Current insights into the management of spinal cord injury

Abstract

Background

Traumatic spinal cord injury (SCI) is a serious disorder that results in severe impairment of neurological function as well as disability, ultimately reducing a patient's quality of life. The pathophysiology of SCI involves a primary and secondary phase, which causes neurological injury.

Methods

Narrative review on current clinical management of spinal cord injury and emerging therapies.

Results

This review explores the management of SCI through early decompressive surgery, optimizing mean arterial pressure, steroid therapy and focused rehabilitation. These management strategies reduce secondary injury mechanisms to prevent the propagation of further neurological damage. The literature regarding emerging research is also explored in cell-based, gene, pharmacological and neuromodulation therapies, which aim to repair the spinal cord following the primary injury mechanism.

Conclusions

Outcomes for patients with SCI can be enhanced and improved if primary and secondary phases of SCI can be addressed.

1. Introduction

Traumatic spinal cord injury (SCI) can cause sensorimotor and autonomic impairment, severely affecting a patient's independence and quality of life.¹,² Complications can occur including respiratory issues, autoimmune dysfunction, autonomic dysreflexia and neuropathic pain. SCIs most commonly occur at the cervical level and are associated with a drastic reduction in the patient's ability to perform activities of daily living such as grooming, feeding and transferring.³ A small improvement in essential muscle groups like those associated with grip and elbow flexion can have a noticeable impact on an individual's quality of life.

The prevalence of SCI lies between 250 and 906 cases per million, with a life expectancy of several decades. The overall cost of care is between 1.2 and 5.1 million US dollars over the lifespan of a patient. This does not include lost wages and productivity.^4,5 Traumatic SCI occurs more commonly in males, with this population accounting for 79.8% of all cases. The majority of SCIs occur at the cervical level (60%), followed by thoracic (32%) and lumbosacral (9%) levels.⁶ A bimodal age distribution exists with the first peak at 15–29yrs and the second⁷ occurring after the age of 50. Younger individuals are more commonly affected by motor accidents and injuries related to sports, while older patients (>60 years) with degenerative conditions are prone to low-energy injury mechanisms such as falls.^7,8

While advancements in subspeciality surgical and medical management have caused a reduction in mortality, the long-term functional recovery is still not optimal.² Neuroprotective strategies are employed in traumatic SCI to prevent secondary injury mechanisms.⁹ Although many regenerative therapies are being investigated, an effective therapy is currently not accessible in the clinic.

This review aims to provide a current overview of clinical management for SCI as well as emerging pharmacological, cell-based, and gene therapy research aimed at improving outcomes post-injury.

2. Pathophysiology and current clinical management

There is a primary and secondary phase to SCI pathophysiology. The primary phase has an initial insult, which permeabilizes neurons and glia.² Then there is a secondary phase, which causes worsening cell death and injury to the spinal cord over the following weeks. During a delayed period there is remodeling of the lesion, which is made up of a glial scar and cystic cavitations, with both components potentially inhibiting regeneration.²

Acute management of SCI is crucial for potential recovery of neurological function. Methods for treating SCI involve the use of pharmacological and non-pharmacological therapies. This includes the option to use the potent anti-inflammatory medication methylprednisolone, decompressive and reconstructive spine surgery to stabilize and optimize the milieu of neurological recovery, blood pressure augmentation, and reducing secondary complications, including cardio-respiratory and other systemic issues, during the recovery phase post-injury. After the acute phase of management, targeted intensive rehabilitation is recommended to maximize functional independence and to facilitate safe discharge into the community when possible.¹⁰

2.1. Decompressive surgery

The Surgical Timing in Acute Spinal Cord Injury Study (STASCIS) was a multi-center non-randomised, prospective cohort study¹¹ which enrolled 313 patients to analyse early surgery for acute SCI. More patients who received surgery within 24hrs had a two or more AIS grade (19.8%) improvement compared to patients who received surgery after 24hrs (8.8%). Once steroid administration and pre-operative neurological status was adjusted, there was a 2.8 greater chance of 2 or more AIS grade improvement for those patients who underwent surgery within 24hrs as opposed to after 24hrs.

