Early surgical intervention for acute spinal cord injury: time is spine.

Acute traumatic spinal cord injury (tSCI) is a devastating occurrence that significantly contributes to global morbidity and mortality. Surgical decompression with stabilization is the most effective way to minimize the damaging sequelae that follow acute tSCI. In recent years, strong evidence has emerged that supports the rationale that early surgical intervention, within 24 h following the initial injury, is associated with a better prognosis and functional outcomes. In this review, we have summarized the evidence and elaborated on the nuances of this concept. Additionally, we have reviewed further concepts that stem from "time is spine," including earlier cutoffs less than 24 h and the challenging entity of central cord syndrome, as well as the emerging concept of adequate surgical decompression. Lastly, we identify barriers to early surgical care for acute tSCI, a key aspect of spine care that needs to be globally addressed via research and policy on an urgent basis.

Degenerative cervical myelopathy: Where have we been? Where are we now? Where are we going?

Degenerative cervical myelopathy (DCM), a recently coined term, encompasses a group of age-related and genetically associated pathologies that affect the cervical spine, including cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament (OPLL). Given the significant contribution of DCM to global disease and disability, there are worldwide efforts to promote research and innovation in this area. An AO Spine effort termed 'RECODE-DCM' was initiated to create an international multistakeholder consensus group, involving patients, caregivers, physicians and researchers, to focus on launching actionable discourse on DCM. In order to improve the management, treatment and results for DCM, the RECODE-DCM consensus group recently identified ten priority areas for translational research. The current article summarizes recent advancements in the field of DCM. We first discuss the comprehensive definition recently refined by the RECODE-DCM group, including steps taken to arrive at this definition and the supporting rationale. We then provide an overview of the recent advancements in our understanding of the pathophysiology of DCM and modalities to clinically assess and diagnose DCM. A focus will be set on advanced imaging techniques that may offer the opportunity to improve characterization and diagnosis of DCM. A summary of treatment modalities, including surgical and nonoperative options, is then provided along with future neuroprotective and neuroregenerative strategies. This review concludes with final remarks pertaining to the genetics involved in DCM and the opportunity to leverage this knowledge toward a personalized medicine approach.

Degenerative Cervical Myelopathy: Towards a Personalized Approach.

Degenerative cervical myelopathy (DCM) is a recently coined term encompassing a variety of age-related and genetically associated pathologies, including cervical spondylotic myelopathy, degenerative disc disease, and ligamentous aberrations such as ossification of the posterior longitudinal ligament. All of these pathologies produce chronic compression of the spinal cord causing a clinical syndrome characterized by decreased hand dexterity, gait imbalance, and potential genitourinary or sensorimotor disturbances. Substantial variability in the underlying etiology of DCM and its natural history has generated heterogeneity in practice patterns. Ongoing debates in DCM management most commonly center around clinical decision-making, timing of intervention, and the ideal surgical approach. Pivotal basic science studies during the past two decades have deepened our understanding of the pathophysiologic mechanisms surrounding DCM. Growing knowledge of the key pathophysiologic processes will help us tailor personalized approaches in an increasingly heterogeneous patient population. This article focuses on summarizing the most exciting approaches in personalizing DCM patient treatments including biomarkers, factors affecting clinical decision-making, and choice of the optimal surgical approach. Throughout we provide a concise review on the conditions encompassing DCM and discuss the underlying pathophysiology of chronic spinal cord compression. We also provide an overview on clinical-radiologic diagnostic modalities as well as operative and nonoperative treatment strategies, thereby addressing knowledge gaps and controversies in the field of DCM.

Acute cerebellar edema after traumatic brain injury in a child. a case report.

