Review Article
Updates in the Early Management of Acute Spinal
Cord Injury
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Mark J. Lambrechts, MD
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/11/2023
Tariq Ziad Issa, BA
Alan S. Hilibrand, MD
From the Rothman Orthopaedic Institute,
Thomas Jefferson University, Philadelphia, PA.
Conflicts of Interest: The authors, their immediate
family, and any research foundation with which
they are affiliated did not receive any financial
payments or other benefits from any commercial
entity related to the subject of this article. There
are no relevant disclosures.
J Am Acad Orthop Surg 2023;31:e619-e632
DOI: 10.5435/JAAOS-D-23-00281
Copyright 2023 by the American Academy of
Orthopaedic Surgeons.
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Copyright © the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
ABSTRACT
Spinal cord injury (SCI) is a leading cause of disability worldwide, and
effective management is necessary to improve clinical outcomes.
Many long-standing therapies including early reduction and spinal cord
decompression, methylprednisolone administration, and optimization
of spinal cord perfusion have been around for decades; however, their
efficacy has remained controversial because of limited high-quality
data. This review article highlights studies surrounding the role of early
surgical decompression and its role in relieving mechanical pressure on
the microvascular circulation thereby reducing intraspinal pressure.
Furthermore, the article touches on the current role of
methylprednisolone and identifies promising studies evaluating
neuroprotective and neuroregenerative agents. Finally, this article
outlines the expanding body of literature evaluating mean arterial
pressure goals, cerebrospinal fluid drainage, and expansive duroplasty
to further optimize vascularization to the spinal cord. Overall, this review
aims to highlight evidence for SCI treatments and ongoing trials that
may markedly affect SCI care in the near future.
A
cute spinal cord injury (ASCI) remains a major cause of disability
worldwide with an incidence of 21 cases per 100,000 individuals in the
United States.1 Although the global incidence has decreased markedly
over the past 30 years, the global age standardized prevalence has increased
by 0.1% each year.2 In recent years, falls have surpassed motor vehicle
collisions as the leading cause of ASCI, due to a combination of improved
automobile safety regulations and more ASCIs in an aging population. Thus,
the average age of ASCI in the United States has risen from 29 to 43 years
between 1970 and 2019.3
As the global burden of spinal cord injury (SCI) remains high and demo-
graphics shift, it is important to understand contemporary evidence-based
treatment options to improve outcomes. The literature suggests that initial SCI
management is dependent on the amount of elapsed time since injury and the
degree of neurologic impairment. Treatment strategies rely on a mix of
hyperacute optimization, early surgical intervention, and medical manage-
ment. In this article, we provide landmark studies and recent clinical trials
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© American Academy of Orthopaedic Surgeons
 Spinal Cord Injury Management
investigating SCI management and provide an outlook
for the role of state-of-the-art therapies.
Acute Spinal Cord Injury Pathophysiology
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The pathophysiology of SCI is characterized by two
distinct stages. The primary hyperacute stage is defined
by direct mechanical trauma to the spinal cord
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and destruction of microvasculature, most commonly
due to compression from bone or disco-ligamentous
structures. The initial trauma can cause notable focal
neuronal damage, axonal injury, and vascular disruption
(Figure 1).
After the immediate mechanical sequelae, the sec-
ondary phase propagates further injury and neurologic
dysfunction. This phase, lasting hours up to
several months, can be temporally characterized as acute
(within 48 hours), hyperacute (48 hours to 2 weeks),
intermediate (2 weeks to 6 months), and chronic
(.6 months). Within minutes, cellular dysfunction leads
to disruption of the blood-spinal cord barrier, cell
membrane permeability, release of proapoptotic factors,
and proinflammatory cytokines including interleukin-
1a (IL-a), interleukin-1b (IL-1b), interleukin-6 (IL-6),
and tumor necrosis factor-a. As cellular transporters
become dysfunctional, intracellular components
including ATP, DNA, and potassium are recruited to the
injury site. Microglial infiltration results in the phago-
cytosis of injured cells and induces the release of free
radicals and glutamate. Glutamate is believed to play a
particularly important role in the acute to subacute
response. Excess extracellular glutamate leads to over
activation of cellular N-methyl-d-aspartate (NMDA)
and a-amino-3-hydroxy-5-methyl-4-isoxazole pro-
pionic acid (AMPA) receptors. These interactions lead
to notable ion shifts, with an influx of intracellular
Na1 and Ca21. Coupled with Na1/K1-ATPase dys-
regulation, this creates an excitotoxic environment that
hastens cell death and proliferates the inflammatory
cascade. As inflammation proliferates, the spinal cord
becomes edematous. This can result in complete
occlusion of cerebrospinal fluid (CSF) across the injury
site and eventually spinal cord compression from the
surrounding dura. This may result in hypoperfusion and
further axonal compromise.
