and experimental perspectives
F. SCHOLTES1, G. BROOK2, and D. MARTIN1
1Department of Neurosurgery, Centre Hospitalier Universitaire, University of Liege,
Liege, Belgium
2Institute 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
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.
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 comincom-pletely 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
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-A
B
C
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)
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
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 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,
–22 F1 (mm) –21 –20 –19 –18 –17 –16 –15 –14 0 –1 –2 –3 –4 –5 F2 (mm)–6 –7 –8 –9 –10 60 50 40 30 20 10 0 A 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 ultra-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)
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-supra-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. Everysome-thing must die, nosome-thing 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]).
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-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 the lesion 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 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).
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 leexten-sion 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
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
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 coordicoordi-nation.
(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-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
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 (uripulmo-nary tract infections). Uripulmo-nary 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-ment of treatdevelop-ment 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
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
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
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 benebene-ficial 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].
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.
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.
References
[1] Blumer CE, Quine S (1995) Prevalence of spinal cord injury: an international comparison. Neuroepidemiology 14: 258–68
[2] Wyndaele M, Wyndaele JJ (2006) Incidence, prevalence and epidemiology of spinal cord injury: what learns a worldwide literature survey? Spinal Cord 44: 523–29
[3] Kennedy P, Lude P, Taylor N (2006) Quality of life, social participation, appraisals and coping post spinal cord injury: a review of four community samples. Spinal Cord 44: 95–105 [4] (2010) Spinal cord injury facts and figures at a glance. J Spinal Cord Med 33: 439–40 [5] (2005) Spinal cord injury. Facts and figures at a glance. J Spinal Cord Med 28: 379–80 [6] Wilson C, Willis C, Hendrikz JK, Le Brocque R, Bellamy N (2010) Speed cameras for the
prevention of road traffic injuries and deaths. Cochrane Database Syst Rev (11): CD004607
[7] MacLeod JB, Digiacomo JC, Tinkoff G (2010) An evidence-based review: helmet efficacy to reduce head injury and mortality in motorcycle crashes: EAST practice management guidelines. J Trauma 69: 1101–11
[8] Crompton JG, Bone C, Oyetunji T et al. (2011) Motorcycle helmets associated with lower risk of cervical spine injury: debunking the myth. J Am Coll Surg 212: 295–300 [9] Jagger J (1992) Prevention of brain trauma by legislation, regulation, and improved
technology: a focus on motor vehicles. J Neurotrauma 9 (Suppl 1): S313–16
[10] Wells S, Mullin B, Norton R et al. (2004) Motorcycle rider conspicuity and crash related injury: case-control study. BMJ 328: 857
[11] Richter ED, Friedman LS, Berman T, Rivkind A (2005) Death and injury from motor vehicle crashes: a tale of two countries. Am J Prev Med 29: 440–49
[12] Salmi LR, Thomas H, Fabry JJ, Girard R (1989) The effect of the 1979 French seat-belt law on the nature and severity of injuries to front-seat occupants. Accid Anal Prev 21: 589–94 [13] Dimitrijevic MR (1988) Residual motor functions in spinal cord injury. Adv Neurol 47:
138–55
[14] Sherwood AM, Dimitrijevic MR, McKay WB (1992) Evidence of subclinical brain influence in clinically complete spinal cord injury: discomplete SCI. J Neurol Sci 110: 90–98
[15] Tator CH, Fehlings MG (1991) Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 75: 15–26
[16] Balentine JD (1978) Pathology of experimental spinal cord trauma. I. The necrotic lesion as a function of vascular injury. Lab Invest 39: 236–53
[17] Hurlbert RJ (2006) Strategies of medical intervention in the management of acute spinal cord injury. Spine (Phila Pa 1976) 31: S16–21; discussion S36
[18] Anthes DL, Theriault E, Tator CH (1995) Characterization of axonal ultrastructural pathology following experimental spinal cord compression injury. Brain Res 702: 1–16
[19] Baptiste DC, Fehlings MG (2006) Pharmacological approaches to repair the injured spinal cord. J Neurotrauma 23: 318–34
[20] Hagg T, Oudega M (2006) Degenerative and spontaneous regenerative processes after spinal cord injury. J Neurotrauma 23: 264–80
[21] Kakulas A (1988) The applied neurobiology of human spinal cord injury: a review. Paraplegia 26: 371–79
[22] Bunge RP, Puckett WR, Hiester ED (1997) Observations on the pathology of several types of human spinal cord injury, with emphasis on the astrocyte response to penetrating injuries. Adv Neurol 72: 305–15
[23] Collignon F, Martin D, Lenelle J, Stevenaert A (2002) Acute traumatic central cord syndrome: magnetic resonance imaging and clinical observations. J Neurosurg 96: 29–33
[24] Martin D, Schoenen J, Lenelle J, Reznik M, Moonen G (1992) MRI-pathological correla-tions in acute traumatic central cord syndrome: case report. Neuroradiology 34: 262–66 [25] Dobkin BH, Havton LA (2004) Basic advances and new avenues in therapy of spinal cord
injury. Annu Rev Med 55: 255–82
[26] Buss A, Brook GA, Kakulas B et al. (2004) Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord. Brain 127: 34–44 [27] Scholtes F, Adriaensens P, Storme L et al. (2006) Correlation of postmortem 9.4 tesla magnetic resonance imaging and immunohistopathology of the human thoracic spinal cord 7 months after traumatic cervical spine injury. Neurosurgery 59: 671–78; discussion 671–78 [28] Cajal SRY (1928) Degeneration and regeneration of the nervous system. New York:
Hafner
[29] Tello F (1911) La influencia del neurotropismo en la regeneration de los centros nerviosos. Trab Lab Invest Univ Madrid 9: 123–59
[30] David S, Aguayo AJ (1981) Axonal elongation into peripheral nervous system ‘‘bridges’’ after central nervous system injury in adult rats. Science 214: 931–33
[31] Munz M, Rasminsky M, Aguayo AJ, Vidal-Sanz M, Devor MG (1985) Functional activity of rat brainstem neurons regenerating axons along peripheral nerve grafts. Brain Res 340: 115–25
[32] Bregman BS, Reier PJ (1986) Neural tissue transplants rescue axotomized rubrospinal cells from retrograde death. J Comp Neurol 244: 86–95
[33] Reier PJ, Bregman BS, Wujek JR (1986) Intraspinal transplantation of embryonic spinal cord tissue in neonatal and adult rats. J Comp Neurol 247: 275–96
[34] Das GD (1983) Neural transplantation in the spinal cord of adult rats. Conditions, survival, cytology and connectivity of the transplants. J Neurol Sci 62: 191–210
[35] Brook GA, Plate D, Franzen R et al. (1998) Spontaneous longitudinally orientated axonal regeneration is associated with the Schwann cell framework within the lesion site following spinal cord compression injury of the rat. J NeurosciRes 53: 51–65
[36] Fawcett JW (2006) Overcoming inhibition in the damaged spinal cord. J Neurotrauma 23: 371–83
[37] Fawcett JW, Asher RA (1999) The glial scar and central nervous system repair. Brain Res Bull 49: 377–91
[38] Schnell L, Schwab ME (1990) Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343: 269–72
[39] Schwab ME, Bartholdi D (1996) Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 76: 319–70
[40] Galtrey CM, Fawcett JW (2007) The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res Rev 54: 1–18 [41] Fournier AE, Strittmatter SM (2001) Repulsive factors and axon regeneration in the CNS.