Early surgical decompression is important to restore spinal cord blood flow and perfusion as well as reducing secondary injury, which has been recognised to improve recovery after SCI. This is highlighted in the concept of “Time is Spine”.³ This study analyzed four prospective multicentre data sources with a total number of 1,548 participants and concluded that early decompression by operating within 24hrs of the injury results in an improvement in sensorimotor recovery.¹² Additionally, another study examined decompressive surgery in the early period (within 24hrs) compared to late (after 24hrs) for central cord syndrome amongst 186 patients, with the ASIA motor score as the primary endpoint. Early surgery improved the recovery of motor function in the upper limb at 1 year in these patients, with the greatest recovery for AIS grade C injuries with a 9.5 mean difference in both upper and lower limb motor function.¹³

Stabilisation without formal decompression is an option if the injury occurred from a reducible mechanism. For example, a unilateral facet dislocation of Chance type ligamentous injury can be managed with reduction and stabilisation. A previous study explored 31 cases of thoracolumbar burst fractures managed with posterior stabilisation without decompression and found that patients with incomplete paraplegia had already shown partial neurological recovery before surgery and had ultimately improved by at least one Frankel grade.¹⁴

A systematic review and meta-analysis on neurological recovery after traumatic SCI showed that the AIS/Frankel conversion rate of at least 1 grade was observed in 19.3% of grade A patients, 73.8% of grade B patients, 87.3% of grade C patients, and 46.5% of grade D patients. Thus, recovery was observed, as best to worst, in the following sequence: C > B > D > A. Additionally, recovery rates dependent on spine location were observed to be, from best to worst, as: lumbar > cervical and thoracolumbar > thoracic.¹⁵

Occasionally there can be difficulty in obtaining an accurate neurological assessment in the early stage of SCI. This can be due to other distracting injuries, reduced conscious level, or spinal shock. Having international training in ISNCSCI standards would facilitate consistency when performing the initial neurological examination and improve data analysis when an assessment is done.¹⁶

2.2. MAPs and spinal cord perfusion

Increasing the systemic mean arterial pressure (MAP) is a neuroprotective measure for SCI as it increases the blood flow in the penumbra of the spinal cord. The AANS/CNS recommend a MAP of >85 mmHg for 7 days in order to prevent hypotension and stop secondary complications.¹⁷

In 2017, a prospective cohort study of 92 patients¹⁸ examined outcomes following insertion of lumbar intrathecal pressure catheters within 48hrs post-injury and maintained for one week. A MAP target of 80–85 mmHg was implemented for five days and MAP as well as spinal cord perfusion pressure (SCPP) were associated with significant neurological improvement with at least one AIS grade at 6 months follow up. Further analysis showed that SCPP drops below 50 mmHg were a significant inverse predictor of conversion status (OR 0.9, 95% CI 0.81 to 0.98, p < 0.05), whilst the frequency of MAP drops below 70 mmHg were not. Data from a series of 105 patients¹⁹ over the first 72hrs post-admission was used to determine the lowest and average hourly MAP to calculate the mean of the MAP and the number of hypotensive events. An increased frequency of hypotensive events correlates with the need for vasopressors but is not related to motor scores at discharge.

2.3. Assessing the adequacy of decompression

Werndle et al.²⁰ made the initial suggestion for expansile duroplasty in relation to monitoring spinal cord perfusion following decompression for spinal cord damage. The local reserve capacity is decreased because there is less CSF present at the lesion site around the spinal cord. Further spinal cord swelling causes the damaged spinal cord to compress against the dura, which impairs autoregulation and causes a localized, abrupt rise in intraspinal pressure (ISP). An elevated SCPP (hyperperfusion) and reduced SCPP (hypoperfusion) are linked to impaired autoregulation, which may cause spinal cord damage similar to intracranial dynamics. Therefore, it was suggested that following bony decompression, a duroplasty is to be performed through an incision in the posterior dura longitudinally in the midline. This improved ISP and SCPP, but also decompressed the damaged spinal cord further compared to laminectomy alone, as demonstrated in postoperative MRI.²¹ A randomized trial is currently investigating the outcomes associated with expansion duraplasty as a novel treatment.²²

