Association Between Preoperative Cannabis Use and Increased Rate of Revision Surgery Following Spinal Fusion: A Systematic Review and Meta-Analysis.

The use of cannabis as a method of chronic pain relief has skyrocketed since its legalization in states across the United States. Clinicians currently have a limited scope regarding the effectiveness of marijuana on surgical procedures. This systematic review aims to determine the effect of current cannabis use on the rate of failure of spinal fusions and overall surgical outcomes. A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement. PubMed, Embase, and Scopus were searched, identifying studies assessing spinal fusion with reported preoperative cannabis use. Outcomes of interest included reoperation due to fusion failure or pseudoarthrosis with a follow-up time of at least six months. Subgroups of cervical fusions alone and lumbar fusions alone were also analyzed. Certainty in evidence and bias was assessed using the GRADE criteria and ROBINS-I tool (PROSPERO #CRD42023463548). Four studies met the inclusion criteria, with a total of 788 patients (188 in the cannabis user group and 600 in the non-user group). The rate of revision surgery among cannabis users was higher than that in non-users for all spinal fusions (RR: 3.58, 95% CI: 1.67 to 7.66, p = 0.001). For cervical fusions alone, there remained a higher rate of revision surgery for cannabis users compared to non-users (RR: 4.47, 95% CI: 1.93 to 10.36, p = 0.0005). For lumbar fusions alone, there was no difference in the rates of revision surgery between cannabis users and non-users (RR: 1.21, 95% CI: 0.28 to 7.73, p = 0.79). Cannabis use was shown to be associated with a higher rate of pseudoarthrosis revisions in spinal fusions on meta-analysis. On subgroup stratification by spine region, cannabis use remained associated with pseudoarthrosis revisions on cervical fusions alone but not lumbar fusions alone. Further research with larger, randomized studies is required to fully elucidate the relationship between cannabis use and fusion, both in general and by spinal region.

Neural Progenitor Cells Expressing Herpes Simplex Virus-Thymidine Kinase for Ablation Have Differential Chemosensitivity to Brivudine and Ganciclovir.

Neural progenitor cell (NPC) transplants are a promising therapy for treating spinal cord injury (SCI), however, their long-term role after engraftment and the relative contribution to ongoing functional recovery remains a key knowledge gap. Selective human cell ablation techniques, currently being developed to improve the safety of progenitor cell transplant therapies in patients, may also be used as tools to probe the regenerative effects attributable to individual grafted cell populations. The Herpes Simplex Virus Thymidine Kinase (HSV-TK) and ganciclovir (GCV) system has been extensively studied in the context of SCI and broader CNS disease. However, the efficacy of brivudine (BVDU), another HSV-TK prodrug with potentially reduced bystander cytotoxic effects and in vivo toxicity, has yet to be investigated for NPC ablation. In this study, we demonstrate successful generation and in vitro ablation of HSV-TK-expressing human iPSC-derived NPCs with a >80% reduction in survival over controls. We validated an HSV-TK and GCV/BVDU synergistic system with iPSC-NPCs using an efficient gene-transfer method and in vivo ablation in a translationally relevant model of SCI. Our findings demonstrate enhanced ablation efficiency and reduced bystander effects when targeting all rapidly dividing cells with combinatorial GCV and BVDU treatment. However, for use in loss of function studies, BVDU alone is optimal due to reduced nonselective cell ablation.

Hepatocyte Growth Factor-Preconditioned Neural Progenitor Cells Attenuate Astrocyte Reactivity and Promote Neurite Outgrowth.

The astroglial scar is a defining hallmark of secondary pathology following central nervous system (CNS) injury that, despite its role in limiting tissue damage, presents a significant barrier to neuroregeneration. Neural progenitor cell (NPC) therapies for tissue repair and regeneration have demonstrated favorable outcomes, the effects of which are ascribed not only to direct cell replacement but trophic support. Cytokines and growth factors secreted by NPCs aid in modifying the inhibitory and cytotoxic post-injury microenvironment. In an effort to harness and enhance the reparative potential of NPC secretome, we utilized the multifunctional and pro-regenerative cytokine, hepatocyte growth factor (HGF), as a cellular preconditioning agent. We first demonstrated the capacity of HGF to promote NPC survival in the presence of oxidative stress. We then assessed the capacity of this modified conditioned media (CM) to attenuate astrocyte reactivity and promote neurite outgrowth in vitro. HGF pre-conditioned NPCs demonstrated significantly increased levels of tissue inhibitor of metalloproteinases-1 and reduced vascular endothelial growth factor compared to untreated NPCs. In reactive astrocytes, HGF-enhanced NPC-CM effectively reduced glial fibrillary acidic protein (GFAP) expression and chondroitin sulfate proteoglycan deposition to a greater extent than either treatment alone, and enhanced neurite outgrowth of co-cultured neurons. in vivo, this combinatorial treatment strategy might enable tactical modification of the post-injury inhibitory astroglial environment to one that is more conducive to regeneration and functional recovery. These findings have important translational implications for the optimization of current cell-based therapies for CNS injury.

