A minimum data set-Core outcome set, core data elements, and core measurement set-For degenerative cervical myelopathy research (AO Spine RECODE DCM): A consensus study.

BACKGROUND: Degenerative cervical myelopathy (DCM) is a progressive chronic spinal cord injury estimated to affect 1 in 50 adults. Without standardised guidance, clinical research studies have selected outcomes at their discretion, often underrepresenting the disease and limiting comparability between studies. Utilising a standard minimum data set formed via multi-stakeholder consensus can address these issues. This combines processes to define a core outcome set (COS)-a list of key outcomes-and core data elements (CDEs), a list of key sampling characteristics required to interpret the outcomes. Further "how" these outcomes should be measured and/or reported is then defined in a core measurement set (CMS). This can include a recommendation of a standardised time point at which outcome data should be reported. This study defines a COS, CDE, and CMS for DCM research. METHODS AND FINDINGS: A minimum data set was developed using a series of modified Delphi processes. Phase 1 involved the setup of an international DCM stakeholder group. Phase 2 involved the development of a longlist of outcomes, data elements, and formation into domains. Phase 3 prioritised the outcomes and CDEs using a two-stage Delphi process. Phase 4 determined the final DCM minimal data set using a consensus meeting. Using the COS, Phase 5 finalised definitions of the measurement construct for each outcome. In Phase 6, a systematic review of the literature was performed, to scope and define the psychometric properties of measurement tools. Phase 7 used a modified Delphi process to inform the short-listing of candidate measurement tools. The final measurement set was then formed through a consensus meeting (Phase 8). To support implementation, the data set was then integrated into template clinical research forms (CRFs) for use in future clinical trials (Phase 9). In total, 28 outcomes and 6 domains (Pain, Neurological Function, Life Impact, Radiology, Economic Impact, and Adverse Events) were entered into the final COS. Thirty two outcomes and 4 domains (Individual, Disease, Investigation, and Intervention) were entered into the final CDE. Finally, 4 outcome instruments (mJOA, NDI, SF-36v2, and SAVES2) were identified for the CMS, with a recommendation for trials evaluating outcomes after surgery, to include baseline measurement and at 6 months from surgery. CONCLUSIONS: The AO Spine RECODE-DCM has produced a minimum data set for use in DCM clinical trials today. These are available at https://myelopathy.org/minimum-dataset/. While it is anticipated the CDE and COS have strong and durable relevance, it is acknowledged that new measurement tools, alongside an increasing transition to study patients not undergoing surgery, may necessitate updates and adaptation, particularly with respect to the CMS.

An Update of a Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Role and Timing of Decompressive Surgery.

STUDY DESIGN: Clinical practice guideline development. OBJECTIVES: Acute spinal cord injury (SCI) can result in devastating motor, sensory, and autonomic impairment; loss of independence; and reduced quality of life. Preclinical evidence suggests that early decompression of the spinal cord may help to limit secondary injury, reduce damage to the neural tissue, and improve functional outcomes. Emerging evidence indicates that "early" surgical decompression completed within 24 hours of injury also improves neurological recovery in patients with acute SCI. The objective of this clinical practice guideline (CPG) is to update the 2017 recommendations on the timing of surgical decompression and to evaluate the evidence with respect to ultra-early surgery (in particular, but not limited to, <12 hours after acute SCI). METHODS: A multidisciplinary, international, guideline development group (GDG) was formed that consisted of spine surgeons, neurologists, critical care specialists, emergency medicine doctors, physical medicine and rehabilitation professionals, as well as individuals living with SCI. A systematic review was conducted based on accepted methodological standards to evaluate the impact of early (within 24 hours of acute SCI) or ultra-early (in particular, but not limited to, within 12 hours of acute SCI) surgery on neurological recovery, functional outcomes, administrative outcomes, safety, and cost-effectiveness. The GRADE approach was used to rate the overall strength of evidence across studies for each primary outcome. Using the "evidence-to-recommendation" framework, recommendations were then developed that considered the balance of benefits and harms, financial impact, patient values, acceptability, and feasibility. The guideline was internally appraised using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. RESULTS: The GDG recommended that early surgery (≤24 hours after injury) be offered as the preferred option for adult patients with acute SCI regardless of level. This recommendation was based on moderate evidence suggesting that patients were 2 times more likely to recover by ≥ 2 ASIA Impairment Score (AIS) grades at 6 months (RR: 2.76, 95% CI 1.60 to 4.98) and 12 months (RR: 1.95, 95% CI 1.26 to 3.18) if they were decompressed within 24 hours compared to after 24 hours. Furthermore, patients undergoing early surgery improved by an additional 4.50 (95% 1.70 to 7.29) points on the ASIA Motor Score compared to patients undergoing surgery after 24 hours post-injury. The GDG also agreed that a recommendation for ultra-early surgery could not be made on the basis of the current evidence because of the small sample sizes, variable definitions of what constituted ultra-early in the literature, and the inconsistency of the evidence. CONCLUSIONS: It is recommended that patients with an acute SCI, regardless of level, undergo surgery within 24 hours after injury when medically feasible. Future research is required to determine the differential effectiveness of early surgery in different subpopulations and the impact of ultra-early surgery on neurological recovery. Moreover, further work is required to define what constitutes effective spinal cord decompression and to individualize care. It is also recognized that a concerted international effort will be required to translate these recommendations into policy.

