Author: Allan D. Levi, MD PhD
In spite of many decades of active research, traumatic spinal cord injury (SCI) is a devastating disease that still lacks robust treatment options. The knowledge base for the pathophysiology of SCI has increased substantially, yet translating preclinical success in the laboratory to human patients remains challenging. There are approximately 17,000 new cases of SCI in the United States each year, and 282,000 people currently live with an SCI.1 The average age at time of injury has climbed substantially over the last five decades, from the age of 29 in the 1970s to the age of 42 currently.1 Pediatric spinal cord injuries for those 15-years-old or younger are rare (3.5 percent), while injuries in retirees are on the rise, particularly due to falls. Given comorbidities, the mortality in the first year after injury is significantly higher in older (>60 years) patients who sustain a spinal cord injury.
In major trauma centers, computer tomographic (CT) images with sagittal and coronal reconstructions have supplanted plain x-rays in evaluating spine fractures for all suspected SCI patients.2 Magnetic resonance imaging (MRI) is crucial in assessing for degree of spinal cord or nerve root compression and any ligamentous injury. Optimizing spinal cord perfusion is a critical consideration in the acute management of traumatic SCI. Recent guidelines make Level III recommendations to avoid episodes of hypotension (defined as SBP < 90 mm Hg) and maintain MAP > 85 to 90 mm Hg for seven days after injury.3 In order to achieve these goals, admission to an intensive care unit and placement of appropriate monitoring devices, such as an arterial line, is recommended.
Timing of Decompressive Surgery for SCI
There is a growing body of literature to support early surgical intervention in spinal cord injury. The definition of early surgery for traumatic SCI in the past has varied anywhere from 8 to 72 hours, and this should be kept in mind in an evaluation of the literature. In 2012, Fehlings et al.,4 published a well-designed, prospective cohort study of 313 patients with cervical traumatic SCI comparing early and late decompressive surgery using a 24-hour cutoff. The study was non-randomized and the patient selection decision in early versus late group was decided by the surgeon based on clinical factors. Importantly, the mean time to surgery in the early and late groups was 14.2 and 48.3 hours, respectively. Patients demonstrated a 19.8 percent and 8.8 percent improvement of 2 AIS grades in the early and late groups, corresponding to 2.8 times higher odds in the early group. Follow-up was conducted at six months after injury. However, this study has several limitations that must be taken into consideration. First and foremost, were the two groups early versus late surgery comparable? In the early surgery group there were 57.7 percent of patients with AIS A and B injury versus 38.2 percent in the late surgery group (p <0.01). This can produce a ceiling effect in the degree of improvement patients with AIS C and D type injuries can achieve.
There are a number of neuroprotective strategies in various stages of investigation including steroids, minocycline, riluzole, and spinal cord cooling. Administration of IV methylprednisolone (MP) is the most highly studied, and perhaps the most controversial therapeutic option, as well as the subject of three National Acute Spinal Cord Injury Studies (NASCIS). MP was chosen due to effects on reduction of membrane lipid peroxidation with possible beneficial effects on blood flow and neuronal excitability.5 A NASCIS II was planned to compare a higher dose MP to naloxone and placebo.6 The primary outcome was the motor and sensory exam at six weeks and six months. Results in NASCIS II showed naloxone and MP given more than eight hours after injury did not lead to neurological improvement, however, when given within eight hours of injury, MP led to increased change in motor (16 vs 11.2 placebo, p=0.03), pinprick (11.4 vs 6.6, p=0.02), and touch (8.9 vs 4.3, p=0.03) scores. Important limitations to interpreting these data were the post-hoc application of the eight-hour limit, and reporting of only unilateral results. Given modest and questionable benefits from MP in the NASCIS trials, combined with higher rates of adverse events in these and other studies, the most recent AANS/ CNS guidelines changed MP from a treatment option to a Level 1 recommendation against utilization.7 The guidelines change was controversial, with leading experts arguing there was no new data since the prior guidelines to support the downgraded MP recommendation.8 Other neuroprotective pharmacological strategies for SCI include Riluzole, a sodium channel blocker, which is FDA approved in the use of amyotrophic lateral sclerosis (ALS), and Minocycline, an antibiotic, that is a tetracycline analogue. Both are in phase II/III studies.