After the inflammatory response subsides, the spinal
cord lesion evolves through intermediate and chronic
phases, resulting in necrosis of central cord gray matter,
cystic degeneration, glial scar formation, and several at-
tempts at remyelination. As glial scar tissue extends,
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axonal regeneration may be blocked, resulting in long-
term Wallerian degeneration.
Early Spinal Cord Decompression
Early reduction and/or decompression is the foundation
of acute SCI treatment. During the secondary phase of
injury, persistent mechanical cord compression ex-
acerbates local ischemia. This is highlighted by a retro-
spective study involving rugby players with ASCI after
cervical facet dislocation.4 Of the 32 who sustained an
American Spinal Injury Association (ASIA) Impairment
Scale (AIS) A injury, eight had reduction through trac-
tion within 4 hours of injury and five had a full neu-
rologic recovery. Only one of the remaining 24 players
who underwent reduction after 4 hours had even a
partial functional motor recovery. This suggests
reducing the length of cord ischemia is a critical factor in
mitigating long-term SCI.
The goal of early reduction and/or surgical interven-
tion is to quickly reduce intraspinal pressure (ISP), thus
restoring perfusion to the spinal cord. The Surgical
Timing in Acute Spinal Cord Injury Study (STACSIS)5
served as the landmark trial demonstrating the efficacy of
early reduction and/or decompression after ASCI. In
their study, 182 patients with cervical ASCI underwent
early intervention (,24 hours), while 131 patients
underwent late intervention (.24 hours). Early inter-
vention was independently associated with higher odds
of two-grade AIS improvement by 6 months (OR = 2.83,
95% CI, 1.10–7.28).5
More recently, evidence is emerging that early
decompression within 24 hours may also lead to sub-
stantially improved neurologic outcomes in central cord
syndrome. An analysis of three international prospec-
tively collected data sets compared intervention before
and after 24 hours in patients with central cord syn-
drome. Six patients undergoing early surgical inter-
vention demonstrated greater improvement in upper
limb motor recovery at 1 year. In addition, subgroup
analysis of patients with AIS C injuries found greater
overall motor recovery in patients receiving early
intervention (Table 1).6
Owing to the limited evidence on the topic at the time,
AO Spine made a weak recommendation favoring sur-
gical decompression within 24 hours of injury in 2017.7
A more recent meta-analysis of four data sets totaling
1,548 patients with acute cervical SCI (528 early
decompression and 1,020 late decompression) identified
patients undergoing early surgery experienced greater
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© American Academy of Orthopaedic Surgeons
 Mark J. Lambrechts, MD, et al

Review Article
Figure 1
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A, Diagram showing that the primary injury to the spinal cord occurs through an inciting compression, shearing, or laceration force. This
propagates the secondary phase of injury during the next 0 to 48 hours and includes a combination of edema, hemorrhage, ischemia,
inflammatory cell infiltration, the release of cytotoxic products, and cell death. This injury phase may result in necrosis and/or apoptosis of neurons
and glial cells, which may cause neuronal demyelination. B, The subacute phase is defined as 2 to 4 days after injury and often is associated with
ischemia because of continued edema, vascular thrombosis, and vasospasm. Persistent inflammatory cell infiltration causes further cell death
along with vacuole formation within the spinal cord. Astrocytes proliferate and deposit extracellular matrix molecules into the perilesional area. C,
The 2-week to 6-month periods are the intermediate and chronic phases, whereby axons continue to degenerate and the astroglial scar matures
to become a potent inhibitor of regeneration. Cystic cavities coalesce to further restrict axonal regrowth and cell migration. This image was
republished with permission of AlphaMed Press, from Concise review: bridging the gap: novel neuroregenerative and neuroprotective strategies in
spinal cord injury, Ahuja, C. S. & Fehlings, M., Stem Cells Transl Med. 5:7;2016, permission conveyed through Copyright Clearance Center, Inc.

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 Spinal Cord Injury Management

Table 1. Studies Evaluating the Effect of Early Surgical Decompression on Neurologic Recovery
Study Patients Design Injury Time to Decompression Conclusion
Fehlings et al, 313 Multicenter, Traumatic Early: ,24h Early surgery is
20125 prospective cervical ASCI Late: .24h associated with 2.8
greater odds
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improvement of at least
two AIS grades.
Dvorak et al, 888 Multicenter, Traumatic ASCI Early: ,24h Early surgery is
201541 retrospectivea Late: .24h associated with 6.3 motor
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points additional recovery

in patients with AIS grade
B, C, or D, but not AIS A.
Early surgery also reduces
LOS.
Badhiwala et al, 1,548 Multicenter, Traumatic ASCI Early: ,24h Early surgery is
20218 retrospectivea Late: .24h associated with improved
sensorimotor recovery.
Badhiwala et al, 186 Multicenter, Central cord Early: ,24h Early surgery is
20226 retrospectivea syndrome Late: .24h associated with improved
upper limb motor recovery
in all patients and overall
motor function in AIS
Grade C patients.