MRI was used to assess the rate of spinal cord compression after surgery. One hundred and eighty-four patients with ASIA A and B injuries were analyzed and multivariate logistic regression showed that a laminectomy procedure increased the chances of a successful decompression as opposed to doing an ACDF alone.²³ A subsequent study by the same group examining 72 AIS grade A, B and C cervical traumatic SCI patients at 6 months after injury confirmed that the pre-operative intramedullary lesion length, and not the timing of surgery, determined the long-term neurological outcome.²⁴ A retrospective study²⁵ reviewed 51 patients comparing completeness of decompression between intraoperative ultrasound and postoperative MRI. On post-operative imaging, severe clinical injury and large intramedullary lesion length were significant predictors of insufficient decompression. The study suggested that intraoperative ultrasound is a useful adjunct to postoperative MRI to assess spinal cord decompression.

2.4. Methylprednisolone

Methylprednisolone sodium succinate (MPSS) is an anti-inflammatory corticosteroid and antioxidant. Blood flow of the spinal cord is improved by MPPS through reducing calcium influx and inhibiting lipid peroxidation.²⁶

In the NASCIS II study, patients who were administered MPSS within 8hrs of injury improved by 4.8 points in motor score in comparison to the placebo group (p = 0.03). All treatment groups had a similar mortality and morbidity, but there was an observation of more wound infections with MPSS (7.1%) as compared to placebo (3.6%).²⁷ In NASCIS III, for patients where treatment was initiated at 3–8hrs after injury, the group which received 48hrs of MPSS had a further 6 points of motor improvement in comparison to the 24hr MPSS category. The recommendation was that patients who were started on MPSS within the first 3hrs of injury should be kept on MPSS for 24hr, whereas those who were started on MPSS 3-8hrs after injury were recommended to receive 48hrs of treatment, which allows for improved motor recovery despite the potential risk of infectious complications.²⁸ Clinical practice guidelines published in 2017 stated that a 24hr high dose MPSS infusion can be administered to SCI patients as a potential treatment option within 8 hrs, as this results in modest motor score improvements.¹⁷

2.5. Hypothermia

Systemic hypothermia is a neuroprotective strategy that will lower the basal metabolic rate and reduce the demand for oxygen in an injured spinal cord with comprised perfusion. Dididze and colleague²⁹ analyzed moderate intravascular hypothermia (33 °C) for 48hrs in acute cervical SCI patients. All patients had presented with complete SCI injury on admission, of which 4 had an improvement to ASIA B within 24hrs, and 43% (n = 15) had an improvement of one ASIA grade at a 10 month follow up. Localized hypothermia of the injured cord, pioneered by Albin et al.,³⁰ has recently been re-explored as a strategy to prevent secondary damage after SCI. Gallagher et al.³¹ presented their results of localized hypothermia using an epidural cooling catheter in 5 patients. After 3 of the 5 patients experienced delayed wound infections the study was terminated early. Only one patient of the 4 presenting with an ASIA A injury converted to ASIA B.

Both systemic and local hypothermia have some associated complications. Patients receiving systemic hypothermia may be more susceptible to coagulopathy because of their lower body temperatures and the presence of an intravenous catheter³²,³³, as demonstrated by Simosa et al.³⁴ in their study of 10 patients undergoing systemic hypothermia for traumatic brain injury, of which 5 patients developed deep vein thrombosis.

2.6. Rehabilitation

Rehabilitation for SCI patients requires a multidisciplinary approach. It is expensive and time consuming, but can enhance recovery for patients with SCI.³⁵ Mechanisms include an increase in regeneration and sprouting of axons, increased activity of neurotrophins (e.g. BDNF) and neuroplastic changes of the spared networks.³⁶)³⁷ The 2017³⁸ guidelines pertaining to the management of patients with acute SCI presented the following recommendations for the timing and type of rehabilitation: (1) Recommendation that rehabilitation should be available for medically stable patients with acute SCI who can endure the intensity of rehabilitation, (2) Proposal for body weight supported treadmill training as an alternative to conventional overground walking for ambulation training, and (3) functional electrical stimulation should be offered as a treatment option to improve upper extremity function and hand for people with cervical SCI in the acute period.

