Spinal cord injury and its treatment: current management

and experimental perspectives

F. SCHOLTES1, G. BROOK2, and D. MARTIN1

1
Department of Neurosurgery, Centre Hospitalier Universitaire, University of Liege,
Liege, Belgium
2
Institute for Neuropathology, University Hospital, RWTH Aachen University,
Aachen, Germany

With 5 Figures

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Incidence and prevalence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Individual and socio-economical impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Neurobiology of SCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Spinal cord syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
The spinal cord lesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Evolution of the lesion after the initial trauma. . . . . . . . . . . . . . . . . . . . . . . . . . 32
Human spinal cord injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Axonal regeneration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
The sub-lesional segment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Influence of spinal cord white matter on neurological recovery . . . . . . . . . . . 39
Fundamental therapeutic approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Repair of the lesion site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Recruiting preserved tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
The locomotor system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Spinal cord plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Current clinical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Acute management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Chronic care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
30 F. SCHOLTES et al.

Clinical trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Neuroprotective strategies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Pharmacological interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Systemic hypothermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Decompression strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Restorative therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Abstract

Clinical management of spinal cord injury (SCI) has significantly improved its
general prognosis. However, to date, traumatic paraplegia and tetraplegia re-
main incurable, despite massive research efforts. Current management focuses
on surgical stabilisation of the spine, intensive neurological rehabilitation, and
the prevention and treatment of acute and chronic complications. Prevention
remains the most efficient strategy and should be the main focus of public
health efforts.
Nevertheless, major advances in the understanding of the pathophysio-
logical mechanisms of SCI open promising new therapeutic perspectives.
Even if complete recovery remains elusive due to the complexity of spinal
cord repair, a strategy combining different approaches may result in some
degree of neurological improvement after SCI. Even slight neurological
recovery can have high impact on the daily functioning of severely handi-
capped patients and, thus, result in significant improvements in quality of
life.
The main investigated strategies are: [1] initial neuroprotection, in order
to decrease secondary injury to the spinal cord parenchyma after the initial
insult; [2] spinal cord repair, in order to bridge the lesion site and re-
establish the connection between the supraspinal centres and the deaffer-
ented cord segment below the lesion; and [3] re-training and enhancing
plasticity of the central nervous system circuitry that was preserved or
rebuilt after the injury.
Now and in the future, treatment strategies that have both a convincing
rationale and seen their efficacy confirmed reproducibly in the experimental
setting must carefully be brought from bench to bedside. In order to obtain
clinically significant results, their introduction into clinical research must be
guided by scientific rigour, and their coordination must be rationally structured
in a long-term perspective.
Keywords: Spinal cord injury; neuroprotection; regeneration; plasticity; human trials.
Spinal cord injury and its treatment 31

Introduction
Clinical management of spinal cord injury (SCI) has significantly improved its
general prognosis. However, to date, traumatic paraplegia and tetraplegia re-
main incurable, despite massive research efforts.

Incidence and prevalence

In 1995, Blumer and Cline estimated the incidence and prevalence of SCI to be
between 13 and 33 cases per million per year, and from 110 to 1120 per million
population, respectively [1]. On this basis, Wyndaele and Wyndaele reviewed
the more recent literature in 2006 and found that, despite considerable varia-
tions among study methods and reporting, incidence and prevalence do not
seem to have changed substantially over recent years. In their review, the
incidence and prevalence ranges are of 10.4 and 83 per million inhabitants
per year and 223–755 per million inhabitants, respectively [2]. These data
may not be sufficiently representative for a worldwide estimate, but, at the
least, give an idea of the magnitude of the problem.

Individual and socio-economical impact

Traumatic SCI is a catastrophe for the individual concerned. Para- and tetra-
plegia deprive their victims of locomotion, sphincter and sexual function, their
autonomy, private and professional perspectives, as well as working capacity.
Many previously basic routines become challenging obstacles and patients are
exposed to specific medical complications [3] (see below). After 35 years of
follow-up in the National SCI database (since 1973), the main causes of death
are pneumonia, septicaemia, and pulmonary embolism [4]. Nevertheless, with
present clinical management, life expectancy of spinal cord injured patients
approaches the population average in developed countries, though without
reaching normal values.
The socio-economical impact of SCI remains considerable. Approximately
80% of patients are young males, with an average age at injury of less than 40
years. About half of patients suffer from tetraplegia, the other half from paraple-
gia. More than half of the patients reported being employed before the injury.
By 20 and 30 years after injury, slightly more than a third are employed again (less
tetraplegics than paraplegics) [4, 5]. Lifetime costs in the United States have been
estimated to range from approximately 500,000 US$ for a 50 year old incom-
pletely injured patient to more than 3,000,000 US$ for a 25 year old completely
tetraplegic patient. This does not include indirect costs of >65,000 US$ per year,
accounting for loss of wages, fringe benefits and productivity [4].
Over the last decades, governments and non-medical, non-governmental
associations and foundations have increasingly participated in the attempts
to reduce the incidence and gravity of traumatic injuries, including brain
32 F. SCHOLTES et al.

and spinal cord injuries. One example is the Think First foundation
(www.thinkfirst.org=) that raises awareness of the gravity of these injuries and
their potential prevention via educational campaigns and advertising, specifi-
cally targeting children and young adults, as well as motor vehicle users. The
widespread introduction of safety measures like the legal requirements for seat
belts and helmets, the reduction of speed limits on roads, and more, appear to
reduce the incidence of head and spine trauma [6–12].