Wutte et al, 43 Single-center, Traumatic Early: ,8h Although early surgery
202042 retrospective thoracic ASCI Late: .8h was not associated with
greater AIS improvement,
patients experienced
significantly improved
functional bladder and
mobility outcomes.
Burke et al, 48 Single-center, Traumatic Ultra-early: ,12h Ultra-early surgery was
201911 retrospective cervical ASCI Early: 12-24h associated with greater
Late: .24h improvement in AIS
grades compared with
early group (1.3 vs 0.5,
P = 0.02).
88.8% of AIS A patients
converted to better AIS
grade in the ultra-early
group, compared with
only 38.4% in the early
and late groups.
Nasi et al, 81 Single-center, Traumatic Ultra-early: ,12h Ultra-early surgical
201943 retrospective cervical ASCI Early: 12-48h decompression was
associated with greater
neurologic improvement.
Jug et al, 20199 64 Single-center, Traumatic ROC analysis to determine Decompression within 4
retrospective cervical ASCI optimal timing among hours (95% CI: 4-9 hours)
patients operated on within was the optimal window
24 for patients to experience
improvement of at least 2
AIS grades.
a
Retrospective analyses were done on prospectively collected and maintained data sets
ASCI = acute spinal cord injury, AIS = American Spinal Injury Association Impairment Scale, LOS = length of stay

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recovery and AIS scores at 1 year.8 The study also
identified that delays to intervention in the first 24 to 36
hours resulted in a steep decline in motor recovery.
However, after the 24- to 36-hour window, motor
recovery reached a stable trough. This study represents
the largest study and the best statistical rigor to strongly
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support early surgical decompression.
Several recent studies have evaluated ultra-early
decompression. A retrospective series of 64 patients
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with cervical ASCI used a bootstrap analysis and found
that the optimal timing to surgical decompression was
within 4 hours of injury to optimize the likelihood of $2
grade AIS improvement.9 Conversely, a separate mul-
ticenter study found that surgery within 5 hours did not
confer any improved outcomes compared with inter-
vention at 5 to 24 hours.10 A small retrospective analysis
of 48 patients with cervical ASCI found that interven-
tion within 12 hours of presentation improved
AIS grades by 1.3 points compared with only 0.5 in
patients who underwent decompression at 12 to 24
hours (Table 2).11
Most studies surrounding ASCI are limited to cervical
spine injuries because of the greater propensity for
improvement after rapid intervention. Thus, there is
limited available literature evaluating thoracolumbar
ASCIs. One retrospective study identified only patients
with thoracolumbar ASCIs and found that bowel and
bladder recovery was more likely in patients undergoing
surgical decompression within 8 hours of injury.12 A
separate study evaluated patients who underwent early
surgical decompression (,24 hours) versus late
decompression and found that motor recovery was
more likely in incomplete SCI, but no patient with
complete SCI regained motor function, regardless of the
time to intervention.13
The 2013 AANS guidelines encourage the earliest
possible transfer of patients with ASCI to appropriate
spinal cord designated medical facilities able to provide
definitive surgery and postsurgical care.15 However,
only 20% of patients with ASCI are transferred within 2
hours.14 In New South Wales, 60% of patients under-
went multiple transfers before reaching a dedicated
spinal cord injury unit, which on average took 12
hours.15 In Canada, only 34.2% of patients with trau-
matic ASCI reached surgery within 12 hours of arrival,
and a greater number of stops at intermediate care
centers were markedly associated with delayed arrival
(IRR = 7.70; 95% CI: 7.54, 7.86) and delayed surgery
(OR = 2.48; 95% CI: 1.35, 4.56).16
From a policy perspective, the threshold of 24 hours
from injury to decompression/injury reduction should
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Mark J. Lambrechts, MD, et al
Review Article
serve as the benchmark. Centers that have an intensive
care unit familiar with ASCI monitoring and on-call
spine surgeons should be a priority when establishing
care networks with emergency medical services. If earlier
timing thresholds are established, spinal cord injury
centers’ experiences with barriers to appropriate care
should initiate guidance on quality improvement ini-
tiatives to drive forward policy efforts.
Methylprednisolone
Steroid use was first conceived as an adjunct for SCI
management in 1969 when intramuscular dexa-
methasone and intrathecal depomethylprednisolone
were used in an animal model. MP has anti-inflammatory
properties including inhibition of proinflammatory
transcription factors NF-kB and AP-1, reduction of cell
autophagy, free radical scavenging, and inhibition of
proinflammatory cytokines, thereby theoretically
reducing the inflammatory response at the lesion site
and attenuating the secondary phase of injury.
Three multicenter double-blind randomized clinical
trials have served as the primary foundation of evidence
supporting the administration of post-SCI MP: National
Acute Spinal Cord Injury Study (NASCIS) I, II, and
III.17-19 In NASCIS I, which was conducted in 1984,
investigators compared high-dose MP (1,000 mg bolus
with 250 mg every 5 hours for 10 days) versus low-dose
MP (100 mg bolus with 25 mg every 6 hours for
10 days).17 They found no difference in recovery of
neurologic function in either group but did not include a
placebo group, presumably because it was deemed
unethical to withhold steroid treatment to patients with
SCI at the time. However, this study highlighted the
risks of high-dose steroids, which resulted in 3.1 times
higher odds of death at 14 days and a 1.92 higher
mortality rate by 28 days resulting in early NASCIS I
study termination.