A workshop with key stakeholders identified focus areas in the current management and emerging approaches to bladder and bowel management in SCI.³⁹ These included education and clinical care standards on current therapeutic approaches, understanding bowel physiology and its relationship to urinary function, sensory awareness of the need to void or system dysfunction, neuromodulation to control GI and urinary function, and how rehabilitation activity and exercise have a positive effect on bowel and bladder function.³⁹ A randomized controlled trial compared interferential electrical stimulation with sham stimulation for 332 SCI participants with neurogenic bladder dysfunction.⁴⁰ The authors concluded that interferential medium frequency current electrostimulation was beneficial for people with AIS levels B and C but not for level A, significantly decreasing the post-void residual volume and quantity of urine lost.⁴⁰

2.7. MRI to guide acute management

As a prognostic tool in acute spinal cord damage, MRI is advised. The T2 sequence has been shown to have significant value. Studies have shown four patterns that can predict neurological prognosis including normal, single level edema, multilevel edema, and mixed hemorrhage with edema.⁴¹ In addition, evidence shows that a longer bleeding extent on an MRI during the acute phase of SCI is indicative of a less successful recovery in neurological function.⁴¹ Furthermore, studies have shown that a longer SCI lesion length on MRI may be associated with lower manual dexterity and dysesthetic discomfort. Finally, swelling of the spinal cord on MRI has been shown to portend a poorer neurologic recovery. Based on these low quality evidence, the AO Spine Guidelines Development Group (GDG) issued a weak recommendation, suggesting “MRI should be performed in adult patients in the acute period following SCI, before or after surgical intervention, to improve prediction of neurologic and functional outcome”.⁴¹

2.8. Biomarkers

Enhanced ability to accurately prognosticate for patients has been attempted in SCI research for a number of years and imaging, serum and CSF biomarkers have been identified as potential modalities to predict neurological outcomes and the severity of neural injury.

A biomarker of white matter injury is the signal intensity of white to gray matter on T2* weighted imaging that correlates with focal motor and sensory deficits.⁴² A cohort of 50 patients recruited to the prospective, multi-center CAMPER (ClinicalTrials.gov NCT01279811) study had levels of CSF biomarkers such as GFAP, tau, IL-6, S100b at 24hrs that had a significant difference between patients⁴³ who had AIS A, B, and C. ASIA improvement in the motor score correlates with all these CSF markers, especially for cervical SCI patients. As compared to MRI biomarkers, CSF biomarkers can predict neurological recovery better and are more likely to identify different injury predictors.⁴⁴ Circulating microRNAs could be used as serum biomarkers for SCIs. A microRNA called MIR21-5p has been shown to regulate neuroinflammation in non-traumatic SCI. Upregulation of MIR-21-5p in studies of degenerative cervical myelopathy involving humans and rodents correlates with the severity of symptoms and decreased treatment outcomes, which can be used as an outcome prediction tool.⁴⁵

Another target for personalized biomarkers has been apolipoprotein E (Apo-E), which is important in the process of CNS repair and regeneration, with a deficiency of this function being associated with a protein coded by the Apoe4 allele.⁴⁶

Patients with cervical spinal cord compression and poor neurologic improvement following decompression of the spinal cord have both been found to be associated with the ApoE4 gene, which was determined through DNA analysis.⁴⁷

3. Emerging research

3.1. Pharmacological therapies

Riluzole is a neuroprotective drug that inhibits activation of glutamate receptors by blocking sodium channels.⁴⁸ It reduces neuronal degeneration in amyotrophic lateral sclerosis and the neuroprotective qualities have been shown in preclinical models of SCI. This is achieved by decreasing glutamatergic excitotoxicity, which is an important part of the secondary injury cascade.¹¹ A multicenter, randomized, controlled trial (RCT) showed that treatment with riluzole for 6 weeks during the perioperative period did not result in improvement of functional recovery achieved above just decompressive surgery alone for patients who had moderate to severe degenerative cervical myelopahty.⁴⁹ Ketorolac is a widely used analgesic and NSAID. It causes a reduction in the neuronal death at the area of ischemic insult causing improvement of hindlimb motor function when compared to the control group.⁵⁰ Minocycline is a second-generation tetracylcine antibiotic. It has been shown to have neuronal protective features by a phase II double-blind RCT that showed an association of improvement in motor scores after patients with acute traumatic SCI received IV minocyline.⁵¹

