spinal cord injury and its treatment: current management ...spinal cord injury and its treatment:...

Spinal cord injury and its treatment: current managementand experimental perspectives

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

1 Department of Neurosurgery, Centre Hospitalier Universitaire, University of Liege,

Liege, Belgium2 Institute for Neuropathology, University Hospital, RWTH Aachen University,

Aachen, Germany

With 5 Figures

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Incidence and prevalence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Individual and socio-economical impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Neurobiology of SCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Spinal cord syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32The spinal cord lesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Evolution of the lesion after the initial trauma. . . . . . . . . . . . . . . . . . . . . . . . . . 32Human spinal cord injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Axonal regeneration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37The sub-lesional segment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39Influence of spinal cord white matter on neurological recovery . . . . . . . . . . . 39

Fundamental therapeutic approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39Neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Repair of the lesion site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Recruiting preserved tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41The locomotor system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41Spinal cord plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Current clinical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Acute management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Chronic care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Clinical trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Neuroprotective strategies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Pharmacological interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Systemic hypothermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Decompression strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Restorative therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Abstract

Clinical management of spinal cord injury (SCI) has significantly improved itsgeneral prognosis. However, to date, traumatic paraplegia and tetraplegia re-main incurable, despite massive research efforts. Current management focuseson surgical stabilisation of the spine, intensive neurological rehabilitation, andthe prevention and treatment of acute and chronic complications. Preventionremains the most efficient strategy and should be the main focus of publichealth 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 spinalcord repair, a strategy combining different approaches may result in somedegree of neurological improvement after SCI. Even slight neurologicalrecovery can have high impact on the daily functioning of severely handi-capped patients and, thus, result in significant improvements in quality oflife.

The main investigated strategies are: [1] initial neuroprotection, in orderto decrease secondary injury to the spinal cord parenchyma after the initialinsult; [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 enhancingplasticity of the central nervous system circuitry that was preserved orrebuilt after the injury.

Now and in the future, treatment strategies that have both a convincingrationale and seen their efficacy confirmed reproducibly in the experimentalsetting must carefully be brought from bench to bedside. In order to obtainclinically significant results, their introduction into clinical research must beguided by scientific rigour, and their coordination must be rationally structuredin a long-term perspective.

Keywords: Spinal cord injury; neuroprotection; regeneration; plasticity; human trials.

30 F. SCHOLTES et al.

Introduction

Clinical management of spinal cord injury (SCI) has significantly improved itsgeneral 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 bebetween 13 and 33 cases per million per year, and from 110 to 1120 per millionpopulation, respectively [1]. On this basis, Wyndaele and Wyndaele reviewedthe more recent literature in 2006 and found that, despite considerable varia-tions among study methods and reporting, incidence and prevalence do notseem to have changed substantially over recent years. In their review, theincidence and prevalence ranges are of 10.4 and 83 per million inhabitantsper year and 223–755 per million inhabitants, respectively [2]. These datamay not be sufficiently representative for a worldwide estimate, but, at theleast, 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, theirautonomy, private and professional perspectives, as well as working capacity.Many previously basic routines become challenging obstacles and patients areexposed to specific medical complications [3] (see below). After 35 years offollow-up in the National SCI database (since 1973), the main causes of deathare pneumonia, septicaemia, and pulmonary embolism [4]. Nevertheless, withpresent clinical management, life expectancy of spinal cord injured patientsapproaches the population average in developed countries, though withoutreaching normal values.

The socio-economical impact of SCI remains considerable. Approximately80% of patients are young males, with an average age at injury of less than 40years. 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 (lesstetraplegics than paraplegics) [4, 5]. Lifetime costs in the United States have beenestimated to range from approximately 500,000US$ for a 50 year old incom-pletely injured patient to more than 3,000,000US$ for a 25 year old completelytetraplegic patient. This does not include indirect costs of >65,000US$ per year,accounting for loss of wages, fringe benefits and productivity [4].