In NASCIS II, patients were randomized to receive
steroids (30 mg/kg bolus with 5.4 mg/kg/hr maintenance
for 23 hours), naloxone, or placebo.18 Plegic patients
with total sensory loss who received steroids within 8
hours of injury experienced statistically significant im-
provements in motor function, pinprick, and touch
compared with placebo, which remained significant at
6 months. However, these differences disappeared in
patients who received MP more than 8 hours after
injury. Patients receiving naloxone had greater neuro-
logic improvements than placebo, but the naloxone and
steroid groups were not compared. Furthermore, it is
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Table 2.
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Summary of the 2017 AO Spine Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury
Category Recommendation
Copyright © the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
We suggest that early surgery (,24 hr) be
considered as an option in adult patients
with traumatic CCS.
We suggest that early surgery be offered
Surgery44 as an option for adult patients with ASCI,
regardless of level.
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We suggest not offering a 24 hr infusion of
September 1, 2023, Vol 31, No 17
high-dose MPSS to adult patients who
present after 8 hours with ASCI.
We suggest a 24-hour infusion of high-
dose MPSS be offered as an option to
----- adult patients with ASCI within 8 hours of
Steroids22
injury.
© American Academy of Orthopaedic Surgeons
We suggest not offering a 48 hr infusion
of high-dose MPSS to adult patients
with ASCI.
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Spinal Cord Injury Management
Quality of Evidence Recommendation Strength Rationale
Low Weak In the absence of strong evidence, the
potential for neurologic and functional
benefit identified in studies is likely of enough
importance that the potential benefits likely
outweigh possible harms.
Low Weak The included studies were downgraded for
imprecision or risk of bias. Although the
studies identified benefits to surgery at all
levels, many members of the GDG were
uncertain if these reported benefits met
clinical significance. However, without
differences in complications, the benefits
likely outweigh costs.
Moderate Weak The anticipated desirable effects are probably
not large relative to the undesirable effects,
given that MPSS administered after 8 hours
of injury does not result in statistically or
clinically significant improvements.
Considering all these factors, the GDG
voted that the undesirable consequences
probably outweigh the desirable
consequences in most settings.
Moderate Weak Pooled results at 6- or 12-month follow-up
indicated improvement in mean motor scores
in the treatment group compared with control
subjects with a clinically important effect size.
Because of the positive effects, the GDG
voted that the clinically significant benefits
probably outweigh the low risk all these
factors, the GDG voted that the undesirable
consequences probably outweigh the low
risk of undesirable consequences.
N/A Weak No studies have demonstrated the efficacy
of 48 vs 24 hr infusion, but NASCIS III
demonstrated a higher risk of
complications. The risk for harm therefore
outweighs any unknown efficacy.
(continued )

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Table 2.
JAAOS®
(continued )
Category Recommendation
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----- We suggest that PPX be offered
routinely to reduce the risk of VTE in the
September 1, 2023, Vol 31, No 17
acute period after SCI.
We suggest that PPX, consisting of
either subcutaneous LMWH or fixed,
Anticoagulant
low-dose UFH, be offered to VTE risk in
thromboprophylaxis45
the acute period after SCI. We suggest
(PPX)
----- against adjusted-dose UFH due to the
increased risk of bleeding events.
© American Academy of Orthopaedic Surgeons
We suggest commencing PPX within the
first 72 hours after injury, if possible.
We suggest that MRI be performed in
adult patients with ASCI before surgery,
when feasible, to facilitate improved
clinical decision making.
The role of MRI in
decision making46
We suggest that MRI should be done in
adult patients with ASCI, before or after
surgical intervention, to improve
prediction of neurologic and functional
outcome.
Clinical Practice Guidelines were abstracted from the AO Spine Clinical Practice Guidelines. Although guidelines regarding the role of therapy were also published, these were not included in
our review.
ASCI = acute spinal cord injury, CCS = central cord syndrome, GDG = guideline development group, MPSS = methylprednisolone sodium succinate, LMWH = low-molecular-weight heparin,
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MRI = magnetic resonance imaging, NASCIS = National Acute Spinal Cord Injury Study, UFH = unfractionated heparin, VTE = venous thromboembolic event
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Quality of Evidence Recommendation Strength Rationale
Low Weak All evidence was rated as low quality.
Despite an absence of significant findings,
the GDG stated that PPX should be
prescribed routinely to reduce the risk of
VTE. The anticipated undesirable effects,
specifically treatment-associated
bleeding, are uncertain and vary between
prophylaxis strategies.
Low Weak The GDG believed that for the
comparisons of enoxaparin, dalteparin,
LMWH, and UFH, the anticipated benefits
and adverse effects were similar.