Repulsive guidance molecule A (RGMa) inhibits axonal growth and regulates neuronal cell death. It is upregulated after neuronal injury and builds up in chronic neurodegenerative diseases.⁵² RGMa antagonists promote neuroregeneration and neuroprotection. Elezanumab, an anti-RGMa antibody, binds N-terminal RGMa, blocks BMP signaling, promotes regeneration of axons and prevents degeneration of the retinal nerve fibre layer in models of optic nerve crush and neuritis. In addition, it also improves functional recovery and promotes axonal regeneration in a rat SCI model and reduces demyelination.⁵²

3.2. Cell-based therapies

Cellular transplantation in SCI as a regenerative therapy has garnered significant interest over the past few decades. This is because many different factors of the pathophysiology for injury are targeted; cell transplantation can give trophic support, control the inflammatory response, re-develop damaged neural circuits, and remyelinate denuded axons.²The most popular cell types analyzed include neural stem cells (NSCs), mesenchymal stem cells (MSCs), oligodendrocyte progenitor cells (OPCs),³ olfactory ensheathing cells (OECs) and schwann cells (SCs).

Neural stem cells have a tripotent self-renewing ability and in animal SCI models were able to provide trophic support to encourage tissue sparing, myelination of denuded axons and improve functional recovery.⁵³ A meta-analysis in 2016 found NSCs to cause significant recovery of neurological function in SCI models (pooled SMD = 1.45; 95% confidence interval [CI]: 1.23–1.67; P < 0.001).⁵⁴ StemCells Inc. transplanted CNS human stem cells through intramedullary injection in a phase II trial of thoracic AIS grade A-C SCI patients and cervical AIS grade B or C. No safety concerns were reported in this study⁵⁵ and at one year follow up, motor gains for the treatment group were seen.

Mesenchymal stem cells are self-renewing multipotent connective tissue progenitor cells found throughout the body. They are able to regenerate bone (osteoblasts), fat (adipocytes), muscles (myocytes) and cartilage (chondrocytes).⁵⁶

Oligodendrocyte progenitor cells are tripotent and can differentiate into myelinating oligodendrocytes that remyelinate axons. Animal studies show these cells can increase the number of surviving oligodendrocytes, reduce cavity volume, and preserve white matter resulting in improvement of motor recovery.⁵⁷ The SCiStar trial, with intramedullary injection of OPCs in AIS grade A and B patients who have an injury level in the subaxial cervical spine, showed 95% (21/22) of patients had a minimum recovery of one motor level on one side, while 32% (7/22) of patients recovered two or more motor levels on one side.⁵⁸

Olfactory ensheathing cells are within the nasal mucosa and in the olfactory bulb. Here, the non-myelinated olfactory neuron axons are protected.⁵⁹ OECs form a medium that injured axons can develop across the site of spinal cord transection.⁶⁰ OECs can be transplanted into the cord from the olfactory bulb or from the nasal mucosa. A meta-analysis (n = 1193) of key clinical trials did not establish efficacy but showed no elevation in serious adverse events.⁶¹

Schwann cells are situated in the peripheral nervous system and are myelinating cells that provide a structural scaffold to guide growing axons, myelinate regenerating axons and express growth promoting factors.⁶² In animal SCI models, remyelination, reduction of cystic cavity formation and enhanced axonal regeneration led to improved functional outcomes.⁶³

A systematic literature review of clinical trials describes the feasibility and safety of stem cell administration to the damaged spinal cord through multiple international studies.⁶⁴ However, efficacy has not been proven yet. The ideal cell type and transplantation strategy to obtain lesion bridging and remodeling, reduce immune rejection and to produce stable circuits is still being studied.⁶⁴