Over the last decades, governments and non-medical, non-governmentalassociations and foundations have increasingly participated in the attemptsto reduce the incidence and gravity of traumatic injuries, including brain

Spinal cord injury and its treatment 31

and spinal cord injuries. One example is the Think First foundation(www.thinkfirst.org=) that raises awareness of the gravity of these injuries andtheir potential prevention via educational campaigns and advertising, specifi-cally targeting children and young adults, as well as motor vehicle users. Thewidespread introduction of safety measures like the legal requirements for seatbelts and helmets, the reduction of speed limits on roads, and more, appear toreduce 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 circuitscaudal to the lesion site, i.e., the deafferentation of the sub-lesional cord. Thisdeafferentation occurs to a variable degree, depending on the extent of thelesion. Therefore, the so-called ‘‘spinal cord syndromes’’ may be incomplete orcomplete. In incomplete cord syndromes (approx. 50% of the cases), the lossof sensory and=or motor function below the level of injury is partial, and thetype of neurologic deficit is variable. In complete cord syndromes (the remain-ing 50%), motor and sensory function below the level of the lesion is entirelylost.

So-called discomplete spinal cord syndromes are clinically complete, butneurophysiologically incomplete. Thus, even in clinically complete SCI, thereis residual brain influence on spinal cord function below the lesion [13]. In onestudy, more than four out of five clinically complete syndromes could beneurophysiologically classified as discomplete [14], and, thus, in many patients,there may be central nervous circuitry above the spinal cord lesion that couldpotentially be recruited to influence the evolution of even clinically completespinal 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 andassociated structures, such as blood vessels and meninges. This is the primaryinjury, which can be worsened at the time of the accident by hypotension, dueto spinal shock and hypoxia. Within the cord, a complex, auto-destructivecascade of secondary events is initiated, leading to hypoxia, ischemia and freeradical production, ion imbalances, excitotoxicity and programmed cell death,protease activation, and inflammation including eicosanoid=prostaglandin pro-


A

B

C

D

Fig. 1. Evolution of SCI. (A) Normal cord. The central, butterfly shaped grey matteris 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)


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 deathoccurs, the three-dimensional organisation of the spinal cord architecture con-tinues to degenerate, and the necrotic lesion spreads, damaging increasinglymore axons in the white matter tracts [18] as well as neuronal cell bodies inthe grey matter (especially in the cervical and lumbar enlargements), resulting inworsened neurological deficits. Although the impact of these secondary injuryprocesses on parenchymal damage and loss of neurological function cannot beprecisely quantified, the phase between the initial trauma and the constitutionof the definitive cord lesion represents a therapeutic window of opportunitywhich has been the focus of a significant neuroprotective research effort [19].

Histopathologicaly, experimental compressive spinal cord lesions in the ratinitially show tissue oedema and petechial bleeding in the grey matter. Overtime, the distal components of severed axons degenerate, neurons and oligo-dendrocytes undergo apoptosis, and an astroglial and connective scar tissueforms. Glial scarring occurs at the lesion site and surprisingly also in thedegenerated fibre tracts (including the human corticospinal tract [20]) at 1 yearafter 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 withvariable degrees of haemorrhage within parenchymal oedema (Fig. 2). Themore 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 scarringresponse that may lead to tethering of the cord to the meninges. About onefifth of the lesions reported in the initial description of these types of injurywere lacerations, due to penetrating wounds (or penetration of the cord bybone fragments), or, in children, to brutal stretching of the cord. All theselesions 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 inneurological 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 theso-called acute traumatic central cord syndrome, which is typically due to com-pression of the cervical spinal cord during sudden hyperextension of an arthroticcervical spine with a spinal canal narrowed by osteophytes and ligamentum