Cervical spinal cord angiography and vessel-selective perfusion imaging in the rat.

Arterial spin labeling (ASL) has been widely used to evaluate arterial blood and perfusion dynamics, particularly in the brain, but its application to the spinal cord has been limited. The purpose of this study was to optimize vessel-selective pseudocontinuous arterial spin labeling (pCASL) for angiographic and perfusion imaging of the rat cervical spinal cord. A pCASL preparation module was combined with a train of gradient echoes for dynamic angiography. The effects of the echo train flip angle, label duration, and a Cartesian or radial readout were compared to examine their effects on visualizing the segmental arteries and anterior spinal artery (ASA) that supply the spinal cord. Lastly, vessel-selective encoding with either vessel-encoded pCASL (VE-pCASL) or super-selective pCASL (SS-pCASL) were compared. Vascular territory maps were obtained with VE-pCASL perfusion imaging of the spinal cord, and the interanimal variability was evaluated. The results demonstrated that longer label durations (200 ms) resulted in greater signal-to-noise ratio in the vertebral arteries, improved the conspicuity of the ASA, and produced better quality maps of blood arrival times. Cartesian and radial readouts demonstrated similar image quality. Both VE-pCASL and SS-pCASL adequately labeled the right or left vertebral arteries, which revealed the interanimal variability in the segmental artery with variations in their location, number, and laterality. VE-pCASL also demonstrated unique interanimal variations in spinal cord perfusion with a right-sided dominance across the six animals. Vessel-selective pCASL successfully achieved visualization of the arterial inflow dynamics and corresponding perfusion territories of the spinal cord. These methodological developments provide unique insights into the interanimal variations in the arterial anatomy and dynamics of spinal cord perfusion.

Mortality in ASIA Impairment Scale grade A to D Patients With Odontoid Fracture and Magnetic Resonance Imaging Evidence of Spinal Cord Injury.

Odontoid fractures are common, often presenting in the elderly after a fall and infrequently associated with traumatic spinal cord injury (tSCI). The goal of this study was to analyze predictors of mortality and neurological outcome when odontoid fractures were associated with signal change on magnetic resonance imaging (MRI) at admission. Over an 18-year period (2001-2019), 33 patients with odontoid fractures and documented tSCI on MRI were identified. Mean age was 65.3 years (standard deviation [SD] = 17.2), and 21 patients were male. The mechanism of injury was falls in 25 patients, motor vehicle accidents in 5, and other causes in 3. Mean Injury Severity Score (ISS) was 40.5 (SD = 30.2), Glasgow Coma Scale (GCS) score was 13 (SD = 3.4), and American Spinal Injury Association (ASIA) motor score (AMS) was 51.6 (SD = 42.7). ASIA Impairment Scale (AIS) grade was A, B, C, and D in 9, 2, 3, and 19 patients, respectively. Mean intramedullary lesion length was 32.3 mm (SD = 18.6). The odontoid peg was displaced ventral or dorsal in 15 patients. Twenty patients had surgical intervention: anterior odontoid screw fixation in 7 and posterior spinal fusion in 13. Eleven (33.3%) patients died in this series: withdrawal of medical care in 5; anoxic brain injury in 4; and failure of critical care management in 2. Univariate logistic regression indicated that GCS score (p < 0.014), AMS (p < 0.002), AIS grade (p < 0.002), and ISS (p < 0.009) were risk factors for mortality. Multi-variate regression analysis indicated that only AMS (p < 0.002) had a significant relationship with mortality when odontoid fracture was associated with tSCI (odds ratio, 0.963; 95% confidence interval, 0.941-0.986).

Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial.

Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

Variability in Early Surgery for Acute Cervical Spinal Cord Injury Patients: An Opportunity for Enhanced Care Delivery.