Traumatic brain injuries (TBI) are a major cause of morbidity and mortality in children. Malignant cerebral edema is described to occur more often in children than in adults. Its infratentorial analogous, a malignant cerebellar edema, has not been reported yet. A 10-year-old boy fell from a height of 3 m where he sustained a TBI. Approximately 36 h after trauma, a significant drop in Glasgow Coma Scale (GCS) occurred accompanied by bilateral fixed and dilated pupils. A computed tomography (CT) scan revealed an underlying acute cerebellar edema without evidence of a sinus vein thrombosis or cerebellar contusions. Immediate suboccipital decompressive surgery and insertion of an external ventricular drain (EVD) were performed. Early postoperative CT imaging showed increasing, space-occupying frontal contusions and perilesional edema, which is why an additional bifrontal craniectomy was performed. A posttraumatic hydrocephalus occurring on the 27th day after trauma was treated with a ventricular-peritoneal shunt. On follow-up, 6 months after trauma, he showed a GCS of 15 with no evident neurological findings. This case report is the first to describe and discuss an acute cerebellar edema occurring after TBI. Its acute complications of brainstem compression and obstructive hydrocephalus are effectively treated by immediate suboccipital decompression and EVD insertion.

Posttraumatic cerebrovascular injuries in children. A systematic review.

INTRODUCTION: Posttraumatic craniocervical vascular injuries in pediatric traumatic brain injury (TBI) are rare, and children-specific, evidence-based standards on screening and therapy of posttraumatic carotid-cavernous fistula (CCF), craniocervical artery dissections (CCAD), traumatic aneurysms (TA), and posttraumatic sinus venous thrombosis (SVT) is lacking. The aim of this review is to summarize the data on epidemiology, clinical presentation, and treatment of these traumatic lesions in a systematic manner. METHODS: We performed a systematic PubMed search for records of CCF, CCAD, TA, and SVT related to pediatric TBI published until June 2019. RESULTS: After screening 2439 records, 42 were included in the quantitative analysis. Incidences for CCAD in blunt TBI were 0.21% (range 0.02-6.82%). 11.7% (range 1.69-15.58%) of pediatric aneurysms were found to be traumatic of origin, whereas 38.2% (range 36.84-40%) of all pediatric SVT were due to blunt TBI. For all of the posttraumatic cerebrovascular pathologies, we found a clear male predominance with 68.75% in CCF, 63.4% in CCAD, 60% in TA, and 58.33% in SVT. Clinical presentation did not differ from the adult population with exception of young child. While there is only recommendation for the therapy of CCAD and SVT in the pediatric population, no such recommendation exists for the treatment of CCF's and TA's, and data from randomized controlled trials is lacking. CONCLUSION: While these results show that posttraumatic CCF, CCAD, TA, and SVT are rarely encountered in children, misdiagnosis may have potentially drastic consequences due to a longer lifetime burden in the pediatric population. Awareness, early recognition, and prompt initiation of the appropriate therapy are essential to avoid morbidity and mortality. Further studies should focus on the development of clinical and radiological screening criteria of posttraumatic vascular lesions in children.

Elderly Patients Show Substantial Improvement in Health-Related Quality of Life After Surgery for Degenerative Cervical Myelopathy Despite Medical Frailty: An Ambispective Analysis of a Multicenter, International Data Set.

BACKGROUND AND OBJECTIVES: We assessed the relationship between Modified Frailty Index-5 (mFI-5) and neurological outcomes, as well as health-related quality of life (HRQoL) measures, in elderly patients with degenerative cervical myelopathy (DCM) after surgery. METHODS: Data from 3 major DCM trials (the Arbeitsgemeinschaft für Osteosynthesefragen Spine Cervical Spondylotic Myelopathy-North America, Cervical Spondylotic Myelopathy-International, and CSM-PROTECT studies) were combined, involving 1047 subjects with moderate to severe myelopathy. Patients older than 60 years with 6-month and 1-year postoperative data were analyzed. Neurological outcome was assessed using the modified Japanese Orthopaedic Association score, while HRQoL was measured using the 36-Item Short Form Health Survey (SF-36) (both Physical Component Summary [SF-36 PCS] and Mental Component Summary [SF-36 MCS] scores) and the Neck Disability Index. Frail (mFI ≥2) and nonfrail (mFI = 0-1) cohorts were compared using univariate paired statistics. RESULTS: The final analysis included 261 patients (62.5% male), with a mean age of 71 years (95% CI 70.7-72). Frail patients (mFI ≥2) had lower baseline modified Japanese Orthopaedic Association scores (10.45 vs 11.96, P < .001), SF-36 PCS scores (32.01 vs 36.51, P < .001), and SF-36 MCS scores (39.32 vs 45.24, P < .001). At 6-month follow-up, SF-36 MCS improved by a mean (SD) of 7.19 (12.89) points in frail vs 2.91 (11.11) points in the nonfrail group (P = .016). At 1 year after surgery, frail patients showed greater improvement in both SF-36 PCS and SF-36 MCS composite scores compared with nonfrail patients (7.81 vs 4.49, P = .038, and 7.93 vs 3.01, P = .007, respectively). Bivariate regression analysis revealed that higher mFI-5 scores correlated with more substantial improvement in overall mental status at 6 months and 1 year (P = .024 and P = .009, respectively). CONCLUSION: mFI-5 is a clinically helpful signature to reflect the HRQoL status among elderly patients with DCM. Despite preoperative medical frailty, elderly patients with DCM experience significant HRQoL improvement after surgery. These findings enable clinicians to identify elderly patients with modifiable comorbidities and provide informed counseling on anticipated outcomes. LEVEL OF EVIDENCE: II.