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


flavum hypertrophy. Traumatic central cord syndrome was initially suspected tobe due to a haemorrhagic lesion in the central part of the spinal cord. As insyringomyelia, such a central haematoma would injure the medial fibres of thecorticospinal tracts and spare the more lateral fibres, resulting in ‘‘cruciate paral-ysis’’ where the motor deficit predominates in the upper limbs. If severe, thiskind of lesion can also result in complete paralysis of the upper limbs. However,

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Fig. 4. Long white matter tract degeneration demonstrated by post-mortem ultra-

high field MRI (9.4 tesla) and immunohistochemistry for neurofilament in the highthoracic 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)


clinical prognosis is much better than in the other types of spinal cord injury. Inmore recent studies, MRI has not shown haematoma but T2 hypersignal in theacute stage, and underlying pathological changes correspond to oedema andaxonal swelling, not to haemorrhage (Fig. 3) [23, 24].

In strict anatomical terms, human SCI is incomplete in most cases, andneurological recovery may be extensive, even when the lesion has damaged asignificant portion of the spinal white matter [25]. Equivalent phenomena tothe axonal degeneration observed in the experimental setting can be observedin humans (Fig. 4) [26, 27].

Axonal regeneration

Since the clinically important neurological deficits after SCI result from the lossof 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 promisingtherapeutic perspective for ‘‘rewiring’’ the spinal cord.

However, it was long thought to be impossible. In his classic treatise onnervous system degeneration and regeneration, Ramon y Cajal argued that

‘‘Once development was ended, the founts of growth and regeneration of the axonsand 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 hadgrafted peripheral nerve segments onto CNS tissue and shown that centralnervous system neurons could regenerate into that environment [29]. At thebeginning of the 1980s, the group of Aguayo published descriptions of thegrowth potential of CNS axons into peripheral nerve [30] and found that theseCNS axons were basically functional, although with limited or altered synapticcontacts (probably due to the absence of their target) [31]. During the sameperiod, donor fetal CNS neurons were shown to integrate into lesioned spinalcord tissue and even to ‘‘rescue’’ injured supraspinal neurons in the neonatalbrainstem [32–34]. In the lesioned adult rat spinal cord, a substantial intrinsicaxonal regenerative attempt was demonstrated (Fig. 5), although it showedsigns 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 CNSaxonal regeneration [36], in particular the axon-growth inhibitory glial scar [37](first described by Cajal [28]). Two environmental factors have been identifiedthat are widely acknowledged to play major roles in preventing axon regenera-tion and plasticity in the injured adult mammalian brain and spinal cord: CNSmyelin-associated molecules [38, 39] and the family of highly sulphated chon-doitin sulphate proteoglycans (CSPGs [40]).


Traumatic injury causes the release, as debris, of several myelin associated axongrowth inhibitory molecules, the most potent of which is the gylcoproteinNOGO-A. It induces the rapid, Nogo-receptor (NgR)-mediated collapse ofaxonal growth cones by the activation of the small GTP-ase RhoA (e.g. [41]).The potent axon growth inhibitory effects of the myelin associated moleculesat 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, andthey represent a ‘‘dual-edged sword’’. Microglia-derived and blood-borne de-rived macrophages are integral components of this inflammatory response in-

A

C

B

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 thelesion site (left) into the lesion itself (towards the right) (from M. Krautstrunk et al.:

Acta Neuropathol 104: 592–600. Springer 2002)


and around the lesion site. The phenotype and activation status of these cellshave been reported to have profound effects on their ability to enhance thesecondary degenerative events or to promote CNS axon regeneration andtissue 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 activitymay have the potential to enhance recovery (possibly, among other roles, byclearing growth inhibitory myelin debris from the lesion site [45, 46]), andmany 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 relayfor 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 structuredneural activity, including rhythmic output, which results in basic locomotorpatterns [48, 49]. After cervical or thoracic SCI, the lumbar circuitry remainsanatomically intact, and plastic alterations (see below) appear to be responsiblefor 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 clinicalpresentation may thus evolve over time. Spasticity develops, bladder functionchanges, and patients may progressively recover some of their lost sensory ormotor function. The spinal cord’s white matter tracts, even when they arepartially damaged, play an important role in functional recovery after SCI,and there is evidence in humans that white matter tracts influence spinal cordplasticity [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 mattersparing at the lesion site is sufficient to influence the functional reorganisationof the sub-lesional cord [52, 53]. Very small increases in spared tissue at thecentre of the lesion have profound effects on basic locomotor recovery, andsparing of 5–10% of the fibres in the white matter tracts is sufficient to helpdrive 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 preservednervous system (enhancing plasticity).