Neurobiology of SCI

Spinal cord syndromes

Paraplegia and tetraplegia due to SCI result from the interruption of the con-
nections between the supra-spinal control centres and the spinal cord circuits
caudal to the lesion site, i.e., the deafferentation of the sub-lesional cord. This
deafferentation occurs to a variable degree, depending on the extent of the
lesion. Therefore, the so-called ‘‘spinal cord syndromes’’ may be incomplete or
complete. In incomplete cord syndromes (approx. 50% of the cases), the loss
of sensory and=or motor function below the level of injury is partial, and the
type of neurologic deficit is variable. In complete cord syndromes (the remain-
ing 50%), motor and sensory function below the level of the lesion is entirely
lost.
So-called discomplete spinal cord syndromes are clinically complete, but
neurophysiologically incomplete. Thus, even in clinically complete SCI, there
is residual brain influence on spinal cord function below the lesion [13]. In one
study, more than four out of five clinically complete syndromes could be
neurophysiologically classified as discomplete [14], and, thus, in many patients,
there may be central nervous circuitry above the spinal cord lesion that could
potentially be recruited to influence the evolution of even clinically complete
spinal cord syndromes.

The spinal cord lesion

Evolution of the lesion after the initial trauma

Displacement of the elements of the spine results in compression, shearing,
laceration and other immediate mechanical damage of the spinal cord and
associated structures, such as blood vessels and meninges. This is the primary
injury, which can be worsened at the time of the accident by hypotension, due
to spinal shock and hypoxia. Within the cord, a complex, auto-destructive
cascade of secondary events is initiated, leading to hypoxia, ischemia and free
radical production, ion imbalances, excitotoxicity and programmed cell death,
protease activation, and inflammation including eicosanoid=prostaglandin pro-
Spinal cord injury and its treatment 33

D
Fig. 1. Evolution of SCI. (A) Normal cord. The central, butterfly shaped grey matter
is depicted in dark grey. (B) Acute lesion. Cord volume is increased at the lesion
site. At the lesion centre, central haemorrhage can be seen (black dots), mainly in
the grey matter areas. Oedema and beginning necrosis have invaded almost the
entire transverse section (clearer shade of grey). (C) Chronic lesion. The scarring
processes have resulted in retraction of the lesion and atrophy of the cord at
the lesion site and haemosiderin deposits where the lesion was haemorrhagic
(black dots). Spared white matter is seen around the lesion centre. (D) Chronic
lesion with a central cyst (white)
34 F. SCHOLTES et al.

duction. Local extension of the damage thus further disrupts the three-dimen-
sional organisation of the cord [14–17].
Over a time period of days to weeks post-injury, progressive cell death
occurs, the three-dimensional organisation of the spinal cord architecture con-
tinues to degenerate, and the necrotic lesion spreads, damaging increasingly
more axons in the white matter tracts [18] as well as neuronal cell bodies in
the grey matter (especially in the cervical and lumbar enlargements), resulting in
worsened neurological deficits. Although the impact of these secondary injury
processes on parenchymal damage and loss of neurological function cannot be
precisely quantified, the phase between the initial trauma and the constitution
of the definitive cord lesion represents a therapeutic window of opportunity
which has been the focus of a significant neuroprotective research effort [19].
Histopathologicaly, experimental compressive spinal cord lesions in the rat
initially show tissue oedema and petechial bleeding in the grey matter. Over
time, the distal components of severed axons degenerate, neurons and oligo-
dendrocytes undergo apoptosis, and an astroglial and connective scar tissue
forms. Glial scarring occurs at the lesion site and surprisingly also in the
degenerated fibre tracts (including the human corticospinal tract [20]) at 1 year
after injury. The spinal cord undergoes atrophic changes, and, in many cases,
cyst formation can be observed (Fig. 1).

Human spinal cord injury

Human spinal cord injury can be classified into four types [21, 22]: contusion,
maceration, laceration, and solid cord injury.
The most common lesion is the contusion-type injury, associated with
variable degrees of haemorrhage within parenchymal oedema (Fig. 2). The
more severe, still common maceration-type injury is due to massive compres-
sion of the cord, interrupting the cord’s surface and resulting in complete sub-
lesional paralysis. Disruption of the meninges activates a fibroblastic scarring
response that may lead to tethering of the cord to the meninges. About one
fifth of the lesions reported in the initial description of these types of injury
were lacerations, due to penetrating wounds (or penetration of the cord by
bone fragments), or, in children, to brutal stretching of the cord. All these
lesions may evolve into a gliotic scar or one or several intramedullary cysts.
When the cord surface is severed, the tethering of the cord may result in
neurological deficits. Syringomyelia may also develop and must always be sus-
pected when neurological deterioration occurs, especially in a previously neu-
rologically stable patient.
‘‘Solid cord injury’’ corresponds to the pathological changes underlying the
so-called acute traumatic central cord syndrome, which is typically due to com-
pression of the cervical spinal cord during sudden hyperextension of an arthrotic
cervical spine with a spinal canal narrowed by osteophytes and ligamentum
Spinal cord injury and its treatment 35