However, when comparing adjusted-dose,
fixed-dose, and low-dose UFH, the
bleeding consequences of adjusted-dose
UFH are higher.
Low Weak The GDG unanimously agreed that the
anticipated desirable effects to early PPX
are probably large, but the
recommendation is weak no VTE events
occurred in early or late groups to be able
identify any difference in risk.
Very low Weak The GDG considered that despite no direct
evidence that MRI influences decision
making, a weak recommendation is
warranted because MRI can identify
features that, if present, could alter clinical
management and, in turn, have a beneficial
effect on outcomes.
Low Weak Although the desirable effects are probably
small, MRI can help manage expectations
Mark J. Lambrechts, MD, et al
and inform patient’s potential outcomes. In
addition, the undesirable effects of
obtaining an MRI are small and providing
MRI is feasible to implement.
Review Article
 Spinal Cord Injury Management
unclear if the differences in sensory and motor recovery
between the steroid and placebo groups are clinically
significant, given the increases ranged from 5 to 11
points on a 70 point scale. In the final NASCIS III trial,
investigators compared the aforementioned steroid dose
for 24 or 48 hours. They found that patients who
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received MP 3 to 8 hours after injury, 48-hour dosing
regimens led to substantially greater recovery in motor
function.19
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The NASCIS trials were subject to notable limitations.
The original decision to stratify patients based on timing
of 8 hours postinjury was not explained. Moreover, the
effect size in neurologic recovery is very small in com-
parison with the risk of substantial complications.17-19
Along with the aforementioned limitations, in NASCIS
I, patients who received high-dose MP were more likely
to experience wound infections, pulmonary embolism,
sepsis, or death,17 and patients receiving MP in NASCIS
II were more likely to experience wound infections and
gastrointestinal bleeding.18 For patients receiving MP
for 48 hours, there was a greater likelihood of severe
sepsis and/or severe pneumonia in NASCIS III.19 More
recent studies have further demonstrated no notable
benefit to MP therapy, but patients have a markedly
greater complication profile casting further doubt about
the risk-benefit profile of steroid administration in pa-
tients with ASCI.20
Owing to the questionable evidence supporting the
benefits of MP, the 2013 AANS/CNS guidelines explicitly
recommend against routine MP administration for
ASCI.21 The most recent clinical practice guidelines
supported by AANS/CNS and AO Spine cited moderate
evidence that the NASCIS II protocol confers no benefit
in neurologic recovery.22 Furthermore, 48-hour MP
infusion, but not 24-hour MP, was associated with
increased risk of complications. Therefore, they offered
weak recommendations to offer a 24-hour infusion of
MP only to patients who present within 8 hours of injury.
Other Neuroprotective Agents
Riluzole
Riluzole, a benzothiazole approved for the treatment of
amyotrophic lateral sclerosis, has undergone several
preclinical trials that suggest it can improve motor
recovery by reducing neuronal loss, microglial infiltra-
tion, and neuronal apoptosis in the dorsal horn of the
gray matter. Riluzole may be neuroprotective by block-
ing ion transporters and mitigating presynaptic gluta-
mate release. A phase I human clinical trial
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(NCT00876889) demonstrated the safety of twice daily
50 mg riluzole for 2 weeks.23 A phase IIb/III trial
sponsored by AO Spine North America
(NCT01597518) had commenced in 2014 based on
early safety profile but was terminated in 2021 because
of enrollment challenges. Therefore, there is insufficient
evidence to recommend riluzole as an appropriate
treatment for patients with an ASCI at this time.
Minocycline
Minocycline is a tetracycline antibiotic that has demon-
strated neuroprotective properties in preclinical animal
models. Minocycline’s neuroprotective mechanisms are
secondary to its inhibition of tumor necrosis factor
alpha, IL-1b, cyclooxygenase-2 (COX2), and nitric
oxide synthase; inhibition of microglia; reduction in
oligodendrocyte apoptosis; and free radical neutraliza-
tion. A phase II trial randomized 52 patients with ASCI
to receive intravenous minocycline or placebo.24
Patients treated with minocycline experienced greater
motor recovery than those receiving placebo. Although
investigators found improved functional outcomes
with minocycline, this did not reach statistical signifi-
cance. A phase III clinical trial is currently under way
(NCT01828203).
Nonsteroidal Anti-inflammatory Drugs
NSAIDs are an alternative class of anti-inflammatory
agents that have shown promise in ASCI management.
Cyclooxygenase inhibition provides neuroprotective
benefits through a reduction in inflammation that is a
hallmark of the secondary phase of injury. Several studies
have found quantifiable reductions in spinal cord edema
after NSAID administration.25 Using myeloperoxidase
as a proxy for neutrophilic infiltration at the site of
injury, preclinical models have found substantial
reduction in MPO activity and cellular apoptosis in
murine models after NSAID administration.
