Axonal Regeneration

CNS neurons of certain fish and amphibians are capable of regeneration. However, regeneration of adult mammalian axons is restricted essentially to the peripheral nervous system. Although some limited sprouting of rodent CNS axons was observed by Ramon y Cajal in the 1920s, facilitated by transplants of peripheral nerve,8 it was not until Richardson et al. demonstrated projection of labeled spinal axons across a 10 mm sciatic nerve graft in 1980⁹ that the regenerative capacity of at least some CNS axons was given serious consideration. Thus began a fruitful search for factors that might explain the reluctance of CNS neurons to regenerate in their native environment. Caroni et al. in the late 1980s demonstrated that the myelin membrane of oligodendrocytes is inhibitory to axonal growth.^10,11 A monoclonal antibody was developed that could block the action of identified inhibitory fractions from myelin in vitro.¹² Administered in vivo, this antibody led to improved functional performance in spinal cord–lesioned rodents.¹³ Ultimately, the antibody was used to isolate and sequence its target antigen, which was subsequently termed Nogo-A.¹⁴ Interestingly, Nogo-A knockout animals showed less consistent regeneration than did wild-type animals treated with Nogo antibodies, suggesting increased inhibition via compensatory pathways.¹⁵ A growing list of other myelin-associated factors, components of the glial scar that forms after injury, now exists, each of which has been shown to inhibit neuronal growth cones in vitro. Examples include chondroitin sulfate proteoglycans (CSPGs), a family of inhibitory molecules in the glial scar, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMG).¹⁶ Enzymatic digestion of CSPG via chondroitinase ABC has been shown to ameliorate growth cone inhibition, though failure of impaired CSPG synthesis to yield similar results raises the possibility that cleaved glycoaminoglycans (GAGs) may promote neurite outgrowth and underlie the improvements seen with chondroitinase ABC.¹⁵ In 2006, Novartis initiated a multicenter open-label phase 1 trial of intrathecal infusion of various doses of ATI355, a humanized Nogo antibody. Results of the anticipated 51 patients were expected in late 2010, but as of this writing they have not been published.

Analysis of the signal transduction pathways of growth-cone inhibitory compounds has revealed that all such identified compounds act via activation of the guanosine triphosphatase Rho, which in turn is activated by, and binds to, Rho kinase (ROCK).¹⁶ ROCK regulates actin cytoskeleton, and, thereby, growth cone dynamics. McKerracher and Higuchi identified a specific inhibitor of Rho called C3 transferase, produced by Clostridium botulinum, which acts at the final common pathway of growth cone regulation¹⁷ and has been shown to promote axonal regeneration and functional recovery in murine SCI.¹⁸ Clinical trials have been initiated by BioAxone Therapeutic, with BA-210, a recombinant version of the C3 transferase with improved membrane permeability. This compound (Cethrin, Alseres Pharmaceuticals, Inc., Hopkinton, MA) was administered epidurally within 7 days of injury during spinal stabilization surgery, in combination with fibrin sealant as a delivery vehicle. Results of the open-label phase 1/2a trial, wherein 27% conversion was observed from American Spinal Injury Association (ASIA) grade A to grade B, C, or D, have prompted efforts to translate this into a phase 2/3 randomized, controlled trial.³

The low endogenous levels of adult neurite outgrowth likely represent a mechanism to preserve complex circuitry in higher organisms, thus therapeutic reversal of this stability may open the door for certain unintended effects on sensorimotor function. Moreover, much remains to be learned regarding optimal timing of growth-cone-promoting therapies, as well as the functionality, activity-dependence, and consolidation of any new synaptic connections.19 Nevertheless, ample proof of principle suggests axonal regeneration is likely to be a fundamental contributor to functional regeneration following SCI and may ideally provide critical substrate for neural plasticity, including regulation of central pattern generators (CPGs).

Stem Cell Therapy and Cellular Transplantation

Although stem cells have been subject to extraordinarily high expectations, founded more on media hype than on scientific data points, they remain among the most versatile and promising potential therapies for SCI. While neurons from both embryonic and neural stem cells (NSCs) have been shown to survive and form synaptic connections in vivo,^20,21 functional benefits in SCI after transplantation of NSCs, MSCs, and other stem or progenitor cells are likely to be attributable in large part to their supportive properties. CNS and bone-marrow-derived stem cells may migrate to the region of injury, modulate inflammation, promote angiogenesis, promote neurite outgrowth, and enhance synaptic plasticity.²² Mechanisms underlying these actions remain incompletely elucidated; however, secretion of a diverse array of neuroprotective compounds has been observed.