A B C
Fig. 2. Contusion injury. (A) and (B): MRI appearance in a sagittal (left) and coronal
(middle) view. (C) Gross pathological appearance of the same spinal cord showing the
haemorragic lesion extending rostrocaudally. In the excised axial slice, the haemor-
rhage is seen mainly in the gray matter, a typical finding (from Okazaki H and
Scheithauer BW: Atlas of neuropathology, p. 276, fig. 7.27, Gower Medical Publishing
1988; with permission from Lippincott Williams & Wilkins)

A B C
Fig. 3. Acute traumatic central cord syndrome, macroscopic pathology. (A & B)
Exterior views of the cord do not show significant injury at the lesion site (arrow).
(C) In transverse sections, no haemorrhage and only edema is demonstrated unilater-
ally in the anterior horn of the central gray matter
36 F. SCHOLTES et al.

flavum hypertrophy. Traumatic central cord syndrome was initially suspected to

be due to a haemorrhagic lesion in the central part of the spinal cord. As in
syringomyelia, such a central haematoma would injure the medial fibres of the
corticospinal tracts and spare the more lateral fibres, resulting in ‘‘cruciate paral-
ysis’’ where the motor deficit predominates in the upper limbs. If severe, this
kind of lesion can also result in complete paralysis of the upper limbs. However,
F1
(mm) 60

–22
50
–21
40
–20

–19 30

–18
20
–17

–16 10

–15 0

–14
0 –1 –2 –3 –4 –5 –6 –7 –8 –9 –10
A F2 (mm)

B
Fig. 4. Long white matter tract degeneration demonstrated by post-mortem ultra-
high field MRI (9.4 tesla) and immunohistochemistry for neurofilament in the high
thoracic cord below a complete C5 injury, shown in the axial plane. (A) In the MR
image, the degenerating descending tracts are hyperintense. They include the lateral
corticospinal tract (white asterisk), lateral reticulospinal tract (short arrow), anterior
cortico- and reticulospinal tracts (long arrow), lateral vestibulospinal tract (arrowhead),
fasciculus interfascicularis or comma or semilunar tract that contains intraspinal des-
cending fibres (black asterisk). The scales indicate the original size of the cord. (B)
Histological reconstruction using neurofilament immunhistochemistry for axons, dem-
onstrating axonal loss in the hyper-intense areas shown in (A) (from Scholtes F et al.:
Neurosurgery 59: 674, fig. 2, 2006; with permission from Wolters Kluwer)
Spinal cord injury and its treatment 37

clinical prognosis is much better than in the other types of spinal cord injury. In
more recent studies, MRI has not shown haematoma but T2 hypersignal in the
acute stage, and underlying pathological changes correspond to oedema and
axonal swelling, not to haemorrhage (Fig. 3) [23, 24].
In strict anatomical terms, human SCI is incomplete in most cases, and
neurological recovery may be extensive, even when the lesion has damaged a
significant portion of the spinal white matter [25]. Equivalent phenomena to
the axonal degeneration observed in the experimental setting can be observed
in humans (Fig. 4) [26, 27].

Axonal regeneration
Since the clinically important neurological deficits after SCI result from the loss
of nerve fibres in white matter tracts, i.e., the axonal connections of the supra-
lesional centres to the sub-lesional cord, axonal regeneration offers a promising
therapeutic perspective for ‘‘rewiring’’ the spinal cord.
However, it was long thought to be impossible. In his classic treatise on
nervous system degeneration and regeneration, Ramon y Cajal argued that
‘‘Once development was ended, the founts of growth and regeneration of the axons
and dendrites dried up irrevocably. In the adult centres, the nerve paths are some-
thing fixed, ended and immutable. Everything must die, nothing may be regener-
ated. It is for the science of the future to change, if possible, this harsh decree’’ [28].
Nonetheless, already a hundred years ago, Cajal’s student J. F. Tello had
grafted peripheral nerve segments onto CNS tissue and shown that central
nervous system neurons could regenerate into that environment [29]. At the
beginning of the 1980s, the group of Aguayo published descriptions of the
growth potential of CNS axons into peripheral nerve [30] and found that these
CNS axons were basically functional, although with limited or altered synaptic
contacts (probably due to the absence of their target) [31]. During the same
period, donor fetal CNS neurons were shown to integrate into lesioned spinal
cord tissue and even to ‘‘rescue’’ injured supraspinal neurons in the neonatal
brainstem [32–34]. In the lesioned adult rat spinal cord, a substantial intrinsic
axonal regenerative attempt was demonstrated (Fig. 5), although it showed
signs of spontaneous regression after a few weeks [35].
Since the experimental demonstration that CNS neurons do have the po-
tential to regenerate, research has focussed on the factors that influence CNS
axonal regeneration [36], in particular the axon-growth inhibitory glial scar [37]
(first described by Cajal [28]). Two environmental factors have been identified
that are widely acknowledged to play major roles in preventing axon regenera-
tion and plasticity in the injured adult mammalian brain and spinal cord: CNS
myelin-associated molecules [38, 39] and the family of highly sulphated chon-
doitin sulphate proteoglycans (CSPGs [40]).
38 F. SCHOLTES et al.