Data supporting the benefits of early surgical intervention in acute spinal cord injury (SCI) is growing. For early surgery to be accomplished, understanding the causes of variabilities that effect the timing of surgery is needed to achieve this goal. The purpose of this analysis is to determine factors that affect the timing of surgery for acute cervical SCI within the North American Clinical Trials Network (NACTN) for SCI registry. Patients in the NACTN SCI registry from 2005 to 2019 with a cervical SCI, excluding acute traumatic central cord syndrome, were analyzed for time elapsed from injury to arrival to the hospital, and time to surgery. Two categories were defined: 1) Early Arrival with Early Surgery (EAES) commenced within 24 h of injury, and 2) Early Arrival but Delayed Surgery (EADS), with surgery occurring between 24 to 72 h post-injury. Patients' demographic features, initial clinical evaluation, medical comorbidities, neurological status, surgical intervention, complications, and outcome data were correlated with respect to the two arrival groups. Of the 222 acute cervical SCI patients undergoing surgery, 163 (73.4%) were EAES, and 59 (26.6%) were EADS. There was no statistical difference in arrival time between the EAES and EADS groups. There was a statistical difference in the median arrival time to surgery between the EAES group (9 h) compared with the EADS group (31 h; p < 0.05). There was no statistical difference in race, sex, age, mechanism of injury, Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores, or medical comorbidities between the two groups, but the EAES group did present with a significantly lower systolic blood pressure (p < 0.05). EADS patients were more likely to present as an American Spinal Injury Association Impairment Scale (AIS) D than EAES (p < 0.05). Early surgery was statistically more likely to occur if the injury occurred over the weekend (p < 0.05). There were variations in the rates of early surgery between the eight NACTN sites within the study, ranging from 57 to 100%. Of the 114 patients with 6-month outcome data, there was no significant change between the two groups regarding AIS grade change and motor/pin prick/light touch score recovery. A trend towards improved motor scores with early surgery was not statistically significant (p = 0.21). Although there is data that surgery within 24 h of injury improves outcomes and can be performed safely, there remain variations in care outside of clinical trials. In the present study of cervical SCI, NACTN achieved its goal of early surgery in 73.4% of patients from 2005-2019 who arrived within 24 h of their injury. Variability in achieving this goal was related to severity of neurological injury, the day of the week, and the treating NACTN center. Evaluating variations within our network improves understanding of potential systemic limitations and our decision-making process to accomplish the goal of early surgery.

Lived experience-centred word clouds may improve research uncertainty gathering in priority setting partnerships.

INTRODUCTION: AO Spine RECODE-DCM was a multi-stakeholder priority setting partnership (PSP) to define the top ten research priorities for degenerative cervical myelopathy (DCM). Priorities were generated and iteratively refined using a series of surveys administered to surgeons, other healthcare professionals (oHCP) and people with DCM (PwDCM). The aim of this work was to utilise word clouds to enable the perspectives of people with the condition to be heard earlier in the PSP process than is traditionally the case. The objective was to evaluate the added value of word clouds in the process of defining research uncertainties in National Institute for Health Research (NIHR) James Lind Alliance (JLA) Priority Setting Partnerships. METHODS: Patient-generated word clouds were created for the four survey subsections of the AO Spine RECODE-DCM PSP: diagnosis, treatment, long-term management and other issues. These were then evaluated as a nested methodological study. Word-clouds were created and iteratively refined by an online support group of people with DCM, before being curated by the RECODE-DCM management committee and expert healthcare professional representatives. The final word clouds were embedded within the surveys administered at random to 50% of participants. DCM research uncertainties suggested by participants were compared pre- and post-word cloud presentation. RESULTS: A total of 215 (50.9%) participants were randomised to the word cloud stream, including 118 (55%) spinal surgeons, 52 (24%) PwDCM and 45 (21%) oHCP. Participants submitted 434 additional uncertainties after word cloud review: word count was lower and more uniform across each survey subsections compared to pre-word cloud uncertainties. Twenty-three (32%) of the final 74 PSP summary questions did not have a post-word cloud contribution and no summary question was formed exclusively on post-word cloud uncertainties. There were differences in mapping of pre- and post-word cloud uncertainties to summary questions, with greater mapping of post-word cloud uncertainties to the number 1 research question priority: raising awareness. Five of the final summary questions were more likely to map to the research uncertainties suggested by participants after having reviewed the word clouds. CONCLUSIONS: Word clouds may increase the perspective of underrepresented stakeholders in the research question gathering stage of priority setting partnerships. This may help steer the process towards research questions that are of highest priority for people with the condition.

Interhospital Transfer Delays Care for Spinal Cord Injury Patients: A Report from the North American Clinical Trials Network for Spinal Cord Injury.