Figure 1 – Hypothermia catheter with several ports. The balloon catheter resides with in the inferior vena cava. A closed loop system exists in which cold saline cools circulates at a rate to achieve the desired systemic temperature by cooling the blood rushing by the catheter.
Induced local or systemic hypothermia is a treatment option for traumatic spinal cord injury and a current topic of active research. Attempts at local cooling in human SCI patients began in the 1970s. When using an epidural cooling system during the time of surgical decompression for cervical or thoracic ASIA A patients, 65 percent improved at least one ASIA grade. Of 14 patients in the cervical cohort, 5 patients converted to ASIA B, 3 to ASIA C, and 1 to ASIA D. Of 6 patients in the thoracic cohort, 1 converted to ASIA B, 2 to ASIA C, and 1 to ASIA D.9 Systemic modest hypothermia, defined as cooling to 32–34°C via a central venous catheter, has recently been the focus of several clinical studies in SCI (Figure 1). In 35 neurologically complete, cervical ASIA Impairment Scale (AIS) A, adult patients who received 48 hours of cooling starting at mean 5.8 hours after injury, 43 percent improved at least one AIS grade by last follow-up.10 23 percent regained some motor function and 11 percent improved to AIS D or better. A four center, Department of Defense funded, prospective, randomized trial comparing intravascular mild hypothermia versus normothermia in AIS A, B, and C cervical SCI subjects is underway.
Traumatic spinal cord injury results in a disruption and loss of spinal cord tissue, such that cell replacement strategies are important restorative targets to make new connections and/or remyelinate damaged axons. Schwann cells are the glial cells of 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 survive post-transplantation, decrease the size of the cystic lesion after SCI, and improve locomotor scores.11,12 On the basis of this preclinical data, a phase I clinical trial was recently completed in subacute SCI (n=6 patients), and another trial is in progress in chronic SCI patients using autologous Schwann cells at the Miami Project to Cure Paralysis.
Figure 2 - Intraoperative photograph of intramedullary injection of human stem cells into the peri-lesional area of a patient with a cervical spinal cord injury.
Stem cell transplantation for spinal cord injury is another area of ongoing investigation that holds great potential for tissue regeneration (Figure 2). Stem cells may mediate repair by secreting growth factors and replacing lost neurons, glial, or other cells. Currently, three main stem cell types are being used in animal models of SCI: Human embryonic stem cells, neural stem cells, and bone marrow mesenchymal stem cells.
Embryonic stem cells taken from blastocysts can develop into more than 200 different cell types in the human body with an unrestricted power of self-renewal. They can be directed toward multipotent neural precursors, motor neurons, and oligodendrocyte progenitor cells, and then transplanted. Transplantation of the latter into rats seven days after injury resulted in enhanced myelination and functional recovery. These results led to the first approved clinical trial using embryonic stem cells in 2009. The Geron trial involved transplantation of GRNOPC1 (a treatment containing oligodendrocyte progenitor cells) into patients with complete thoracic spinal cord injuries. While no safety concerns were reported, in 2011 Geron stopped the trial prematurely largely due to financial reasons. 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 an alternative pluripotent cell with the potential to differentiate into neurons, oligodendrocytes, and astrocytes in vitro and in vivo. StemCells, Inc. created HuCNS-SC, an adult stem cell from purified human neural stem cells taken from a single fetal brain tissue. A phase I/II trial involving transplantation in HuCNS-SC in 12 patients (AIS categories A and B with chronic paraplegia and an average post-injury time of 11 months) with SCI has recently been completed. Thus far, no safety concerns have been reported, and early results show below injury-level sensory improvements in several patients.
The cervical trial recruited 17 patients who were then transplanted. The dose escalation cohort demonstrated safety and tolerability in perilesional injection up to doses of 40 million cells. In cohort II, randomization was complete in half the anticipated subjects, however, the magnitude of improvement in cohort I at one year, and an interim analysis of cohort 2 at six months, fell below the required clinical efficacy threshold set by the sponsor to support further development, resulting in early study termination.
Bone marrow derived mesenchymal stem cells (MSC) 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. A phase I clinical trial has been completed and establishes safety and potential efficacy of autologous bone marrow MSC transplantation at least six 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.