A B

C
Fig. 5. Histology of axonal regeneration in the rat spinal cord, 14 days after compres-
sive injury. (A) S-100 immunohistochemistry showing invasion of the lesion site by
Schwann cells, establishing a framework associated with axonal invasion as demon-
strated with double fluorescence immunohistochemistry (B) for S-100 and neurofila-
ment (axons). (C) Camera lucida drawing on the basis of NF-immunohistochemistry
illustrating the penetration of the axons from the parenchyma at the border of the
lesion site (left) into the lesion itself (towards the right) (from M. Krautstrunk et al.:
Acta Neuropathol 104: 592–600. Springer 2002)

Traumatic injury causes the release, as debris, of several myelin associated axon
growth inhibitory molecules, the most potent of which is the gylcoprotein
NOGO-A. It induces the rapid, Nogo-receptor (NgR)-mediated collapse of
axonal growth cones by the activation of the small GTP-ase RhoA (e.g. [41]).
The potent axon growth inhibitory effects of the myelin associated molecules
at the lesion site is supported by the rapid expression of the axon-repulsive,
highly sulphated proteoglycans in- and around the lesion site [42].
In addition, complex inflammatory processes occur after acute SCI, and
they represent a ‘‘dual-edged sword’’. Microglia-derived and blood-borne de-
rived macrophages are integral components of this inflammatory response in-
Spinal cord injury and its treatment 39

and around the lesion site. The phenotype and activation status of these cells
have been reported to have profound effects on their ability to enhance the
secondary degenerative events or to promote CNS axon regeneration and
tissue repair [43, 44]. Various cytokines influence the evolution of the second-
ary injury cascade in a sometimes detrimental, sometimes favourable manner.
The macrophage response to SCI is complex, but modulation of their activity
may have the potential to enhance recovery (possibly, among other roles, by
clearing growth inhibitory myelin debris from the lesion site [45, 46]), and
many experimental treatments interact with these macrophages [47].

The sub-lesional segment

The spinal cord, as part of the CNS, is more than a passive conduit and relay
for neural messages between the supraspinal centres and the peripheral nerves.
A complex intrinsic circuitry exists, mainly in the cervical and lumbar enlarge-
ments of the spinal cord. These circuits autonomously generate structured
neural activity, including rhythmic output, which results in basic locomotor
patterns [48, 49]. After cervical or thoracic SCI, the lumbar circuitry remains
anatomically intact, and plastic alterations (see below) appear to be responsible
for change in neurological presentation that can be observed over time.

Influence of spinal cord white matter on neurological recovery

Although the neurological deficits are for the most part irreversible, the clinical
presentation may thus evolve over time. Spasticity develops, bladder function
changes, and patients may progressively recover some of their lost sensory or
motor function. The spinal cord’s white matter tracts, even when they are
partially damaged, play an important role in functional recovery after SCI,
and there is evidence in humans that white matter tracts influence spinal cord
plasticity [50]. In the experimental setting, white matter tract preservation di-
rectly mediates recovery after SCI [51]. After complete transection of the cord,
there is usually no significant locomotor recovery, but very limited white matter
sparing at the lesion site is sufficient to influence the functional reorganisation
of the sub-lesional cord [52, 53]. Very small increases in spared tissue at the
centre of the lesion have profound effects on basic locomotor recovery, and
sparing of 5–10% of the fibres in the white matter tracts is sufficient to help
drive circuits involved locomotion [53, 54].

Fundamental therapeutic approaches

Three types of potential treatment strategies for SCI result from the above:
neuroprotection, repair of the lesion site and recruitment of the preserved
nervous system (enhancing plasticity).
40 F. SCHOLTES et al.

Neuroprotection
Neuroprotective treatments are designed to interfere with the cascade of events
that lead to secondary tissue injury in order to decrease the progressive exten-
sion of the lesion and damage to the spinal cord parenchyma, in particular the
white matter tracts. Some degree of preservation of the connections between
the supraspinal centres and the sub-lesional cord would lead to lessened neu-
rological deficits. However, although neuroprotective strategies were designed
for potentially rapid clinical application and have been intensively investigated
(see below), the ‘‘magic bullet’’ has yet to be found (for detailed recent reviews,
see [55, 56]).

Repair of the lesion site

Once the lesion has been established and the sub-lesional cord deafferented,
the ideal therapeutic approach would be the repair of the lesion with the
appropriate reconnection or synaptic re-establishment being accomplished by
regrowing axons. Axonal regeneration is, however, only a first step in the
complex sequence which could potentially lead to useful spinal cord repair:
after nerve fibre regrowth into the lesion site through a fibroglial scar, an axon
would have to grow in an orientated manner over a sufficient distance of lesion
tissue to cross the entire lesion site. It would then be required to exit the lesion
site and continue its growth in the sub-lesional central nervous parenchyma,
where it would have to reach an appropriate target, stop its growth and form
synaptic contacts with remaining, intact neuronal circuits. Many of the regen-
erating axons would also require myelination, to finally re-establish impulse
conduction and the reformation of a viable, functional circuitry. This sets an
ambitious goal. Achieving it will depend on the combination of a number of
different strategies addressing these obstacles:

 Removal or blockade of the major axon growth inhibitory influences in the environment
of the injured CNS. Antibodies against NOGO-A (see above) have been
demonstrated to enhance axonal regeneration from lesioned fibres and to
increase compensatory nerve fibre sprouting from non lesioned fibres in
numerous animal models. This has been associated with improved functional
outcome (e.g., [57, 58]). Also, the infusion of the enzyme chondroitinase
ABC into damaged CNS tissues results in the digestion of the inhibitory
sulphated glycosaminoglycan side-chains of the CSPGs and promotes en-
hanced axon regeneration and plasticity of long-distance projecting sensory
axons as well as the return of some degree of motor and sensory function
[59].
 Stimulate axonal regeneration and enhance plasticity. Since the fate of severed- and
spared axons within the lesioned CNS depends on the balance between axon
Spinal cord injury and its treatment 41

growth-promoting factors and axon growth-inhibitory factors, enormous

effort has been expended in devising strategies that tip the balance in favour
of axon regeneration and enhanced plasticity. Strategies include the direct
infusion of neurotrophic growth factors or their local production by geneti-
cally engineered donor cells [60], and the implantation of axon growth-pro-
moting cells (e.g. Schwann cells, olfactory nerve ensheathing cells and bone
marrow derived stromal cells) that intrinsically express a range of molecules
extracellular matrix molecules, cell surface adhesion molecules and growth
factors known to support nerve fibre growth [61].
 Provision of an orientated 3D structure to guide growth polymer scaffolds. A number of
guidance structures or scaffolds of increasingly sophisticated design have been
investigated for this purpose. Such designs range from the use of simple
hollow conduits to more complex devices with microstructures intended to
reproduce the general architecture of spinal cord grey- and white matter. Both
synthetic and natural polymers have investigated for such devices but the ideal
scaffold with optimal functionalisation (e.g. in combination with axon growth
promoting cells) has yet to be determined (for a recent review, see [62]). Part
of the impetus for such strategies aiming to reconnect severed nerve fibres
to their original targets has come from the fact that only a small percentage (1–
10%) of the original nerve fibre projection is needed for the maintenance of
useful motor or sensory function [63, 64].
Currently, the measurable functional improvement after experimental re-
pair remains moderate at best [65]. Nonetheless, an impressive number of
repair strategies have already found their way into clinical trials (see below).

Recruiting preserved tissue

The third therapeutic access is the recruitment of remaining, preserved nervous
tissue, including the remaining intrinsic circuitry of the spinal cord. This
includes enhanced plasticity of the sub-lesional locomotor circuits and the long
white matter tracts that control these circuits. The goal is to modulate neuronal
activity in order to increase neurological recovery, while avoiding undesirable
effects such as excessive spasticity.

The locomotor system

The locomotor activity in the lower limbs of mammals is based on the finely
tuned interaction of a tripartite system. The three components are:

(1) The basic, rhythmic neuronal activity of a cellular network located in the
lumbar spinal cord called the locomotor ‘‘central pattern generator’’
(CPG). This neural network can be found in the spinal cord of all
42 F. SCHOLTES et al.

vertebrates, like the lamprey [66] and mammals [48] including humans
[49, 67, 68]. The locomotor CPG may produce coordinated motor
patterns in isolation. In the human newborn (before the maturation
and myelination of the corticospinal tract which controls voluntary
movement), and even in anencephalic children, stepping movements
can be observed, both in the absence of peripheral stimuli, or in re-
sponse to the latter [69].
(2) Supraspinal input modulating the locomotor activity of the CPG. This
results in the supraspinal activation of rhythmic walking, ipsilateral coordi-
nation of flexors and extensors, and left-right coordination.
(3) Sensory feedback from the lower limbs, reaching the CPG through periph-
eral nerves. This creates dynamic sensorimotor interactions, either directly
with the CPG, or, via ascending and descending long white matter tracts,
after processing by supraspinal motor centres [70], modulating the rhyth-
mic activity of the CPG to adapt to complex external requirements. For
example, when needed, voluntary commands and subconscious control
mecanisms maintain balanced locomotion even when exterior constraints
change, for example during walking on uneven ground.
Most human spinal cord injuries are located in the thoracic or cervical cord.
Thus, the CPG is generally caudal to the lesion and not directly injured itself.
Anatomically intact, it is deafferented through interruption of the white matter
tracts and loss of supraspinal control. Therefore, functional locomotor output
may be recovered if the interplay between supraspinal control, persisting pe-
ripheral input, and the CPG could be reconstructed. This depends on CNS
plasticity.

Spinal cord plasticity

The spinal cord’s circuitry is capable of plasticity throughout life and neuronal
circuits within the human spinal cord also appear to be capable of a certain
degree of ‘‘learning’’ [71–73]. After SCI, spontaneous motor recovery, devel-
opment of spasticity, central neuropathic pain, autonomic dysreflexia, and
emergence of bladder and sphincter dyssynergy after initial areflexia (all relying
on lumbar spinal cord circuitry) result from plastic changes in the deafferented
cord. This plasticity can be exploited. The spinal cord can learn to perform a
task that it practices and exercise can modulate plasticity [74] and enhance the
expression of growth factors in the central nervous system [74], suggesting a
link between exercise, the expression of neurotrophins such as BDNF and
NT-3, as well as possible functional recovery [74–77]. Treadmill locomotor
training has been investigated in the experimental setting [78] and in human
neurorehabilitation. In addition, pharmacological studies have investigated the
possibility of increasing functional recovery by restoring the disturbed neuro-
Spinal cord injury and its treatment 43

chemical environment in the preserved spinal cord in order to influence the

caudal cord circuitry [79].