Intradural cystic schwannomas of the spine: A case-based systematic review of an unusual tumor.

Introduction: Cystic schwannomas have only been reported in a few case reports/series. As a result, they may be misdiagnosed and a standardized management approach remains challenging to establish. Research question: The aim of this study was to compile all reported cases of cystic schwannomas and analyze the perioperative course based on a systematic review of the literature with an additional two cases from the authors' experience. Material and methods: We conducted a search of MEDLINE and CENTRAL databases for spinal intradural extramedullary cystic schwannomas, in accordance to the PRISMA statement. All title/abstracts were screened, and a full-text review of the remaining articles was conducted. The results were compiled in tables and summarized using means and standard deviation (SD), median and interquartile range, and percentage and 95% confidence intervals. Results: We identified 263 articles, of which 35, which reported 54 cases, were included. Including our case-reports (n = 56), patients had a mean age of 47.7 years (SD ± 13.0 years) at presentation, 57% were males, and most lesions were lumbar (43%). The most common symptoms were pain (82%) and muscle weakness (68%) with 84% of patients showing neurological findings. 70% of patients showed a complete relief of symptoms after surgery and 96% reported improvement. Only four complications were reported. Discussion and conclusion: Schwannomas should be considered in the differential diagnosis of intradural extramedullary cystic lesions. Patients typically present with subacute to chronic pain and/or neurologic changes. Surgical resection is the primary therapeutic modality and usually has a good to excellent outcome.

Advancements in neuroregenerative and neuroprotective therapies for traumatic spinal cord injury.

Traumatic spinal cord injuries (SCIs) continue to be a major healthcare concern, with a rising prevalence worldwide. In response to this growing medical challenge, considerable scientific attention has been devoted to developing neuroprotective and neuroregenerative strategies aimed at improving the prognosis and quality of life for individuals with SCIs. This comprehensive review aims to provide an up-to-date and thorough overview of the latest neuroregenerative and neuroprotective therapies currently under investigation. These strategies encompass a multifaceted approach that include neuropharmacological interventions, cell-based therapies, and other promising strategies such as biomaterial scaffolds and neuro-modulation therapies. In addition, the review discusses the importance of acute clinical management, including the role of hemodynamic management as well as timing and technical aspects of surgery as key factors mitigating the secondary injury following SCI. In conclusion, this review underscores the ongoing scientific efforts to enhance patient outcomes and quality of life, focusing on upcoming strategies for the management of traumatic SCI. Each section provides a working knowledge of the fundamental preclinical and patient trials relevant to clinicians while underscoring the pathophysiologic rationale for the therapies.