NSCs are known to exist in the hippocampus and forebrain subventricular zone throughout life. However, numerous groups have additionally reported isolation of NSCs from spinal cord. The exact etiology of such cells is controversial; whereas some argue a latent subventricular zone NSC population exists throughout the neuraxis,²³ findings that oligodendrocyte progenitor cells may dedifferentiate into NSCs under in vitro conditions challenge the assumption that NSCs necessarily exist as such in the spinal cord.²⁴ Several attempts have been made to mobilize endogenous stem or progenitor cells via genetic manipulation and infusion of cytokines²⁵; however, a neurogenic response has largely been minimal, and functional consequences may likely be attributable to the treatment itself rather than any new neurons that might be generated as a result.²⁶ Endogenous bone marrow mono-nuclear cells, including macrophages, are mobilized to the site of CNS injury and have been found to be responsible for significant spontaneous recovery.²⁷ Amplification of this response via administration of GCSF²⁸ or even direct transplantation of autologous macrophages has also been shown to yield marked benefit. Transplantation of autologous macrophages at the time of spinal stabilization surgery has been investigated in an open-label phase 1 clinical trial by Procord.²⁹ ASIA score improvement was noted in five of 16 enrolled patients and a phase 2 study was initiated. Benefits from macrophages may be attributable to secretion of prosurvival cytokines and enhanced phagocytosis of potentially harmful injury-associated debris. T cell-based vaccination is based similarly on the principle of timely removal of harmful degradation products as well as provision of growth factors.³⁰ The phase 2 Procord study was halted prematurely due to financial challenges experienced by the sponsoring company.

Secondary neuronal death after SCI may be due in part to demyelination. Oligodendrocyte precursor cells (OPCs) from hESCs have been shown to spontaneously remyelinate congenitally myelin-deficient mice. Functional recovery in rats with SCI after hESC-derived OPC transplantation has been robust, and Geron was granted US Food and Drug Administration (FDA) approval for a clinical trial in early 2009.³¹ The first patients have now been enrolled in the trial. Given the capacity of hESCs to form teratomas, careful attention is appropriately being paid to preclinical safety studies; the trial is currently on hold during investigation of small cysts observed in transplanted animals at later time points. Used in appropriate combinations with other trials, stem cells may have the capacity to mediate significant functional benefits. A recent open-label trial for chronic SCI by Moviglia employed a sequential combination of intraarterial bone marrow mononuclear cells to improve angiogenesis followed by T cell therapy and finally by infusion of autologous NSCs. Although results remain to be replicated by other groups or validated via a randomized double-blind placebo-controlled trial, five of eight treated patients evolved from ASIA A to ASIA D, regaining at least some capacity for ambulation.31

Plasticity

The breakthrough here is the realization that significant plasticity and reorganization occur in the neuraxis after SCI. Transcranial magnetic stimulation and functional magnetic resonance imaging studies have provided evidence of significant plasticity in the sensorimotor cortex after SCI (see Chapter 46 for review). This involves activation of new areas and displacements of activation maxima. This plasticity is dynamic and evolves with time. There is also evidence that significant plasticity accompanies training and rehabilitation.^32,33 Clinical implications are unclear at the present time, but the extent and pattern of plasticity may be used as potential markers of recovery. There is significant rewiring of circuits after partial lesions. There is a modest regrowth of axons and a rewiring of circuits so that the cortex can reach the spinal cord through different circuits (via reticulospinal or propriospinal circuits). In that context, the implication of propriospinal pathways has become important.^34–36

An area of plasticity research involves attempts to modulate spinal cord plasticity to improve recovery. This area of research is in its infancy and involves modulation of the Hoffmann reflex (H-reflex) and other spinal reflexes, such as reciprocal inhibition, to improve recovery.^37–39

Techniques for understanding plasticity and development of new plasticity-enhancing techniques, such as paired association stimulation, prolonged somatosensory stimulation, theta burst stimulation, transcranial direct current stimulation and repetitive transcranial stimulation, represent breakthroughs that are likely to lead to greater enhancement of plasticity and a greater understanding of the relationship between plasticity and recovery.^40–48

Central Pattern Generator

The breakthrough here was the establishment of the role of the CPG in neurological recovery after SCI. The notion of the CPG is unique and refers to the ability of spinal circuitry to generate an organized rhythmic activity all by itself (of course normally under the control of descending commands and afferents).⁴⁹ The activity of the CPG is rhythmic, automatic, activated by neurotransmitter or proprioceptive information (e.g., from activity-based training). It can also be activated by pharmacology or electrical stimulation. It is under supraspinal control and can undergo plasticity during training. Significant evidence now exists implicating the CPG in the recovery of locomotion after partial spinal lesions.^50,51 There is increasing evidence for a human CPG.^52–56 The role of the human CPG in SCI is discussed in detail in Chapter 49.

