Neurosurg Focus 25 (5):E14, 2008
Protection and repair of the injured spinal cord: a review of
completed, ongoing, and planned clinical trials for acute
spinal cord injury
A review
Gregory W. J. Hawryluk, M.D.,1,2 James Rowland, B.Sc.,1 Brian K. Kwon, M.D., Ph.D.,
F.R.C.S.C.,4 and Michael G. Fehlings, M.D., Ph.D., F.R.C.S.C.1–3
Division of Genetics and Development, Toronto Western Research Institute; 2Division of Neurosurgery,
University of Toronto; 3Spinal Program, University Health Network, Toronto Western Hospital, Toronto,
Ontario; and 4Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia,
Canada
1
Over the past 2 decades, advances in understanding the pathophysiology of spinal cord injury (SCI) have stimulated the recent emergence of several therapeutic strategies that are being examined in Phase I/II clinical trials. Ten
randomized controlled trials examining methylprednisolone sodium succinate, tirilizad mesylate, monosialotetrahexosylganglioside, thyrotropin releasing hormone, gacyclidine, naloxone, and nimodipine have been completed.
Although the primary outcomes in these trials were laregely negative, a secondary analysis of the North American
Spinal Cord Injury Study II demonstrated that when administered within 8 hours of injury, methylprednisolone sodium succinate was associated with modest clinical benefits, which need to be weighed against potential complications. Thyrotropin releasing hormone (Phase II trial) and monosialotetrahexosylganglioside (Phase II and III trials)
also showed some promise, but we are unaware of plans for future trials with these agents. These studies have,
however, yielded many insights into the conduct of clinical trials for SCI. Several current or planned clinical trials
are exploring interventions such as early surgical decompression (Surgical Treatment of Acute Spinal Cord Injury
Study) and electrical field stimulation, neuroprotective strategies such as riluzole and minocycline, the inactivation
of myelin inhibition by blocking Nogo and Rho, and the transplantation of various cellular substrates into the injured
cord. Unfortunately, some experimental and poorly characterized SCI therapies are being offered outside a formal
investigational structure, which will yield findings of limited scientific value and risk harm to patients with SCI who
are understandably desperate for any intervention that might improve their function. Taken together, recent advances
suggest that optimism for patients and clinicians alike is justified, as there is real hope that several safe and effective
therapies for SCI may become available over the next decade. (DOI: 10.3171/FOC.2008.25.11.E14)
I
Key Words • cell-replacement therapy • neuroprotection • spinal cord injury • stem cell • surgical timing • translational research
the progress seen in other areas of
surgery, advances in understanding the basic neurobiology of SCI and development of therapeutic strategies have been slower to realize. This is unfortunate,
given that SCI costs society in excess of $7 billion ann comparison with
Abbreviations used in this paper: ALS = amyotrophic lateral
sclerosis; ASIA = American Spinal Injury Association; BMSC =
bone marrow stromal cell; CNS = central nervous system; CSF =
cerebrospinal fluid; FDA = Food and Drug Administration; FIM =
Functional Independence Measure; GM-1 = monosialotetrahexosylganglioside; MPSS = methylprednisolone sodium succinate;
NASCIS = North American Spinal Cord Injury Study; OEC =
olfactory ensheathing cell; PNS = peripheral nervous system; SCI
= spinal cord injury; SCIM = Spinal Cord Independence Measure;
STASCIS = Surgical Treatment of Acute Spinal Cord Injury Study;
TRH = thyrotropin releasing hormone.
Neurosurg. Focus / Volume 25 / November 2008
nually33,130 and bears the greater cost of human suffering
related to impaired ambulation; sensation; and bowel,
bladder, and sexual functions.
During the last decade, new hope emerged for patients who have suffered SCI, as intensive research
brought a number of promising therapies to clinical trial. Unfortunately, none of these therapies demonstrated
sufficiently robust efficacy to be widely accepted by the
clinical community.5,87,90,139
Although MPSS showed modest benefits in a secondary analysis of the NASCIS II trial and continues to
be commonly used in the US, this treatment remains controversial because of the small neuroprotective effects,
which must be weighed against potential side effects including susceptibility to infection and wound complications.
An indisputable gain that has emerged from these
1
G. W. J. Hawryluk et al.
TABLE 1: Completed prospective randomized controlled SCI clinical trials*
Year
No. of
Patients
NASCIS I
1984
330
Phase III RCT
I, 48
NASCIS II
1990
487
Phase III RCT
C/I, 12
Maryland
GM-1
Otani et al.
1991
34
I, 72
1994
158
Phase II RCT—pilot
study
nonblinded RCT
TRH
1995
20
Phase II RCT—pilot
study
C/I, 2
TRH
placebo
NASCIS III
1997
499
Phase III RCT
I, 12
MPSS (24 hr)
MPSS (48 hr)
MPSS bolus then TM
Nimodipine
1998
100
Phase III RCT
C/I, 6
Gacyclidine
1999
280
Phase II RCT
C/I, 2
Pointillart et al.
2000
106
blinded RCT
?, 8
Sygen (GM-1)
2001
797
Phase III RCT
I, 72
nimodipine
MPSS (24 hr)
nimodipine + MPSS (24 hr)
placebo
gacyclidine (0.005 mg/kg)
gacyclidine (0.01 mg/kg)
gacyclidine (0.02 mg/kg)
placebo
MPSS (NASCIS II 24 hr)
nimodipine
MPSS & nimodipine
placebo
MPSS & low-dose GM-1
MPSS & high-dose GM-1
MPSS & placebo
Trial Name
Study Design
SCI Type, Treatment Window (hrs)
?, 8
Treatment Arms
MPSS 100 mg × 10 days
MPSS 1000 mg × 10 days
MPSS (24 hr)
naloxone
placebo
GM-1
placebo
MPSS (NASCIS II 24 hr)
placebo
Conclusions
no difference
negative primary analysis; secondary
analysis showed improved recovery if
treated w/ MPSS w/in 8 hrs of injury;
naloxone negative
improved neurological recovery w/
GM-1 in this small pilot study
significantly more steroid-treated
patients had some sensory improvement; no motor differences
suggestion of improved neurological
recovery w/ TRH in this small pilot
study
improved neurological recovery w/
MPSS if administered early (w/in 3
hrs after SCI); TM not superior to
MPSS
no difference; study likely underpowered to detect a difference
negative study; trend to improved
motor recovery w/ incomplete cervical injuries
no neurological differences btwn
groups; trend to increased infections
in groups receiving MPSS
negative primary outcomes; trend to
improved secondary outcomes
* Further trials are not planned for any of the agents presented in this table, to the knowledge of the authors. Abbreviations: C = complete; I = incomplete; RCT = randomized controlled clinical trial; TM = tirilizad mesylate; ? = unpublished or unclear data.
studies has been insight into the conduct of SCI clinical
trials. These insights are now being paired with novel scientific advances to bring a new generation of therapies to
the bedside. The challenges of the last decade have thus
given way to a new-found optimism as a number of new
agents are showing great promise in early stage clinical
trials. Based on this research, it is anticipated that effective therapies for SCI will emerge in the next decade.
In this review we seek to familiarize clinicians with
ongoing clinical trials and promising treatments, which
may soon revolutionize management of acute SCI, in the
context of pertinent scientific advances and recently completed trials. Care for chronic SCI is also an important
and active area of research,6,71 but we will not review it
here.
2
Completed Prospective Randomized
Controlled Trials for Acute SCI
A number of agents have been subject to intensive
investigation in large multicenter prospective randomized controlled trials, including MPSS and the related
compound tirilizad mesylate, GM-1, TRH, gacyclidine,
naloxone, and nimodipine (Table 1). Despite promising
preclinical animal data, the primary outcomes of these
clinical trials were largely negative, although as will be
briefly discussed later, MPSS showed some promise in
the secondary analyses. These trials have been reviewed
extensively elsewhere,64,87,139 and therefore we will recount them only briefly here as a prelude to a discussion
of ongoing clinical trials and lessons learned about the
Neurosurg. Focus / Volume 25 / November 2008
Advances in spinal cord injury therapeutics
methodological challenges associated with evaluating
novel SCI therapies.
Methylprednisolone Sodium Succinate (Solu-Medrol)
Corticosteroids have been used in neurotrauma for
decades but have only recently been subject to intensive
scientific scrutiny. Their neuroprotective effects include
antioxidant properties, which are associated with a reduction in tumor necrosis factor–α synthesis and nuclear factor κB activity, enhancement of spinal cord blood flow,
reduced calcium influx, reduced posttraumatic axonal die
back, and attenuated lipid peroxidation.63,113 Following
the accumulation of preclinical data63 that was generally
(but not universally) supportive of a neuroprotective role
for steroids in animal models of acute SCI, methylprednisolone was studied in 5 prospective acute SCI trials in
humans,75 making it the most extensively studied drug in
acute SCI.
Three landmark NASCIS studies examined the use
of MPSS for acute SCI. The first NASCIS study, published in 1984,13 compared a high-dose with a low-dose
group; placebo was judged unethical because benefit
from steroid administration was presumed.5 Neurological improvement was not significantly different between
the 2 groups, although a statistically significant increase
in wound infection was noted in the high-dose group, as
well as increased rates of gastrointestinal hemorrhage,
sepsis, pulmonary embolism, delayed wound healing, and
death.74
Animal studies completed subsequent to NASCIS
I suggested that higher doses were required for neuroprotection.16 The NASCIS II trial12 was thus designed to
examine a higher dose of MPSS compared with placebo
and the opioid antagonist naloxone given within 24 hours
of injury. In the overall analysis of all patients randomized within 24 hours, there was no neurological benefit in
the MPSS-treated group, and hence, this trial was negative.12 However, a post hoc analysis (reportedly planned
a priori11) demonstrated that patients receiving the drug
within 8 hours of injury benefited neurologically, notably
those whose injury was initially complete (ASIA Grade
A).74 As in NASCIS I, a trend toward an increased incidence of wound infection and pulmonary embolism was
associated with MPSS administration.74
The NASCIS III trial14,15 was designed and powered
to further explore the beneficial effects of MPSS administration within 8 hours of injury, as reported in NASCIS
II. Additionally the trial assessed functional outcome (by
using the FIM), which was not previously analyzed in
NASCIS trials. This study compared the 24-hour infusion used in NASCIS II to a 48-hour MPSS infusion, and
it also included a treatment group that received tirilizad
mesylate, a 21-aminosteroid believed to be an antioxidant
without glucocorticoid effects.62 Like NASCIS II, when
considering all patients recruited, this trial demonstrated
no sustained benefit to MPSS with respect to motor and
sensory scores in treatment groups. A post hoc analysis
noted that patients receiving the MPSS bolus 3–8 hours
after injury demonstrated improved neurological function
at 6 weeks and 6 months (but not at 1 year) when they
were given MPSS for 48 hours rather than 24 hours. This
Neurosurg. Focus / Volume 25 / November 2008
led to the recommendation that within 3 hours of injury,
the 24-hour infusion would suffice but, if initiated within
3–8 hours of injury, a 48-hour MPSS regimen was better
than the 24-hour regimen of the NASCIS II protocol. The
48-hour regimen represents the highest dose of MPSS
prescribed for any clinical condition122 and was associated with a 2-times higher rate of severe pneumonia, a
4-times higher rate of severe sepsis, and a 6-times higher
incidence of death in the 48-hour group than in the 24hour group.74
Two other prospective SCI trials in humans involving
corticosteroids have been published, including the work
of Otani et al.112 and Pointillart et al.120 The former authors
noted some neurological benefit from methylprednisolone
administration, whereas the latter authors reported none.