Early evidence suggests that certain NSAIDs including
indomethacin and ibuprofen may also play a neuro-
regenerative role through Rho-A inhibition. The Rho-
A/ROCK pathway is an inhibitory pathway that blocks
neuron regeneration. Rho-A inhibition may therefore
increase axonal myelination, elongation, and sprouting.
Few studies have evaluated this specific mechanism, with
mixed results as to whether NSAIDs result in increased
axonal sprouting.25 Overall, 70% of studies found that
NSAIDs promoted greater recovery in neurologic
function than control groups.25 A separate meta-
analysis of 30 preclinical studies identified that Rho-
A/ROCK inhibition was associated with markedly
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© American Academy of Orthopaedic Surgeons

improved locomotor outcomes.26 To evaluate the role of
NSAIDs in humans, a recent European clinical trial
(NCT02096913) evaluated the pharmacokinetics and
safety of ibuprofen’s Rho-A inhibition in 12 patients
with SCI, although the results have not been published.
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Cellular Transplantation
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Stem cell therapy has ushered in a new frontier in SCI
research. Stem cells have the capacity for self-renewal,
differentiation into multiple cell lineages and can act to
directly replace injured cells or promote angiogenesis and
neural regeneration. Although human embryonic stem
cells (hESCs) are the archetypal stem cell, their use has
generated notable ethical and medico-legal debate
because of their oncogenicity and derivation from the
inner cell mass of a developing blastocyst, resulting in its
destruction. Attention has therefore shifted to stem cells
derived from other cell lineages. Bone marrow mesen-
chymal stem cells (BM-MSCs), in particular, have
emerged as a key driver of stem-cell research, comprising
more than 60% of currently registered trials investigating
MSCs in SCI.
A recent meta-analysis identified 11 comparative
studies comprising 499 total patients that compared
transplantation of MSCs with rehabilitation alone in
patients with ASCI.27 They identified notable improve-
ments in total AIS grade, sensory scores, and bladder
function in the MSC group without any serious or
permanent adverse events after cell transplantation.27 A
prospective randomized control trial of 70 patients with
chronic thoracic SCI (AIS A or B) compared monthly
intrathecal injections of autologous BM-MSCs with
physiotherapy with physiotherapy alone.28 In their
study, 34% of individuals receiving BM-MSCs
demonstrated improvement in AIS grade compared
with none of the patients in the physiotherapy-only
group.28 However, a phase III clinical trial of intra-
medullary and subdural autologous BM-MSCs found
that only 2 of 16 patients experienced improvement in
neurologic function, concluding that our current form
of stem-cell therapies, while safe, demonstrate little
therapeutic benefit (Table 3).29
Remarkably few human clinical trials exist evaluating
the use of stem-cell therapies in ASCI because most early
phase trials evaluate stem cells in patients with chronic
injury. Current technologies and cell expansion techni-
ques preclude the creation of enough autologous cells to
effectively use them in the early injury period. The only
clinical trial evaluating stem-cell therapies within the first
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Mark J. Lambrechts, MD, et al
Review Article
24 hours of injury used allogeneic umbilical MSCs
(U-MSCs) with collagen scaffolding in two patients with
complete ASCI.30 Both patients improved from AIS
grade A to C.30 Geffner et al administered BM-MSCs to
four patients with grade AIS A thoracic ASCI who
presented 5 days, 13 days, 1.5 months, and 4 months
after injury, respectively.31 Three of the four patients
experienced improvement to AIS C.31
Recent studies have provided the first evidence that
hESC-derived oligodendrocyte precursor cells (OPCs)
(LCTOPC1) in human trials may have clinical efficacy,
although robust data are lacking. OPC transplantation
may mediate demyelination and promote remyelination
of damaged axons near the injury site. A phase I safety
trial of OPC cell transplantation in five patients with
thoracic SCI (NCT01217008) was completed,32 with
10-year follow-up finding no complications or adverse
events associated with LCTOPC1 implantation. The
same investigators launched a phase I/IIa dose-
escalation study (SCiStar, NCT02302157) in 25
patients with cervical ASCI because of the promising
results seen in patients with thoracic SCI.33 Promisingly,
96% of patients in the intention-to-treat group recov-
ered one or more levels of neurologic function, and 32%
recovered at least two levels of neurologic function.
These two early human trials may set the stage for larger
clinical trials evaluating the efficacy of hESCs.
Cellular Adjuncts and Biomaterials
Several adjuncts have recently emerged as potential
therapeutic options in addition to stem-cell therapy.
MSCs often require biomaterial scaffolds as a vehicle for
delivery. However, these scaffolds also play a role in SCI
because they can help guide axonal growth by bridging
the gap of the spinal cord lesion.
The primary barriers to stem-cell therapy in human
subjects are the worrisome effects of cell proliferation
with resultant oncogenicity and the low survival rate of
transplanted MSCs. Moreover, identifying methods to
capitalize on the benefits of MSCs in a cell-free manner
may markedly improve therapeutic outlooks. One
promising option is cellular exosomes derived from
MSCs. It is hypothesized that most of the effect of stem
cells is derived from paracrine secretory mechanisms.