Curr Opin Neurobiol 11: 89–94
[42] Fawcett JW (2006) Overcoming inhibition in the damaged spinal cord. J Neurotrauma 23: 371–83
[43] Bethea JR (2000) Spinal cord injury-induced inflammation: a dual-edged sword. Prog Brain Res 128: 33–42
[44] Chan CC (2008) Inflammation: beneficial or detrimental after spinal cord injury? Recent Pat CNS Drug Discov 3: 189–99
[45] Schwartz M (2010) ‘‘Tissue-repairing’’ blood-derived macrophages are essential for healing of the injured spinal cord: from skin-activated macrophages to infiltrating blood-derived cells? Brain Behav Immun 24: 1054–57
[46] Schwartz M, Lazarov-Spiegler O, Rapalino O, Agranov I, Velan G, Hadani M (1999) Potential repair of rat spinal cord injuries using stimulated homologous macrophages. Neurosurgery 44: 1041–45; discussion 1045–46
[47] Gensel JC, Donnelly DJ, Popovich PG (2011) Spinal cord injury therapies in humans: an overview of current clinical trials and their potential effects on intrinsic CNS macrophages. Expert Opin Ther Targets 15(4): 505–18
[48] Grillner S, Zangger P (1979) On the central generation of locomotion in the low spinal cat. Exp Brain Res 34: 241–61
[49] Dietz V (2003) Spinal cord pattern generators for locomotion. Clin Neurophysiol 114: 1379–89
[50] Dietz V, Wirz M, Colombo G, Curt A (1998) Locomotor capacity and recovery of spinal cord function in paraplegic patients: a clinical and electrophysiological evaluation. Elec-troencephalogr Clin Neurophysiol 109: 140–53
[51] Basso DM, Beattie MS, Bresnahan JC (2002) Descending systems contributing to locomotor recovery after mild or moderate spinal cord injury in rats: experimental evidence and a review of literature. Restor Neurol Neurosci 20: 189–218
[52] Basso DM (2000) Neuroanatomical substrates of functional recovery after experimental spinal cord injury: implications of basic science research for human spinal cord injury. Phys Ther 80: 808–17
[53] Basso DM, Beattie MS, Bresnahan JC (1996) Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol 139: 244–56
[54] Blight AR (1983) Cellular morphology of chronic spinal cord injury in the cat: analysis of myelinated axons by line-sampling. Neuroscience 10: 521–43
[55] Tsai EC, Tator CH (2005) Neuroprotection and regeneration strategies for spinal cord repair. Curr Pharm Des 11: 1211–22
[56] Kwon BK, Okon E, Hillyer J et al. (2010) A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury. J Neurotrauma 28: 1545–88
[57] Thallmair M, Metz GA, Z’Graggen WJ, Raineteau O, Kartje GL, Schwab ME (1998) Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions. Nat Neurosci 1: 124–31
[58] Maier IC, Schwab ME (2006) Sprouting, regeneration and circuit formation in the injured spinal cord: factors and activity. Philos Trans R Soc Lond B Biol Sci 361: 1611–34
[59] Bradbury EJ, Moon LD, Popat RJ et al. (2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416: 636–40
[60] Franz S, Weidner N, Blesch A (2011) Gene therapy approaches to enhancing plasticity and regeneration after spinal cord injury. Exp Neurol [Epub ahead of print]
[61] Ruff CA, Wilcox JT, Fehlings MG (2011) Cell-based transplantation strategies to promote plasticity following spinal cord injury. Exp Neurol [Epub ahead of print]
[62] F€uuhrmann T, Gerardo-Nava J, Brook GA (2011) Central nervous system. In: Pallua N, Suschek CV (eds) Tissue engineering: from lab to clinic. Springer, Heidelberg Dordrecht London New York, chap. 12, pp. 221–44
[63] Fehlings MG, Tator CH (1995) The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury. Exp Neurol 132: 220–28
[64] Li Y, Field PM, Raisman G (1998) Regeneration of adult rat corticospinal axons induced by transplanted olfactory ensheathing cells. J Neurosci 18: 10514–24
[65] Woolf CJ (2003) No Nogo: now where to go? Neuron 38: 153–56