Nonetheless, both of these studies were small and plagued
by substantial methodological problems, which limit their
interpretation as either positive or negative studies.
Intense and systematic scrutiny of these data has led
to tremendous controversy around the use of MPSS for
acute SCI.28,75,76,108 Two predominant concerns have arisen. First, the benefits noted have not only been modest,
but in both NASCIS II and III they were only detected in
the secondary analysis of a fraction of the enrolled population. Second, high rates of adverse events were consistently associated with MPSS administration. The scrutiny surrounding the execution and interpretation of the
NASCIS trials culminating in the American Association
of Neurological Surgeons/Congress of Neurological Surgeons systematic review of this literature in 2002, which
concluded that “treatment with methylprednisolone for
either 24 or 48 hours is recommended as an option in the
treatment of patients with acute spinal cord injuries that
should be undertaken only with the knowledge that the
evidence suggesting harmful side effects is more consistent than any suggestion of clinical benefit.”1
Although many continue to administer steroids, the
rationale for this administration has changed. A survey
published in 2006 revealed that the majority of respondents continue to administer methylprednisolone, but
they are motivated predominantly by fear of litigation.41
The view of the senior author (M.G.F.) is that MPSS
administration remains justified for acute SCI (within 8
hours) in nondiabetic and nonimmunocompromised patients given the severity of SCI deficits and current lack
of alternatives.44
The Ganglioside GM-1 (Sygen)
Gangliosides are complex glycolipids abundant in
the membranes of nervous tissue. Exogenous administration of GM-1, a ganglioside also known as Sygen, was
found to promote neural repair and functional recovery
in a number of animal models.9 In 1991, the prospective
randomized Maryland GM-1 study of 37 patients reported that GM-1 treatment resulted in statistically significant
improvement in ASIA motor score compared with placebo.56 Efficacy was noted as late as 48 hours after injury,
and its predominant effect on lower-extremity function
suggested an effect on axons traversing the injury.5 This
led to the largest prospective randomized clinical trial in
acute SCI to date, the Sygen Multi-Center Acute Spinal
3
G. W. J. Hawryluk et al.
Cord Injury Study, which enrolled > 750 patients from
28 institutions over 5 years.55 This study failed to demonstrate a significant difference in its primary outcome
measure—a 2-point improvement on the modified Benzel
walking scale. This was, in retrospect, an ambitious end
point, considering the number of patients enrolled in the
trial with complete ASIA Grade A injuries who attained
less benefit than patients with incomplete injuries.55 The
patients treated with GM-1 did demonstrate more rapid
neurological recovery as well as a trend to improved bowel/bladder function and sacral sensation. It has also been
postulated that greater efficacy with GM-1 may have been
seen had it been given earlier after injury. Because the
patients enrolled in this study were obligated to receive
MPSS first, GM-1 was not administered, on average, until
55 hours after injury. We are unaware of any plans for
future trials with this agent,5 although this data set continues to produce invaluable insights into study design,
which will be discussed later.
Thyrotropin Releasing Hormone
In addition to the hormonal functions well known
to physicians, TRH has been shown to antagonize secondary injury mediators such as excitotoxic amino acids,
peptidoleukotrienes, endogenous opioids, and plateletactivating factor,39 likely underlying its dose-dependent
functional improvement in rats following experimental
SCI.66 In 1995 the only clinical trial ever conducted with
TRH in acute SCI was published.119 This randomized,
double-blind, placebo-controlled trial included complete
and incomplete injuries and compared TRH with placebo. Based on a secondary analysis of a smaller cohort of
patients, those with incomplete SCI (but not those with
complete SCI) achieved statistically significant functional improvements on the NASCIS and Sunnybrook scales.
This result must be interpreted with caution, however, as
the trial was plagued by attrition; because only 20 patients were ultimately analyzed, this result may represent
Type I error. No further clinical SCI studies to investigate
TRH have been initiated.
Gacyclidine (GK-11)
Glutamate is the main excitatory neurotransmitter
in the CNS, but its excess following CNS injury leads
to excitotoxicity, which now has a well-established role
in secondary injury. Antagonism of glutamate receptors
has proven a challenging therapeutic approach, however.
Previous trials of antiglutamatergic agents have been unsuccessful because of significant cognitive side effects,
including agitation, sedation, hallucinations, and memory
deficits, even with competitive antagonists such as Selfotel.31,106 Interestingly, a noncompetitive N-methyl-d-aspartate receptor antagonist, gacyclidine, showed promise as
a neuroprotective agent.
Gacyclidine or GK-11 (Beaufour-Ipsen Pharma) has
shown evidence of improved function, histology, and
electrophysiology in a rat model,69 in addition to substantially better tolerability than other N-methyl-d-aspartate
antagonists.53 A double-blind Phase II human trial that
was completed in France randomized more than 200 pa4
tients to receive 3 escalating doses of gacyclidine.138 Early
benefit was seen in the treatment groups, but this was not
maintained at 1 year. At 1 year postinjury, however, those
with incomplete cervical injuries receiving high doses of
gacyclidine exhibited a nonsignificant trend toward improved motor function. Despite the fact that this negative result likely stems from insufficient statistical power,
this agent is no longer being pursued for SCI. Its use is,
however, being explored in traumatic brain injury,95,105 organophosphate poisoning,88 and tinnitus (patent number
20060205789).
Nimodipine
Intracellular calcium levels are tightly regulated, as
high concentrations can activate calpains and other destructive enzymes within the cell that lead to apoptosis.
Excitotoxic glutamate release is also calcium-dependent.
Nimodipine is an L-type calcium channel blocker that
may antagonize these processes.99 Indeed, its potential
(albeit modest) benefit in subarachnoid hemorrhage is believed to result from neuroprotective effects rather than
a smooth-muscle relaxing effect on blood vessels. The
latter effect can, however, cause hypotension and spinal
cord ischemia in the context of injury. When hypotension
is avoided, animal studies of nimodipine have demonstrated improvement in spinal cord function.46 A human
trial for SCI was completed in France in 1996.118 This trial
comprised 100 patients in 4 treatment arms: nimodipine,
MPSS (NASCIS II protocol), both agents, and placebo.
Benefit over placebo was not demonstrated in any treatment group, although it is quite likely that this study was
also underpowered to reveal a therapeutic effect.
Opioid Antagonism
Dynorphin A, an endogenous opioid, is released following SCI and has neurotoxic effects; it also reduces
spinal cord blood flow by nonopioid mechanisms.98 Concordantly, opioid antagonism following SCI has led to
improved electrophysiology and reduction in edema,7,148
free-radical generation,25 as well as decreased levels of
excitotoxic amino acids.85 In the 1980s the opioid antagonist naloxone was examined in a Phase I SCI trial
in humans.49 The results suggested benefit, but imbalance
between experimental groups make this result difficult to
interpret. A more definitive examination of this agent was
performed in the NASCIS II trial12 where, unlike MPSS,
naloxone unfortunately showed no neuroprotective benefit.
Toward the Next Generation of Trials
Lessons From Completed Trials
Although the completed trials in SCI failed to bring
a robustly neuroprotective compound to the clinic, much
has been learned from these studies. The high quality
of the trials and the intense scrutiny of their design and
interpretation of outcome measures are playing a critical role in shaping the next generation of trials. In particular, the NASCIS and Sygen studies continue to serve
Neurosurg. Focus / Volume 25 / November 2008
Advances in spinal cord injury therapeutics
Table 2: Summarized recommendations for the conduct of SCI clinical trials*
—Trials of treatments that are most efficacious when given soon after injury will require larger patient numbers than those effective at later time
points.1
—Trials involving motor incomplete SCI patients, or trials in which an accurate assessment of ASIA impairment scale grade cannot be made before
the start of the trial, will require large patient numbers &/or better objective assessment methods.1
—The ASIA impairment scale forms the standard basis for measuring neurological outcomes.3
—An improvement in the measurable performance of a meaningful function or behavior is necessary for any therapeutic intervention to be universally
accepted as clinically beneficial.3
—The SCIM assessment may be a more specific & accurate outcome tool for detecting clinical end points in SCI than the FIM.3
—Clinical trials for SCI should include blinded assessments.5
—The most rigorous & valid SCI clinical trial would be a prospective double-blind RCT using appropriate placebo controls. However, in specific situations, it is recognized that other trial procedures may have to be considered.2
—The use of external controls in SCI clinical trials is strongly discouraged.2
—Experimental therapies should have proven benefit in >1 animal model before translation to humans.4
—Consideration should be given to using novel trial designs such as adaptive randomization & Bayesian statistics.4
—Clinical trials require follow-up of appropriate duration: 6–12 mos for neuroprotection trials, 12–24 mos for regenerative therapies.4
—Clinical management should follow recently published guidelines regarding acute & chronic SCI management.4
*The following references apply to this table and Table 4:
1. Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynski MH, Lammertse D, et al: Guidelines for the conduct of clinical trials for spinal cord injury
as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord
45:190–205, 2007
2. Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW, Rask C, et al: Guidelines for the conduct of clinical trials for spinal cord injury as
developed by the ICCP panel: clinical trial design. Spinal Cord 45:232–242, 2007
3. Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Ditunno JF, et al: Guidelines for the conduct of clinical trials for spinal cord injury (SCI)
as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord 45:206–221, 2007
4. Tator, CH: Review of treatment trials in human spinal cord injury: issues, difficulties, and recommendations. Neurosurgery 59:957–987, 2006
5. Tuszynski MH, Steeves JD, Fawcett JW, Lammertse D, Kalichman M, Rask C, et al: Guidelines for the conduct of clinical trials for spinal cord injury
as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics. Spinal Cord 45:222–231, 2007
as the reference trials in the translational SCI field. For
example, analysis of the large Sygen database has been
valuable for defining the variance in spontaneous neurological recovery among patients deemed to have the same
injury severity.43
Subsequently, a number of authors have published
recommendations for the scientific and ethical conduct of
future trials, including Tator139 (select recommendations
are provided in Table 2), Cesaro,24 and Sagen127 with the
latter 2 addressing cell replacement therapies. A parallel effort has come from the International Campaign for
Cures of Spinal Cord Injury Paralysis, which published
4 documents in 200743,89,135,143 designed to improve SCI
clinical trials (a summary of these recommendations is
provided in Table 2). These documents provide recommendations related to the following: 1) statistical power
needed for clinical trials in relation to injury severity and
timing of administration of the experimental therapy; 2)
appropriate clinical trial outcome measures; 3) inclusion/
exclusion criteria and ethics; and 4) clinical trial design.