Neuroprotection

Neuroprotective treatments are designed to interfere with the cascade of eventsthat 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 thewhite matter tracts. Some degree of preservation of the connections betweenthe supraspinal centres and the sub-lesional cord would lead to lessened neu-rological deficits. However, although neuroprotective strategies were designedfor 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 theappropriate reconnection or synaptic re-establishment being accomplished byregrowing axons. Axonal regeneration is, however, only a first step in thecomplex sequence which could potentially lead to useful spinal cord repair:after nerve fibre regrowth into the lesion site through a fibroglial scar, an axonwould have to grow in an orientated manner over a sufficient distance of lesiontissue to cross the entire lesion site. It would then be required to exit the lesionsite and continue its growth in the sub-lesional central nervous parenchyma,where it would have to reach an appropriate target, stop its growth and formsynaptic contacts with remaining, intact neuronal circuits. Many of the regen-erating axons would also require myelination, to finally re-establish impulseconduction and the reformation of a viable, functional circuitry. This sets anambitious goal. Achieving it will depend on the combination of a number ofdifferent strategies addressing these obstacles:

� Removal or blockade of the major axon growth inhibitory influences in the environmentof the injured CNS. Antibodies against NOGO-A (see above) have beendemonstrated to enhance axonal regeneration from lesioned fibres and toincrease compensatory nerve fibre sprouting from non lesioned fibres innumerous animal models. This has been associated with improved functionaloutcome (e.g., [57, 58]). Also, the infusion of the enzyme chondroitinaseABC into damaged CNS tissues results in the digestion of the inhibitorysulphated glycosaminoglycan side-chains of the CSPGs and promotes en-hanced axon regeneration and plasticity of long-distance projecting sensoryaxons 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- andspared axons within the lesioned CNS depends on the balance between axon


growth-promoting factors and axon growth-inhibitory factors, enormouseffort has been expended in devising strategies that tip the balance in favourof axon regeneration and enhanced plasticity. Strategies include the directinfusion 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 bonemarrow derived stromal cells) that intrinsically express a range of moleculesextracellular matrix molecules, cell surface adhesion molecules and growthfactors known to support nerve fibre growth [61].

� Provision of an orientated 3D structure to guide growth polymer scaffolds. A number ofguidance structures or scaffolds of increasingly sophisticated design have beeninvestigated for this purpose. Such designs range from the use of simplehollow conduits to more complex devices with microstructures intended toreproduce the general architecture of spinal cord grey- and white matter. Bothsynthetic and natural polymers have investigated for such devices but the idealscaffold with optimal functionalisation (e.g. in combination with axon growthpromoting cells) has yet to be determined (for a recent review, see [62]). Partof the impetus for such strategies aiming to reconnect severed nerve fibresto 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 ofuseful motor or sensory function [63, 64].

Currently, the measurable functional improvement after experimental re-pair remains moderate at best [65]. Nonetheless, an impressive number ofrepair strategies have already found their way into clinical trials (see below).

Recruiting preserved tissue

The third therapeutic access is the recruitment of remaining, preserved nervoustissue, including the remaining intrinsic circuitry of the spinal cord. Thisincludes enhanced plasticity of the sub-lesional locomotor circuits and the longwhite matter tracts that control these circuits. The goal is to modulate neuronalactivity in order to increase neurological recovery, while avoiding undesirableeffects such as excessive spasticity.