The leading edge: Emerging neuroprotective and neuroregenerative cell-based therapies for spinal cord injury.

Spinal cord injuries (SCIs) are associated with tremendous physical, social, and financial costs for millions of individuals and families worldwide. Rapid delivery of specialized medical and surgical care has reduced mortality; however, long-term functional recovery remains limited. Cell-based therapies represent an exciting neuroprotective and neuroregenerative strategy for SCI. This article summarizes the most promising preclinical and clinical cell approaches to date including transplantation of mesenchymal stem cells, neural stem cells, oligodendrocyte progenitor cells, Schwann cells, and olfactory ensheathing cells, as well as strategies to activate endogenous multipotent cell pools. Throughout, we emphasize the fundamental biology of cell-based therapies, critical features in the pathophysiology of spinal cord injury, and the strengths and limitations of each approach. We also highlight salient completed and ongoing clinical trials worldwide and the bidirectional translation of their findings. We then provide an overview of key adjunct strategies such as trophic factor support to optimize graft survival and differentiation, engineered biomaterials to provide a support scaffold, electrical fields to stimulate migration, and novel approaches to degrade the glial scar. We also discuss important considerations when initiating a clinical trial for a cell therapy such as the logistics of clinical-grade cell line scale-up, cell storage and transportation, and the delivery of cells into humans. We conclude with an outlook on the future of cell-based treatments for SCI and opportunities for interdisciplinary collaboration in the field.

Navigating the Postgraduate Research Fellowship: A Roadmap for Surgical Residents.

BACKGROUND: To preserve the future of surgical innovation, opportunities for surgical residents to receive structured research training are paramount. The objective of this article is to help surgical residents navigate a research fellowship by overviewing key topics such as choosing an area of focus and supervisor, applying for external funding, transitioning away from clinical duties, managing intellectual property, integrating family planning, and incorporating research experience into independent career development. MATERIALS AND METHODS: Using the framework of the University of Toronto's graduate degree-awarding Surgeon-Scientist Training Program, the authors outline key considerations, decisions, and pearls for surgical residents considering or currently enrolled in a full-time research fellowship training program. RESULTS: Full-time research fellowships offer a unique opportunity for residents interested in an academic career. Such full-time research fellowships away from clinical duties allow surgical trainees to focus on developing key research competencies, including how to generate hypotheses, apply research methodology, gain experience presenting and publishing manuscripts, and ultimately apply these skills as independent investigators to improve patient and population health. Research fellowships may also be an opportunity to develop intellectual property or facilitate family planning. Practical tips are provided for the transition back into clinical training and how to effectively market one's research skills for career advancement. CONCLUSIONS: The authors outline key considerations, decisions, and pearls for surgical residents considering or currently enrolled in a full-time research fellowship training program. By adhering to the principles highlighted in this article, residents will be able to successfully navigate a full-time research fellowship to optimize their intellectual development, maximize their academic productivity, and facilitate their transition into an independent investigator.

Degenerative cervical myelopathy - update and future directions.

Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord dysfunction in adults worldwide. DCM encompasses various acquired (age-related) and congenital pathologies related to degeneration of the cervical spinal column, including hypertrophy and/or calcification of the ligaments, intervertebral discs and osseous tissues. These pathologies narrow the spinal canal, leading to chronic spinal cord compression and disability. Owing to the ageing population, rates of DCM are increasing. Expeditious diagnosis and treatment of DCM are needed to avoid permanent disability. Over the past 10 years, advances in basic science and in translational and clinical research have improved our understanding of the pathophysiology of DCM and helped delineate evidence-based practices for diagnosis and treatment. Surgical decompression is recommended for moderate and severe DCM; the best strategy for mild myelopathy remains unclear. Next-generation quantitative microstructural MRI and neurophysiological recordings promise to enable quantification of spinal cord tissue damage and help predict clinical outcomes. Here, we provide a comprehensive, evidence-based review of DCM, including its definition, epidemiology, pathophysiology, clinical presentation, diagnosis and differential diagnosis, and non-operative and operative management. With this Review, we aim to equip physicians across broad disciplines with the knowledge necessary to make a timely diagnosis of DCM, recognize the clinical features that influence management and identify when urgent surgical intervention is warranted.

GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents.

Neural progenitor cell (NPC) transplantation is a promising strategy for the treatment of spinal cord injury (SCI). In this study, we show that injury-induced Notch activation in the spinal cord microenvironment biases the fate of transplanted NPCs toward astrocytes in rodents. In a screen for potential clinically relevant factors to modulate Notch signaling, we identified glial cell-derived neurotrophic factor (GDNF). GDNF attenuates Notch signaling by mediating delta-like 1 homolog (DLK1) expression, which is independent of GDNF's effect on cell survival. When transplanted into a rodent model of cervical SCI, GDNF-expressing human-induced pluripotent stem cell-derived NPCs (hiPSC-NPCs) demonstrated higher differentiation toward a neuronal fate compared to control cells. In addition, expression of GDNF promoted endogenous tissue sparing and enhanced electrical integration of transplanted cells, which collectively resulted in improved neurobehavioral recovery. CRISPR-induced knockouts of the DLK1 gene in GDNF-expressing hiPSC-NPCs attenuated the effect on functional recovery, demonstrating that this effect is partially mediated through DLK1 expression. These results represent a mechanistically driven optimization of hiPSC-NPC therapy to redirect transplanted cells toward a neuronal fate and enhance their integration.

A Systematic Review of Definitions for Neurological Complications and Disease Progression in Patients Treated Surgically for Degenerative Cervical Myelopathy.

STUDY DESIGN: Systematic review. OBJECTIVE: This review aims to (1) outline how neurological complications and disease progression are defined in the literature and (2) evaluate the quality of definitions using a novel four-point rating system. SUMMARY OF BACKGROUND DATA: Degenerative cervical myelopathy (DCM) is a progressive, degenerative spine disease that is often treated surgically. Although uncommon, surgical decompression can be associated with neurological complications, such as C5 nerve root palsy, perioperative worsening of myelopathy, and longer-term deterioration. Unfortunately, important questions surrounding these complications cannot be fully addressed due to the heterogeneity in definitions used across studies. Given this variability, there is a pressing need to develop guidelines for the reporting of surgical complications in order to accurately evaluate the safety of surgical procedures. METHODS: An electronic database search was conducted in MEDLINE, MEDLINE in Process, EMBASE and Cochrane Central Register of Controlled Trials for studies that reported on complications related to DCM surgery and included at least 10 surgically treated patients. Data extracted included study design, surgical details, as well as definitions and rates of surgical complications. A four-point rating scale was developed to assess definition quality for each complication. RESULTS: Our search yielded 2673 unique citations, 42 of which met eligibility criteria and were summarized in this review. Defined complications included neurological deterioration, late onset deterioration, perioperative worsening of myelopathy, C5 palsy, nerve root or upper limb palsy or radiculopathy, surgery failure, inadequate decompression and progression of ossified lesions. Reported rates of these complications varied substantially, especially those for neurological deterioration (0.2%-33.3%) and progression of ossified lesions (0.0%-86.7%). CONCLUSION: Reported incidences of various complications vary widely in DCM surgery, especially for neurological deterioration and progression of ossified lesions. This summary serves as a first step for standardizing definitions and developing guidelines for accurately reporting surgical complications. LEVEL OF EVIDENCE: 2.

Arachnoiditis Ossificans: A Rare Etiology of Oil-Based Spinal Myelography and Review of the Literature.