These recommendations will be extremely helpful for the
SCI community in its further clinical evaluation of novel
therapies.
It is a paradox that despite this enlightenment, more
experimental therapies in SCI than ever before are being pursued in an environment of questionable scientific
rigor and ethics. In particular, recent years have seen
Neurosurg. Focus / Volume 25 / November 2008
many patients travel appreciable distances at great personal cost and risk to seek cell or tissue transplantation
therapies, which are at best unproven and at worst very
dangerous.3,37 Additionally, information surrounding the
conduct and results of many current SCI clinical trials is
not in the public domain,139 in contravention of the current
effort to promote registration of trials embodied by the
Ottawa Statement.84 It will be important for future trials
to adhere to these recommendations.
Largely in response to this issue, the International
Campaign for Cures of Spinal Cord Injury Paralysis has
produced an additional document designed for patients
considering enrollment in an SCI clinical trial.134 This excellent resource aims to educate patients about the clinical trials process and encourages them to participate in
studies of high scientific and ethical quality. These new
publications thus provide patients and clinicians with important tools that will be essential to the conduct of future
trials.
New Clinical Tools
In recent years, clinical guidelines have been
published for the management of acute and chronic
SCI.61,114Adherence to these guidelines in future trials
should decrease variability and increase the chance of
detecting clinical effects. Standardized care would also
make comparison of trial results more facile.
5
G. W. J. Hawryluk et al.
Table 3: Summary of recently published and ongoing, well-documented, unpublished experimental trials for acute and subacute SCI*
Trial Name
Intervention
Lead Center/
Organization
Date of Initiation
Proposed No.
of Patients
Complete, Published Phases
?
20
pre-2005
6
2005
61, suspended at 50
10 patients,
Phase I
Phase I, singleblinded
w/ control
Phase I
?
20
?
Inha U Hospital
2001
35
U of Toronto,
Thomas Jefferson U,
Spine Trauma
Study Group
U of Maryland
2003
recently published studies
OEF stimulation device implanta- Indiana U Medition
cal Center
Australian OEC OEC transplan- Australia
trial
tation
PROCORD
(enrollment
suspended)
activated
autologous
macrophages
Prague BMSC
BMSC transplantransplantation tation
Korean BMSC
BMSC transplantransplantation tation
ongoing, unpublished studies
STASCIS
timing of surgical
decompression
early & late
surgery for
traumatic central
cord syndrome
systemic hypothermia
minocycline
riluzole
ATI-355
Cethrin
CSF drainage
surgical decompression
hypothermia
(cooled to 33°C
at 0.5°C/hr,
maintained for
48 hrs)
250 mg IV bid ×
7 days
Na+ channel
blockade, antiglutamatergic
50 mg PO bid
Nogo-blockade
Rho inhibition
72 hrs of CSF
drainage
Proneuron
Prague
Miami
Calgary
U of Toronto,
North American
Clinical Trials
Network
Novartis
BioAxone Therapeutics/
Alseres Pharmaceutical
U of British
Columbia
Current Study
Type
Registration
Information†
Phase I/II
NR
?
NR
Phase II,
randomized,
multicenter
controlled trial
?
NR
Phase I/II nonrandomized
?
NR
450
NA
nonrandomized
prospective
observational
NR
May 2007
30
?
Phase II
NCT00475748
January 2007
100
NA
Phase I/II
NR
?
?
Phase I
Phase II
NR
late 2007
36
NA
Phase I
NR
May 2006
February 2005
16
47
NA
NA
Phase I
Phase I/II
NCT00406016
NCT00500812
March 2008
22 enrolled
to date
NA
Phase I
NCT00135278
NR
* To the authors’ knowledge, all therapies presented here are currently being investigated in clinical trials, or further trials are planned. Abbreviations:
bid = twice daily administration; IV = intravenous; NA = not applicable; NR = not registered; OEF = oscillating electrical field; PO = by mouth; U = University.
† At http://www.clinicaltrials.gov.
A number of new clinical assessment tools have also
been devised. The ASIA Impairment Scale, alternatively
known as the International Standard for Neurological
Classification of Spinal Cord Injury, was first published in
1982 and now forms the international standard for postinjury evaluation of neurological function.4 The simplified
6
form of the ASIA Impairment Scale bears the same form
as the earlier Frankel scale and maintains backward compatibility with it. The Modified Benzel Classification system,54,55 used in the GM-1 trial, may be used in future
trials as it addresses some of the perceived deficits of the
ASIA Impairment Scale: it subdivides ASIA Grade D
Neurosurg. Focus / Volume 25 / November 2008
Advances in spinal cord injury therapeutics
TABLE 4: Human therapy considered experimental, with uncertain methodology or status*
Trial Name
?
minocycline/
tacromilus
Russian OEC
transplantation
Huang OEC
transplantation
China BMSC
transplantation
Russian BMSC
transplantation
Schwann cells
Intervention
Location
No. of
Treated
Patients
pulsed electrical
stimulation
coadministration
Beijing
100+
Riyadh
?
OEC transplantation
Russia
many
? fetal OEC transplantation
BMSC transplantation
fetal BMSC/peri­
pheral blood cell
transplantation
cellular transplantation
Beijing
300+
?
90
2 centers
15
2 groups
in China
?
* Most studies presented here have been reported only by Tator.4
into 3 different grades to reduce ceiling effect and additionally assesses walking and sphincter function. Some
believe that this scale is not valid, however, as it cannot
be applied immediately following injury when a patient is
unable to ambulate.139
The SCI-specific quality of life measures will undoubtedly receive increased emphasis in future trials.
Although the FIM has been perhaps most widely used
in the SCI literature thus far, it is likely that the SCIM,
published in 2001,22 will be increasingly applied as it
has demonstrated more sensitivity to functional changes
in patients who have suffered SCI than the FIM.22 The
SCIM assesses self-care, respiration, sphincter management, and mobility and has been revised to increase interobserver reproducibility.23 Also emerging are scales that
assess walking following SCI. The Walking Index for
Spinal Cord Injury, published in 200035 and more recently in revised form,36 represents an international effort to
produce a complex, valid, and reliable tool for assessing
walking independent of burden of care. Other walking
tests include the Timed Up and Go, the 10-Meter Walk
test, and the 6-Minute Walk Test, all 3 of which were recently compared using the same cohort of patients, and all
were found to be valid and reliable.144 In addition, a multinational collaboration, led by the Toronto SCI team and
including several centers in Canada, the US, and Europe
is developing a novel outcome measure to quantitatively
assess hand and upper-extremity function in tetraplegics
(the GRASSP outcome measure).
Clinical Trial Networks
Because of the relatively low incidence of SCI, clinical trial networks will undoubtedly play a key role in
recruiting patients into clinical trials of novel therapies.
Neurosurg. Focus / Volume 25 / November 2008
In addition to the International Campaign for Cures of
Spinal Cord Injury Paralysis, the North American Clinical Trials Network, the European Union Clinical Trials
Network, the China Spinal Cord Injury Clinical Network,
and the Canadian Spinal Cord Injury Translational Research Network have formed in recent years. Older networks include the US Models System and the NASCIS
(no longer active).
Ongoing Clinical Trials
More than 70 clinical trials for SCI are registered online at http://www.clinicaltrials.gov; however, the majority of these relate to interventions for chronic SCI and will
not be reviewed here. Here we describe registered interventional trials involving patients with acute and subacute
SCI as well as others we have identified and of which we
have some knowledge (Tables 3 and 4).
Surgical Trials and
Nonpharmacological Interventions
Surgical Treatment of Acute Spinal Cord Injury Study
It is surprising that in our modern age a question as
fundamental as whether early decompression for acute
human SCI is or is not beneficial for neurological recovery remains incompletely answered.45 While a significant
body of animal research has demonstrated neurological
benefit to early decompression of the injured spinal cord,
some clinicians prefer to delay decompression in patients
with multiple trauma in light of the medical instability
often seen in the acute postinjury phase.34,45,140
In an effort to address this question with evidence of
the highest possible quality, the STASCIS was initiated in
2003 by Drs. Fehlings and Vaccaro of the University of
Toronto and Thomas Jefferson University (Philadelphia,
PA), respectively. This trial was designed to be randomized; however, resistance to randomizing to an intentionally delayed decompression led to restructuring as a prospective observational study. This study has an accrual
target of 450 patients with traumatic cervical SCIs ranging in age from 16 to 70 years. A 2-year follow-up period
postinjury is planned. Preliminary analysis suggests a
benefit to early decompression based on an operational
definition of “early” being < 24 hours.
As a result of this and a belief that there may be benefit from “ultra-early” decompression, the University of
Toronto has established the practice of performing decompression (by traction or open surgery) immediately
following initial imaging in patients with isolated cervical SCI (whenever feasible within 12 hours of injury). The
greatest barriers to achieving early decompression in the
SCI population are likely based on delays in transfer and
challenges with accessing imaging and operating room
facilities. Implementation of the STASCIS protocol will
require major efforts to influence public policy.
Early Versus Late Decompression of Central Cord Syndrome
Central cord syndrome is uniquely challenging with
respect to determining the optimal timing of interven7
G. W. J. Hawryluk et al.
tion; most patients present without spinal instability and
experience substantial spontaneous neurological improvement. Although attempts have been made to identify factors that influence the neurological outcome after
central cord syndrome2,40,78,149 and to specifically address
whether early surgery is beneficial,27,59,103 a prospective
trial is needed. Fortunately, investigators at the University of Maryland have registered a Phase II, single-center
randomized clinical trial examining the timing of decompression in central cord syndrome. This trial seeks
to randomize 30 patients to decompression within 5 days
or after 6 weeks of injury. The study will compare ASIA,
FIM, and SCIM scores; degree of canal compromise; spinal cord compression; and syrinx size. A 1-year followup has been planned. Unfortunately, it appears that this
trial is being plagued by resistance to randomization as
the STASCIS was, and therefore the future of this trial is
currently uncertain.
