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Spinal Cord Injury—What Are the Controversies?

Ahuja, Christopher S. MD*,†,‡; Schroeder, Gregory D. MD§; Vaccaro, Alexander R. MD, PhD, MBA§; Fehlings, Michael G. MD, PhD, FACS, FRCSC*,†,‡,‖,¶,**

Author Information
Journal of Orthopaedic Trauma: September 2017 - Volume 31 - Issue - p S7-S13
doi: 10.1097/BOT.0000000000000943
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Abstract

INTRODUCTION

Traumatic spinal cord injuries (SCI) have a tremendous impact on the quality of life of patients and families. In North America alone, over 1 million people are affected with direct lifetime costs estimated at $1.1–4.6 million USD each.1,2 Incidence follows a bimodal distribution with varying mechanisms of injury in each peak from high-energy impacts (eg, Motor Vehicle Accidents, sport-related injuries) in adolescents and young adults to low-energy injuries (eg, falls from standing in the context of preexisting stenosis) in older individuals.3,4 This article begins by highlighting the heterogeneity of SCI and its importance when interpreting the literature and treating individual patients. We then outline the core principles of managing patients in accordance with the internationally recognized AANS/CNS and AOSpine guidelines. We also discuss the pertinent controversies in the field related to diagnosis, acute management and specific subpopulations (eg, pediatric SCI, central cord syndrome). We conclude with an overview of the salient debates around clinical trial design and the future of SCI research.

HETEROGENEITY OF SCI

Individuals with SCI have highly heterogeneous baseline demographics, injury profiles, clinical presentations, and long-term outcomes. This has generated, and is compounded by, variations in practice patterns between geographic regions, hospitals, and individual surgeons. To appropriately address the management controversies discussed in this article, we will likely need to refine our clinical trials to better stratify patients into subpopulations based on their specific underlying pathophysiology. This will allow us to reduce within-group variability and recognize modest treatment effects more readily. Two types of quantifiable, high-fidelity biomarkers have recently emerged which may find applicability in SCI trials—advanced MRI and biochemical biomarkers.

Despite widespread adoption of MRI in the evaluation of central nervous system pathologies, its use in SCI trials has been limited. This is likely due to the limited prognostic value of measuring gross hemorrhage and cord compression on T1- and T2-weighted images. The next generation of MRI now has the capability of providing quantifiable microstructural data to allow injury and recovery assessments. Key upcoming techniques to remain aware of include diffusion tensor imaging to assess axon integrity, myelin water fraction to assess myelination, functional MRI to assess connectivity, and MR spectroscopy to quantify markers of ischemia and gliosis (Fig. 1).5,6 As imaging protocols are further refined, these metrics will provide additional granularity to complement clinical scores and descriptors of injury level.

F1
FIGURE 1.:
“Representative images. Images showing FA maps (A), MTR maps (B), and T2*WI (C) with probabilistic maps of LCSTs (blue) and dorsal columns (red-yellow) overlaid (D–F) following registration to the SCT atlas. FA, fractional anisotropy; LCST, lateral corticospinal tract; MTR, magnetization transfer ratio; SCT, spinal cord toolbox.” Reprinted with permission from Martin AR et al.56 Clinically Feasible microstructural MRI to quantify cervical spinal cord tissue injury using DTI, MT, and T2*-weighted imaging: Assessment of Normative data and Reliability. AJNR. 2017, in press.

Biochemical and transcriptomic biomarkers will also be important and are currently being explored at several centers. The ongoing “Canadian Multicentre CSF Monitoring and Biomarker Study” (CAMPER; clinicaltrials.gov identifier NCT01279811) is analyzing the cerebrospinal fluid of acutely injured patients for 5 days to assess interleukins, inflammatory cell proteins, and other cytokines.7,8 In collaboration with the Rick Hansen Institute, CAMPER will also be assessing short, noncoding RNAs called micro RNAs (miRNA) which are highly responsive regulators of posttranscriptional gene expression. Depending on the degree and region of SCI, different miRNAs are up- or down-regulated providing additional information about a patient's underlying pathophysiology.9 Furthermore, specific secondary injury events can be linked to changes in select miRNAs such as immune cell infiltration (miR-223, miR-126, miR-142) oxidative stress and cell death (miR-124, miR-96, miR-98, miR-145), and astrogliosis (miR-146, miR-181).9 Together, these biomarkers will allow us to better assess the efficacy of current and upcoming treatment approaches, prognosticate with greater certainty, and tailor combinatorial therapies to the biology of individual patients.

