Spinal cord injury remains an incurable disease with an enormous impact functionally, financially, and emotionally on affected individuals and their families. Current treatment modalities are focused on minimizing secondary injury and maximizing residual function via rehabilitation. In this article, the authors discuss ambitious advancements under investigation aimed at restoring function. These promising experimental treatments focus on neuroprotection with hypothermia and pharmacologic therapies, regeneration via cell transplantation, and rewiring with electrical stimulation.
Key points
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Therapeutic hypothermia after spinal cord injury may prevent secondary damage after spinal cord injury.
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Cell transplantation with glial cells, stem cells, or a combination may enhance spinal cord regeneration and functional recovery after spinal cord injury.
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Electrical stimulation may assist in recruiting new motor circuits to improve function after spinal cord injury.
Introduction
Spinal cord injury (SCI) occurs in approximately 10,000 to 12,000 individuals per year in North America, and 250,000 individuals are living with an SCI. Current treatment is focused on limiting secondary complications and maximizing residual function. However, with the life expectancy of individuals with SCI increasing, therapeutic strategies focused on restoring functional independence is becoming increasingly important. In this article, the authors discuss the range of strategies that are currently being used and researched in order to restore function after SCI.
Introduction
Spinal cord injury (SCI) occurs in approximately 10,000 to 12,000 individuals per year in North America, and 250,000 individuals are living with an SCI. Current treatment is focused on limiting secondary complications and maximizing residual function. However, with the life expectancy of individuals with SCI increasing, therapeutic strategies focused on restoring functional independence is becoming increasingly important. In this article, the authors discuss the range of strategies that are currently being used and researched in order to restore function after SCI.
Neuroprotection
After the initial trauma of SCI, cell death and tissue loss continue over several weeks. During this initial window the main strategies used to restrict secondary damage are surgical decompression, therapeutic hypothermia, and drugs targeting inflammation or excitotoxicity.
Therapeutic Hypothermia
Therapeutic hypothermia slows biological reactions and processes resulting in improved electrophysiologic, histologic, and motor outcomes in experimental models of SCI. The mechanism of protection includes reducing excitotoxicity, vasogenic edema, neuroinflammation, ischemia, oxidative stress, and apoptosis. This increasing body of evidence of efficacy has been derived primarily from animal studies and case series.
Several case series in the 1970s described potential benefits with the use of local spinal cord cooling after SCI. In these experimental models, cooling was performed by application of an extradural heat exchanger or perfusion of subarachnoid space with cold solution. However, the results were mixed and the procedure invasive; thus, the technique was gradually abandoned. However, in a recent case series, 20 patients with complete cervical or thoracic SCI underwent triple therapy including dexamethasone, surgical decompression, and deep cord cooling with extradural saddles (dural temperature of 6°C). At 1 year after injury, 16 patients (80%) regained some sensory or motor function. Although this study is exciting, the evidence is preliminary and merits further investigation.
Systemic cooling with intravascular heat exchange cooling catheter techniques is of great modern interest as it has been shown to be safe and potentially beneficial in a case control study ( Fig. 1 ). In this study of 31 patients with complete cervical SCI (who showed no improvement within 24 hours of injury), 11 (35%) of patients regained some sensory or motor function with systemic intravascular cooling ( Fig. 2 ). The finding is promising as the rate of spontaneous recovery is reported to be approximately 15% to 20% in complete cervical SCI. The surmounting body of evidence of efficacy will be further elucidated by the results of an ongoing clinical trial (NCT01739010) to test modest systemic hypothermia.
Pharmacologic Therapies
Pharmacologic therapies are also being studied to target secondary damage from inflammation and excitotoxicity. The most heavily studied pharmacotherapy agent for SCI has been methylprednisolone, which is thought to limit the inflammatory response after SCI. However after 4 prospective blinded randomized controlled trials, there is no class I medical evidence of any benefit. Furthermore, methylprednisolone may have harmful effects, including increased rates of wound infections, gastrointestinal hemorrhage, and hyperglycemia. Thus, the most recent guidelines from the Congress of Neurological Surgeons/American Association of Neurological Surgeons recommends against the use of methylprednisolone for the treatment of acute SCI.
Other agents currently being studied include minocycline and riluzole. Minocycline is a semisynthetic tetracycline antibiotic, which is currently in a phase 3 clinical trial for neuroprotective benefits after acute SCI. It has been shown to reduce inflammatory cytokines, free radicals, and matrix metalloproteinases. Riluzole is a glutamate antagonist and sodium channel blocker that is currently being tested in a phase 1 trial for acute SCI, with initial data suggesting that riluzole is well tolerated and may have neuroprotective efficacy. Further discussion of the pharmacologic agents for SCI (see Michael Karsy and Gregory Hawryluk’s article, “ Pharmacologic Management of Acute Spinal Cord Injury ,” in this issue).