Accuracy of Intraoperative Neuromonitoring in the Diagnosis of Intraoperative Neurological Decline in the Setting of Spinal Surgery-A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVES: In an effort to prevent intraoperative neurological injury during spine surgery, the use of intraoperative neurophysiological monitoring (IONM) has increased significantly in recent years. Using IONM, spinal cord function can be evaluated intraoperatively by recording signals from specific nerve roots, motor tracts, and sensory tracts. We performed a systematic review and meta-analysis of diagnostic test accuracy (DTA) studies to evaluate the efficacy of IONM among patients undergoing spine surgery for any indication. METHODS: The current systematic review and meta-analysis was performed using the Preferred Reporting Items for a Systematic Review and Meta-analysis statement for Diagnostic Test Accuracy Studies (PRISMA-DTA) and was registered on PROSPERO. A comprehensive search was performed using MEDLINE, EMBASE and SCOPUS for all studies assessing the diagnostic accuracy of neuromonitoring, including somatosensory evoked potential (SSEP), motor evoked potential (MEP) and electromyography (EMG), either on their own or in combination (multimodal). Studies were included if they reported raw numbers for True Positives (TP), False Negatives (FN), False Positives (FP) and True Negative (TN) either in a 2 × 2 contingency table or in text, and if they used postoperative neurologic exam as a reference standard. Pooled sensitivity and specificity were calculated to evaluate the overall efficacy of each modality type using a bivariate model adapted by Reitsma et al, for all spine surgeries and for individual disease groups and regions of spine. The risk of bias (ROB) of included studies was assessed using the quality assessment tool for diagnostic accuracy studies (QUADAS-2). RESULTS: A total of 163 studies were included; 52 of these studies with 16,310 patients reported data for SSEP, 68 studies with 71,144 patients reported data for MEP, 16 studies with 7888 patients reported data for EMG and 69 studies with 17,968 patients reported data for multimodal monitoring. The overall sensitivity, specificity, DOR and AUC for SSEP were 71.4% (95% CI 54.8-83.7), 97.1% (95% CI 95.3-98.3), 41.9 (95% CI 24.1-73.1) and .899, respectively; for MEP, these were 90.2% (95% CI 86.2-93.1), 96% (95% CI 94.3-97.2), 103.25 (95% CI 69.98-152.34) and .927; for EMG, these were 48.3% (95% CI 31.4-65.6), 92.9% (95% CI 84.4-96.9), 11.2 (95% CI 4.84-25.97) and .773; for multimodal, these were found to be 83.5% (95% CI 81-85.7), 93.8% (95% CI 90.6-95.9), 60 (95% CI 35.6-101.3) and .895, respectively. Using the QUADAS-2 ROB analysis, of the 52 studies reporting on SSEP, 13 (25%) were high-risk, 10 (19.2%) had some concerns and 29 (55.8%) were low-risk; for MEP, 8 (11.7%) were high-risk, 21 had some concerns and 39 (57.3%) were low-risk; for EMG, 4 (25%) were high-risk, 3 (18.75%) had some concerns and 9 (56.25%) were low-risk; for multimodal, 14 (20.3%) were high-risk, 13 (18.8%) had some concerns and 42 (60.7%) were low-risk. CONCLUSIONS: These results indicate that all neuromonitoring modalities have diagnostic utility in successfully detecting impending or incident intraoperative neurologic injuries among patients undergoing spine surgery for any condition, although it is clear that the accuracy of each modality differs.PROSPERO Registration Number: CRD42023384158.

Definition, Frequency and Risk Factors for Intra-Operative Spinal Cord Injury: A Knowledge Synthesis.

STUDY DESIGN: Mixed-methods approach. OBJECTIVES: Intra-operative spinal cord injury (ISCI) is a devastating complication of spinal surgery. Presently, a uniform definition for ISCI does not exist. Consequently, the reported frequency of ISCI and important risk factors vary in the existing literature. To address these gaps in knowledge, a mixed-methods knowledge synthesis was undertaken. METHODS: A scoping review was conducted to review the definitions used for ISCI and to ascertain the frequency of ISCI. The definition of ISCI underwent formal review, revision and voting by the Guidelines Development Group (GDG). A systematic review of the literature was conducted to determine the risk factors for ISCI. Based on this systematic review and GDG input, a table was created to summarize the factors deemed to increase the risk for ISCI. All reviews were done according to PRISMA standards and were registered on PROSPERO. RESULTS: The frequency of ISCI ranged from 0 to 61%. Older age, male sex, cardiovascular disease including hypertension, severe myelopathy, blood loss, requirement for osteotomy, coronal deformity angular ratio, and curve magnitude were associated with an increased risk of ISCI. Better pre-operative neurological status and use of intra-operative neuromonitoring (IONM) were associated with a decreased risk of ISCI. The risk factors for ISCI included a rigid thoracic curve with high deformity angular ratio, revision congenital deformity with significant cord compression and myelopathy, extrinsic intradural or extradural lesions with cord compression and myelopathy, intramedullary spinal cord tumor, unstable spine fractures (bilateral facet dislocation and disc herniation), extension distraction injury with ankylosing spondylitis, ossification of posterior longitudinal ligament (OPLL) with severe cord compression, and moderate to severe myelopathy. CONCLUSIONS: ISCI has been defined as "a new or worsening neurological deficit attributable to spinal cord dysfunction during spine surgery that is diagnosed intra-operatively via neurophysiologic monitoring or by an intraoperative wake-up test, or immediately post-operatively based on clinical assessment". This paper defines clinical and imaging factors which increase the risk for ISCI and that could assist clinicians in decision making.