Activity-Based Restorative Therapy

The breakthrough here is the increasing evidence that recovery can be achieved by specific activity-based therapies and the notion that plasticity of spinal circuits is activity dependent. This represents a significant departure from previous rehabilitation philosophies that focused more on development of compensatory strategies. Repetitive practice using task-specific sensory input can engage key spinal locomotor networks and improve recovery.57 Potential mechanisms include increased gene expression, synaptogenesis, increased reorganization, and repair along the neural axis and engagement of the CPG. Physiological benefits include optimization of cardiovascular functioning and musculoskeletal restoration, including increase in bone mineral density, muscle strength, and tone.⁵⁸ Locomotor training is probably the most well known activity-based therapy and has been shown to increase supraspinal plasticity.^32,33 Great interest in human locomotor studies followed the observation that cats with complete transections of the spinal cord recovered locomotor stepping response after intense treadmill training involving partial body weight support and optimization of assistance during stance cycle. Subsequently, several locomotor training regimens have been investigated, including manual and robotic body weight support treadmill training (BWSTT) and functional electrical stimulation augmented ergometry and training methods. The roles in rehabilitation are discussed in detail in the sections on plasticity and rehabilitation (see Chapters 48, 49, and 50).

Management of Blood Pressure

The significant breakthrough here was the realization of the importance of vascular changes in the injured spinal cord with resultant loss of autoregulation and ischemia.⁵⁹ This basic science knowledge has been translated into the clinical recognition of the importance of blood pressure management in the prevention of secondary injury after acute SCI. Significant evidence has accumulated regarding benefits of close monitoring and aggressive maintenance of blood pressure after significant injury.^60–62 An extensive evidence-based guideline recommends avoidance of systolic blood pressure < 90 mmHg or corrected as soon as possible and maintenance of mean arterial pressure at 85 to 90 mmHg during the first 7 days after SCI.^63,64 The lack of clinically relevant methods to directly measure spinal cord blood flow remains an ongoing challenge and represents an opportunity for innovation. These are discussed in more detail in Chapter 9.

Development of Diffusion Tensor Imaging

The breakthrough here is the development of imaging technology with the potential to visualize preserved white matter pathways in SCI. This will likely revolutionalize the classification of SCIs based on direct visualization of anatomical tracts. The ASIA scale and motor scores, as well as magnetic resonance imaging (MRI) parameters like the presence of hematoma, have proven valuable in predicting recovery. However, both the ASIA scale and MRI are unable to identify potentially salvageable white matter tracts. This disadvantage will be overcome by diffusion tensor imaging (DTI). DTI also provides quantitative markers of injury, such as the fractional anisotropy and apparent diffusion coefficient, that may become important surrogate markers of recovery (see Chapter 46 for further discussion).

Functional Electrical Stimulation

Despite major advances in our understanding of neuroregenerative processes, effective regeneration therapy for people with SCI remains elusive. In fact, the improved quality of life, function, and life expectancy after SCI have risen largely from work in specialized SCI medical care and comprehensive rehabilitation. Many medical complications associated with SCI are now preventable or managed more efficiently—thromboembolic disease, pressure ulcers, respiratory insufficiency, male sexual dysfunction, constipation, and renal failure, to name a few. In the absence of a cure for the site of injury, we have sought ways to overcome specific deficits created by SCI—functional electrical stimulation (FES) is the epitome of such endeavors.