CURRENT MANAGEMENT

Care of a patient with SCI begins with early recognition and appropriate triage by first responders in the field. Securing the airway, breathing, and circulation according to advanced traumatic life support protocols is a priority while remaining cognizant of spinal precautions to protect the potentially vulnerable cord.10 Current American Association of Neurological Surgeons (AANS) and Congress of Neurological Surgeons (CNS) joint guidelines recommend rapid referral to specialized centers after initial stabilization for the delivery of time-sensitive interventions. During this period, and until definitive spinal stabilization, all patients should be immobilized.10 Typically, this involves a transport backboard, rigid cervical collar and logroll/inline manual cervical stabilization for transfers.

Hypotension (SBP <90 mm Hg) should be avoided even for brief periods as this is associated with significantly worse long-term outcomes.10 This can be particularly difficult in the setting of polytrauma where hypovolemia is common, or in injuries above T6 which can interrupt sympathetic tracts to induce profound bradycardic hypotension (neurogenic shock). Treatment is generally with large volumes of crystalloids though adjunctive mixed alpha/beta agonists (eg, dopamine) or alpha agonists (eg, phenylephrine) may be required.

As soon as possible postresuscitation, an American Spinal Injury Association (ASIA) International Standards for Neurological Classification of SCI (ISNCSCI) examination should be completed to establish the level of neurologic injury and extent of baseline function.10 CT is the recommended imaging modality as plain radiographs can fail to detect up to 6% of fractures.11 Thoracolumbar imaging is also recommended in confirmed cases of cervical injury to rule out concomitant occult injuries.12 The utility of MRI in the early evaluation of a patient with SCI is controversial and further discussed below.

Ongoing early care pre- and postoperatively should be delivered in a critical care unit capable of continuous cardiorespiratory and hemodynamic monitoring.10 Stabilization of other injuries should continue as needed while carefully maintaining spinal immobilization. This necessitates clear communication between multidisciplinary teams to adapt practices and procedures accordingly (eg, fiberoptic intubation, modified surgical positioning, logroll transfers, etc).

CONTROVERSIES IN DIAGNOSIS

Radiographic Evaluation

The role of MRI in the initial assessment of patients remains controversial given resource limitations at many centers around the world. MRI can also be challenging in critically ill patients due to transfer requirements and relatively long scan times.13 Urgent MRI is recommended by the authors for patients with unexplained neurological deficits to rule out occult ligamentous disruption or time-sensitive compressive pathologies such as critical disc herniations and epidermal hematomas. MRI is also useful in unconscious or unexaminable patients with spinal trauma. In those with clear osseous and/or ligamentous disruption and matching neurologic findings, the diagnostic and prognostic value of advanced imaging is under debate. A recent study compared AOSpine fracture classifications by an international cohort of 41 spine surgeons. They found X-rays alone to be insufficient in classifying A- and B-type fractures, while CT was sufficient to classify most injuries except B2 injuries where MRI was more sensitive. Overall, the decision to operate was not influenced by the presence or absence of MRI data.14 However, it has also been shown that CT is specific but not adequately sensitive to detect ongoing cord compression. In cases with >25% canal compromise on sagittal CT imaging, MRI found cord compression in 100% of patients, however, in cases with <25% canal compromise on CT many cases of ongoing compression seen on MRI were missed.15

Beyond diagnosis, MRI has demonstrated modest value in predicting neurologic outcomes.16 A recently published prognostication score integrates clinical status with MRI evidence of hemorrhage or edema to reliably predict functional independence at 1 year (Fig. 2).17 A systematic review by Bozzo et al16 using Downs and Black scoring and a Delphi vote made strong recommendations for the use of T2 MRI as a prognostic tool in acute SCI with emphasis on stepwise levels of cord signal with predictive value (normal vs. single-level edema vs. multi-level edema vs. mixed hemorrhage and edema). The generalizability and ecological validity of these tools remains to be established as they see increased adoption.