Cell transplantation and regrowth
Traumatic SCI results in a disruption of axonal myelination, resulting in a loss of function. Glial cell transplantation has emerged as a potential target for axonal regeneration after SCI. Schwann cells are the most common glial cell in the peripheral nervous system. Their therapeutic potential is thought to be due to their ability to secrete high levels of neurotrophic growth factors and extracellular matrix molecules that promote axon growth. Schwann cell grafts have been extensively studied in animal models and have been shown to increase cell survival, decrease the size of the cystic lesion after SCI, and improve locomotion scores. However, only 3 studies have reported the use of Schwann cells in humans with SCI ( Fig. 3 ). The largest of these studies involved 33 patients with chronic American Spinal Injury Association (ASIA) grade A or B SCI in which there was a marked improvement in sensory scores but no improvement in motor function. From this preclinical data, a phase 2 clinical trial of autologous Schwann cells in chronically spinal cord injured subjects is presently underway in the Miami Project to Cure Paralysis.
Another cell type that is being studied for axonal regeneration after SCI is the olfactory ensheathing cell (OEC). OECs are a distinct population of cells that wrap the axons of olfactory receptor axons in their entire length as they extend from the olfactory epithelium in the peripheral nervous system to the olfactory bulb in the central nervous system (CNS). In animal models of SCI they can limit neuronal cell death and be myelinated and stimulate axonal growth. Ramon-Cueto and colleagues reported regeneration of corticospinal axons and improvement in motor behavior in rats after injury. Small preliminary studies of OECs have been studied in humans and have established feasibility and safety; however, results of efficacy have been mixed. Mackay-Sim and colleagues reported that only 1 of 6 patients with a chronic SCI had any neurologic improvement (ie, a mild improvement in sensation) after treatment with OECs. Lima and colleagues reported that 11 of 20 patients (55%) with chronic SCI had an improvement in ASIA grade after such treatment, including 5 patients who recovered voluntary bowel control and 1 who recovered bladder control.
Stem Cell Transplantation
Stem cell transplantation for SCI is another area of ongoing investigation that holds great potential for tissue regeneration. Stem cells may mediate repair by secreting growth factors and replacing lost neurons, glial, or other cells. However, the progenitor cell type that is most effective has yet to be elucidated. Currently, 3 main stem cell types are being used in animal modes of SCI: human embryonic stem cells, neural stem cells, and bone marrow mesenchymal stem cells.
Embryonic stem cells are taken from blastocysts and can develop into more than 200 different cell types in the human body with an unrestricted power of self-renewal. Thus, they have the highest potency but also the greatest risk for tumorigenicity as well as immune rejection. They can be directed toward multipotent neural precursors, motor neurons, and oligodendrocyte progenitor cells and then transplanted. Transplantation of human embryonic stem cell derived oligodendrocyte progenitor cells into rats 7 days after injury resulted in enhanced myelination and functional recovery. This finding led to the first approved clinical trial using embryonic stem cells in 2009. The Geron sponsored trial (Geron of Menlo Park, California) involved transplantation of GRNOPC1 (a treatment containing oligodendrocyte progenitor cells) into patients with complete thoracic SCIs. Although no safety concerns were reported, in 2011 Geron stopped the trial prematurely largely because of financial reasons, raising several ethical concerns. In 2013, Asterias Biotherapeutics acquired GRNOPC1 (now AST-OPC1) and have since initiated a phase I clinical trial transplanting AST-OPC1 in patients with complete cervical SCI ( NCT02302157 ).
Neural stem/progenitor cells (NSC) are alternative pluripotent cells with the potential to differentiate into neurons, oligodendrocytes, and astrocytes in vitro and in vivo. These cells can be obtained from the central canal of the spinal cord or subventricular zone of the brain. In most cases, in vivo transplanted NSCs preferentially differentiate into glial cells, particularly astrocytes. With certain pretreatments, however, grafted NSCs can differentiate into neurons or oligodendrocytes, which may enhance synaptic contact reformation or remyelination. In 2000, StemCells, Inc created HuCNS-SC, an adult neuro stem cell from purified human neural stem cells from a single fetal brain tissue. A phase I/II trial involving transplantation in HuCNS-SC in 12 patients (ASIA categories A and B with chronic paraplegia and an average postinjury time of 11 months) with SCI has recently been completed. Thus far, no safety concerns have been reported; early results show below-injury-level sensory improvements in several patients ( Fig. 4 ).