BACKGROUND: Arachnoiditis ossificans (AO) is a rare entity characterized by the presence of calcified plaques formed by the metaplasia of arachnoid cells. Over 50 cases of AO have been reported, with predisposing factors including spinal trauma, hemorrhage, vascular abnormalities, and infection. The administration of oil-based contrast during myelography as an independent risk factor or in conjunction with other spinal pathology has been described in 9 cases. CASE DESCRIPTION: A 70-year-old woman presented for neurosurgical consultation in 2013 with a 2-year history of progressive midthoracic pain, right-sided chest wall allodynia, lower extremity weakness, and gait ataxia. Approximately 30 years ago, she received an oil-based contrast myelogram for investigation of spontaneous spinal hemorrhage. The procedure was well tolerated, and the patient experienced no allergic, hemorrhagic, traumatic, or infectious complications. No etiology was found for the spinal hemorrhage, and the patient recovered fully from that episode. Magnetic resonance imaging (MRI) of the thoracolumbar spine demonstrated multiple compressive intradural lesions in the upper thoracic spine and ventral tethering of the spinal cord at T7. MRI also demonstrated syringomyelia throughout the thoracic spine. Initially, the diagnosis of epidural mass or diastematomyelia was considered. To further characterize the epidural lesion, an unenhanced computed tomography (CT) scan was obtained, demonstrating a long segment of extensive calcification in the periphery of the thoracolumbar spine, with near-complete circumferential involvement from T5 to T11. The diagnosis of AO with extensive thoracic spine calcifications, syringomyelia, and spine cord tethering was made and confirmed at surgery. CONCLUSIONS: In addition to acute inflammation, oil-based contrast myelography also leads to arachnoiditis, calcification, and retained mass lesions because of its chronic inflammatory properties and slow resorptive rate. Three decades after its replacement with water-based contrast material, the chronic sequelae of oil-based contrast myelography may continue to manifest clinically and on CT imaging. Because of calcifications often encasing the spinal cord or nerve roots, management of AO is challenging, and neurologic deficits may persist even after surgery.

Generation of Definitive Neural Progenitor Cells from Human Pluripotent Stem Cells for Transplantation into Spinal Cord Injury.

In this chapter, we first describe two interchangeable protocols optimized in our lab for deriving definitive neuronal progenitor cells from human pluripotent stem cells (hPSCs). The resultant NPCs can then be propagated and differentiated to produce differing proportions of neurons, oligodendrocytes, and astrocytes as required for in vitro cell culture studies or in vivo transplantation. Following these protocols, we explain the method for transplanting these cells into the rat model of spinal cord injury (SCI).

Human Oligodendrogenic Neural Progenitor Cells Delivered with Chondroitinase ABC Facilitate Functional Repair of Chronic Spinal Cord Injury.

Treatment of chronic spinal cord injury (SCI) is challenging due to cell loss, cyst formation, and the glial scar. Previously, we reported on the therapeutic potential of a neural progenitor cell (NPC) and chondroitinase ABC (ChABC) combinatorial therapy for chronic SCI. However, the source of NPCs and delivery system required for ChABC remained barriers to clinical application. Here, we investigated directly reprogrammed human NPCs biased toward an oligodendrogenic fate (oNPCs) in combination with sustained delivery of ChABC using an innovative affinity release strategy in a crosslinked methylcellulose biomaterial for the treatment of chronic SCI in an immunodeficient rat model. This combinatorial therapy increased long-term survival of oNPCs around the lesion epicenter, facilitated greater oligodendrocyte differentiation, remyelination of the spared axons by engrafted oNPCs, enhanced synaptic connectivity with anterior horn cells and neurobehavioral recovery. This combinatorial therapy is a promising strategy to regenerate the chronically injured spinal cord.

Human Spinal Oligodendrogenic Neural Progenitor Cells Promote Functional Recovery After Spinal Cord Injury by Axonal Remyelination and Tissue Sparing.

Cell transplantation therapy utilizing neural precursor cells (NPCs) is a conceptually attractive strategy for traumatic spinal cord injury (SCI) to replace lost cells, remyelinate denuded host axons and promote tissue sparing. However, the number of mature oligodendrocytes that differentiate from typical NPCs remains limited. Herein, we describe a novel approach to bias the differentiation of directly reprogrammed human NPCs (drNPCs) toward a more oligodendrogenic fate (oNPCs) while preserving their tripotency. The oNPCs derived from different lines of human NPCs showed similar characteristics in vitro. To assess the in vivo efficacy of this approach, we used oNPCs derived from drNPCs and transplanted them into a SCI model in immunodeficient Rowett Nude (RNU) rats. The transplanted cells showed significant migration along the rostrocaudal axis and proportionally greater differentiation into oligodendrocytes. These cells promoted perilesional tissue sparing and axonal remyelination, which resulted in recovery of motor function. Moreover, after transplantation of the oNPCs into intact spinal cords of immunodeficient NOD/SCID mice, we detected no evidence of tumor formation even after 5 months of observation. Thus, biasing drNPC differentiation along an oligodendroglial lineage represents a promising approach to promote tissue sparing, axonal remyelination, and neural repair after traumatic SCI. Stem Cells Translational Medicine 2018;7:806-818.