Current clinical treatment

Acute management
On the one hand, any victim of significant trauma must be considered to have
a spinal injury until the opposite can be ascertained by clinical or radiological
assessment. Suspected spinal injuries and SCI may thus complicate manage-
ment of trauma patients because they require specific manoeuvres.
 In order to avoid secondary injury to the spinal cord from an injured and
displaced spinal segment, trauma patients must be moved and transported in
a secure and stable position, achieved by the placement of a rigid cervical
collar, en bloc handling of the patient, and transport in the supine position on
a backboard or a deflatable transport mattress.
 Airway management in trauma patients must take into consideration the
possibility of a cervical spine injury. In addition, the immobilisation of the
patient must still allow 90% rotation of the patients body to protect the airway
in case of emesis.
 Perfusion pressure of the injured spinal cord must be maintained. Hypoten-
sion may be due to or worsened by neurogenic peripheral vasoplegia. The
diagnosis of blood loss due to associated injuries is essential. Fluid resuscita-
tion aims for a minimal systolic blood pressure of approximately 100 mmHg
and an ideal heart rate of 80 beats per minute [60–100].
 Oxygen supplementation should be given not only for pulmonary complica-
tions, but also to maintain oxygenation in the injured cord.
On the other hand, associated injuries must be actively investigated and treated,
especially intracranial lesions and occult bleeding.
Immediately after the impact on the cord, neurological function is lost.
After reversal of the initial ‘‘spinal shock’’ (i.e., an acute, reversible functional
silencing of neurological spinal cord activity due to the impact), the remaining
neurological deficit over the first few days is quite predictive of the final out-
come. If the deficit is complete and remains so over the first days, recovery is
highly unlikely. Incomplete injuries have more favourable prognosis and very
significant recovery may be seen over the months that follow the initial injury.

Surgery
Once medically stabilised, those spinal injuries that are sufficiently severe to
have resulted in spinal cord injury and neurological deficits should be surgically
44 F. SCHOLTES et al.

stabilised, although this approach is not formally supported by currently avail-

able evidence according to a recent Cochrane review [80]. For complete inju-
ries, timing of surgery depends more on the surgeons conviction of the
usefulness of spinal decompression in a neuroprotective perspective than on
spinal stability. The latter must however be obtained in order to facilitate
general care of the patient, e.g. positioning to avoid pulmonary complications,
and early mobilisation for rehabilitation.

Chronic care
Ultimately, 90% of patients will return home and gain a certain degree of
independence. Medical complications remain common, especially with more
severe deficits and in older patients, and are responsible for a high rate of re-
admissions (55% in the first year, then more than a third of the patients per
year). The most significant complications are due to immobilisation of the body
(i.e., pressure ulcers, pulmonary infections, deep vein thrombosis with pulmo-
nary embolism) and sphincter deficits (urinary tract infections). Urinary tract
and bowel dysfunction are common and have a significant impact on the
quality of life. Spasticity appears over time. Although it may be painful and
result in incapacitating muscle spasms (and should thus be treated either orally
or by implantation of an intrathecal drug-delivering pump), spasticity may be
beneficial by providing useful some degree of muscle tone for mobilisation.
Chronic pain may develop, possibly due to plastic alterations in the sublesional
cord circuits, and treatment is difficult. In the presence of neurological deteri-
oration, it is important to search for a cause, since it can be due to the appear-
ance of- or aggravation of syringomyelia. More than half of SCI patients
develop heterotopic ossification; in symptomatic cases, treatment is initially
conservative (physiotherapy and anti-inflammatory drugs) but can be surgical
(resection). In addition, patients are more easily subject to bone fractures in the
unused limbs because of osteoporosis due tu underuse. Orthostatic hyperten-
sion occurs but tends to resolve over time. SCI above the mid-thoracic cord
may result in autonomic dysreflexia with headache, sweating and blood pres-
sure fluctuations, in response to noxious stimuli such as bladder distention and
fecal impaction (giving important clinical cues). Maintaining sufficient fluid
intake, maximal exercise including neurological rehabilitation, and attentiveness
to unusual manifestations (due to loss of sensation below the injury level) of
commons problems like urinary tract infections are mandatory [81].

Clinical trials
There is an impressive number of clinical trials that have been reviewed in great
detail by Tator in 2006 [82], who also addressed deficiencies in the develop-
Spinal cord injury and its treatment 45

ment of treatment strategies and trial design. In addition, he considered future

perspectives, and an up-dated review was provided two years later by Hawryluk
and colleagues [83]. The ‘‘bench to bedside’’ translation of even encouraging
results is hindered by:

(i) the variety of treatment strategies that are available, the magic bullet not having
been found, and the probable necessity of using a combination of strategies
in order to obtain clinically significant improvement in recovery, and,
(ii) the difficulty to compare treatment strategies due to the wide variability in
the extent of recovery, even in patient groups with initially homogeneous
neurological deficits.
Recent publications addressing the requirements for publication of the results
of clinical treatments of SCI have highlighted these difficulties [84].