FES, once merely a sci-fi fantasy, has been enabled by achievements in electronics, microprocessing, neuroscience, and rehabilitation. FES systems now allow certain people with SCI to reclaim meaningful use of their hands, to stand, or to take steps. Some have regained some control of bladder and bowel evacuation,65 others the ability to overcome male sexual dysfunction. Beyond enabling specific motor functions, FES has been shown to increase muscle bulk, improve cardiovascular performance, prevent pressure ulcers, treat osteoporosis and contractures, control spasticity, and improve depression.^66,67

The majority of FES systems work by direction stimulation of a peripheral nerve. The energy required to activate muscle contraction via direct muscle fiber stimulation is roughly 100 times that of nerve stimulation—too unsafe to be applied multiple times. The main components of FES systems are basically the same—a power source, command processor, stimulator, lead wires, electrodes, and sensors. Delivery of the stimulation is through a variable number of lead wires to either surface, percutaneous, or implanted electrodes. An external control unit typically houses the power source (batteries), receives information from the user and sensors, and transforms this information into commands that are sent to the stimulator for a specific motor end effect. In open loop control programs, a stimulation results in a specific function (e.g., knee extension) without autocorrection through processing of feedback sensor information. Closed loop programs incorporate information on muscle force and joint motion from sensors and modify the output stimulation accordingly for more complex functions (e.g., taking a step).

Surface systems are inexpensive and can be safely placed in the clinic, but accurate placement is difficult, and stimulation often lacks specificity, can be painful, and can be cosmetically unacceptable. Surface systems are best for diagnostics and short-term therapeutic use. Percutaneous leads are often used temporarily for muscle conditioning. They are easier to place accurately than surface electrodes, but long-term use carries the risk of infection and granuloma formation. In implanted FES systems, the electrodes, lead wires, and stimulators are internalized while the control unit and battery are external—they communicate through radio frequency telemetry. Unfortunately, no implantable battery today can meet the energy demand of a multichannel FES system.

Naturally, the lower motor neuron (LMN) must be intact for an FES system to work. Other criteria for effective application of FES include the following: (1) the strength of muscle contraction must be forceful, controllable, and repeatable; (2) neural structures must not be damaged by the stimulus; and (3) the method of stimulus delivery must be acceptable to the patient and not be unbearably painful. Several FES systems have been approved by the FDA; a select few are available only in Europe or Japan.

Cervical SCI patients with preserved C7 and C8 segments or higher benefit most from upper limb FES systems, given that hand grasp, hold, and release may be restored. Significant spasticity or joint contractures make meaningful use of the hand or arm difficult. Current systems provide some patients the ability to hold and release larger objects like bottles and cans, or even to use finer items like keys.

For lower limb function, FES currently enables SCI patients to stand and perform limited transfers, but no system allows for functional walking. In many ways, locomotion is far more complex than it may seem—beyond the loss of large muscles in the lower extremities, most patients with SCI lose proprioceptive feedback as well as control of trunk muscles for maintaining erect posture and balance. Technology limitations include high energy expenditure (due to inadequate efficient coordination of muscle activation), heavy batteries, unreliable hardware, and reliance on visual feedback, among others. FES systems will not replace wheelchairs as the main means of mobility for SCI patients in the foreseeable future.

Direct stimulation of the phrenic nerve (i.e., electrophrenic respiration or EPR) either in the cervical or thoracic region allows for some high cervical SCI patients to become independent of ventilatory support.68 Because spontaneous recovery of diaphragm function sometimes occurs even a year after initial injury, people generally wait 4 to 6 months before EPR is considered. The diaphragm often suffers from disuse atrophy, thus commonly 2 to 3 months of diaphragm reconditioning must occur after implantation for complete independence from a ventilator. With adequate teaching, reconditioning, and support, respiratory complications from EPR are equivalent to the current standard and afford patients dramatically improved quality of life.

Regular bladder catheterization has dramatically reduced morbidity and mortality from urinary retention in SCI patients. Sacral anterior root stimulation for bladder control has been reported since the 1970s. Refinement of this approach led to development of the Finetech-Brindley bladder system (formerly marketed as “Vocare” in the United States), which has been shown to produce bladder emptying and continence in select SCI patients. The biggest drawback of this technique is the need to perform a dorsal S2-4 rhizotomy, which leads to irreversible loss of reflex erection and ejaculation, to secure continence between stimulation and decrease detrusor and sphincter dyssynergy. Studies show that 80 to 90% of users can urinate on demand, with postvoid residuals of less than 50 mL; between-stimulus continence is preserved in more than 85%. Similar but less well-documented achievements have been made with regard to bowel evacuation. As for male sexual dysfunction, FES of intact anterior sacral nerve roots, especially S2, produces sustained penile erection for the duration of stimulation. Likewise, ejaculation can be generated by stimulation of the presacral sympathetic plexus. However, because other methods of achieving erection and ejaculation exist, FES systems are not typically implanted solely for treatment of male sexual dysfunction.