Abstract The North America Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of tertiary medical centers that has maintained a prospective SCI registry since 2004, and it has espoused that early surgical intervention is associated with improved outcome. It has previously been shown that initial presentation to a lower acuity center and necessity of transfer to a higher acuity center reduce rates of early surgery. The NACTN database was evaluated to examine the association between interhospital transfer (IHT), early surgery, and outcome, taking into account distance traveled and site of origin for the patient. Data from a 15-year period of the NACTN SCI Registry were analyzed (years 2005-2019). Patients were stratified into transfers directly from the scene to a Level 1 trauma center (NACTN site) versus IHT from a Level 2 or 3 trauma facility. The main outcome was surgery within 24 hours of injury (yes/no), whereas secondary outcomes were length of stay, death, discharge disposition, and 6-month American Spinal Injury Association Impairment Scale (AIS) grade conversion. For the IHT patients, distance traveled for transfer was calculated by measuring the shortest distance between origin and NACTN hospital. Analysis was performed with Brown-Mood test and chi-square tests. Of 724 patients with transfer data, 295 (40%) underwent IHT and 429 (60%) were admitted directly from the scene of injury. Patients who underwent IHT were more likely to have a less severe SCI (AIS D; p = 0.002), have a central cord injury (p = 0.004), and have a fall as their mechanism of injury (p < 0.0001) than those directly admitted to an NACTN center. Of the 634 patients who had surgery, direct admission to an NACTN site was more likely to result in surgery within 24 hours compared with IHT patients (52% vs. 38%) (p < 0.0003). Median IHT distance was 28 miles (interquartile range [IQR] = 13-62 miles). There was no significant difference in death, length of stay, discharge to a rehab facility versus home, or 6-month AIS grade conversion rates between the two groups. Patients who underwent IHT to an NACTN site were less likely to have surgery within 24 hours of injury, compared with those directly admitted to the Level 1 trauma facility. Although there was no difference in mortality rates, length of stay, or 6-month AIS conversion between groups, patients with IHT were more likely be older with a less severe level of injury (AIS D). This study suggests there are barriers to timely recognition of SCI in the field, appropriate admission to a higher level of care after recognition, and challenges related to the management of individuals with less severe SCI.

Bulbocavernosus Reflex Has No Prognostic Features During the Acute Evaluation of Spinal Cord Injuries.

The bulbocavernosus reflex (BCR) has been used during the initial evaluation of a spinal cord injury patient as a metric to determine prognosis and whether the patient is in "spinal shock." This reflex has been less utilized over the last decade, and therefore a review was performed to assess the value of BCR in patient prognosis. The North American Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of tertiary medical centers that includes a prospective SCI registry. The NACTN registry data was analyzed to evaluate the prognostic implication of the BCR during the initial evaluation of a spinal cord injury patient. SCI patients were divided into those with an intact or absent BCR during their initial evaluation. Associations of participants' descriptors and neurological status on follow-up were performed, followed by associations with the presence of a BCR. A total of 769 registry patients with recorded BCRs were included in the study. The median age was 49 years (32-61 years), and the majority were male (n = 566, 77%) and white (n = 519, 73%). Among included patients, high blood pressure was the most common comorbidity (n = 230, 31%). Cervical spinal cord injury was the most common (n = 470, 76%) with fall (n = 320, 43%) being the most frequent mechanism of injury. BCR was present in 311 patients (40.4%), while 458 (59.6%) had a negative BCR within 7 days of injury or before surgery. At 6 months post-injury, 230 patients (29.9%) followed up, of which 145 had a positive BCR, while 85 had a negative BCR. The presence/absence of BCR was significantly different in patients with cervical (p = 0.0015) or thoracic SCI (p = 0.0089), or conus medullaris syndrome (p = 0.0035), and in those who were American Spinal Injury Association Impairment Scale grade A (p = 0.0313). No significant relationship was observed between BCR results and demographics, AIS grade conversion, motor score changes (p = 0.1669), and changes in pin prick (p = 0.3795) and light touch scores (p = 0.8178). In addition, cohorts were not different in surgery decision (p = 0.7762) and injury to surgery time (p = 0.0681). In our review of the NACTN spinal cord registry, the BCR did not provide prognostic utility in the acute evaluation of spinal cord injury patients. Therefore, it should not be used as a reliable marker for predicting neurological outcomes post-injury.

Comparison and optimization of pCASL and VSASL for rat thoracolumbar spinal cord MRI at 9.4 T.