Neuroprotective strategies

Pharmacological interventions
The majority of prospective randomised trials have tested pharmacological
neuroprotective strategies. In the series of National Acute Spinal Cord
Injury Study (NASCIS) trials in the USA, the steroid anti-inflammatory
drug methylprednisolone appeared to have shown some promise as a neu-
roprotective agent at very high doses [85, 86]. However, the NASCIS stud-
ies have been criticised [87], among other things for the inaccessibility of
the data, resulting in a tempering of the initial enthusiasm [88]. Thus,
despite positive conclusions of a Cochrane review (notably written by the
main author of the NASCIS trials himself [89]), many clinicians do not
consider high dose methylprednisolone to be the gold-standard of care,
but rather to be a treatment option [90]. According to a set of 2002
Guidelines for Management of Acute Cervical Spinal Cord Injuries, ‘‘treat-
ment 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’’ [91]. Nonetheless,
methylprednisolone is still often used in clinical practice, ‘‘despite the well-
founded criticisms that have been directed against the [NASCIS] trials,
given the devastating impact of SCI and the evidence of a modest, benefi-
cial effect of MP’’ [92].
Other substances that have been investigated in the clinic include tirilazad,
a (non-glucocorticoid) steroid with more specific anti-oxidant, and potentially
fewer glucocorticoid side-effects. It appeared to be neither more efficive, nor
46 F. SCHOLTES et al.

better tolerated than methylprednisolone [82]. Another compound which was

experimentally promising was the monosialoganglioside compound GM1.
However, this drug has, so far, not shown any significant clinical benefit
[93]. Thyrotropin-releasing hormone (TSH) demonstrated modest neurological
benefit in incompletely injured patients, but this was in a small study in which
the authors themselves advised caution in the interpretation of the results [94].
At present, there are five on-going pharmacological neuroprotection trials,
assessing methylprednisolone, minocycline, erythropoietin, Riluzole, and HP-
184 [47].

Systemic hypothermia
The use of hypothermia after acute traumatic SCI has raised sustained inter-
est in the research community and recently been re-evaluated retrospectively
in humans [95], providing evidence for the safety of the treatment without
proving, at present, a beneficial effect on neurological recovery. A multi-
centre trial has been designed in order to obtain these data (http:==www.
miamiproject.miami.edu=page.aspx?pid¼844, accessed 3=3=2011).

Decompression strategies
Early decompression surgery has long been thought by many to provide some
degree of neuroprotection by avoiding secondary SCI due to cord compres-
sion, based on consistently published favourable results of decompression in
animal studies [96–98]. Early surgery does not appear to be associated with an
increased rate of complications [99]. However, clinical evidence for increased
neurological recovery remains, at best, tenuous based on the existing trials
[100–104].
An additional actively investigated approach is the lowering of intrathecal
pressure by removal of cerebrospinal fluid, which is thought to decrease tissue
ischemia in the injured spinal cord [105].

Restorative therapies

Overcoming growth inhibition: ‘‘peripheralisation’’ of the CNS

Restorative therapies have mainly concentrated on overcoming the inhibitory
nature of the lesioned, reactive environment within the spinal cord, in order to
make the spinal cord permissive to axonal regeneration. In humans, after
completion of a phase I trial, a phase II trial of the anti-NOGO antibody is
presently under development [106]. Cethrin (BA-210), an antagonist of Rho
GTPase, interferes with pathways associated with the inhibition of axonal
regeneration. Despite encouraging results in phase I and the beginning of phase
Spinal cord injury and its treatment 47

II trials, insufficient funding led to the premature termination of this investi-

gation. However, more recently another pharmaceutical company (BioAxone)
has expressed interest in the development of the strategy (http:==www.
canparaplegic.org=en=Research_32=items=22.html, accessed 3=3=2011). The potential
beneficial effects of the oral drug lithium are also being investigated (http:==
clinicaltrials.gov=ct2=results?term¼lithiumþspinalþcord, accessed 3=3=2011 ).
Another approach being actively investigated is to overcome the axon-
growth inhibitory influences of the lesioned spinal cord by the transplantation
of axon-growth promoting cells to modify the local CNS environment, to make
it more permissive to axon regrowth. In the first strategy, autologous macro-
phages (from the patient) which were ‘‘activated’’ in vitro, prior to surgical
implantation [107]. In an alternative approach, olfactory ensheathing cells have
been transplanted into the spinal cord in order to provide a growth permissive
environment. This treatment appears to be safe [108], and a phase I clinical trial
is currently under way:
(http:==clinicaltrials.gov=ct2=show=NCT01231893?term¼olfactoryþensheathingþ
cells&rank¼1, accessed 3=3=2011).

Providing CNS components with regenerative potential

Stem cells, obtained from umbilical blood or the bone marrow, have been thor-
oughly investigated in the preclinical setting [108], and several trials
have recently been completed or are still under way (http:==clinicaltrials.gov=ct2=
results?term¼stemþcellþspinalþcordþinjury, accessed 3=3=2011). Some investiga-
tions in this area have been criticised for lacking scientific rigour [83, 84, 109,
110].
Stem cell-based strategies have included the use of embryonic stem cells
with the caveat of their potential to form teratomas, or the use of differentiated
or non-differentiated neural progenitor cells. For SCI repair strategies, pre-
differentiation of neural progenitors to defined glial phenotypes (e.g. astroglia)
or their manipulation to form populations of committed, cell-type specific
progenitors (e.g. for the production of oligodendrocytes) have both demon-
strated beneficial effects.