Prevention, Diagnosis, and Management of Intraoperative Spinal Cord Injury in the Setting of Spine Surgery: A Proposed Care Pathway.

STUDY DESIGN: This study is a mixed methods approach. OBJECTIVES: Intraoperative spinal cord injury (ISCI) is a challenging complication in spine surgery. Intra-operative neuromonitoring (IONM) has been developed to detect changes in neural function. We report on the first multidisciplinary, international effort through AO Spine and the Praxis Spinal Cord Institute to develop a comprehensive guideline and care pathway for the prevention, diagnosis, and management of ISCI. METHODS: Three literature reviews were registered on PROSPERO (CRD 42022298841) and performed according to PRISMA guidelines: (1) Definitions, frequency, and risk factors for ISCI, (2) Meta-analysis of the accuracy of IONM for diagnosis of ISCI, (3) Reported management approaches for ISCI and related events. The results were presented in a consensus session to decide the definition of IONM and recommendation of its use in high-risk cases. Based on a literature review of management strategies for ISCI, an intra-operative checklist and overall care pathway was developed by the study team. RESULTS: An operational definition and high-risk patient categories for ISCI were established. The reported incidence of deficits was documented to be higher in intramedullary tumour spine surgery. Multimodality IONM has a high sensitivity and specificity. A guideline recommendation of IONM to be employed for high-risk spine cases was made. The different sections of the intraoperative checklist include surgery, anaesthetic and neurophysiology. The care pathway includes steps (1) initial clinical assessment, (2) pre-operative planning, (3) surgical/anaesthetic planning, (4) intra-operative management, and (5) post-operative management. CONCLUSIONS: This is the first evidence based comprehensive guideline and care pathway for ISCI using the GRADE methodology. This will facilitate a reduction in the incidence of ISCI and improved outcomes from this complication. We welcome the wide implementation and validation of these guidelines and care pathways in prospective, multicentre studies.

The Management of Intraoperative Spinal Cord Injury - A Scoping Review.

STUDY DESIGN: Scoping Review. OBJECTIVE: To review the literature and summarize information on checklists and algorithms for responding to intraoperative neuromonitoring (IONM) alerts and management of intraoperative spinal cord injuries (ISCIs). METHODS: MEDLINE® was searched from inception through January 26, 2022 as were sources of grey literature. We attempted to obtain guidelines and/or consensus statements from the following sources: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), American Academy of Neurology (AAN), American Clinical Neurophysiology Society, NASS (North American Spine Society), and other spine surgery organizations. RESULTS: Of 16 studies reporting on management strategies for ISCIs, two were publications of consensus meetings which were conducted according to the Delphi method and eight were retrospective cohort studies. The remaining six studies were narrative reviews that proposed intraoperative checklists and management strategies for IONM alerts. Of note, 56% of included studies focused only on patients undergoing spinal deformity surgery. Intraoperative considerations and measures taken in the event of an ISCI are divided and reported in three categories of i) Anesthesiologic, ii) Neurophysiological/Technical, and iii) Surgical management strategies. CONCLUSION: There is a paucity of literature on comparative effectiveness and harms of management strategies in response to an IONM alert and possible ISCI. There is a pressing need to develop a standardized checklist and care pathway to avoid and minimize the risk of postoperative neurologic sequelae.

A Clinical Practice Guideline for Prevention, Diagnosis and Management of Intraoperative Spinal Cord Injury: Recommendations for Use of Intraoperative Neuromonitoring and for the Use of Preoperative and Intraoperative Protocols for Patients Undergoing Spine Surgery.