PURPOSE: To evaluate pseudo-continuous arterial spin labeling (pCASL) and velocity-selective arterial spin labeling (VSASL) for quantification of spinal cord blood flow (SCBF) in the rat thoracolumbar spinal cord. METHODS: Labeling efficiency (LE) was compared between pCASL and three VSASL variants in simulations and both phantom and in vivo experiments at 9.4 T. For pCASL, the effects of label plane position and shimming were systematically evaluated. For VSASL, the effects of composite pulses and phase cycling were evaluated to reduce artifacts. Additionally, vessel suppression, respiratory, and cardiac gating were evaluated to reduce motion artifacts. pCASL and VSASL maps of spinal cord blood flow were acquired with the optimized protocols. RESULTS: LE of the descending aorta was larger in pCASL compared to VSASL variants. In pCASL, LE off-isocenter was improved by local shimming positioned at the label plane and the anatomical level of labeling for the thoracic cord was only viable at the level of the T10 vertebra. Cardiac gating was essential to reduce motion artifacts. Both pCASL and VSASL successfully demonstrated comparable SCBF values in the thoracolumbar cord. CONCLUSION: pCASL demonstrated high and consistent LE in the thoracic aorta, and VSASL was also feasible, but with reduced efficiency. A combination of cardiac gating and recording of actual post-label delays was important for accurate SCBF quantification. These results highlight the challenges and solutions to achieve sufficient ASL labeling and contrast at high field in organs prone to motion.

Trends in the Use of Corticosteroids in the Management of Acute Spinal Cord Injury in North American Clinical Trials Network Sites.

Immunomodulatory therapeutics represent a potential neuroprotective strategy for the management of acute spinal cord injury (SCI). One of the most intensely debated neuroprotective drugs has been methylprednisolone sodium succinate (MPSS), which was investigated initially for its role in mitigating lipid peroxidation. More recently, the anti-inflammatory/immunomodulatory properties of MPSS have been increasingly appreciated. Over the past two decades, several systematic reviews and clinical practice guidelines related to MPSS use in SCI have been published. The goal of this study was to investigate the temporal changes in the use of steroids at North American Clinical Trials Network (NACTN) centers and to correlate these changes with the evolution in published literature and guidelines. Data on patients enrolled from 2008-2018 in the prospective, multi-center NACTN registry, and in whom information related to the use of steroids was available, were analyzed. Patients were stratified based on whether they received steroids or not. The primary outcome was the change in the rate of steroid use per year between 2008 and 2018. Secondary outcomes included cardiac, gastrointestinal and genitourinary (GIGU), pulmonary, and dermatological complications. We identified 608 patients, of whom 171 (28.1%) were given steroids. In 2008 and 2009, the prevailing paradigm across NACTN centers was in favor of steroid administration and as such 70% (n = 56) of patients received steroids in 2008 and 71.9% (n = 46) in 2009. An abrupt practice reversal was observed in 2010, whereby only 19.7% of patients (n = 14) received steroids, a trend that continued over subsequent years. Increasing literature in the 2000s arguing against the use of steroids culminated in the 2013 CNS/AANS practice guidelines for the management of acute SCI. These guidelines recommended against the use of MPSS for the treatment of those with acute SCI. Over the following years (2013-2018), steroids continued to be an uncommonly used therapeutic option in NACTN centers (range 3.9-16.9%). Patients receiving steroids had significantly higher rates of pulmonary complications (87%, n = 147) compared with those not receiving steroids (73%, n = 265; p = 0.0003). Compared with patients receiving steroids, however, those who did not receive steroids had significantly higher rates of cardiac (40%, [n = 146] versus 23%, [n = 39]; p = 0.0001) and gastrointestinal/genitourinary complications (55%, [n = 189], versus 31%, [n = 52]; p < 0.0001). The 2013 AANS/CNS guidelines and preceding literature appeared to have an impact on dramatically lowering the rates of corticosteroid use for acute SCI in NACTN sites after 2009. Of note, this analysis may not reflect the impact of the 2017 AO Spine Clinical Practice guidelines, which suggested the use of methylprednisolone as a valid practice option for acute SCI, especially for cervical injuries. Enhanced patient involvement in the clinical decision-making process and opportunities to personalize SCI management exist in reference to the use of MPSS in acute SCI.

Evolving Profile of Acute Spinal Cord Injury Demographics, Outcomes, and Surgical Treatment in North America: Analysis of a Prospective Multi-Center Dataset of 989 Patients.