Exosomes are small secretory microvesicles that can
carry site-specific messenger RNAs, micro-RNAs, and
proteins, or they could theoretically be loaded with
targeted drugs or si-RNA therapeutics, which could
expand this benefit. In animal models, MSC-exosomes
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 Spinal Cord Injury Management

Table 3. Selected Trials Involving the Role of Bone Marrow–derived Mesenchymal Stem Cells
Number of Experimental Adverse
Study Patients Route of Delivery Key Findings Effects
Vaquero et al, 201847 11 Intrathecal 3/9 patients demonstrated None
improvement in AIS grade, 6/9
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demonstrated improved
bladder function, and 4/9
improved voluntary muscle
contractions.
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Oh et al, 201629 16 Intramedullary, Only 2/16 patients None

intradural demonstrated improvement in
neurologic status.
Jarocha et al, 201548 1 Intrathecal, The single patient demonstrated None
intravenous improvement from AIS A to C/D.
El-Kheir et al, 201428 50 Intrathecal 17/50 patients (34%) treated None
with cell therapy 1
physiotherapy showed
improvement in AIS grade
compared with 0/20 control
subjects.
At 18 months, 23/50 cell
therapy-treated cases (46%)
showed sustained functional
improvement.
Mendonca et al, 14 Intraspinal 7/14 experienced improvement None
201449 from AIS A to B or C.
Dai et al, 201350 20 Intraspinal 10/20 patients had a significant None
clinical improvement in motor,
light touch, pin prick sensory,
and residual urine volume, and
9/20 demonstrated
improvement from AIS A to B.
Jiang et al, 201351 20 Intraspinal 4/8 AIS A, 3/4 AIS B, and 8/8 None
AIC C patients demonstrated
neurologic improvement.
Karamouzian et al, 11 Intrathecal 5/11 (45.5%) in the study group None
201252 and three patients in the control
group (15%) improved from AIS
A to C compared with 3/20
control subjects (15%).
Saito et al, 201253 5 Intrathecal Patients with AIS grade B or C None
demonstrated neurologic
improvement, whereas those
with AIS a did not.
Park et al, 201254 10 Intramedullary 6/10 showed neurologic None
improvement in upper
extremity.
3/10 showed improvement
upper extremity power,
activities of daily living, and
significant MRI changes at
long-term follow-up.
Pal et al, 200955 30 Intrathecal No changes in AIS grade, SSEP, None
MEP, or NCV.

AIS = American Spinal Injury Association Impairment Scale, BM-MSC = bone marrow–derived mesenchymal stem cell, SSEP =
somatosensory-evoked potential, MEP = motor-evoked potential, NCV = nerve conduction velocity
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promote angiogenesis, reduce cell apoptosis, and regu-
late important inflammatory factors both upregulating
antiapoptotic and anti-inflammatory factors while
downregulating proapoptotic and proinflammatory
factors.34 Translation of preclinical animal studies to
human clinical trials may help address many of the
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Other Investigational Modalities
Mean Arterial Pressure Goals
One of the mainstays of ASCI is targeted mean arterial
pressure (MAP) of 85 to 90 mmHg. Deficits in spinal
cord perfusion cause a relative hypoxic environment
resulting in inadequate clearance of inflammatory
cytokines that can be destructive to the local cellular
structure. Augmentation of blood pressure, especially
with norepinephrine and/or phenylephrine is often
required to maintain appropriate MAP. The current
AANS guidelines support maintenance of target MAP
for 7 days.35 However, most of the benefit seems to
occur within the first 3 days, where MAP maintenance
of .85 mmHg results in improved neurologic
recovery.36 MAP goals after ASCI have been
championed at the University of California, San
Francisco, where multiple studies have found better
neurologic outcomes, especially in patients with
complete injuries, when MAP goals are maintained at
85 to 90 mmHg.
Hypothermia
Therapeutic hypothermia is a concept that was intro-
duced into modern neurosurgery at the beginning of the
20th century, but it regained notable recognition after
an experimental treatment for a cervical spine injury in a
high-profile athlete in 2006. Hypothermia has been
used extensively in the treatment of traumatic brain
injuries, which led to studies evaluating its role in other
central nervous system pathologies such as ASCI. By
inducing systemic hypothermia, SCI response can be
slowed because of reduction in cellular metabolism
thereby reducing ischemic damage due to less free rad-
ical accumulation. Despite these suggested effects,
enthusiasm for hypothermia as a treatment modality
has been reduced by the notable adverse events includ-
ing risk of thromboembolic, respiratory, and wound
complications and lack of statistical evidence support-
ing its efficacy. Current efforts investigating the efficacy
include a multicenter randomized trial of 120 patients
investigating systemic hypothermia after acute cervical
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Mark J. Lambrechts, MD, et al
Review Article
SCI (NCT02991690). The protocol of modest hypo-
thermia administration involves inserting cooling
catheters into the femoral vein with cooling at a maxi-
mum rate (2 to 2.5°C/hr.) until a target of 33°C is
reached. Patients are maintained at this temperature
for 48 hours at which point a slow rewarming at 0.1
ºC/hr is commenced until normothermia (T 37°C) is
achieved. Preliminary results found no increased risk of
overall, pulmonary, or thromboembolic complica-
tions.37 This prospective study is still recruiting and
may shed additional insight into the risk-benefit ratio
for hypothermia induction after ASCI.