The locomotor system

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

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


vertebrates, like the lamprey [66] and mammals [48] including humans[49, 67, 68]. The locomotor CPG may produce coordinated motorpatterns in isolation. In the human newborn (before the maturationand myelination of the corticospinal tract which controls voluntarymovement), and even in anencephalic children, stepping movementscan 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. Thisresults 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 directlywith 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. Forexample, when needed, voluntary commands and subconscious controlmecanisms maintain balanced locomotion even when exterior constraintschange, 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 mattertracts and loss of supraspinal control. Therefore, functional locomotor outputmay be recovered if the interplay between supraspinal control, persisting pe-ripheral input, and the CPG could be reconstructed. This depends on CNSplasticity.

Spinal cord plasticity

The spinal cord’s circuitry is capable of plasticity throughout life and neuronalcircuits within the human spinal cord also appear to be capable of a certaindegree of ‘‘learning’’ [71–73]. After SCI, spontaneous motor recovery, devel-opment of spasticity, central neuropathic pain, autonomic dysreflexia, andemergence of bladder and sphincter dyssynergy after initial areflexia (all relyingon lumbar spinal cord circuitry) result from plastic changes in the deafferentedcord. This plasticity can be exploited. The spinal cord can learn to perform atask that it practices and exercise can modulate plasticity [74] and enhance theexpression of growth factors in the central nervous system [74], suggesting alink between exercise, the expression of neurotrophins such as BDNF andNT-3, as well as possible functional recovery [74–77]. Treadmill locomotortraining has been investigated in the experimental setting [78] and in humanneurorehabilitation. In addition, pharmacological studies have investigated thepossibility of increasing functional recovery by restoring the disturbed neuro-


chemical environment in the preserved spinal cord in order to influence thecaudal cord circuitry [79].

Current clinical treatment

Acute management

On the one hand, any victim of significant trauma must be considered to havea spinal injury until the opposite can be ascertained by clinical or radiologicalassessment. 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 anddisplaced spinal segment, trauma patients must be moved and transported ina secure and stable position, achieved by the placement of a rigid cervicalcollar, en bloc handling of the patient, and transport in the supine position ona backboard or a deflatable transport mattress.

� Airway management in trauma patients must take into consideration thepossibility of a cervical spine injury. In addition, the immobilisation of thepatient must still allow 90% rotation of the patients body to protect the airwayin 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. Thediagnosis of blood loss due to associated injuries is essential. Fluid resuscita-tion aims for a minimal systolic blood pressure of approximately 100mmHgand 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 functionalsilencing of neurological spinal cord activity due to the impact), the remainingneurological 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 ishighly unlikely. Incomplete injuries have more favourable prognosis and verysignificant recovery may be seen over the months that follow the initial injury.

Surgery

Once medically stabilised, those spinal injuries that are sufficiently severe tohave resulted in spinal cord injury and neurological deficits should be surgically


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 theusefulness of spinal decompression in a neuroprotective perspective than onspinal stability. The latter must however be obtained in order to facilitategeneral 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 ofindependence. Medical complications remain common, especially with moresevere 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 peryear). 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 tractand bowel dysfunction are common and have a significant impact on thequality of life. Spasticity appears over time. Although it may be painful andresult in incapacitating muscle spasms (and should thus be treated either orallyor by implantation of an intrathecal drug-delivering pump), spasticity may bebeneficial by providing useful some degree of muscle tone for mobilisation.Chronic pain may develop, possibly due to plastic alterations in the sublesionalcord 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 patientsdevelop heterotopic ossification; in symptomatic cases, treatment is initiallyconservative (physiotherapy and anti-inflammatory drugs) but can be surgical(resection). In addition, patients are more easily subject to bone fractures in theunused limbs because of osteoporosis due tu underuse. Orthostatic hyperten-sion occurs but tends to resolve over time. SCI above the mid-thoracic cordmay result in autonomic dysreflexia with headache, sweating and blood pres-sure fluctuations, in response to noxious stimuli such as bladder distention andfecal impaction (giving important clinical cues). Maintaining sufficient fluidintake, maximal exercise including neurological rehabilitation, and attentivenessto unusual manifestations (due to loss of sensation below the injury level) ofcommons problems like urinary tract infections are mandatory [81].