Changes in demography and injury patterns have altered the profile and outcome of acute spinal cord injury (SCI) over time. This study sought to describe recent trends in epidemiology and early clinical outcomes using the multi-center North American Clinical Trial Network (NACTN) for Spinal Cord Injury Registry. All participants with blunt acute traumatic SCI (n = 782) were grouped into three five-year time intervals from 2005 to 2019 (2005-2009, 2010-2014, and 2015-2019). Baseline demographics, clinical scores, medical co-morbidities, as well as early clinical outcomes were extracted. Categorical and continuous variables were analyzed to determine between-group differences. Subgroup analysis was performed for participants <50 and ≥50 years of age. Over the duration of the study period, there was an increase in age at presentation (p = 0.0077) as well as a greater incidence of falls as the mechanism of injury. Participants who were ≥50 years of age were more likely to sustain incomplete SCI (<0.0003) and central cord syndrome (< 0.0001). In the most recent period (2015-2019), a greater proportion of NACTN participants underwent surgery within 24 h of injury (63% vs. 41% vs. 41%, p = 0.0001). There was a statistically significant increase in cardiac complications (p < 0.0001) and decrease in pulmonary complications (p < 0.0001) during the study period. Data from the NACTN registry shows that the age of participants with acute SCI is increasing, falls have become the major mechanism of injury, and central cord injury is becoming increasingly prevalent. While early surgical intervention for acute SCI is more common in recent years, cardiac complications are more prevalent while pulmonary complications are less prevalent.

Differential Trajectory of Diffusion and Perfusion Magnetic Resonance Imaging of Rat Spinal Cord Injury.

Traumatic spinal cord injury causes rapid neuronal and vascular injury, and predictive biomarkers are needed to facilitate acute patient management. This study examined the progression of magnetic resonance imaging (MRI) biomarkers after spinal cord injury and their ability to predict long-term neurological outcomes in a rodent model, with an emphasis on diffusion-weighted imaging (DWI) markers of axonal injury and perfusion-weighted imaging of spinal cord blood flow (SCBF). Adult Sprague-Dawley rats received a cervical contusion injury of varying severity (injured = 30, sham = 9). MRI at 4 h, 48-h, and 12-weeks post-injury included T1, T2, perfusion, and DWI. Locomotor outcome was assessed up to 12 weeks post-injury. At 4 h, the deficit in SCBF was larger than the DWI lesion, and although SCBF partially recovered by 48 h, the DWI lesion expanded. At 4 h, the volume of the SCBF deficit (R2 = 0.56, padj < 0.01) was significantly correlated with 12-week locomotor outcome, whereas DWI (R2 = 0.30, padj < 0.01) was less predictive of outcome. At 48 h, SCBF (R2 = 0.41, padj < 0.01) became less associated with outcome, and DWI (R2 = 0.38, padj < 0.01) lesion volume became more closely related to outcome. Spinal cord perfusion has unique spatiotemporal dynamics compared with diffusion measures of axonal damage and highlights the importance of acute perfusion abnormalities. Perfusion and diffusion offer complementary and clinically relevant insight into physiological and structural abnormalities following spinal cord injury beyond those afforded by T1 or T2 contrasts.

We Choose to Call it 'Degenerative Cervical Myelopathy': Findings of AO Spine RECODE-DCM, an International and Multi-Stakeholder Partnership to Agree a Standard Unifying Term and Definition for a Disease.

STUDY DESIGN: Modified DELPHI Consensus Process. OBJECTIVE: To agree a single unifying term and definition. Globally, cervical myelopathy caused by degenerative changes to the spine is known by over 11 different names. This inconsistency contributes to many clinical and research challenges, including a lack of awareness. METHOD: AO Spine RECODE-DCM (Research objectives and Common Data Elements Degenerative Cervical Myelopathy). To determine the index term, a longlist of candidate terms and their rationale, was created using a literature review and interviews. This was shared with the community, to select their preferred terms (248 members (58%) including 149 (60%) surgeons, 45 (18%) other healthcare professionals and 54 (22%) People with DCM or their supporters) and finalized using a consensus meeting. To determine a definition, a medical definition framework was created using inductive thematic analysis of selected International Classification of Disease definitions. Separately, stakeholders submitted their suggested definition which also underwent inductive thematic analysis (317 members (76%), 190 (59%) surgeons, 62 (20%) other healthcare professionals and 72 (23%) persons living with DCM or their supporters). Using this definition framework, a working definition was created based on submitted content, and finalized using consensus meetings. RESULTS: Degenerative Cervical Myelopathy was selected as the unifying term, defined in short, as a progressive spinal cord injury caused by narrowing of the cervical spinal canal. CONCLUSION: A consistent term and definition can support education and research initiatives. This was selected using a structured and iterative methodology, which may serve as an exemplar for others in the future.

Acute Magnetic Resonance Imaging Predictors of Chronic Motor Function and Tissue Sparing in Rat Cervical Spinal Cord Injury.