Oscillating Field Stimulation
Neurites grow toward the negative pole (cathode) in
an electrical field.68,79 Researchers at the Indiana University Medical Center have developed an implantable oscillating field stimulator, which is capable of creating an
electrical field along the rostrocaudal axis of the spinal
cord, and they hope to capitalize on this finding. Because
neurite outgrowth is stimulated only toward the negative pole, the device oscillates, changing polarity every
15 minutes to promote axonal growth in both directions.
This device underwent trial in 10 patients with complete
SCI from C-5 to T-10 who also received methylprednisolone per the NASCIS III protocol. The oscillating field
stimulator was implanted within 18 days and removed at
15 weeks postinjury. In that study, reported in 2005,131
patients were assessed for 1 year after the procedure by
using the ASIA grade, visual analog scale pain score, and
somatosensory evoked potentials. The mean improvement in light touch was 25.5 points (p = 0.02), the mean
improvement in pinprick sensation was 20.4 points (p =
0.02), and the mean improvement in motor status was 6.3
points (p = 0.02). Based on comparison with patients in
the NASCIS III trial, efficacy is suggested; however, as
these are historical controls from a distinct trial protocol,
the neurological improvement must be interpreted with
caution. Of note, the complications observed in this trial
were low (1 wound infection and 1 device failure), and
the FDA has reportedly approved enrollment of additional patients in this study. Cyberkinetics Neurotechnology
Systems, Inc. (Foxborough, Massachusetts) has purchased
the intellectual property for this technology, and we look
forward to additional data from the investigators.
A similar trial involving pulsed electrical stimulation
has been conducted in 100 patients in Beijing by investigators Xu and Liu, as reported by Tator.139 The results of
this work are uncertain, however.
Cerebrospinal Fluid Drainage
In thoracoabdominal aortic aneurysm surgery, CSF
drainage has been found to significantly reduce the incidence of ischemic paraplegia.29 This suggests that lower-
8
ing intrathecal pressure improves spinal cord perfusion
pressure, attenuating ischemia and providing neuroprotection. Investigators at the University of British Columbia have initiated a safety and feasibility study to evaluate
CSF drainage as a neuroprotective strategy after acute
SCI (clinicaltrials.gov identifier NCT00135278). This
study involves CSF drainage through a lumbar intrathecal line. Twenty-two patients have been enrolled to date,
and there have been no adverse events attributed to the
drainage of CSF (for example, neurological deterioration,
meningitis, or headache/nausea/vomiting). Neurological
recovery is a secondary measure in this pilot study, although the planned enrollment will not be sufficient to
make strong statements about the influence of CSF drainage on neurological outcome.
Hypothermia
Hypothermia has long been explored for its putative
neuroprotective effects despite risks that include coagulopathy, sepsis, and cardiac dysrhythmia. In addition to
reducing metabolic rate, hypothermia also appears to reduce extracellular glutamate, vasogenic edema, apoptosis, neutrophil and macrophage invasion and activation,
and oxidative stress.42,57,60,72,77,94,97,111,154 Indeed, therapeutic hypothermia has become a treatment guideline for
patients resuscitated from an out-of-hospital cardiac arrest.110 In traumatic brain injury, a number of trials have
demonstrated inconsistent effects.80 In animal models of
traumatic spinal cord injury, both regional and systemic
hypothermia have been studied and have demonstrated
mixed results.65,86 Until recently, only regional hypothermia has been described in acute human SCI;65 however, researchers from the Miami Project to Cure Paralysis
have begun to explore the role of systemic hypothermia in
SCI. In 2007 they initiated a clinical trial which involves
rapid cooling with chilled intravenous saline to decrease
the core body temperature to ~ 34°C in comparison with
historical controls. We anxiously await the results of this
trial.
Minocycline
Pharmacological Trials
Minocycline is a synthetic tetracycline derivative
commonly used in the treatment of dermatological conditions such as acne and rosacea. It has also demonstrated
neuroprotective effects in animal models of stroke, Parkinson disease, Huntington disease, ALS, and multiple
sclerosis.150 A number of independent laboratories have
reported that minocycline attenuates secondary injury
and enhances functional recovery in various animal
models of SCI.93,136,141,147 Its mechanism of action in SCI
appears to be mediated in part by the inhibition of microglial activation,48,67,142,152 in addition to antiapoptotic
properties;48,142,153 the latter may stem from a reduction in
levels of pro-neural growth factor and inhibition of cytochrome c release. These promising preclinical results
have led to 2 clinical trials, which are now ongoing. The
first, led by researchers at the University of Calgary, is
a prospective randomized placebo controlled Phase I/II
Neurosurg. Focus / Volume 25 / November 2008
Advances in spinal cord injury therapeutics
human trial of intravenous minocycline in which patients
are randomized within 12 hours of their injury. The investigators recently reported that trial enrollment will be
halted in November 2008 with a subsequent decision on
whether a Phase III study is warranted. We eagerly await
further information about this trial.
Less is known about the second study, being conducted by investigators at Riyadh Armed Forces Hospital,
Saudi Arabia. This trial is reportedly assessing the effectiveness of minocycline when administered in combination with the immunosuppressant tacrolimus (FK506),
which inhibits the enzyme calcineurin.139
Riluzole
Riluzole or Rilutek (Sanofi-Aventis) is a benzothia­
zole anticonvulsant which has been licensed for patients
with ALS for ~ 10 years,8 perhaps prolonging their lives
by 2–3 months.104 Its neuroprotective effects appear to result from blockade of voltage-sensitive sodium channels
whose persistent activation following injury has been associated with degeneration of neural tissue,129 as well as
antagonism of presynaptic calcium-dependent glutamate
release.146 Of interest in SCI, it demonstrates synergy with
MPSS,107 and animal models of SCI have demonstrated
neuroprotective effects when administered as late as 10
days after injury.109,129 Recent in vitro studies additionally have suggested that riluzole may promote outgrowth
of sensory neurons.132 Hepatotoxicity may be an important side effect of this therapy; however, this treatment
has been well-tolerated in the ALS population, and the
changes in liver enzymes are reversible after stopping this
medication.91
Based on these promising experimental results and
an established track record in ALS, it is anticipated that
a human multicenter SCI trial will begin in mid-2008,
enrolling patients (with a target of 36) with ASIA Grade
A, B, or C and injuries between neurological levels C-4
and T-10. Patients will be enrolled within 12 hours of injury and given the same daily dose as that given to ALS
patients. A 10-day course will be given as glutamate, and
sodium-mediated secondary injury is maximal during
this period.115,129 A 1-year follow-up is planned, with the
primary safety end point assessed at 3 months and neurological assessment at 6 months, including ASIA grade,
SCIM, and Brief Pain Inventory. Coadministration of
MPSS will be permitted.
Targeting Myelin-Associated
Inhibitors of Regeneration
Work by David and Aguayo30 performed many years
ago at the Montreal Neurological Institute demonstrated
the very important finding that central neurons have the
capacity to regenerate across peripheral nerve grafts. The
conclusion of this work was that components of the CNS
environment must inhibit axonal regrowth after injury
and that CNS neurons do have the capacity to regenerate their disrupted axons. A number of inhibitory proteins
present largely in myelin have subsequently been identified, Nogo being the first.73,100 Work is underway to interrupt the inhibitory effect that these molecules have on
Neurosurg. Focus / Volume 25 / November 2008
axonal regrowth following injury. Two such agents that
have reached clinical trials are ATI-355 and Cethrin.
ATI-355
In the late 1980s, pioneering work by Caroni et al.19,21
demonstrated that oligodendrocytes and their myelin
membranes are major inhibitors of axonal growth within
the CNS. Caroni and Schwab20 biochemically separated
35- and 250-kD inhibitory fractions within CNS myelin
(NI-35 and NI-250) and developed a monoclonal antibody,
IN-1, that could block their inhibitory properties in vitro.
Subsequent in vivo application of IN-1 in rodents resulted
in substantial axonal sprouting and some long distance
corticospinal axonal regeneration within the adult mammalian CNS.128 Importantly, this antibody treatment was
associated with improved performance on a variety of
functional tests, including open field locomotion, rope
climbing, and food pellet reaching.17,50 The IN-1 antibody
was then instrumental in the characterization and protein
sequencing of its target antigen,133 which led to the cloning of what is now known as Nogo.26,58,121
The humanized anti-Nogo antibody has been shown
to promote axonal sprouting and functional recovery following SCI in numerous animal models, including primates.51,52 In May 2006 a human Phase I clinical trial
was initiated by Novartis in Europe to assess the safety,
feasibility, and pharmacokinetics of this antibody in patients with complete SCI between C-5 and T-12, who are
4–14 days postinjury. The agent is being administered via
continuous intrathecal infusion, and patients are being
enrolled in 4 increasing dose regimens, with the highest dose being delivered over 28 days. The FDA has expressed concerns with the external nature of the infusion
pump, and hence the clinical evaluation has been limited
to Europe and Canada. In addition, neutropenia was recently reported as a severe adverse event associated with
this therapy, and it will be interesting to see how this impacts the trial.
Cethrin
McKerracher and Higuchi102 have developed a therapy
that exploits the fact that all known myelin and extracellular matrix inhibitors identified thus far signal via activation of the guanosine triphosphatase Rho. When activated,
Rho binds to Rho kinase (ROCK), noted to be a key regulator of axonal growth cone dynamics and cellular apoptosis. Their work involves a toxin produced by Clostridium
botulinum, C3 transferase, which is a specific inhibitor of
Rho. Interruption of this final common pathway thus has
the potential to be more potent than efforts to antagonize
any single myelin inhibitor. This agent facilitated axonal
growth and promoted functional recovery in a mouse
model of SCI.32 The early neurological improvement observed in the C3-treated animals suggested an additional
neuroprotective effect. Supporting this, Dubreuil et al.38
subsequently demonstrated a reduction in p75-dependent
apoptosis in association with their therapy.
To improve cellular permeability, McKerracher’s
group created a recombinant version incorporating a
transport sequence. The resulting protein, referred to as
9
G. W. J. Hawryluk et al.
BA-210, was commercialized by BioAxone Therapeutic
and brought to clinical trial. In the human application,
BA-210 is mixed with Tisseal (the combination being
called Cethrin), which is applied to the dura at the time
of spinal decompression. A Phase I/IIa multicenter, doseescalation trial in humans was initiated under the leadership of the senior author (M.G.F.) at the University of
Toronto. Thirty-seven patients with complete SCIs were
recruited from 10 North American sites. Cethrin was
given within 7 days of injury during spinal stabilization/
decompression surgery. Injuries from T-2 to T-12 and
C-4 to T-1 were subject to separate analysis, and 6-month
follow-up is planned. Some results from this trial have
been released and appear very promising. No significant
adverse events have been associated with the Cethrin administration. Of greater interest, a 27% conversion rate
from ASIA Grade A to B, C, or D was observed. This
must be interpreted with caution given the early phase of
this trial and its unrandomized nature; however, this rate
of improved neurological function was deemed promising, and a subsequent Phase II study is being conducted
under the sponsorship of Alseres Pharmaceuticals.