Functional Electrical Stimulation (FES)
FES for the upper extremity has the potential to restore important daily hand function 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 either placed on the surface, within a brace, or percutaneously. Robotic training strategies utilize electromechanical, pneumatic, and hydraulic forces to actively move limbs or assist voluntary movement. Robotic assist devices include driven (i.e., motorized) gait orthoses (DGO) as well as robotic upper extremity assist devices. DGOs such as the Lokomat, generally consist of an exoskeleton that fits over the patient’s legs and assists the physical therapist in stabilizing the lower limbs and gait training.
Epidural stimulation has been used in experimental models to increase central pattern generator or lower motor neuron excitability. In one clinical case series a 16-electrode array epidural stimulator is placed over the L1-S1 cord in combination with months of intensive rehabilitation before and after implantation. Four patients with complete motor paralysis (two ASI-B and two ASI-A) were able to execute on-command voluntary movement after implantation. With continuous stimulation, all four participants could stand independently with full weight-bearing for several minutes, move their legs in response to cues, and recruit appropriate muscles to make specific movements in response to cues. It is thought that epidural stimulation improves lower extremity function by bringing spinal circuits closer to threshold, such that the descending input from the brain or peripheral sensation is sufficient to trigger volitional movement.
Brain computer interfaces are an emerging technology aiming to translate cerebral electrical activity into meaningful commands or movements in order to assist patients with SCI and other debilitating neurologic diseases. There are two general forms; invasive and noninvasive. Noninvasive BCI derive the user’s intent from scalp-recorded electroencephalographic (EEG) electrode activity, whereas invasive BCI receives input from surgically placed electrodes directly on the brain’s surface. Several small studies show promise in this arena.
- Spinal Cord Injury: Facts and Figures at a Glance. National Spinal Cord Injury Statistical Center. https:// www.nscisc.uab.edu/Public/Facts%202016.pdf. University of Alabama at Birmingham; Published 2016.
- Panczykowski DM, Tomycz ND, Okonkwo DO. Comparative effectiveness of using computed tomography alone to exclude cervical spine injuries in obtunded or intubated patients: meta-analysis of 14,327 patients with blunt trauma. Journal of Neurosurgery. 2011;115(3):541-549.
- Ryken TC, Hurlbert RJ, Hadley MN, et al. The acute cardiopulmonary management of patients with cervical spinal cord injuries. Neurosurgery. 2013;72 Suppl 2:84-92.
- Consortium for Spinal Cord M. Early acute management in adults with spinal cord injury: a clinical practice guideline for health-care professionals. J Spinal Cord Med. 2008;31(4):403-479.
- Hall ED, Braughler JM. Glucocorticoid mechanisms in acute spinal cord injury: a review and therapeutic rationale. Surg Neurol. 1982;18(5):320-327.
- Bracken MB, Shepard MJ, Collins WF, et al. 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. 1990;322(20):1405-1411.
- Hurlbert RJ, Hadley MN, Walters BC, et al. Pharmacological therapy for acute spinal cord injury. Neurosurgery. 2013;72 Suppl 2:93-105.
- Fehlings MG, Wilson JR, Cho N. Methylprednisolone for the treatment of acute spinal cord injury: counterpoint. Neurosurgery. 2014;61 Suppl 1:36-42.
- Hansebout RR, Hansebout CR. Local cooling for traumatic spinal cord injury: outcomes in 20 patients and review of the literature. Journal of Neurosurgery. Spine. 2014;20(5):550-561.
- Dididze M, Green BA, Dietrich WD, Vanni S, Wang MY, Levi AD. Systemic hypothermia in acute cervical spinal cord injury: a case-controlled study. Spinal cord. 2013;51(5):395-400.
- Guest JD, Rao A, Olson L, Bunge MB, Bunge RP. The ability of human Schwann cell grafts to promote regeneration in the transected nude rat spinal cord. Experimental Neurology. 1997;148(2):502-522.
- Takami T, Oudega M, Bates ML, Wood PM, Kleitman N, Bunge MB. Schwann cell but not olfactory ensheathing glia transplants improve hindlimb locomotor performance in the moderately contused adult rat thoracic spinal cord. The Journal of Neuroscience : the official journal of the Society for Neuroscience. 2002;22(15):6670-6681.