F2
FIGURE 2.:
“Predictive model equations (AIS, ASIA impairment scale; AMS, ASIA motor score; ASIA, American Spinal Injury Association; FIM, functional independence measure; MRI, magnetic resonance imaging).” Adapted from Ref. 17. Reprinted with permission from Mary Ann Liebert, Inc.

In the coming years, rapidly evolving advanced imagining techniques are likely to see increased integration, particularly as more efficient acquisition and processing protocols are developed. MRI sequences to quantify microstructural changes within the cord will be especially helpful to improve our ability to prognosticate and measure subclinical recovery/deterioration.18 Techniques to remain aware of include diffusion tensor imaging, myelin water transfer, magnetization transfer, MR spectroscopy, and functional MRI.5

CONTROVERSIES IN EARLY MANAGEMENT

Methylprednisolone

Methylprednisolone (MPSS) is a synthetic glucocorticoid with the ability to interfere with proinflammatory cytokine signaling and arachidonic acid metabolites, while also upregulating the expression of antiinflammatory factors. In numerous animal models of SCI, MPSS has been shown to be neuroprotective against inflammatory cell activation/infiltration and oxidative stress resulting in enhanced tissue sparing and neuron survival.19,20 MPSS has also been successfully used in the treatment of acute and chronic systemic inflammatory and autoimmune conditions (eg, systemic lupus erythematosus, multiple sclerosis).21–23 These promising results have resulted in a series of clinical trials over the last 30 years which continue to be a vibrant source of debate. This section summarizes the landmark trials in the field while highlighting the need to interpret results in the context of a highly heterogeneous SCI population.

The 1984 National Acute Spinal Cord Injury Study (NASCIS; N = 330) was a prospective, multicenter, randomized trial of low (100 mg bolus + 25 mg q6h) versus high (1000 mg bolus + 250 mg q6h) dose MPSS for 10 days.24 No differences were found in neurologic outcomes, however, concurrent animal studies found that the dosing was likely inadequate to achieve neuroprotective peak serum levels.24

The 1990 NASCIS II (N = 487) randomized trial attempted to address this by evaluating a higher dose of MPSS (30 mg/kg bolus + 5.4 mg·kg−1·h−1 × 23 hours) versus placebo. While there was no significant difference in long-term outcomes between the groups overall, the authors' had hypothesized a priori that injury-to-treatment time was critically important, and thus, stratified the comparisons by time (≤8 hours or >8 hours). Whether this decision was truly a priori using the median time-to-treatment as a cutoff or a post hoc analysis has been a point of contention. Furthermore, multiple t test comparisons were not statistically corrected which increased the risk of type I statistical errors. Nonetheless, at 6 months follow-up, patients receiving MPSS within 8 hours of injury demonstrated significantly enhanced recovery of ASIA motor (16.0 vs. 11.2; P = 0.03) and sensory (8.9 vs. 4.3; P = 0.03) scores versus placebo. Complication rates between the groups were comparable with a statistically nonsignificant trend towards increased gastrointestinal bleed (4.5% vs. 3.0%) and wound infection (7.1% vs. 3.6%) with MPSS administration. No difference in all-cause mortality was found.25 Numerous randomized trials attempted to reproduce the results of NASCIS II but were unable to confirm or refute the findings due to methodological concerns which further sparked debate.26 In parallel, animal studies began demonstrating the time course of the secondary injury cascade suggesting longer immunosuppression regimens may yield even greater benefits.

As a result, the 1997 NASCIS III (N = 499) randomized trial compared 24 versus 48 hours of MPSS (30 mg/kg bolus + 5.4 mg·kg−1·h−1). The study provided further evidence that early treatment is important by demonstrating enhanced long-term neurological outcomes for patients receiving 48 hours of MPSS within 3–8 hours of injury versus those receiving the 24-hour dose. Unfortunately, the 48-hour dose resulted in higher rates of severe sepsis and pneumonia which outweighed any potential benefit. While the NASCIS II and III complication rates are frequently cited by both proponents of MPSS and those opposed to the treatment, it is critically important to distinguish between the 24 and 48 hours dosing regimens as the 24 hours treatment has not been associated with significant increases in adverse events. A 2012 Cochrane Review metaanalysis pooled data from numerous randomized clinical trials and found that 24 hours of MPSS administered within 8 hours of injury resulted in a 4-point ASIA motor score improvement at 6 months with no increase in all-cause mortality rates.27