CSF Drainage and Expansive Duroplasty
An adjunctive measure to surgical decompression,
CSF drainage acutely reduces ISP in animal models
thereby improving vascularity to the injury site.
Although similar, ISP and CSF pressures frequently
vary by 5 mmHg with the degree of dissimilarity
dependent on cord swelling and occlusion of the CSF
at the injury site. Measuring either ISP or CSF pres-
sures has benefits and drawbacks. ISPs are more
accurate but require surgical intervention with a
microscope to place a probe under the dura at the
injury site. For CSF pressures, a lumbar drain may be
placed in the thecal sac in the intensive care unit.
Although ISP is more invasive, it is far more accurate
when cord edema is present because cord swelling may
reduce lumbar CSF pressure while raising cranial CSF
pressure. Although small reductions in CSF pressure
and ISP may be obtained with lumbar drains, they are
usually ineffective at reducing intrathecal pressure and
their efficacy further declines when there is occlusion
of the CSF due to cord swelling.38 In these instances,
an expansive duroplasty may remove the compressive
pressure caused by the dura thereby enhancing the
space available for the cord.
An expansive duroplasty consists of a longitudinal dur-
otomy that is then closed without tension by using an
elliptical artificial dura sutured to the native dura (Figure 2).
A case series of 16 patients treated with laminectomy and
duroplasty within 72 hours found that 14 (87.5%)
demonstrated at least two grades of AIS improvement.39
Interestingly, the ISP remained unchanged after laminec-
tomy but steadily declined after duroplasty. A separate
study found that duroplasty patients experienced greater
improvements in ISP and cord perfusion pressure (SCPP)
compared with those undergoing laminectomy alone.40
However, 4 patients (15%) developed a CSF leak that
required a lumbar drain, and 5 (19%) developed a pseu-
domeningocele that resolved without treatment.39,40 A
e629
© American Academy of Orthopaedic Surgeons
 Spinal Cord Injury Management

Figure 2
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Diagram showing the duroplasty technique and CT/MRI. A, Left: exposed dura after laminectomy. Middle: durotomy held open with
forceps showing injured spinal cord and intraspinal pressure probe. Right: sutured dural patch. B, Preoperative T2 MRI showing high
signal at the site of traumatic spinal cord injury. C, Postoperative CT (left) showing the ISP probe and T2-weighted MRI (right), which
shows the duroplasty. Republished with permission of Mary Ann Liebert, Inc, from Expansion Duroplasty Improves Intraspinal
Pressure, Phang, I., Werndle, M., Saadoun, S., et al, Spinal Cord Perfusion Pressure, and Vascular Pressure Reactivity Index in Patients
with Traumatic Spinal Cord Injury: Injured Spinal Cord Pressure Evaluation Study, J. Neurotrauma. 2015, permission conveyed through
Copyright Clearance Center, Inc.

recent multicenter clinical trial, Duroplasty for Injured
Cervical Spinal Cord with Uncontrolled Swelling (DISCUS)
trial (NCT04936620), began enrolling patients in the
United Kingdom. The DISCUS trial plans to enroll 222 to
260 patients with cervical ASCI and randomize patients to
laminectomy 1 duroplasty or laminectomy alone. This
large clinical trial, once completed, will provide a sub-
stantial contribution to our literature to guide surgical
management and explore the risk of CSF leak in these
patients.
Functional Electrical Stimulation and Robotic
Exoskeletons
Functional electrical simulation (FES) has been available
since the 1960s. FES produces targeted electrical stimuli that
are believed to reduce the activation stimuli of targeted
muscles. When coupled with a patient’s intention to move,
this may induce neuronal plasticity that allows functional
motor improvement. In recent years, FES has also been
coupled with robotic exoskeletons, which then minimize
muscle fatigue and provide functional rigidity and torque.
This technology has immense potential, but continued
advances are required before it can obtain widespread
implementation in patients with ASCI.
Summary
Acute SCI is devastating and leads to notable disability for
affected patients. Our understanding of SCI and the effec-
tive management of patients with acute SCI has grown
substantially in recent years. Yet, many of the pharmaco-
logic management agents remain controversial or
unproven. At this point in time, the only clear evidence is
that “time is spine.” There is an obvious impetus to
optimize patients for early decompressive surgery and

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create care pathways to support timely surgical interven-
tion. Ongoing clinical trials and translational studies have
the potential to continue to augment SCI care in coming
years.
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