Bone marrow–derived mesenchymal stem cells (MSCs) display broad potency, with the ability to differentiate not only into multiple mesodermal cells such as blood, bone, and muscle but also CNS cells. Transplantation of MSC confers the advantage of relatively easy procurement from bone marrow aspirate and autologous transplantation, avoiding the need for immunosuppression. Furthermore, in vivo tumor development has not been reported. A phase I clinical trial has been completed and establishes safety and potential efficacy of autologous bone marrow MSC transplantation at least 6 months after the procedure in subjects with chronic thoracic and lumbar SCI. However, results regarding efficacy from clinical studies using MSCs for SCI are mixed. Park and colleagues showed significant improvement in 3 of 10 subjects who received intramedullary and intrathecal injections of MSCs, whereas Bhanot and colleagues reported intralesional and intrathecal injection of MSC enhanced rehabilitation in only one of 67 subjects with chronic SCI. These variable results may be due to the degree of heterogeneity in how the cells are harvested, cultured, and administered.
Electrical stimulation
Functional Electrical Stimulation
Functional electrical stimulation (FES) uses stimulators, surface electrodes, and frames to create purposeful contractions for the restoration of gait, upright posture, cycling, and hand movement.
FES was originally designed for the restoration for walking in paraplegic patients. FES gait systems, such as the Parastep 1 (Sigmedics Inc., Fairborn, OH), consist of a multichannel stimulator, surface electrodes, and walking frames. The stand command delivers continuous stimulation to the gluteal muscles and quadriceps to maintain erect posture while pulse generators stimulate opposing muscles in order to create stepping motions. Nightingale and colleagues conducted a systematic review of previous published studies on patients with SCIs and the efficacy of FES gait and concluded that the use of FES gait training in incomplete SCI populations improves walking ability and overall independence in the community. However, there was not sufficient evidence to support changes in bone mineral density, joint movements, and overall reduced energy cost of gait.
FES cycling has evolved as a therapeutic tool for the rehabilitation of people with paraplegia. In contrast to FES gait training exercises, FES cycling can be maintained for longer periods of time and fall risk is minimal. In FES cycling, electrodes are placed on opposing muscle groups: the quadriceps and hamstrings and the plantar flexors and dorsiflexors of the ankle. Their legs are then placed in a rigid orthosis that restricts lateral bending movements, and a throttle on the steering handle controls electrode stimulation intensity. Following an FES cycling program instituted for several weeks, Gerrits and colleagues have demonstrated restoration of muscle bulk and strength, a return of the contractile properties of the quadriceps muscle toward normal, as well as increases in capillary numbers. However, patients’ power outputs remain too low for travel on uneven terrain.
FES for the upper extremity has the potential to restore important daily hand functions to patients with quadriplegia. All of these upper extremity neuroprosthetic devices currently consist of a stimulator with electrodes that activate the muscles of the arm and hand as well as a controller. There are multiple systems available at this time wherein electrodes are placed on the surface, within a brace, or percutaneously.
Robotic Training Strategies
Robotic training strategies use electromechanical, pneumatic, and hydraulic forces to actively move limbs or assist voluntary movement. Furthermore, these therapy robots have the potential measure therapy progress and provide feedback both to patients and therapists. Robotic-assist devices include driven (ie, motorized) gait orthoses (DGO) as well as robotic upper extremity–assist devices. DGOs, such as the Lokomat (Hocoma, Volketswil, Switzerland), generally consist of an exoskeleton that fits over patients’ legs and assists the physical therapist in stabilizing the lower limbs and gait training ( Fig. 5 ). Wirz and colleagues conducted a multicenter study of 20 patients with incomplete SCI (ASIA grades C and D) using the Lokomat DGO wherein patients underwent an 8-week robotic training period. In this small study they concluded that the DGO resulted in significant improvement in the subjects’ gait velocity, endurance, and performance of functional tasks. There were no changes, however, in the use of walking aids, orthoses, or external physical assistance following conclusion of the study.
Related posts:
Update on New Imaging Techniques for Trauma
Thoracolumbar Trauma Classification
Classification and Management of Pediatric Subaxial Cervical Spine Injuries
Pediatric Thoracolumbar Spine Trauma
Treatment of Odontoid Fractures in the Aging Population
Complications in the Management of Patients with Spine Trauma
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