nervous system.118 Several studies have shown
the ganglioside GM1 to attenuate the effects of EAAs, be
neuroprotective in acute CNS injury, and to potentiate the
effect of neurotrophic factors.118 The ganglioside GM1 was
tested for efficacy in improving the outcome of acute spinal
cord injury in a small-scale clinical trial in humans and was
found to be beneficial when given as late as 48–72 hours
after injury at a dosage of 100 mg IV per day for 3–4
weeks.119 A subsequent experimental study failed to dem-
onstrate a beneficial effect of GM1 when used to treat spi-
nal cord trauma in the rat, and in addition suggested that
GM1 antagonized the effect of MPSS.58 Larger-scale clin-
ical trials using GM1 in combination with an initial IV bo-
lus of MPSS have just been completed and suggest that
GM1 has a small beneficial effect when used in this way.120
Hypothermia
A decrease in brain temperature is remarkably neuropro-
tective after an ischemic insult.121 The neuroprotective
mechanisms of hypothermia include decreasing the rate of
depletion of high-energy phosphates, decreasing the extra-
cellular concentrations of glutamate and other neurotrans-
mitters, and decreasing activation of enzymes such as pro-
tein kinase II.121 The effect of hypothermia on acute spinal
cord injury also has been evaluated. The original trials per-
formed in the 1970s involved prolonged perfusion (2.5
hours) of previously injured spinal cord with isotonic saline
(58C) to achieve a spinal cord temperature of approximately
108C. These studies demonstrated neuroprotection even
when hypothermia was initiated 3–6 hours after injury.122
This finding led to trials in humans that failed because of
a high mortality rate (apparently due to respiratory com-
plications in cervical injuries) and the difficulty of a tech-
nique that required early surgical intervention to perform a
multilevel laminectomy to expose the spinal cord.122 More
recently, very modest decreases in brain temperature (1–
38C) were found to be neuroprotective121 and interest in the
use of modest hypothermia as a treatment of spinal cord
injury has been renewed. A 1–38C drop in spinal cord tem-
perature may be achieved by decreasing rectal temperature
404
to 31–328C and studies are underway to assess the efficacy
of this approach.122
Cerebrospinal Fluid (CSF) Drainage
Recently CSF drainage has been adopted as a means of
maintaining cerebral perfusion pressure following acute
brain injury.123 The efficacy of CSF drainage at improving
the outcome of ischemic spinal cord injury has now been
evaluated.124 An increase in CSF pressure has been dem-
onstrated to decrease spinal cord blood flow.125 The aim of
CSF drainage is to maintain perfusion pressure within the
spinal cord and to prevent the decrease in spinal cord blood
flow that occurs after acute injury. The cited study found
that a combination of CSF drainage and the 21-aminoster-
oid tirilazad was most effective at reducing the severity of
spinal cord injury after acute spinal cord ischemia in the
rabbit.124
Conclusions
The experimental and clinical findings to date suggest
that the functional outcome of acute spinal cord injury in
humans, rats, and cats can be influenced by management
of systemic blood pressure and by the use of MPSS within
8 hours of injury. At present, whether use of MPSS in this
way is beneficial to dogs with acute spinal cord injuries is
not clear, but the efficacy of MPSS in other species is com-
pelling. Unfortunately, the clinical experience in humans
indicates that MPSS should be used only if it can be ad-
ministered within 8 hours of injury. In view of the time that
often elapses between injury and presentation of animals to
the veterinarian, treatment paradigms that can be instituted
after a longer delay from the time of injury (eg, TRH an-
alogs, GM1) and drugs that have not as yet been shown to
have the same detrimental effects as MPSS (eg, 21-ami-
nosteroids) should be studied. Little support exists for the
use of dexamethasone to treat acute spinal cord injuries,
and this practice is to be discouraged in light of the high
frequency of adverse gastrointestinal effects associated with
this drug and its potential detrimental effects on the recov-
ering nervous system. For those animals that are to undergo
elective procedures during which acute spinal cord injury
could occur, experimental evidence exists that prophylactic
use of a combination of vitamin E and selenium could be
beneficial.
New experimental treatment paradigms for acute spinal
cord injury are emerging, and a critical evaluation of each
study should be made in order to identify those that are
worth pursuing further. Double-blinded clinical trials form
the standard for adoption of treatment protocols in human
medicine, but few such trials have been performed on drugs
used in veterinary neurology. In order to establish the most
appropriate way of managing acute spinal cord injury in
small animals, large-scale prospective clinical trials should
be performed.
Acknowledgments
I would like to thank Dr Karen Muñana and Dr Nick
Sharp for their comments on this manuscript.
Olby
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