While the 2002 AANS/CNS guideline listed MPSS as an option in the treatment of acute SCI, the 2013 update reversed this position and recommended against the use of MPSS despite no new RCT data.10 An upcoming 2017 AOSpine guideline developed by an interdisciplinary and international committee of experts will recommend 24 hours of MPSS be considered as a treatment option within 8 hours of injury for patients with acute, nonpenetrating SCI and no significant medical contraindications. The AOSpine guideline will also differentiate between the 2 NASCIS III regimens by recommending against the use of 48 hours of MPSS; potentially reconciling the discrepancy between the 2002 and 2013 AANS/CNS publications.28

Blood Pressure Augmentation

Edema, elevated cord pressure, and vessel injuries all contribute to ongoing ischemia in the perilesional region for days postinjury.29 Enhancing perfusion to this spinal cord “penumbra” by elevating the systemic mean arterial pressure (MAP) has emerged as an important neuroprotective strategy.

Several retrospective and prospective reports form the basis for a set of Class III evidence in favor of MAP elevation for SCI. Vale et al (1997) published a prospective report on 77 acute SCI patients who received aggressive interventions to maintain MAP >85 mm Hg for 7 days. Minimal morbidity was found with the intervention, and neurologic recovery at 1 year was reportedly enhanced compared with expected outcomes for this cohort. Wolf et al (1991) and Levi et al (1993) found similar results using MAP targets of 85 and 90 mm Hg, respectively. Unfortunately, no prospective, randomized, controlled trial data exists to definitively assess the efficacy of MAP augmentation and the risks associated with invasive blood pressure monitoring, central venous access, large volume crystalloids and vasopressor therapies.30 Furthermore, maintaining targets in this patient population can be challenging from a practical perspective. A recent prospective, observational study from a Canadian Level-1 trauma center found that even in a specialized center, continuously achieving MAP targets was not possible with all 21 of their patients recording at least 1 MAP below 80 mm Hg and 81% recording a MAP below 70 mm Hg.

The 2013 AANS/CNS guidelines provide Level III recommendations for the maintenance of MAP between 85 and 90 mm Hg for 7 days postinjury, however, as outlined above, the quality of evidence behind these recommendations and the risk of the intervention continues to be debated.10 Currently, a noninferiority trial is underway entitled “Mean Arterial Blood Pressure Treatment for Acute Spinal Cord Injury” (MAPS; ClinicalTrials.gov Idenitfier #NCT02232165) to compare MAP ≥85 mm Hg with a less aggressive MAP ≥65 mm Hg target. Results are expected by 2018.31

Surgical Decompression

Ongoing mechanical compression by bone, blood, or disc fragments can impair perfusion causing localized ischemia leading to progressive neuronal loss in the perilesional region. Surgical decompression partially relieves this pressure to enhance blood flow and reduce compression of cells thereby sparing the spinal cord “penumbra.” Decompression in the early acute period has been shown in numerous animal models to help limit secondary injury and substantially improve behavioral recovery.32 Despite this, initial clinical studies failed to find support for early decompressive surgery. Wagner and Chehrazi33 published an observational study finding no difference in 1-year outcomes for 44 patients with cervical SCI decompressed either within 8 hours or between 9 and 48 hours after injury. A prospective study by Marshal et al34 reported deterioration in patients with cervical injuries operated on within the first 5 days, and advocated for late surgery in these patients. Moreover, several authors have also described improvements in neurologic function with nonoperative treatment in retrospective and prospective case series involving hundreds of patients.35 These early studies led to clinical equipoise regarding the most appropriate time point for decompression in the 1990s and 2000s. Despite this, a 2010 international survey of 971 orthopedic and neurological surgeons found that the majority prefer decompression within 24 hours of injury.36