Clinical trials

There is an impressive number of clinical trials that have been reviewed in greatdetail by Tator in 2006 [82], who also addressed deficiencies in the develop-


ment of treatment strategies and trial design. In addition, he considered futureperspectives, and an up-dated review was provided two years later by Hawrylukand colleagues [83]. The ‘‘bench to bedside’’ translation of even encouragingresults is hindered by:

(i) the variety of treatment strategies that are available, the magic bullet not havingbeen found, and the probable necessity of using a combination of strategiesin order to obtain clinically significant improvement in recovery, and,

(ii) the difficulty to compare treatment strategies due to the wide variability inthe extent of recovery, even in patient groups with initially homogeneousneurological deficits.

Recent publications addressing the requirements for publication of the resultsof clinical treatments of SCI have highlighted these difficulties [84].

Neuroprotective strategies

Pharmacological interventions

The majority of prospective randomised trials have tested pharmacologicalneuroprotective strategies. In the series of National Acute Spinal CordInjury Study (NASCIS) trials in the USA, the steroid anti-inflammatorydrug 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 ofthe data, resulting in a tempering of the initial enthusiasm [88]. Thus,despite positive conclusions of a Cochrane review (notably written by themain author of the NASCIS trials himself [89]), many clinicians do notconsider high dose methylprednisolone to be the gold-standard of care,but rather to be a treatment option [90]. According to a set of 2002Guidelines for Management of Acute Cervical Spinal Cord Injuries, ‘‘treat-ment with methylprednisolone for either 24 or 48 hours is recommended asan option in the treatment of patients with acute spinal cord injuries thatshould 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 potentiallyfewer glucocorticoid side-effects. It appeared to be neither more efficive, nor


better tolerated than methylprednisolone [82]. Another compound which wasexperimentally 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 neurologicalbenefit in incompletely injured patients, but this was in a small study in whichthe 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 retrospectivelyin humans [95], providing evidence for the safety of the treatment withoutproving, 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 somedegree of neuroprotection by avoiding secondary SCI due to cord compres-sion, based on consistently published favourable results of decompression inanimal studies [96–98]. Early surgery does not appear to be associated with anincreased rate of complications [99]. However, clinical evidence for increasedneurological recovery remains, at best, tenuous based on the existing trials[100–104].

An additional actively investigated approach is the lowering of intrathecalpressure by removal of cerebrospinal fluid, which is thought to decrease tissueischemia in the injured spinal cord [105].

Restorative therapies

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

Restorative therapies have mainly concentrated on overcoming the inhibitorynature of the lesioned, reactive environment within the spinal cord, in order tomake the spinal cord permissive to axonal regeneration. In humans, aftercompletion of a phase I trial, a phase II trial of the anti-NOGO antibody ispresently under development [106]. Cethrin (BA-210), an antagonist of RhoGTPase, interferes with pathways associated with the inhibition of axonalregeneration. Despite encouraging results in phase I and the beginning of phase


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 potentialbeneficial 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 transplantationof axon-growth promoting cells to modify the local CNS environment, to makeit more permissive to axon regrowth. In the first strategy, autologous macro-phages (from the patient) which were ‘‘activated’’ in vitro, prior to surgicalimplantation [107]. In an alternative approach, olfactory ensheathing cells havebeen transplanted into the spinal cord in order to provide a growth permissiveenvironment. This treatment appears to be safe [108], and a phase I clinical trialis currently under way:

(http:==clinicaltrials.gov=ct2=show=NCT01231893?term¼olfactoryþensheathingþcells&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 trialshave 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 cellswith the caveat of their potential to form teratomas, or the use of differentiatedor 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 specificprogenitors (e.g. for the production of oligodendrocytes) have both demon-strated beneficial effects.