Cellular Transplantation Therapies
Because limited substrate for neural repair is a significant obstacle following SCI, cell replacement strategies
are believed to be among the most promising new strategies for treating SCI. A multitude of cell types have been
tried, including neural precursor cells, olfactory ensheathing cells, bone marrow–derived stromal cells, and others.
The goals of these strategies differ among researchers
with some aiming to produce new neurons that will integrate into functional circuits; groups such as our own
have sought and achieved oligodendrocyte differentiation
and remyelination.81 Despite diverse strategies, functional
benefit has been consistently seen, though the magnitude
of this benefit has been uniformly modest and important
controversies exist regarding the purported mechanism of
action of various cell types.
Unfortunately, in the field of cell transplantation, excitement and enthusiasm have exceeded the science supporting this approach; cell transplantation into injured
human spinal cords is being conducted in numerous
centers outside North America. Many believe that these
approaches require greater optimization and understanding before human trials are undertaken. For instance, evidence suggests that some transplantation regimens may
be complicated by genesis or exacerbation of neuropathic
pain,70,101 which is currently poorly understood. Other
serious complications have been described such as in a
patient who developed tumorlike overgrowth following
a procedure performed in Russia, as reported by neurosurgeons from the University of British Columbia. Even
if these strategies are associated with benefit free from
harm, lack of appropriate trial methodology will greatly
limit any conclusions that can be drawn from this work.
Nonetheless, many patients continue to travel great distances at enormous financial cost to undergo such experimental transplantation procedures despite the inherent
risk and questionable gains.
10
Activated Autologous Macrophages (PROCORD)
Activated autologous macrophages were the first
cellular substrate to be transplanted into patients with
SCI in a carefully designed, rigorous clinical trial. This
strategy is based on the notion that differences in the
ability of axons within the CNS and PNS to regenerate
are related to differences in the macrophage response
within the 2 environments. For instance, in contrast to
the CNS, macrophages in the PNS are abundant, rapidly clear myelin debris, and also secrete nerve growth
factor.117 In the 1990s, pioneering work in an animal
model of SCI by Schwartz’s group (reported by Rapalino and colleagues125) demonstrated that autologous
macrophages activated ex vivo by peripheral myelin
could promote functional recovery when injected into
the injured spinal cord. Additionally, transplanted, autologous macrophages were associated with enhanced
synthesis of beneficial trophic factors interleukin-1β and
brain-derived neurotrophic factor while decreasing the
synthesis of tumor necrosis factor–α, which is known to
have neurotoxic effects. This technology was then commercialized by Proneuron Biotechnologics, Inc., and a
clinical trial for human SCI was launched in Israel. In
the initial trial 8 patients with complete SCI were enrolled, and they underwent transplantation within 14
days of injury.83 The results were published in 2005, and
the investigators reported that 3 of the 8 patients with
ASIA Grade A recovered to ASIA Grade C, and no major adverse events related to the cell transplant were encountered. This encouraging result led to the subsequent
multicenter Phase II ProCord trial in Israel and the US.
Unfortunately this trial was suspended prematurely in
the spring of 2006 for financial reasons, and there are
currently no plans to continue this study. Fortunately,
1-year data on safety and neurological recovery in the
50 patients enrolled will be published in 2008 (D. Lammertse, personal communication).
Schwann Cells
Schwann cells, the myelinating cells of the PNS,
may represent an environment permissive of regeneration
similar to the peripheral nerve grafts used by Richardson
and colleagues.126 Another potential benefit of these cells
is the ability to harvest them from an autologous source,
such as the sural nerve. The work of Bunge18 at the Miami
Project has explored this possibility since the early 1990s.
A limitation of this technique, however, appears to be that
regenerating CNS axons readily grow into the permissive
environment that these cells provide; however, they are
not prone to growing out of them and back into the hostile
CNS environment. Nonetheless, a formal clinical trial in
Schwann cell transplantation for SCI is being planned at
the Miami Project, which, if initiated, would represent
the realization of nearly a generation of pioneering scientific work in SCI for the investigators. It should also be
noted that 2 groups in China have reportedly performed
transplantation of peripheral nerve–derived Schwann
cells into the injured human spinal cord,139 but this work
has not been formally reported.
Neurosurg. Focus / Volume 25 / November 2008
Advances in spinal cord injury therapeutics
Olfactory Ensheathing Cells
Olfactory ensheathing cells are specialized glia of
the olfactory system, which may address the PNS to CNS
barrier inherent to Schwann cells. The OECs escort regenerating axons of olfactory receptor neurons from the
PNS of the nasal epithelium to the “hostile” CNS of the
olfactory bulb. A host of promising preclinical data culminated in a report of OEC transplantation promoting
axonal regeneration and functional recovery in a model
of complete spinal cord transection.124 Amid these encouraging findings, however, significant controversies
exist about the myelinating potential of OECs. Evidence
suggests that remyelination may instead be mediated by
the contaminating Schwann cells, which also bear the p75
marker.10 Nonetheless, interest remains high in this autologous transplantation strategy, and a number of centers
are currently implanting OECs or tissue acquired from
the olfactory region consisting of OECs and other cells in
patients with SCI.
In an uncontrolled Portuguese pilot study,96 7 patients
with ASIA Grade A injuries were reportedly treated with
autologous olfactory mucosal implants at 6 months–6.5
years postinjury. Apparently, all patients had improvement in ASIA motor grades, and 2 progressed from ASIA
Grade A to C. Additionally, 2 patients reported return of
sensation in their bladders, and 1 regained voluntary anal
sphincter contraction. One patient had a decline in ASIA
sensory grade related to the procedure, and several patients experienced temporary pain in the trunk or lower
limbs that was relieved by gabapentin and resolved after
2–3 months. However, this work has not been subjected
to independent analysis, and it is unclear what to conclude
from this preliminary work.
An Australian center conducted a single-blinded trial
of “purified” autologous olfactory ensheathing cells in 3
patients with complete thoracic SCI within 6–32 months
of injury. A comparison was made to matched but untransplanted controls.47 Before and after surgery the patients were assessed using MR imaging, medical, neurological, and psychosocial assessments, as well as ASIA
and FIM scoring. One-year follow-up data revealed no
motor improvement, but also absence of surgical complications or neurological worsening.47 The investigators
intend to observe these patients for 3 years.
A group in China, led by Huang, is believed to have
the world’s largest experience with a cell transplantation
approach for SCI, having transplanted olfactory tissue from
aborted fetuses into the spinal cords of > 300 patients.37
Given this experience, it is unfortunate that there is a lack
of scientific methodology being applied to the selection of
patients, acquisition and characterization of the transplanted tissue, and outcome evaluation, although neurological
recovery is being measured according to ASIA standards
in recent patients. Of note, although 1 case of rapid neurological recovery has been reported following the Huang
procedure,59 surgeons in Miami found no benefit in patients assessed at their center before and after the therapy.37
It should also be noted that in Russia, Bryukhovetskiy is
performing many OEC transplantations in patients with
chronic SCIs as late as a decade postinjury, but little else is
known about this experimental initiative.139
Neurosurg. Focus / Volume 25 / November 2008
Bone Marrow Stromal Cells
Bone marrow stromal cells demonstrate a surprising ability to migrate to the site of CNS injury following intravascular or intrathecal administration, albeit at
a low rate. Importantly, they can also be transplanted in
autologous fashion like Schwann cells and OECs. A number of groups are currently transplanting BMSCs into the
injured spinal cords of humans and are reporting benefit.
These claims of neurological efficacy need to be interpreted very cautiously as these trials are small and generally conducted without controls or blinded observers.
A Korean group has reported the results of autologous
human BMSC transplantation combined with administration of granulocyte macrophage-colony stimulating factor in a Phase I/II open-label, nonrandomized study.116,151
This trial involved 35 patients with ASIA Grade A who
underwent transplantation within 14 days (17 patients),
between 14 days and 8 weeks (6 patients), or at > 8 weeks
(12 patients) after injury compared with 13 control patients treated with decompression and fusion only. At the
time of publication, the mean follow-up was 10.4 months
after injury, and neurological function was reportedly improved in 30.4% of the acute and subacute groups, but
no significant improvement was observed in the chronic
group. No serious adverse clinical events were noted.
Investigators in Prague have also pursued a human
BMSC trial.137,139 Their trial involved 20 patients with
complete SCI who underwent transplantation 10–467
days postinjury. Follow-up examinations were completed
by 2 independent neurologists using the ASIA scale, and
motor and somatosensory evoked potentials. Improvement in motor and/or sensory functions was noted in 5 of
7 acute, and 1 of 13 chronic patients leading the authors
to suggest a therapeutic window of 3–4 weeks following
injury. In 11 patients observed for > 2 years, no complications were observed.
According to Tator,139 90 patients have received similar transplants in China, and in Russia, 2 groups are using
these cells in humans. In 2003, one of the Russian groups
reported that of the 15 patients with ASIA Grade A in
whom they transplanted fetal nervous and hematopoietic
tissues, 6 improved to ASIA Grade C, and 5 improved to
Grade B.123 In addition, groups in Brazil and Russia are
transplanting stem cells obtained from peripheral blood,
but little is known about this work.139
Human Embryonic Stem Cells
Researchers at the University of California, Irvine,
led by Dr. Hans Keirstead, have reported promising results in a rat SCI model with the transplantation of human embryonic stem cells. These cells differentiate into
oligodendrocyte progenitors and achieve remyelination
of spared, demyelinated spinal cord axons.82,92 They have
developed a technique to ensure high purity of their cell
isolates, as well as techniques for culturing these cells
without the need for feeder cells which could theoretically lead to viral contamination, or nonhuman polysaccharide epitopes on the surface of transplanted cells.145 These
have been critical steps in making these cells suitable for
human transplantation.
11
G. W. J. Hawryluk et al.
Indeed, the biopharmaceutical corporation Geron is
attempting to bring this cell type into human clinical trials. A Phase I trial had been proposed as early as 2006.145
Geron had hoped to initiate this clinical trial in 2008;
however, the FDA recently placed this trial on clinical
hold for reasons that are not known at the time of this
writing. Formal release of this information will be of
great importance to the field as the FDA’s response to this
proposed trial will set precedents of monumental importance to future cell replacement therapies in humans.145
Conclusions
With lessons from recently completed trials in hand,
over a dozen new clinical trials are underway. The possibility that at least one of these treatments will be effective
for SCI is high. Furthermore, many more promising therapies are currently in preclinical studies with the promise
of entering clinical trials in the near future. There is thus
clear reason for researchers, clinicians, and patients to be
optimistic. It is unfortunate that despite the lessons of the
past, many experimental therapies and are being tested or
used in an unsatisfactory fashion. Hopefully, the promotion of recently published guidelines will increase what
can be learned from the patients who participate in such
trials.