3.3. Biomaterials and scaffolds

A range of biomaterial scaffolds were analyzed for localised and sustained drug delivery.⁶⁵ They provide the site of injury with an environment and scaffold for regeneration of endogenous networks,⁶⁶ as well as encouraging exogenous stem cells into an area to promote cell survival, growth, and plasticity.⁶⁷ In the INSPIRE study, implantation of the Neuro-Spinal Scaffold through open surgery was tested in 19 patients within 96hrs of injury. There were no long-term neurological issues at 24 months and favourable AIS conversions were seen at 12 months and beyond.⁶⁸ QL6 is a biodegradable peptide that develops into nanofiber scaffolds, which reduce inflammation, apoptosis and astrogliosis when injected into the cavity of the spinal cord, resulting in behavioral and electrophysiological improvements. Furthermore, when QL6 was transplanted with NPCs, it improved survival of the graft and encouraged oligodendroglial and neuronal cell differentiation. ⁶⁹,⁷⁰

3.4. Gene therapy

The delivery of genetic material to change faulty transcription within a cell or introduction of novel or downregulated genes is the concept of gene therapy.⁷¹ Two methods to apply gene therapy in SCI would be for in vivo delivery of the gene to the spinal cord or ex vivo cell transduction in preparation for transplantation into the spinal cord. Preclinical investigations show that in vivo gene therapy in SCI (1) increase pro-regenerative factors expression, (2) leads to neural circuit modulation, (3) blocks detrimental proteins expression, and (4) introduces enzymes that cause degradation of inhibitory particles⁷² Functional recovery after SCI and improvement of regeneration has been shown in pre-clinical studies by the use of bacterial enzyme chondroitinase ABC (ChABC) for breaking down the glial scar.⁷³ A form of delivery for ChABC is gene therapy, as it would preclude the requirement for repeated invasive infusions.

3.5. Neuromodulation

Lumbosacral spinal cord stimulation (SCS) implantation in people that have chronic SCI has improved ambulation and stepping when coupled with intense rehabilitation⁷⁴,⁷⁵. After one year of intense training, continuous epidural SCS enhances overground walking⁷⁴,⁷⁵ but further technical refinement has allowed locomotion after one week.⁷⁶ Larger studies are required to confirm this cohort.

There has been an increase in the use of brain-computer interfaces (BCIs) for the control of upper extremity function, which involves grasping and reaching, over the last 20 years.⁷⁷ Moving this technology into a community setting of patients closer to home is important for patients to benefit. Most of these interfaces are based on one of two technical infrastructures: functional electrical stimulation (FES) or soft-robotics (SR). In a traditional FES therapy, patients are taught to actively use their muscles to carry out a specific action while the FES system stimulates the muscles with surface-level or implanted electrodes. This method postulates that intentional movements arise concurrently with brain activity (caused by the deliberate attempt) and peripheral stimuli. The FES increases practice-induced brain and spinal plasticity by producing more afferent information.78, 79, 80

SR devices increase comfort and flexibility while adjusting to the curves of the human body by using soft actuators (often back-drivable) and flexible connections. In order to promote treatment compliance and to address assistance demands in ADLs, SR devices for hand function are designed to be portable and lightweight to facilitate use at home for rehabilitation. ⁸¹,⁸²

4. Conclusion

There is proven worth in early decompressive surgery for SCI, optimizing MAP, steroid therapy, and focused rehabilitation in SCI management. However, the current clinical management of acute spinal cord injury is still predominantly focused on limiting secondary injury mechanisms and preventing propagation of further neurological damage. Emerging research in cell-based, gene and pharmacological therapies aims to address repair of the primary injury mechanism. Translation of these therapies and implementation in the acute presentation of SCI will be key to permanently improving patient outcomes.

Source(s) of support

No funding was received for this work.

Funding/sponsorship

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Informed consent

Not applicable.

Institutional Ethical Committee Approval: Not applicable.

Authors contribution

Nisaharan Srikandarajah: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Roles/Writing – original draft; Writing – review & editing., Mohammed Ali Alvi: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Roles/Writing – original draft; Writing – review & editing., Michael G. Fehlings: Conceptualization; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Writing – review & editing.

Declaration of competing interest

None.