Predicting functional outcomes from spinal cord injury (SCI) at the acute setting is important for patient management. This work investigated the relationship of early magnetic resonance imaging (MRI) biomarkers in a rat model of cervical contusion SCI with long-term functional outcome and tissue sparing. Forty rats with contusion injury at C5 at either the spinal cord midline (bilateral) or over the lateral cord (unilateral) were examined using in vivo multi-modal quantitative MRI at 1 day post-injury. The extent of T2-weighted hyperintensity reflecting edema was greater in the bilateral model compared with the unilateral injury. Diffusion tensor imaging (DTI) exhibited microscopic damage in similar regions of the cord as reductions in fractional anisotropy (FA) and mean diffusivity (MD), but DTI parameter maps were also confounded by the presence of vasogenic edema that locally increased FA and MD. In comparison, filtered diffusion-weighted imaging (fDWI) more clearly delineated the location of acute axonal damage without effects of vasogenic edema. Pairwise correlation analysis revealed that 28-day motor functional outcomes were most strongly associated with the extent of edema (R = -0.69). Principal component analysis identified close associations of motor functional score with tissue sparing, the extent of edema, lesion area, and injury type (unilateral or bilateral). Among the diffusion MRI parameters, lesion areas measured with fDWI had the strongest association with functional outcome (R = -0.41). Voxelwise correlation analysis identified a locus of white matter damage associated with function in the dorsal white matter, although this was likely driven by variance across the two injury patterns (unilateral and bilateral injury). Nonetheless, correlation with motor function within the damaged region found in the voxelwise analysis outperformed morphological lesion area measurement as a predictor of chronic function. Collectively, this study characterized anatomical and diffusion MRI signatures of acute SCI at cervical spine and their association with chronic functional outcomes and histological results.

Developing Novel Therapies for Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 7]: Opportunities From Restorative Neurobiology.

STUDY DESIGN: Narrative review. OBJECTIVES: To provide an overview of contemporary therapies for the James Lind Alliance priority setting partnership for degenerative cervical myelopathy (DCM) question: 'Can novel therapies, including stem-cell, gene, pharmacological and neuroprotective therapies, be identified to improve the health and wellbeing of people living with DCM and slow down disease progression?' METHODS: A review of the literature was conducted to outline the pathophysiology of DCM and present contemporary therapies that may hold therapeutic value in 3 broad categories of neuroprotection, neuroregeneration, and neuromodulation. RESULTS: Chronic spinal cord compression leads to ischaemia, neuroinflammation, demyelination, and neuronal loss. Surgical intervention may halt progression and improve symptoms, though the majority do not make a full recovery leading to lifelong disability. Neuroprotective agents disrupt deleterious secondary injury pathways, and one agent, Riluzole, has undergone Phase-III investigation in DCM. Although it did not show efficacy on the primary outcome modified Japanese Orthopaedic Association scale, it showed promising results in pain reduction. Regenerative approaches are in the early stage, with one agent, Ibudilast, currently in a phase-III investigation. Neuromodulation approaches aim to therapeutically alter the state of spinal cord excitation by electrical stimulation with a variety of approaches. Case studies using electrical neuromuscular and spinal cord stimulation have shown positive therapeutic utility. CONCLUSION: There is limited research into interventions in the 3 broad areas of neuroprotection, neuroregeneration, and neuromodulation for DCM. Contemporary and novel therapies for DCM are now a top 10 priority, and whilst research in these areas is limited in DCM, it is hoped that this review will encourage research into this priority.

Degenerative Cervical Myelopathy: Development and Natural History [AO Spine RECODE-DCM Research Priority Number 2].

STUDY DESIGN: Narrative review. OBJECTIVES: To discuss the current understanding of the natural history of degenerative cervical myelopathy (DCM). METHODS: Literature review summarizing current evidence pertaining to the natural history and risk factors of DCM. RESULTS: DCM is a common condition in which progressive arthritic disease of the cervical spine leads to spinal cord compression resulting in a constellation of neurological symptoms, in particular upper extremity dysfunction and gait impairment. Anatomical factors including cord-canal mismatch, congenitally fused vertebrae and genetic factors may increase individuals' risk for DCM development. Non-myelopathic spinal cord compression (NMSCC) is a common phenomenon with a prevalence of 24.2% in the healthy population, and 35.3% among individuals >60 years of age. Clinical radiculopathy and/or electrophysiological signs of cervical cord dysfunction appear to be risk factors for myelopathy development. Radiological progression of incidental Ossification of the Posterior Longitudinal Ligament (OPLL) is estimated at 18.3% over 81-months and development of myelopathy ranges between 0-61.5% (follow-up ranging from 40 to 124 months between studies) among studies. In patients with symptomatic DCM undergoing non-operative treatment, 20-62% will experience neurological deterioration within 3-6 years. CONCLUSION: Current estimates surrounding the natural history of DCM, particularly those individuals with mild or minimal impairment, lack precision. Clear predictors of clinical deterioration for those treated with non-operative care are yet to be identified. Future studies are needed on this topic to help improve treatment counseling and clinical prognostication.