Disclaimer
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this
paper.
Acknowledgments
The authors thank Stefania Spano and Dr. Darryl Baptiste for
their assistance in preparing this manuscript.
References
1. AANS/CNS: Pharmacological therapy after acute cervical
spinal cord injury. Neurosurgery 50:S63–S72, 2002
2. Aito S, D’Andrea M, Werhagen L, Farsetti L, Cappelli S, Bandini B, et al: Neurological and functional outcome in traumatic central cord syndrome. Spinal Cord 45:292–297, 2007
3. Anstett P: We have to overcome this hope barrier. Detriot, MI:
Detroit Free Press, June 7, 2005
4. Baptiste DC, Fehlings M: Update on the treatment of spinal
cord injury. Prog Brain Res 161:217–233, 2007
5. Baptiste DC, Fehlings MG: Pharmacological approaches to
repair the injured spinal cord. J Neurotrauma 23:318–334,
2006
6. Barbeau H, Ladouceur M, Mirbagheri MM, Kearney RE: The
effect of locomotor training combined with functional electrical stimulation in chronic spinal cord injured subjects: walking and reflex studies. Brain Res Brain Res Rev 40:274–291,
2002
7. Baskin DS, Simpson RK Jr, Browning JL, Dudley AW, Rothenberg F, Bogue L: The effect of long-term high-dose naloxone infusion in experimental blunt spinal cord injury. J Spinal Disord 6:38–43, 1993
8. Bhatt JM, Gordon PH: Current clinical trials in amyotrophic
lateral sclerosis. Expert Opin Investig Drugs 16:1197–1207,
2007
9. Bose B, Osterholm JL, Kalia M: Ganglioside-induced regen-
12
eration and reestablishment of axonal continuity in spinal
cord-transected rats. Neurosci Lett 63:165–169, 1986
10. Boyd JG, Doucette R, Kawaja MD: Defining the role of olfactory ensheathing cells in facilitating axon remyelination
following damage to the spinal cord. FASEB J 19:694–703,
2005
11. Bracken MB: Methylprednisolone and acute spinal cord injury: an update of the randomized evidence. Spine 26:S47–S54,
2001
12. Bracken MB, Shepard MJ, Collins WF, Holford TR, Young
W, Baskin DS, et al: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinalcord injury. Results of the Second National Acute Spinal Cord
Injury Study. N Engl J Med 322:1405–1411, 1990
13. Bracken MB, Shepard MJ, Hellenbrand KG, Collins WF, Leo
LS, Freeman DF, et al: Methylprednisolone and neurological
function 1 year after spinal cord injury: results of the National
Acute Spinal Cord Injury Study. J Neurosurg 63:704–713,
1985
14. Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, et al: Administration of methylprednisolone
for 24 or 48 hours or tirilizad mesylate for 48 hours in the
treatment of acute spinal cord injury. JAMA 277:1597–1604,
1997
15. Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, et al: Methylprednisolone or tirilizad mesylate administration after acute spinal cord injury: 1-year
follow-up. J Neurosurg 89:699–706, 1998
16. Braughler JM, Hall ED: Effects of multi-dose methylprednisolone sodium succinate administration on injured cat spinal
cord neurofilament degradation and energy metabolism. J
Neurosurg 61:290–295, 1984
17. Bregman BS, Kunkel-Bagden E, Schnell L, Dai HN, Gao D,
Schwab ME: Recovery from spinal cord injury mediated by
antibodies to neurite growth inhibitors. Nature 378:498–501,
1995
18. Bunge RP: Schwann cells in central regeneration. Ann N Y
Acad Sci 633:229–233, 1991
19. Caroni P, Savio T, Schwab ME: Central nervous system regeneration: oligodendrocytes and myelin as non-permissive
substrates for neurite growth. Prog Brain Res 78:363–370,
1988
20. Caroni P, Schwab ME: Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate
properties of CNS white matter. Neuron 1:85–96, 1988
21. Caroni P, Schwab ME: Two membrane protein fractions from
rat central myelin with inhibitory properties for neurite growth
and fibroblast spreading. J Cell Biol 106:1281–1288, 1988
22. Catz A, Agranov E, Ring H, Tamir A: The spinal cord independence measure (SCIM): sensitivity to functional changes
in subgroups of spinal cord lesion patients. Spinal Cord
39:97–100, 2001
23. Catz A, Itzkovich M, Steinberg F, Philo O, Ring H, Ronen J, et
al: The Catz-Itzkovich SCIM: a revised version of the Spinal
Cord Independence Measure. Disabil Rehabil 23:263–268,
2001
24. Cesaro P: The design of clinical trials for cell transplantation into the central nervous system. NeuroRx 1:492–499,
2004
25. Chang RC, Rota C, Glover RE, Mason RP, Hong JS: A novel
effect of an opioid receptor antagonist, naloxone, on the production of reactive oxygen species by microglia: a study by
electron paramagnetic resonance spectroscopy. Brain Res
854:224–229, 2000
26. Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L,
Spillmann AA, et al: Nogo-A is a myelin-associated neurite
outgrowth inhibitor and an antigen for monoclonal antibody
IN-1. Nature 403:434–439, 2000
27. Chen TY, Lee ST, Lui TN, Wong CW, Yeh YS, Tzaan WC,
Neurosurg. Focus / Volume 25 / November 2008
Advances in spinal cord injury therapeutics
et al: Efficacy of surgical treatment in traumatic central cord
syndrome. Surg Neurol 48:435–440, 1997
28. Coleman WP, Benzel D, Cahill DW, Ducker T, Geisler F,
Green B, et al: A critical appraisal of the reporting of the
National Acute Spinal Cord Injury Studies. J Spinal Disord
13:185–199, 2000
29. Coselli JS, Lemaire SA, Köksoy C, Schmittling ZC, Curling
PE: Cerebrospinal fluid drainage reduces paraplegia after thoracoabdominal aortic aneurysm repair: results of a randomized clinical trial. J Vasc Surg 35:631–639, 2002
30. David S, Aguayo AJ: Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in
adult rats. Science 214:931–933, 1981
31. Davis SM, Albers GW, Diener HC, Lees KR, Norris J: Termination of acute stroke studies involving selfotel treatment.
ASSIST Steering Committed. Lancet 349:32, 1997
32. Dergham P, Ellezam B, Essagian C, Avedissian H, Lubell
WD, McKerracher L: Rho signaling pathway targeted to promote spinal cord repair. J Neurosci 22:6570–6577, 2002
33. DeVivo MJ: Causes and costs of spinal cord injury in the United States. Spinal Cord 35:809–813, 1997
34. Dimar JR II, Glassman SD, Raque GH, Zhang YP, Shields
CB: The influence of spinal canal narrowing and timing of
decompression on neurologic recovery after spinal cord contusion in a rat model. Spine 24:1623–1633, 1999
35. Ditunno JF Jr, Ditunno PL, Gravazi V, Scivoletto G, Bernardi
M, Castellano V, et al: Walking index for spinal cord injury
(WISCI): an international multicenter validity and reliability
study. Spinal Cord 38:234–243, 2000
36. Dittuno PL, Dittuno JF Jr: Walking index for spinal cord injury
(WISCI II): scale revision. Spinal Cord 39:654–656, 2001
37. Dobkin BH, Curt A, Guest J: Cellular transplants in China:
observational study from the largest human experiment in
chronic spinal cord injury. Neurorehabil Neural Repair
20:5–13, 2006
38. Dubreuil CI, Winton MJ, McKerracher L: Rho activation patterns after spinal cord injury and the role of activated Rho in
apoptosis in the central nervous system. J Cell Biol 162:233–
243, 2003
39. Dumont RJ, Verma S, Okonkwo DO, Hurlbert RJ, Boulos PT,
Ellegala DB, et al: Acute spinal cord injury, part II: contemporary pharmacotherapy. Clin Neuropharmacol 24:265–279,
2001
40. Dvorak MF, Fisher CG, Hoekema J, Boyd M, Noonan V, Wing
PC, et al: Factors predicting motor recovery and functional
outcome after traumatic central cord syndrome: a long-term
follow-up. Spine 30:2303–2311, 2005
41. Eck JC, Nachtigall D, Humphreys SC, Hodges SD: Questionnaire survey of spine surgeons on the use of methylprednisolone for acute spinal cord injury. Spine 31:E250–E253, 2006
42. Erecinska M, Thoresen M, Silver IA: Effects of hypothermia
on energy metabolism in Mammalian central nervous system.
J Cereb Blood Flow Metab 23:513–530, 2003
43. Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynski
MH, Lammertse D, et al: Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord
45:190–205, 2007
44. Fehlings MG: Editorial: recommendations regarding the use
of methylprednisolone in acute spinal cord injury: making
sense out of the controversy. Spine 26:S56–S57, 2001
45. Fehlings MG, Perrin RG: The role and timing of early decompression for cervical spinal cord injury: update with a review
of recent clinical evidence. Injury 36:B13–B26, 2005
46. Fehlings MG, Tator CH, Linden RD: The effect of nimodipine
and dextran on axonal function and blood flow following experimental spinal cord injury. J Neurosurg 71:403–416,
1989
Neurosurg. Focus / Volume 25 / November 2008
47. Féron F, Perry C, Cochrane J, Licina P, Nowitzke A, Urquhart
S, et al: Autologous olfactory ensheathing cell transplantation in human spinal cord injury. Brain 128:2951–2960,
2005
48. Festoff BW, Ameenuddin S, Arnold PM, Wong A, Santacruz
KS, Citron BA: Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after
spinal cord injury. J Neurochem 97:1314–1326, 2006
49. Flamm ES, Young W, Collins WF, Piepmeier J, Clifton GL,
Fischer B: A phase I trial of naloxone treatment in acute spinal
cord injury. J Neurosurg 63:390–397, 1985
50. Fouad K, Dietz V, Schwab ME: Improving axonal growth and
functional recovery after experimental spinal cord injury by
neutralizing myelin associated inhibitors. Brain Res Brain
Res Rev 36:204–212, 2001
51. Freund P, Schmidlin E, Wannier T, Bloch J, Mir A, Schwab
ME, et al: Nogo-A-specific antibody treatment enhances
sprouting and functional recovery after cervical lesion in
adult primates. Nat Med 12:790–792, 2006
52. Freund P, Wannier T, Schmidlin E, Bloch J, Mir A, Schwab
ME, et al: Anti-Nogo-A antibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey. J Comp Neurol
502:644–659, 2007
53. Gaviria M, Privat A, d’Arbigny P, Kamenka J, Haton H, Ohanna F: Neuroprotective effects of a novel NMDA antagonist,
Gacyclidine, after experimental contusive spinal cord injury
in adult rats. Brain Res 874:200–209, 2000
54. Geisler FH: GM-1 ganglioside and motor recovery following
human spinal cord injury. J Emerg Med 11:49–55, 1993
55. Geisler FH, Coleman WP, Grieco G, Poonian D : The Sygen
multicenter acute spinal cord injury study. Spine 26:S87–S98,
2001
56. Geisler FH, Dorsey FC, Coleman WP: Recovery of motor
function after spinal-cord injury—a randomized, placebocontrolled trial with GM-1 ganglioside. N Engl J Med
324:1829–1838, 1991
57. Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD:
Glutamate release and free radical production following brain
injury: effects of posttraumatic hypothermia. J Neurochem
65:1704–1711, 1995
58. GrandPré T, Nakamura F, Vartanian T, Strittmatter SM: Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403:439–444, 2000
59. Guest J, Herrera LP, Qian T: Rapid recovery of segmental
neurological function in a tetraplegic patient following transplantation of fetal olfactory bulb-derived cells. Spinal Cord
44:135–142, 2006
60. Hachimi-Idrissi S, Van Hemelrijck A, Michotte A, Smolders
I, Sarre S, Ebinger G, et al: Postischemic mild hypothermia
reduces neurotransmitter release and astroglial cell proliferation during reperfusion after asphyxial cardiac arrest in rats.