STUDY DESIGN: Development of a clinical practice guideline following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) process. OBJECTIVE: The objectives of this study were to develop guidelines that outline the utility of intraoperative neuromonitoring (IONM) to detect intraoperative spinal cord injury (ISCI) among patients undergoing spine surgery, to define a subset of patients undergoing spine surgery at higher risk for ISCI and to develop protocols to prevent, diagnose, and manage ISCI. METHODS: All systematic reviews were performed according to PRISMA standards and registered on PROSPERO. A multidisciplinary, international Guidelines Development Group (GDG) reviewed and discussed the evidence using GRADE protocols. Consensus was defined by 80% agreement among GDG members. A systematic review and diagnostic test accuracy (DTA) meta-analysis was performed to synthesize pooled evidence on the diagnostic accuracy of IONM to detect ISCI among patients undergoing spinal surgery. The IONM modalities evaluated included somatosensory evoked potentials (SSEPs), motor evoked potentials (MEPs), electromyography (EMG), and multimodal neuromonitoring. Utilizing this knowledge and their clinical experience, the multidisciplinary GDG created recommendations for the use of IONM to identify ISCI in patients undergoing spine surgery. The evidence related to existing care pathways to manage ISCI was summarized and based on this a novel AO Spine-PRAXIS care pathway was created. RESULTS: Our recommendations are as follows: (1) We recommend that intraoperative neurophysiological monitoring be employed for high risk patients undergoing spine surgery, and (2) We suggest that patients at "high risk" for ISCI during spine surgery be proactively identified, that after identification of such patients, multi-disciplinary team discussions be undertaken to manage patients, and that an intraoperative protocol including the use of IONM be implemented. A care pathway for the prevention, diagnosis, and management of ISCI has been developed by the GDG. CONCLUSION: We anticipate that these guidelines will promote the use of IONM to detect and manage ISCI, and promote the use of preoperative and intraoperative checklists by surgeons and other team members for high risk patients undergoing spine surgery. We welcome teams to implement and evaluate the care pathway created by our GDG.

Facial nerve motor evoked potentials during skull base surgery to monitor facial nerve function using the threshold-level method.

OBJECT: During surgeries that put the facial nerve at risk for injury, its function can be continuously monitored by transcranial facial nerve motor evoked potentials (FNMEPs) in facial nerve target muscles. Despite their advantages, FNMEPs are not yet widely used. While most authors use a 50% reduction in FNMEP response amplitudes as a warning criterion, in this paper the authors' approach was to keep the response amplitude constant by increasing the stimulation intensity and to establish a warning criterion based on the "threshold-level" method. METHODS: The authors included 34 consecutive procedures involving 33 adult patients (median age 47 years) in whom FNMEPs were monitored. A threshold increase greater than 20 mA for eliciting FNMEPs in the most reliable facial nerve target muscle was considered a prediction of reduced postoperative facial nerve function, and subsequently a warning was issued to the surgeon. Preoperative and early postoperative function was documented using the House-Brackmann grading system. RESULTS: Monitoring of FNMEPs was feasible in all 34 surgeries in at least one facial nerve target muscle. The mentalis muscle yielded the best results. The House-Brackmann grade deteriorated in 17 (50%) of 34 cases. The warning criterion was reached in 18 (53%) of 34 cases, which predicted an 83% risk of House-Brackmann grade deterioration. Sensitivity amounted to 88% (CI 64%-99%) and specificity to 82% (CI 57%-96%). Deterioration of FNMEPs and a worse House-Brackmann grade showed a high degree of association (p < 0.001). The impact of FNMEP monitoring on surgical strategy is exemplified in an illustrative case. CONCLUSIONS: In surgeries that put the facial nerve at risk, the intraoperative increase in FNMEP stimulation threshold was closely correlated to postoperative facial nerve dysfunction. Monitoring of FNMEPs is a valid indicator of facial nerve function in skull base surgery. It should be used as an adjunct to direct electrical facial nerve stimulation and continuous electromyographic monitoring of facial nerve target muscles.

How can clinical safety and efficacy concerns in stem cell therapy for spinal cord injury be overcome?