 Differentiation of neural progenitors to type I astroglial phenotypes have

been demonstrated to promote neuroprotection and axon regeneration with
improved locomotor function [111].
 The strategy of differentiation of stem cells to generate populations of
oligodendrocytes progenitors is targeted towards implantation in the acute
stages of injury with the goal of remyelination of demyelinated, spared
axons after SCI. Such a strategy, using human embryonic stem cell de-
rived oligodendrocyte progenitors has been demonstrated to promote
48 F. SCHOLTES et al.

remyelination of denuded axons and some degree of functional improve-

ment [111].
 Apart from ethical considerations in the development of such interven-
tion strategies, a significant challenge for most of these stem-cell based
strategies is the allogenic nature of the donor cells, requiring immunosup-
pression to prevent rejection by the host. In an attempt to obtain more
clinically relevant, autologous donor cells, induced pluripotent stem cell
(iPSC) technology has been developed. This technology allows the re-
programming of somatic cells to a stem cell-like phenotype, thus avoiding
ethical issues [112]. However, the re-programming of cells appears to be a
rather inefficient and concerns regarding tumour or teratoma formation
persist.

Rehabilitation
In SCI patients, body weight supported treadmill training (BWSTT) and other
intensive neurorehabilitative measures have been increasingly used since the
first reports of the potential benefits of BWSTT almost two decades ago
[49, 113]. Encouraging preliminary clinical and electrophysiological results have
been obtained [114]. It has been reported that a single patient, after several
years of stability in the absence of nearly all sensori-motor function below the
shoulders, recovered some function (evolution from ASIA grades A to grade
C) following highly sophisticated and intense rehabilitative measures, including
bicycle training and functional electrical stimulation [115]. These potential ben-
eficial effects may, however, be largely limited to incompletely injured patients
[116]: in a comparative study of the effect of training on complete and incom-
plete cord syndromes, improvements in the neurological outcome only oc-
curred in patients with the incomplete SCI syndromes over the training
period [50].
At present, the available clinical evidence for a reproducible and signifi-
cant positive effect on locomotion still remains somewhat tenuous, because
of the heterogeneity of the clinical presentation, the limited range of bene-
ficial effects, the possibility for spontaneous beneficial evolution, the limited
number of patients, and the lack of randomised studies. Even if over-
ground training in the setting of subacute incomplete motor spinal cord
injury results in increased independent walking, more randomized controlled
trials will be needed to clarify the effectiveness of sophisticated, SCI-specific
rehabilitation techniques such as body weight-supported gait training and
robotic training. Such trials must include beneficial effects on locomotion as
well as on activities required for ‘‘normal’’ daily living, and the quality of life
[117, 118].
Spinal cord injury and its treatment 49

Conclusion
SCI remains a challenge for the clinician and the scientist. Treatment strategies
are steadily evolving, though, and major advances in the understanding of the
pathophysiological mechanisms of SCI open promising new therapeutic per-
spectives. Even if complete recovery remains at present an elusive goal, due the
complexity of the task to repair the spinal cord and retrain its neural circuitry, a
strategy which combines several of the different approaches described above
may result in some degree of useful neurological improvement for spinal cord
injured patients.
The conceptual framework for the combination of treatment strategies
includes initial neuroprotection in order to minimise secondary progression
of the injury, followed by the enhancement of CNS regeneration, including
the implantation of a three dimensional scaffold as an axon growth promot-
ing bridge to reconnect the disconnected neuronal circuits, and, finally, re-
training and enhancing plasticity of the preserved (and hopefully re-built)
parenchyma.
Even if the significant research efforts presently under way may lead to only
moderate functional results, two aspects of this complex issue must be taken
into account in order to put this into perspective. First, the anatomical recon-
struction of the spinal cord and its three dimensional architecture does not
have to be ‘‘complete’’ for enhancing recovery; the reestablishment of a mi-
nority of long tracts may suffice to obtain major neurological recovery. Second,
even small increments in function may have much more significant effects on
patient health and autonomy than their pure ‘‘neurological magnitude’’. For
example, a slight increase in lower limb motor function may make the differ-
ence between a completely dependent bed-ridden patient and a patient who can
stand with crutches, or between a patient who can only stand and a patient who
will be able to make a few steps and move independently without a wheelchair.
Preservation of one spinal segment in the low cervical spine may result in
useful function of the distal upper limb muscles, i.e., those of the hand, coor-
dinating finger movements. A slight increase in sphincter function may increase
the duration a patient can spend away from the facilities he=she had become
dependent upon and decrease the number of urinary tract infections.
In order to maximise potential treatment effects, it is crucial to structure
research efforts efficiently. Experimentally well-confirmed treatment strategies
(and their combinations) must be carefully brought from the bench to the
bedside, and their introduction into clinical research must be guided by scien-
tific rigour. This must take into account the necessity to recruit high numbers
of subjects from a relatively small patient population. If research efforts are
coordinated and joined rationally, we may witness, within the coming decades,
the achievement of reproducible neurological treatment effects and, hopefully,
significant improvements in the quality of life of SCI patients.
50 F. SCHOLTES et al.

In the meantime, prevention of the injury remains the most efficient strat-
egy, and the implementation of preventive strategies must be the focus of
public health efforts in the area of SCI. Among those strategies that have been
reliably evaluated in humans, all patients should be offered multidisciplinary
rehabilitation, as intensely as feasible in given local settings.

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