A New Framework for Investigating the Biological Basis of Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 5]: Mechanical Stress, Vulnerability and Time.

STUDY DESIGN: Literature Review (Narrative). OBJECTIVE: To propose a new framework, to support the investigation and understanding of the pathobiology of DCM, AO Spine RECODE-DCM research priority number 5. METHODS: Degenerative cervical myelopathy is a common and disabling spinal cord disorder. In this perspective, we review key knowledge gaps between the clinical phenotype and our biological models. We then propose a reappraisal of the key driving forces behind DCM and an individual's susceptibility, including the proposal of a new framework. RESULTS: Present pathobiological and mechanistic knowledge does not adequately explain the disease phenotype; why only a subset of patients with visualized cord compression show clinical myelopathy, and the amount of cord compression only weakly correlates with disability. We propose that DCM is better represented as a function of several interacting mechanical forces, such as shear, tension and compression, alongside an individual's vulnerability to spinal cord injury, influenced by factors such as age, genetics, their cardiovascular, gastrointestinal and nervous system status, and time. CONCLUSION: Understanding the disease pathobiology is a fundamental research priority. We believe a framework of mechanical stress, vulnerability, and time may better represent the disease as a whole. Whilst this remains theoretical, we hope that at the very least it will inspire new avenues of research that better encapsulate the full spectrum of disease.

Establishing the Socio-Economic Impact of Degenerative Cervical Myelopathy Is Fundamental to Improving Outcomes [AO Spine RECODE-DCM Research Priority Number 8].

STUDY DESIGN: Literature Review (Narrative). OBJECTIVE: To contextualize AO Spine RECODE-DCM research priority number 5: What is the socio-economic impact of DCM? (The financial impact of living with DCM to the individual, their supporters, and society as a whole). METHODS: In this review, we introduce the methodology of health-economic investigation, including potential techniques and approaches. We summarize the current health-economic evidence within DCM, so far focused on surgical treatment. We also cover the first national estimate, in partnership with Myelopathy.org from the United Kingdom, of the cost of DCM to society. We then demonstrate the significance of this question to advancing care and outcomes in the field. RESULTS: DCM is a common and often disabling condition, with a significant lack of recognition. While evidence demonstrates the cost-effectives of surgery, even among higher income countries, health inequalities exist. Further the prevalent residual disability in myelopathy, despite treatment affects both the individual and society as a whole. A report from the United Kingdom provides the first cost-estimate to their society; an annual cost of ∼£681.6 million per year, but this is likely a significant underestimate. CONCLUSION: A clear quantification of the impact of DCM is needed to raise the profile of a common and disabling condition. Current evidence suggests this is likely to be globally substantial.

James Lind Alliance Priority Setting Partnership for Degenerative Cervical Myelopathy [AO Spine RECODE-DCM]: An Overview of the Methodology Used to Process and Short-List Research Uncertainties.

STUDY DESIGN: Overview of the methods used for a James Lind Alliance (JLA) Priority Setting Partnership (PSP). OBJECTIVES: The objectives of this article are to (i) provide a brief overview of the JLA-facilitated PSP process; (ii) outline how research uncertainties were initially processed in the AO Spine RECODE-DCM PSP; and (iii) delineate the methods for interim prioritization and the priority setting workshop. METHODS: A steering group was created to define the scope for the PSP, organize its activities, and establish protocols for decision-making. A survey was created asking what questions on the diagnosis, treatment, and long-term management of DCM should be answered by future research. Results from the survey were sorted into summary questions. Several databases were searched to identify literature that already answered these summary questions. The final list of summary questions was distributed by survey for interim prioritization. Participants were asked to select the top ten most important summary questions. The questions that were ranked the highest were discussed at an in-person consensus workshop. RESULTS: The initial survey yielded a total of 3404 potential research questions. Of the in-scope submissions, 988 were related to diagnosis, 1324 to treatment, and 615 to long-term management of DCM. A total of 76 summary questions were developed to reflect the original submissions. Following a second survey, a list of the top 26 interim priorities was generated and discussed at the in-person priority setting workshop. CONCLUSIONS: PSPs enable research priorities to be identified that consider the perspectives and interests of all relevant stakeholders.