To provide a higher-quality assessment of efficacy and the surgical therapeutic window, the Surgical Timing in Acute Spinal Cord Injury (STASCIS; N = 313) study was published in 2012 comparing early (<24 hours) versus late (>24 hours) surgery for cervical injuries. Those undergoing early surgery had a 2.8 times greater chance (95% CI, 1.1–7.3) of having a ≥2 AIS grade improvement in neurologic outcome at 6 months follow-up.37 Additionally, there was a nonsignificant trend towards decreased in-hospital cardiopulmonary and urinary complications. Another Canadian prospective cohort study (N = 84) found that early decompression was associated with greater ASIA motor scores at the time of discharge from rehabilitation. The majority of patients in this study had cervical injuries.38 Finally, a recent observational cohort study showed that early decompression was associated with shorter hospital lengths of stay for patients with AIS grades A and B injuries, and 6.3 additional points of motor recovery for patients with AIS B, C, and D injuries.39 Together, these results provide support for the important concept of “Time is Spine” for cervical-level injuries, which is analogous to other CNS insults such as stroke and traumatic brain injury where early interventions can dramatically impact long-term functional outcomes. In the thoracic spine, further evidence is required to determine the influence of timing on long-term outcomes.

Additional studies are also required to assess the role of durotomy and duraplasty as part of surgical decompression. A rodent model of SCI induced after laminectomy found early decompressive durotomy and duroplasty to be associated with decreased cystic cavitation, reduced scar formation, and enhanced behavioral recovery.40 Support for this approach has also been published in a small historical case series41 and in an MRI study (N = 65) of thoracic SCI where 26% of patients were found to have ongoing cord compression due to dural, as opposed to extradural, causes.42 More recently, an open-label prospective study of ASIA A-C thoracic SCI (N = 21) found expansile duroplasty to be associated with improved vascular pressure reactivity and increased spinal cord perfusion pressure versus laminectomy alone. Unfortunately, the study was underpowered to detect neurological recovery.43 A larger (N = 100) “Injured Spinal Cord Pressure Evaluation” (ISCOPE; clinicaltrials.gov NCT02721615) study is now underway to assess the effect of laminectomy, duroplasty, and/or hypothermia on acute intraspinal pressure and spinal cord metabolites, with results expected by 2019.31

Intraoperative Electrophysiologic Monitoring

Intraoperative neuroelectrophysiologic monitoring (IONM) attempts to decrease the risk of reinjuring the cord during patient positioning and surgical decompression. IONM provides real-time neurologic data in anesthetized patients via somatosensory evoked potentials and motor-evoked potentials most commonly. Ideally, any IONM must be able to identify impending or ongoing injury early enough to allow an adjustment to be made. The feedback must also be highly specific to limit false positives and improve the positive predictive value.44

At present, the equipment, specialized personnel (surgical neurophysiologists), and unique anesthetic techniques required to monitor outputs for the length of a case are an impediment to widespread adoption. Few studies exist for assessing outcomes related to IONM in SCI, with most data being drawn from elective spine procedures.45 A 2010 systematic review by Fehlings et al reviewing 32 articles determined that IONM is sensitive and specific for detecting intraoperative injury. A low level of evidence existed to support IONM to reduce the occurrence of these injuries, thus it was recommended that IONM be considered as an option in procedures where the cord or roots are at risk (eg, instrumentation, deformity correction, etc).46 A 2012 cost-effectiveness study using a Monte Carlo simulation by Ney et al47 found that multimodal IONM is associated with a 49% relative risk reduction (P < 0.001) in postoperative neurologic complications at a cost of US$ 63,387 per deficit averted—well under most societies' willingness-to-pay thresholds. The routine use of IONM for cases of SCI continues to be debated with local resources likely playing a significant role.

Central Cord Syndrome

Central cord syndrome (CCS) is the most common presentation of incomplete SCI typically occurring in patients with preexisting stenosis and without spinal instability at presentation. It is characterized by greater upper extremity than lower extremity weakness and a variable pattern of sensory loss. Most patients experience significant spontaneous recovery within days to weeks, making surgical decompression in these cases particularly controversial. Historically, early surgical decompression was avoided to allow patients to declare their trajectory, and because of reports of poor surgical outcomes by intervening on an already susceptible cord.48