Brain Res 1019:217–225, 2004
61. Hadley MN, Walters BC, Grabb PA, Oyesiku NM, Przbylski GJ, Resnick DK, et al: Guidelines for the management of
acute cervical spine and spinal cord injuries. Clin Neurosurg
49:407–498, 2002
62. Hall ED: Neuroprotective actions of glucocorticoid and non­
glucocorticoid steroids in acute neuronal injury. Cell Mol
Neurobiol 13:415–432, 1993
63. Hall ED: The neuroprotective pharmacology of methylprednisolone. J Neurosurg 76:13–22, 1992
64. Hall ED, Springer JE: Neuroprotection and acute spinal cord
injury: a reappraisal. NeuroRx 1:80–100, 2004
65. Hansebout RR, Tanner JA, Romero-Sierra C: Current status
of spinal cord cooling in the treatment of acute spinal cord
injury. Spine 9:508–511, 1984
66. Hashimoto T, Fukuda N: Effect of thyrotropin-releasing hormone on the neurologic impairment in rats with spinal cord
13
G. W. J. Hawryluk et al.
injury: treatment starting 24 h and 7 days after injury. Eur J
Pharmacol 203:25–32, 1991
67. He Y, Appel S, Le W: Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain Res 909:187–193, 2001
68. Hinkle L, McCaig CD, Robinson KR: The direction of growth
of differentiating neurones and myoblasts from frog embryos
in an applied electric field. J Physiol 314:121–135, 1981
69. Hirbec H, Gaviria M, Vignon J: Gacyclidine: a new neuroprotective agent acting at the N-methyl-D-aspartate receptor.
CNS Drug Rev 7:172–198, 2001
70. Hofstetter CP, Holmström NA, Lilja JA, Schweinhardt P, Hao
J, Spenger C, et al: Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves
outcome. Nat Neurosci 8:346–353, 2005
71. Houle JD, Tessler A: Repair of chronic spinal cord injury. Exp
Neurol 182:247–260, 2003
72. Huang ZG, Xue D, Preston E, Karbalai H, Buchan AM: Biphasic opening of the blood-brain barrier following transient
focal ischemia: effects of hypothermia. Can J Neurol Sci
26:298–304, 1999
73. Huber AB, Schwab ME: Nogo-A, a potent inhibitor of neurite
outgrowth and regeneration. Biol Chem 381:407–419, 2000
74. Hurlbert RJ: Methylprednisolone for acute spinal cord injury:
an inappropriate standard of care. J Neurosurg 93:1–7, 2000
75. Hurlbert RJ: The role of steroids in acute spinal cord injury: an
evidence-based analysis. Spine 26:S39–S46, 2001
76. Hurlbert RJ, Moulton R: Why do you prescribe methylprednisolone for acute spinal cord injury? A Canadian perspective and a position statement. Can J Neurol Sci 29:236–239,
2002
77. Inamasu J, Suga S, Sato S, Horiguchi T, Akaji K, Mayanagi
K, et al: Post-ischemic hypothermia delayed neutrophil accumulation and microglial activation following transient focal
ischemia in rats. J Neuroimmunol 109:66–74, 2000
78. Ishida Y, Tominaga T: Predictors of neurologic recovery in
acute central cervical cord injury with only upper extremity
impairment. Spine 27:1652–1658, 2002
79. Jaffe LF, Poo MM: Neurites grow faster towards the cathode
than the anode in a steady field. J Exp Zool 209:115–128,
1979
80. Jiang JY, Yang XF: Current status of cerebral protection with
mild-to-moderate hypothermia after traumatic brain injury.
Curr Opin Crit Care 13:153–155, 2007
81. Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Morshead
CM, Fehlings MG: Delayed transplantation of adult neural
precursor cells promotes remyelination and functional neurological recovery after spinal cord injury. J Neurosci 26:3377–
3389, 2006
82. Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp
K, et al: Human embryonic stem cell-derived oligodendrocyte
progenitor cell transplants remyelinate and restore locomotion
after spinal cord injury. J Neurosci 25:4694–4705, 2005
83. Knoller N, Auerbach G, Fulga V, Zelig G, Attias J, Bakimer
R, et al: Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase
I study results. J Neurosurg Spine 3:173–181, 2005
84. Krleza-Jeric K, Chan AW, Dickersin K, Sim I, Grimshaw J,
Gluud C: Principles for international registration of protocol
information and results from human trials of health related
interventions: Ottawa statement (part 1). BMJ 330:956–958,
2005
85. Kunihara T, Matsuzaki K, Shiiya N, Saijo Y, Yasuda K:
Naloxone lowers cerebrospinal fluid levels of excitatory amino acids after thoracoabdominal aortic surgery. J Vasc Surg
40:681–690, 2004
86. Kwon BK, Mann C, Sohn HM, Hilibrand AS, Phillips FM,
Wang JC, et al: Hypothermia for spinal cord injury. Spine J
[epub ahead of print], 2008
14
87. Kwon BK, Tetzlaff W, Grauer JN, Beiner J, Vaccaro AR:
Pathophysiology and pharmacologic treatment of acute spinal
cord injury. Spine J 4:451–464, 2004
88. Lallement G, Baubichon D, Clarençon D, Galonnier M, Peoc’h
M, Carpentier P: Review of the value of gacyclidine (GK-11) as
adjuvant medication to conventional treatments of organophosphate poisoning: primate experiments mimicking various scenarios of military or terrorist attack by soman. Neurotoxicology
20:675–684, 1999
89. Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW,
Rask C, et al: Guidelines for the conduct of clinical trials for
spinal cord injury as developed by the ICCP panel: clinical trial
design. Spinal Cord 45:232–242, 2007
90. Lammertse DP: Update on pharmaceutical trials in acute spinal
cord injury. J Spinal Cord Med 27:319–325, 2004
91. Landwehrmeyer GB, Dubois B, de Yébenes JG, Kremer B, Gaus
W, Kraus PH, et al: Riluzole in Huntington’s disease: a 3-year,
randomized controlled study. Ann Neurol 62:262–272, 2007
92. Lebkowski JS, Gold J, Xu C, Funk W, Chiu CP, Carpenter
MK: Human embryonic stem cells: culture, differentiation, and
genetic modification for regenerative medicine applications.
Cancer J 7:83–93, 2001
93. Lee SM, Yune TY, Kim SJ, Park DW, Lee YK, Kim YC, et al:
Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma
20:1017–1027, 2003
94. Lei B, Tan X, Cai H, Xu Q, Guo Q: Effect of moderate hypothermia on lipid peroxidation in canine brain tissue after cardiac
arrest and resuscitation. Stroke 25:147–152, 1994
95. Lepeintre JF, D’Arbigny P, Mathé JF, Vigué B, Loubert G,
Delcour J, et al: Neuroprotective effect of gacyclidine. A multicenter double-blind pilot trial in patients with acute traumatic
brain injury. Neurochirurgie 50:83–95, 2004
96. Lima C, Pratas-Vital J, Escada P, Hasse-Ferreira A, Capucho C,
Peduzzi JD: Olfactory mucosa autografts in human spinal cord
injury: a pilot clinical study. J Spinal Cord Med 29:191–203,
2006
97. Liu L, Yenari MA: Therapeutic hypothermia: neuroprotective
mechanisms. Front Biosci 12:816–825, 2007
98. Long JB, Kinney RC, Malcolm DS, Graeber GM, Holaday JW:
Intrathecal dynorphin A1-13 and dynorphin A3-13 reduce rat
spinal cord blood flow by non-opioid mechanisms. Brain Res
436:374–379, 1987
99. Lyden P, Wahlgren NG: Mechanisms of action of neuroprotectants in stroke. J Stroke Cerebrovasc Dis 9:9–14, 2000
100. Ma QH, Yang WL, Nie DY, Dawe GS, Xiao ZC: Physiological
roles of neurite outgrowth inhibitors in myelinated axons of
the central nervous system—implications for the therapeutic
neutralization of neurite outgrowth inhibitors. Curr Pharm Des
13:2529–2537, 2007
101. Macias MY, Syring MB, Pizzi MA, Crowe MJ, Alexanian
AR, Kurpad SN: Pain with no gain: allodynia following neural
stem cell transplantation in spinal cord injury. Exp Neurol
201:335–348, 2006
102. McKerracher L, Higuchi H: Targeting Rho to stimulate
repair after spinal cord injury. J Neurotrauma 23:309–317,
2006
103. McKinley W, Meade M, Kirshblum S, Barnard B: Outcomes of
early surgical management versus late or no surgical intervention after acute spinal cord injury. Arch Phys Med Rehabil
85:1818–1825, 2004
104. Miller RG, Mitchell JD, Lyon M, Moore DH: Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).
Cochrane Database Syst Rev 1:CD001447, 2007
105. Mitha AP, Maynard KI: Gacyclidine (Beaufour-Ipsen). Curr
Opin Investig Drugs 2:814–819, 2001
106. Morris GF, Bullock R, Marshall SB, Marmarou A, Maas A,
Marshall LF: Failure of the competitive N-methyl-D-aspartate
antagonist Selfotel (CGS 19755) in the treatment of severe
Neurosurg. Focus / Volume 25 / November 2008
Advances in spinal cord injury therapeutics
head injury: results of two phase III clinical trials. The Selfotel
Investigators. J Neurosurg 91:737–743, 1999
107. Mu X, Azbill RD, Springer JE: Riluzole and methylprednisolone
combined treatment improves functional recovery in traumatic
spinal cord injury. J Neurotrauma 17:773–780, 2000
108. Nesathurai S: Steroids and spinal cord injury: revisiting the
NASCIS 2 and NASCIS 3 trials. J Trauma 45:1088–1093,
1998
109. Nógrádi A, Szabó A, Pintér S, Vrbová G: Delayed riluzole
treatment is able to rescue injured rat spinal motoneurons.