INTRODUCTION: Spinal cord injury (SCI) can lead to severe neurological dysfunction. Despite scientific and medical advances, clinically effective regenerative therapies including stem cells are lacking for SCI. AREAS COVERED: This paper discusses translational challenges related to the safe, effective use of stem cells for SCI, with a focus on mesenchymal stem cells (MSCs), neural stem cells (NSCs), Schwann cells (SCs), olfactory ensheathing cells (OECs), oligodendrocyte precursor cells (OPCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). We discuss approaches to enhance the efficacy of cell-based strategies by i) addressing patient heterogeneity and enhancing patient selection; ii) selecting cell type, cell source, cell developmental stage, and delivery technique; iii) enhancing graft integration and mitigating immune-mediated graft rejection; and iv) ensuring availability of cells. Additionally, we review strategies to optimize outcomes including combinatorial use of rehabilitation and discuss ways to mitigate potential risks of tumor formation associated with stem cell-based strategies. EXPERT OPINION: Basic science research will drive translational advances to develop stem cell-based therapies for SCI. Genetic, serological, and imaging biomarkers may enable individualization of cell-based treatments. Moreover, combinatorial strategies will be required to enhance graft survival, migration and functional integration, to enable precision-based intervention.

Clinical trials for neuroregenerative therapies for spinal cord injury: what have we learnt so far?

INTRODUCTION: There remains a lack of effective regenerative therapies to treat traumatic spinal cord injury (SCI). On a global level, patients living with SCI, their families, and the healthcare system are impacted by the extensive financial burden associated with the management of SCI. Clinical trials are crucial to assess the real-world efficacy of the different emerging neuroregenerative approaches that have shown promise in the pre-clinical stages of research. AREAS COVERED: This perspective summarizes and discusses potential solutions to several key challenges that clinical investigators evaluating novel therapeutic strategies to treat SCI might face: 1) the challenges in patient recruitment and meeting enrollment targets with adequate statistical power; 2) the loss of patients to follow-up; 3) the heterogeneity in patient presentation and recovery trajectories; 4) the complex multifaceted pathophysiology of SCI that renders investigations of single therapeutic approaches difficult; 5) the challenge of capturing positive treatment effects of investigative therapies; 6) the high costs associated with conducting clinical trials; 7) the implementation of current guidelines for treating SCI to optimize care delivery and clinical trial conduct; 8) the shift in SCI patient demographics reflective of an aging population; and 9) navigating regulatory bodies to translate therapies into the clinic. EXPERT OPINION: There are challenges when conducting SCI clinical trials that span broadly across medical, social, political, and economic considerations. Thus, we should employ an interdisciplinary approach when addressing these challenges in order to facilitate the evaluation of novel treatments for SCI.

An Introduction to the North American Clinical Trials Network for Spinal Cord Injury Special Edition: Reflections on Accomplishments and a Look to the Future.

The North American Clinical Trials Network (NACTN) has been established as a network of translational clinical research centers focused on traumatic spinal cord injury (SCI) with the goals of facilitating clinical translational research, promotion of enhanced clinical care protocols including the principle of early surgery for SCI, and improving outcomes for individuals with acute SCI. Since its foundation in 2004 by Dr. Robert Grossman, NACTN has evolved into a powerful multi-stakeholder consortium of eight neurosurgical department faculties at university-affiliated institutions in the United States and Canada, a data management center, and a pharmacological center. To date, high-quality data from more than 1000 patients have been prospectively collected, providing us with a strong body of evidence surrounding SCI epidemiology, the natural history, and complications of acute and subacute SCI management. Key accomplishments of NACTN are summarized in this Focus issue. They include the launch, in collaboration with AO Spine, of the international, multi-center, placebo-controlled, Phase III Riluzole in Acute Spinal Cord Injury Study (RISCIS) that recruited 192 patients. While the primary analyses did not achieve the predetermined endpoint of efficacy for Riluzole, likely related to insufficient power, pre-planned secondary analyses demonstrated that all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with Riluzole showed significant gains in functional recovery. The Focus Issue also includes a detailed analysis of the pharmacokinetics and pharmacodynamics of riluzole in the setting of acute SCI (RISCIS-PK study). Additional achievements include key contributions to the evidence supporting the role of early surgery in acute SCI, and a better understanding of the impact of complications on the outcomes of SCI. Future directions of NACTN will build on past accomplishments and focus on enhanced collaborations with other SCI networks, advanced analytics to examine large datasets, and a greater focus on chronic SCI.

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.