[66] Grillner S (2003) The motor infrastructure: from ion channels to neuronal networks. Nat Rev Neurosci 4: 573–86
[67] Dimitrijevic MR, Gerasimenko Y, Pinter MM (1998) Evidence for a spinal central pattern generator in humans. Ann NY Acad Sci 860: 360–76
[68] Zehr EP, Duysens J (2004) Regulation of arm and leg movement during human locomotion. Neuroscientist 10: 347–61
[69] Forssberg H (1986) A developmental model of human locomotion. Neurobiology of vertebrate locomotion. In: Grillner S, Stein PSG, Stuart H, Forssberg H, Herman RM (eds). Macmillan, London, pp. 485–501
[70] Rossignol S, Dubuc R, Gossard JP (2006) Dynamic sensorimotor interactions in locomo-tion. Physiol Rev 86: 89–154
[71] Wolpaw JR (2007) Spinal cord plasticity in acquisition and maintenance of motor skills. Acta Physiol (Oxf) 189: 155–69
[72] Evatt ML, Wolf SL, Segal RL (1989) Modification of human spinal stretch reflexes: preliminary studies. Neurosci Lett 105: 350–55
[73] Muir GD, Steeves JD (1997) Sensorimotor stimulation to improve locomotor recovery after spinal cord injury. Trends Neurosci 20: 72–77
[74] Wolpaw JR, Tennissen AM (2001) Activity-dependent spinal cord plasticity in health and disease. Annu Rev Neurosci 24: 807–43
[75] Edgerton VR, Tillakaratne NJ, Bigbee AJ, de L, R. D., Roy RR (2004) Plasticity of the spinal neural circuitry after injury. Annu Rev Neurosci 27: 145–67
[76] Neeper SA, Gomez-Pinilla F, Choi J, Cotman C (1995) Exercise and brain neurotrophins. Nature 373: 109
[77] Schinder AF, Poo M (2000) The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci 23: 639–45
[78] Multon S, Franzen R, Poirrier AL, Scholtes F, Schoenen J (2003) The effect of treadmill training on motor recovery after a partial spinal cord compression-injury in the adult rat. J Neurotrauma 20: 699–706
[79] Parker D (2005) Pharmacological approaches to functional recovery after spinal injury. Curr Drug Targets CNS Neurol Disord 4: 195–210
[80] Bagnall AM, Jones L, Duffy S, Riemsma RP (2008) Spinal fixation surgery for acute traumatic spinal cord injury. Cochrane Database Syst Rev (1): CD004725
[81] Abrams GM, Wakasa M.: Chronic complications of spinal cord injury. www. uptodate.com/contents/chronic-complications-of-spinal-cord-injury
[82] Tator CH (2006) Review of treatment trials in human spinal cord injury: issues, difficulties, and recommendations. Neurosurgery 59: 957–82; discussion 982–87
[83] Hawryluk GW, Rowland J, Kwon BK, Fehlings MG (2008) Protection and repair of the injured spinal cord: a review of completed, ongoing, and planned clinical trials for acute spinal cord injury. Neurosurg Focus 25: E14
[84] Dobkin BH (2010) Recommendations for publishing case studies of cell transplantation for spinal cord injury. Neurorehabil Neural Repair 24: 687–91
[85] Bracken MB (2002) Methylprednisolone and spinal cord injury. J Neurosurg 96: 140–41 [86] Bracken MB, Shepard MJ, Collins WF et al. (1990) A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 322: 1405–11 [87] Nesathurai S (1998) Steroids and spinal cord injury: revisiting the NASCIS 2 and NASCIS
3 trials. J Trauma 45: 1088–93
[88] Hurlbert RJ (2000) Methylprednisolone for acute spinal cord injury: an inappropriate standard of care. J Neurosurg 93: 1–7
[89] Bracken MB (2002) Steroids for acute spinal cord injury. Cochrane Database Syst Rev (3): CD001046
[90] Hugenholtz H, Cass DE, Dvorak MF et al. (2002) High-dose methylprednisolone for acute closed spinal cord injury – only a treatment option. Can J Neurol Sci 29: 227–35 [91] (2002) Pharmacological therapy after acute cervical spinal cord injury. Neurosurgery 50:
S63–72
[92] Fehlings MG (2001) Editorial: recommendations regarding the use of methylprednisolone in acute spinal cord injury: making sense out of the controversy. Spine 26: S56–57 [93] Hall ED, Springer JE (2004) Neuroprotection and acute spinal cord injury: a reappraisal.