Advances in microelectronics, computer technologies, and neurophysiology have helped create decent FES systems. As components are miniaturized and our understanding of the physiology of myoelectric systems improves, FES systems will surely boast improved functionality and accessibility. With recent research in brain–machine interfaces showing the promise of enabling tetraplegic patients to perform motor tasks by thought, we can be optimistic about the future for SCI patients⁶⁹ (see Chapters 52 and 54 for further discussion).

Early Interventions after Spinal Cord Injury: Steroids and Surgical Decompression in Acute Spinal Cord Injury

For decades, the prevailing attitude about SCI was that all the damage to the CNS occurs at the time of injury and that the damage is irreversible. Hemodynamic stabilization of the trauma patient claimed top priority. Because outcomes were thought to be totally determined by the extent of initial injury, little attention was paid to examining the effect of prompt interventions, such as drugs or decompressive surgery, on the “natural course” of SCI. It is now recognized that much of the degeneration of the spinal cord after SCI is due to a multifactorial secondary injury process that occurs over minutes, to hours, to days. For instance, production of reactive oxygen-induced lipid peroxidation (LP) has been found to play a key role in this process. Demonstration of LP inhibition by the glucocortico steroid methylprednisolone (MP) in animal SCI models led to important clinical trials in humans, the results of which have been the focus of intense debate for nearly 20 years.^70–74 However, due to concerns regarding the relatively small effect sizes seen in the National Acute Spinal Cord Injury Study 2 (NASCIS-2) and NASCIS-3 trials, coupled with potential adverse effects of immunosuppression on wound healing and resistance to infection, many clinicians have questioned whether steroids should be routinely used in acute traumatic SCI. Currently, the use of steroids is not considered standard of care by several evidence-based guidelines.70,75–78 To clarify, the guidelines committee of the AANS/CNS Joint Section on Disorders of the Spine and Peripheral Nerves concluded that use of methylprednisolone in treatment of acute SCI in adults can only be supported as a “treatment option” and not a standard of care.⁷⁵ The controversy surrounding the use of steroids is discussed in detail in Chapter 11.

Early surgical decompression for acute SCI is another area of controversy where recent research seems to be pushing practice paradigms in a new direction. Decompression of the injured spinal cord is thought to prevent or attenuate secondary injury mechanisms. This theory is supported by work done in purebred dogs,^79,80 where a time-dependent benefit in hindleg motor function from early surgical decompression done within 6 hours of injury was observed. Rabinowitz et al.⁷⁹ further showed that this effect was independent of administration of methylprednisolone.

Despite the widespread use of surgery in patients with SCI, its application varies widely. The presence and duration of a therapeutic window were merely suggested by numerous Class III and limited Class II studies.^81–83 The Surgical Treatment for Acute Spinal Cord Injury Study (STASCIS) group was formed in 1992 by the Spinal Cord Injury Committee of the Joint Section on Neurotrauma and Critical Care of the AANS and CNS, with the goal of conducting prospective, controlled trials to determine the role and timing of decompressive surgery after acute SCI.^74,84 Of the 222 patients with follow-up available at 6 months postinjury, 19.8% of patients undergoing early surgery showed a 2 grade improvement in AIS, compared to 8.8% in the late decompression group (OR = 2.57, 95% Cl:1.11,5.97). In the multivariate analysis, adjusted for preoperative neurological status and steroid administration, the odds of at least a 2 grade AIS improvement were 2.8 times higher amongst those who underwent early surgery as compared to those who underwent late surgery (OR = 2.83, 95% Cl:1.10,7.28). They concluded that “Decompression prior to 24 hours after SCI can be performed safely and is associated with improved neurologic outcome, defined as at least a 2 grade AIS improvement at 6 months follow-up.”⁸⁵

It is important to note that the STASCIS study enrolled only patients with subaxial cervical spine injury. Upon conclusion of the study and publication of the results, careful analysis must be done before any new treatment guidelines are made, but positive results may shift current practice paradigms toward more urgent management of spinal cord compression (see Chapter 27 for further discussion). It is noteworthy that a consensus panel of the Spine Trauma Study Group has recommended early intervention for patients with traumatic SCI and that this approach is favored by the vast majority of clinicians, as determined by a recently published international survey.^86,87

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