� Differentiation of neural progenitors to type I astroglial phenotypes havebeen demonstrated to promote neuroprotection and axon regeneration withimproved locomotor function [111].

� The strategy of differentiation of stem cells to generate populations ofoligodendrocytes progenitors is targeted towards implantation in the acutestages of injury with the goal of remyelination of demyelinated, sparedaxons after SCI. Such a strategy, using human embryonic stem cell de-rived oligodendrocyte progenitors has been demonstrated to promote


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 basedstrategies is the allogenic nature of the donor cells, requiring immunosup-pression to prevent rejection by the host. In an attempt to obtain moreclinically 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 avoidingethical issues [112]. However, the re-programming of cells appears to be arather inefficient and concerns regarding tumour or teratoma formationpersist.

Rehabilitation

In SCI patients, body weight supported treadmill training (BWSTT) and otherintensive neurorehabilitative measures have been increasingly used since thefirst reports of the potential benefits of BWSTT almost two decades ago[49, 113]. Encouraging preliminary clinical and electrophysiological results havebeen obtained [114]. It has been reported that a single patient, after severalyears of stability in the absence of nearly all sensori-motor function below theshoulders, recovered some function (evolution from ASIA grades A to gradeC) following highly sophisticated and intense rehabilitative measures, includingbicycle 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 trainingperiod [50].

At present, the available clinical evidence for a reproducible and signifi-cant positive effect on locomotion still remains somewhat tenuous, becauseof the heterogeneity of the clinical presentation, the limited range of bene-ficial effects, the possibility for spontaneous beneficial evolution, the limitednumber of patients, and the lack of randomised studies. Even if over-ground training in the setting of subacute incomplete motor spinal cordinjury results in increased independent walking, more randomized controlledtrials will be needed to clarify the effectiveness of sophisticated, SCI-specificrehabilitation techniques such as body weight-supported gait training androbotic training. Such trials must include beneficial effects on locomotion aswell as on activities required for ‘‘normal’’ daily living, and the quality of life[117, 118].


Conclusion

SCI remains a challenge for the clinician and the scientist. Treatment strategiesare steadily evolving, though, and major advances in the understanding of thepathophysiological mechanisms of SCI open promising new therapeutic per-spectives. Even if complete recovery remains at present an elusive goal, due thecomplexity of the task to repair the spinal cord and retrain its neural circuitry, astrategy which combines several of the different approaches described abovemay result in some degree of useful neurological improvement for spinal cordinjured patients.

The conceptual framework for the combination of treatment strategiesincludes initial neuroprotection in order to minimise secondary progressionof the injury, followed by the enhancement of CNS regeneration, includingthe 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 onlymoderate functional results, two aspects of this complex issue must be takeninto account in order to put this into perspective. First, the anatomical recon-struction of the spinal cord and its three dimensional architecture does nothave 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 onpatient health and autonomy than their pure ‘‘neurological magnitude’’. Forexample, a slight increase in lower limb motor function may make the differ-ence between a completely dependent bed-ridden patient and a patient who canstand with crutches, or between a patient who can only stand and a patient whowill 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 inuseful function of the distal upper limb muscles, i.e., those of the hand, coor-dinating finger movements. A slight increase in sphincter function may increasethe duration a patient can spend away from the facilities he=she had becomedependent upon and decrease the number of urinary tract infections.

In order to maximise potential treatment effects, it is crucial to structureresearch efforts efficiently. Experimentally well-confirmed treatment strategies(and their combinations) must be carefully brought from the bench to thebedside, and their introduction into clinical research must be guided by scien-tific rigour. This must take into account the necessity to recruit high numbersof subjects from a relatively small patient population. If research efforts arecoordinated 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.


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

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