Neuroscience 144:431–438, 2007
110. Nolan JP, Morley PT, Hoek TL, Hickey RW: Advancement
Life support Task Force of the International Liaison committee
on Resuscitation: therapeutic hypothermia after cardiac arrest.
An advisory statement by the Advancement Life support Task
Force of the International Liaison committee on Resuscitation.
Resuscitation 57:231–235, 2003
111. Ohmura A, Nakajima W, Ishida A, Yasuoka N, Kawamura M,
Miura S, et al: Prolonged hypothermia protects neonatal rat brain
against hypoxic-ischemia by reducing both apoptosis and necrosis. Brain Dev 27:517–526, 2005
112. Otani K, Abe H, Kadoya S, Nakagawa H, Ikata T, Tominaga S,
et al: Beneficial effects of methylprednisolone sodium succinate
in the treatment of acute spinal cord injury. Sekitsy Sekizui
7:633–647, 1994
113. Oudega M, Vargas CG, Weber AB, Kleitman N, Bunge MB:
Long-term effects of methylprednisolone following transection
of adult rat spinal cord. Eur J Neurosci 11:2453–2464, 1999
114. Paralyzed Veterans of America Consortium for Spinal Cord
Medicine: Preservation of upper limb function following spinal
cord injury: a clinical practice guideline for health-care professionals. J Spinal Cord Med 28:434–470, 2005
115. Park E, Velumian AA, Fehlings MG: The role of excitotoxicity
in secondary mechanisms of spinal cord injury: a review with an
emphasis on the implications for white matter degeneration. J
Neurotrauma 21:754–774, 2004
116. Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BH, et al:
Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of
granulocyte-macrophage colony stimulating factor. Tissue Eng
11:913–922, 2005
117. Perry VH, Brown MC, Gordon S: The macrophage response
to central and peripheral nerve injury. A possible role for macrophages in regeneration. J Exp Med 165:1218–1223, 1987
118. Petitjean ME, Pointillart V, Dixmerias F, Wiart L, Sztark F,
Lassié P, et al: Medical treatment of spinal cord injury in the
acute stage. Ann Fr Anesth Reanim 17:114–122, 1998
119. Pitts LH, Ross A, Chase GA, Faden AI: Treatment with thyrotropin-releasing hormone (TRH) in patients with traumatic spinal
cord injuries. J Neurotrauma 12:235–243, 1995
120. Pointillart V, Petitjean ME, Wiart L, Vital JM, Lassié P, Thicoipé
M, et al: Pharmacological therapy of spinal cord injury during
the acute phase. Spinal Cord 38:71–76, 2000
121. Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie
G, et al: Inhibitor of neurite outgrowth in humans. Nature
403:383–384, 2000
122. Qian T, Campagnolo D, Kirshblum S: High-dose methylprednisolone may do more harm for spinal cord injury. Med
Hypotheses 55:452–453, 2000
123. Rabinovich SS, Seledtsov VI, Poveschenko OV, Senuykov VV,
Taraban VY, Yarochno VI, et al: Transplantation treatment of
spinal cord injury patients. Biomed Pharmacother 57:428–433,
2003
124. Ramón-Cueto A, Cordero MI, Santos-Benito FF, Avila J:
Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron
25:425–435, 2000
125. Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles
E, Fraidakis M, et al: Implantation of stimulated homologous
Neurosurg. Focus / Volume 25 / November 2008
macrophages results in partial recovery of paraplegic rats. Nat
Med 4:814–821, 1998
126. Richardson PM, McGuinness UM, Aguayo AJ: Axons from
CNS neurons regenerate into PNS grafts. Nature 284:264–265,
1980
127. Sagen J: Cellular therapies for spinal cord injury: what will the
FDA need to approve moving from the laboratory to the human?
J Rehabil Res Dev 40:71–79, 2003
128. Schnell L, Schwab ME: Axonal regeneration in the rat spinal
cord produced by an antibody against myelin-associated neurite
growth inhibitors. Nature 343:269–272, 1990
129. Schwartz G, Fehlings MG: Evaluation of the neuroprotective
effects of sodium channel blockers after spinal cord injury:
improved behavioral and neuroanatomical recovery with riluzole. J Neurosurg 94:245–256, 2001
130. Sekhon LH, Fehlings M: Epidemiology, demographics, and
pathophysiology of acute spinal cord injury. Spine 26:S2–S12,
2001
131. Shapiro S, Borgens R, Pascuzzi R, Roos K, Groff M, Purvines S,
et al: Oscillating field stimulation for complete spinal cord injury
in humans: a phase 1 trial. J Neurosurg Spine 2:3–10, 2005
132. Shortland PJ, Leinster VH, White W, Robson LG: Riluzole promotes cell survival and neurite outgrowth in rat sensory neurones
in vitro. Eur J Neurosci 24:3343–3353, 2006
133. Spillmann AA, Bandtlow CE, Lottspeich F, Keller F, Schwab
ME: Identification and characterization of a bovine neurite
growth inhibitor (bNI-220). J Biol Chem 273:19283–19293,
1998
134. Steeves JD, Fawcett JW, Tuszynski MH, Lammertse D, Curt A,
Ditunno JF, et al: Experimental Treatments for Spinal Cord
Injury: What You Should Know if You Are Considering
Participation in a Clinical Trial. Vancouver, BC: International
Campaign for Cures of Spinal Cord Injury Paralysis, 2007
(http://www.icord.org/ICCP/Experimental_treatment_for_SCIsummary_nc.pdf) [Accessed 22 September 2008]
135. Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH,
Ditunno JF, et al: Guidelines for the conduct of clinical trials for
spinal cord injury (SCI) as developed by the ICCP panel: clinical
trial outcome measures. Spinal Cord 45:206–221, 2007
136. Stirling DP, Khodarahmi K, Liu J, McPhail LT, McBride CB,
Steeves JD, et al: Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci 24:2182–
2190, 2004
137. Syková E, Homola A, Mazanec R, Lachmann H, Konrádová
SL, Kobylka P, et al: Autologous bone marrow transplantation
in patients with subacute and chronic spinal cord injury. Cell
Transplant 15:675–687, 2006
138. Tadie M, D’Arbigny P, Mathé J, Loubert G, Saint-Marc C,
Menthonnex P, et al: Acute spinal cord injury: early care and
treatment in a multicenter study with gacyclidine. Soc Neurosci
25:1090, 1999 (Abstract)
139. Tator CH: Review of treatment trials in human spinal cord
injury: issues, difficulties, and recommendations. Neurosurgery
59:957–982, 2006
140. Tator CH, Fehlings MG, Thorpe K, Taylor W: Current use and
timing of spinal surgery for management of acute spinal surgery
for management of acute spinal cord injury in North America:
results of a retrospective multicenter study. J Neurosurg
91:12–18, 1999
141. Teng YD, Choi H, Onario RC, Zhu S, Desilets FC, Lan S, et al:
Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal
cord injury. Proc Natl Acad Sci U S A 101:3071–3076, 2004
142. Tikka TM, Koistinaho JE: Minocycline provides neuroprotection
against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol 166:7527–7533, 2001
143. Tuszynski MH, Steeves JD, Fawcett JW, Lammertse D,
Kalichman M, Rask C, et al: Guidelines for the conduct of clini-
15
G. W. J. Hawryluk et al.
cal trials for spinal cord injury as developed by the ICCP Panel:
clinical trial inclusion/exclusion criteria and ethics. Spinal Cord
45:222–231, 2007
144. van Hedel HJ, Wirz M, Dietz V: Assessing walking ability in
subjects with spinal cord injury: validity and reliability of 3 walking tests. Arch Phys Med Rehabil 86:190–196, 2005
145. Vogel G: Cell biology. Ready or not? Human ES cells head
toward the clinic. Science 308:1534–1538, 2005
146. Wang SJ, Wang KY, Wang WC: Mechanisms underlying the
riluzole inhibition of glutamate release from rat cerebral cortex
nerve terminals (synaptosomes). Neuroscience 125:191–201,
2004
147. Wells JE, Hurlbert RJ, Fehlings MG, Yong VW: Neuroprotection
by minocycline facilitates significant recovery from spinal cord
injury in mice. Brain 126:1628–1637, 2003
148. Winkler T, Sharma HS, Stålberg E, Olsson Y, Nyberg F:
Naloxone reduces alterations in evoked potentials and edema
in trauma to the rat spinal cord. Acta Neurochir Suppl (Wien)
60:511–515, 1994
149. Yamazaki T, Yanaka K, Fujita K, Kamezaki T, Uemura K, Nose
T: Traumatic central cord syndrome: analysis of factors affecting
the outcome. Surg Neurol 63:95–99, 2005
150. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM:
The promise of minocycline in neurology. Lancet Neurol
3:744–751, 2004
16
151. Yoon SH, Shim YS, Park YH, Chung JK, Nam JH, Kim MO, et
al: Complete spinal cord injury treatment using autologous bone
marrow cell transplantation and bone marrow stimulation with
granulocyte macrophage-colony stimulating factor: Phase I/II
clinical trial. Stem Cells 25:2066–2073, 2007
152. Yrjänheikki J, Keinänen R, Pellikka M, Hökfelt T, Koistinaho
J: Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A
95:15769–15774, 1998
153. Yune TY, Lee JY, Jung GY, Kim SJ, Jiang MH, Kim YC, et al:
Minocycline alleviates death of oligodendrocytes by inhibiting
pro-nerve growth factor production in microglia after spinal cord
injury. J Neurosci 27:7751–7761, 2007
154. Zornow MH: Inhibition of glutamate release: a possible mechanism of hypothermic neuroprotection. J Neurosurg Anesthesiol
7:148–151, 1995
Manuscript submitted July 8, 2008.
Accepted September 4, 2008.
Address correspondence to: Michael G. Fehlings, M.D., Ph.D.,
F.R.C.S.C., Spinal Program, University Health Network, Toronto
Western Hospital, McLaughlin Pavilion, 12th Floor Room 407, 399
Bathurst Street, Toronto, Ontario, Canada M5T 2S8. email: Michael.
[email protected].
Neurosurg. Focus / Volume 25 / November 2008