Neuro Rx 1: 80–100
[94] Pitts LH, Ross A, Chase GA, Faden AI (1995) Treatment with thyrotropin-releasing hormone (TRH) in patients with traumatic spinal cord injuries. J Neurotrauma 12: 235–43
[95] Levi AD, Casella G, Green BA et al. (2010) Clinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury. Neurosurgery 66: 670–77
[96] Fehlings MG, Rabin D, Sears W, Cadotte DW, Aarabi B (2010) Current practice in the timing of surgical intervention in spinal cord injury. Spine (Phila Pa 1976) 35: S166–73 [97] Fehlings MG, Tator CH (1999) An evidence-based review of decompressive surgery in acute spinal cord injury: rationale, indications, and timing based on experimental and clinical studies. J Neurosurg 91: 1–11
[98] Tator CH, Fehlings MG, Thorpe K, Taylor W (1999) Current use and timing of spinal surgery for management of acute spinal surgery for management of acute spinal cord injury in North America: results of a retrospective multicenter study. J Neurosurg 91: 12– 18
[99] Waters RL, Meyer PRJ, Adkins RH, Felton D (1999) Emergency, acute, and surgical management of spine trauma. Arch Phys Med Rehabil 80: 1383–90
[100] Pointillart V, Petitjean ME, Wiart L et al. (2000) Pharmacological therapy of spinal cord injury during the acute phase. Spinal Cord 38: 71–76
[101] Cengiz SL, Kalkan E, Bayir A, Ilik K, Basefer A (2008) Timing of thoracolomber spine stabilization in trauma patients; impact on neurological outcome and clinical course. A real prospective (rct) randomized controlled study. Arch Orthop Trauma Surg 128: 959–66 [102] Papadopoulos SM, Selden NR, Quint DJ, Patel N, Gillespie B, Grube S (2002) Immediate spinal cord decovmpression for cervical spinal cord injury: feasibility and outcome. J Trauma 52: 323–32
[103] Vale FL, Burns J, Jackson AB, Hadley MN (1997) Combined medical and surgical treatment after acute spinal cord injury: results of a prospective pilot study to assess the merits of aggressive medical resuscitation and blood pressure management. J Neurosurg 87: 239–46
[104] Vaccaro AR, Daugherty RJ, Sheehan TP et al. (1997) Neurologic outcome of early versus late surgery for cervical spinal cord injury. Spine (Phila Pa 1976) 22: 2609–13
[105] Kwon BK, Curt A, Belanger LM et al. (2009) Intrathecal pressure monitoring and cerebrospinal fluid drainage in acute spinal cord injury: a prospective randomized trial. J Neurosurg Spine 10: 181–93
[106] Zorner B, Schwab ME (2010) Anti-Nogo on the go: from animal models to a clinical trial. Ann N Y Acad Sci 1198 (Suppl 1): E22–34
[107] Knoller N, Auerbach G, Fulga V et al. (2005) Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine 3: 173–81
[108] Lima C, Pratas-Vital J, Escada P, Hasse-Ferreira A, Capucho C, Peduzzi JD (2006) Olfactory mucosa autografts in human spinal cord injury: a pilot clinical study. J Spinal Cord Med 29: 191–203; discussion 204–06
[109] Cyranoski D (2007) Chinese network to start trials of spinal surgery. Nature 446: 476–77 [110] Cyranoski D (2006) Patients warned about unproven spinal surgery. Nature 440: 850–51 [111] Davies SJ, Shih CH, Noble M, Mayer-Proschel M, Davies JE, Proschel C (2011) Transplantation of specific human astrocytes promotes functional recovery after spinal cord injury. PLoS One 6: e17328
[112] Nakagawa M, Koyanagi M, Tanabe K et al. (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26: 101–106 [113] Wernig A, Muller S (1992) Laufband locomotion with body weight support improved
walking in persons with severe spinal cord injuries. Paraplegia 30: 229–38
[114] Barbeau H, Nadeau S, Garneau C (2006) Physical determinants, emerging concepts, and training approvaches in gait of individuals with spinal cord injury. J Neurotrauma 23: 571–85
[115] McDonald JW, Becker D, Sadowsky CL, Jane JA sr, Conturo TE, Schultz LM (2002) Late recovery following spinal cord injury. Case report and review of the literature. J Neurosurg 97: 252–65
[116] Van de Crommert HW, Mulder T, Duysens J (1998) Neural control of locomotion: sensory control of the central pattern generator and its relation to treadmill training. GaitPosture 7: 251–63
[117] Wessels M, Lucas C, Eriks I, de Groot S (2010) Body weight-supported gait training for restoration of walking in people with an incomplete spinal cord injury: a systematic review. J Rehabil Med 42: 513–19
[118] Swinnen E, Duerinck S, Baeyens JP, Meeusen R, Kerckhofs E (2010) Effectiveness of robot-assisted gait training in persons with spinal cord injury: a systematic review. J Rehabil Med 42: 520–26