Guest et al (2002) retrospectively reviewed 50 patients undergoing early (<24 hours) versus late (>24 hours) surgical decompression for central cord syndrome. They found that early surgery was safe and more cost effective for patients with fractures or acute disc herniations. They also found that it was safe for those with stenosis or spondylosis but did not result in improved motor outcomes compared with late surgery.49 Koyanagi et al50 (2003) retrospectively described 28 patients with ossification of the posterior longitudinal ligament, and found that the early surgery group (<72 hours) had 83% of patients showing significant improvement versus 58% in the delayed surgery group. Chen et al51 later published a single-center study (N = 49) finding no difference in ASIA motor scores at 6 months with early decompression (<4 days) versus late decompression (>4 days). A recent systematic review pooling data from multiple studies concluded that it is safe and reasonable to consider early surgical decompression in patients with ASIA C injuries and ongoing cord compression due to congenital central canal stenosis and not due to instability or fracture. They found that patients undergoing early surgery (<24 hours) had a 6.3 point greater motor score improvement at 1 year (P = 0.036) and a 3.4 times higher chance of improving by at least 1 ASIA grade than patients undergoing late decompression (>24 hours). The authors also suggested that patients with less severe ASIA D injuries can be treated initially with conservative management leaving surgical decompression as an option if absolute recovery or the rate of recovery is insufficient.52

CONTROVERSIES IN TRIAL DESIGN

Translation of Preclinical Results

Most treatment algorithms and neuroprotective interventions for SCI today are derived from sound preclinical research, however, not all promising therapeutics in the lab are brought to clinical practice. Challenges emerge at all junctures along the translational pipeline including head-to-head efficacy comparisons of preclinical therapies, translational readiness (eg, safety/toxicity testing, pharmacokinetic studies in higher-order animals, etc), regulatory barriers, and funding for large-scale trials. For this reason, Tator et al53 reviewed strategies to enhance translation of promising neuroprotective interventions. They proposed a framework to develop and validate translational readiness scoring systems which could help identify therapies with the highest likelihood of success to narrow thousands of potential agents down to the strongest few. Kwon et al54 established such a scoring system based on the species of animal used, injury paradigm, therapeutic window, types of outcomes, and independent replication of results. This unique approach serves a dual purpose of both a guide for researchers looking to advance their therapy and an objective filter to improve the yield of translation.

Minimal Clinically Important Difference

Numerous therapies have undergone testing in large-scale clinical trials but continue to have their utility debated (eg, MPSS, surgical decompression, etc). This may stem from the modest benefits in long-term neurologic outcomes seen with these treatments. While preclinical research continues to make tremendous advances, we unfortunately do not yet have a definitive treatment for SCI. This makes it critical for the field to establish a minimal clinically important difference (MCID) representing the threshold level of additional recovery required to designate a treatment as beneficial.55 As an example, the relatively modest 4-point ASIA motor score improvement seen with 24-hour MPSS treatment is small in absolute terms but may have a tremendous impact on patients' quality of life if that recovery occurs in key functional myotomes (eg, grip, biceps, and/or deltoid function allowing basic self-care). In these situations, a clearly defined MCID can be the critical difference between translation to clinical trial and translation to patients.

Targeted Trials

A common debate in trial design continues to be the balance of targeted participant populations with generalizability. Homogenous subpopulations decrease the variability within groups allowing treatment effects to be brought out more readily without excessively large sample sizes, however, the generalizability of the therapy drops as subpopulations are further refined. Most landmark trials, thus far, have studied broad SCI populations which are highly heterogenous in their presentation, demographics, and intrinsic recovery potential. The next generation of trials, such as the Riluzole in Spinal Cord Injury Study (RISCIS; N = 351; NCT01597518), are studying specific subpopulations of patients (eg, C4-8 AIS A, B or C injuries) which will, hopefully, reduce the need for highly debated post hoc subgroup analyses and provide better estimates of effect size.

CONCLUSIONS

While a number of longstanding controversies exist in the field, the breadth of collaborative research being undertaken by the international community of surgeons, physicians, scientists, and allied professionals continues to be inspiring. Each iteration of insightful debates moves us closer to providing patients with a definitive treatment for SCI.

ACKNOWLEDGMENTS

The authors thank AOSpine for sponsoring this work, and Madeleine O'Higgins for the copyediting.

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Keywords:

spinal cord injury; trauma; MRI; central cord syndrome; electrophysiology; biomarkers; treatment

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