Canadian Neurosurgery Educators' Views on Stereotactic Radiosurgery in Residency Training.

OBJECTIVE: Despite the increasing prominence of stereotactic radiosurgery (SRS) in treating intracranial and spinal pathologies, there is currently a dearth of exposure to this modality in the neurosurgical residency. To address this gap, the aim of this study is to assess neurosurgery educators' views regarding the current state of SRS exposure, and to identify potential approaches to improve residency education in this domain. METHODS: Qualitative thematic analysis and constructivist grounded theory methodology were employed. Semistructured telephone-based interviews were conducted with current or past residency program directors, as well as current departmental chairs across neurosurgical departments in Canada. Interviews were transcribed and subjected to thematic analysis using open and axial coding. RESULTS: Of the 34 eligible participants, the overall response rate was 41.1% (14/34), with a 35.3% participation rate (12/34). Participants represented 9 of the 12 Canadian institutions surveyed. The majority of participants were current program directors (n = 8), followed by past program directors (n = 2), and departmental chairs (n = 2). Most respondents 75% (9/12) view an increasing role for SRS in neurosurgery. Unanimously, respondents endorse greater exposure to SRS during residency through formal residency rotations and engagement in interdisciplinary tumor boards to facilitate involvement in clinical decision-making. CONCLUSIONS: This is the first study to systematically collate neurosurgery educators' views on SRS in residency in Canada and demonstrates recognition of the discordance between SRS in practice and residency training. Neurosurgery educators broadly endorse increased exposure to this modality. Future work is needed to delineate the requirements necessary to achieve adequate competency in SRS.

Time is spine: a review of translational advances in spinal cord injury.

Acute traumatic spinal cord injury (SCI) is a devastating event with far-reaching physical, emotional, and economic consequences for patients, families, and society at large. Timely delivery of specialized care has reduced mortality; however, long-term neurological recovery continues to be limited. In recent years, a number of exciting neuroprotective and regenerative strategies have emerged and have come under active investigation in clinical trials, and several more are coming down the translational pipeline. Among ongoing trials are RISCIS (riluzole), INSPIRE (Neuro-Spinal Scaffold), MASC (minocycline), and SPRING (VX-210). Microstructural MRI techniques have improved our ability to image the injured spinal cord at high resolution. This innovation, combined with serum and cerebrospinal fluid (CSF) analysis, holds the promise of providing a quantitative biomarker readout of spinal cord neural tissue injury, which may improve prognostication and facilitate stratification of patients for enrollment into clinical trials. Given evidence of the effectiveness of early surgical decompression and growing recognition of the concept that "time is spine," infrastructural changes at a systems level are being implemented in many regions around the world to provide a streamlined process for transfer of patients with acute SCI to a specialized unit. With the continued aging of the population, central cord syndrome is soon expected to become the most common form of acute traumatic SCI; characterization of the pathophysiology, natural history, and optimal treatment of these injuries is hence a key public health priority. Collaborative international efforts have led to the development of clinical practice guidelines for traumatic SCI based on robust evaluation of current evidence. The current article provides an in-depth review of progress in SCI, covering the above areas.

Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury.

Traumatic spinal cord injuries (SCIs) affect millions of people worldwide; the majority of whom are in the chronic phase of their injury. Unfortunately, most current treatments target the acute/subacute injury phase as the microenvironment of chronically injured cord consists of a well-established glial scar with inhibitory chondroitin sulfate proteoglycans (CSPGs) which acts as a potent barrier to regeneration. It has been shown that CSPGs can be degraded in vivo by intrathecal Chondroitinase ABC (ChABC) to produce a more permissive environment for regeneration by endogenous cells or transplanted neural stem cells (NSCs) in the subacute phase of injury. Using a translationally-relevant clip-contusion model of cervical spinal cord injury in mice we sought to determine if ChABC pretreatment could modify the harsh chronic microenvironment to enhance subsequent regeneration by induced pluripotent stem cell-derived NSCs (iPS-NSC). Seven weeks after injury-during the chronic phase-we delivered ChABC by intrathecal osmotic pump for one week followed by intraparenchymal iPS-NSC transplant rostral and caudal to the injury epicenter. ChABC administration reduced chronic-injury scar and resulted in significantly improved iPSC-NSC survival with clear differentiation into all three neuroglial lineages. Neurons derived from transplanted cells also formed functional synapses with host circuits on patch clamp analysis. Furthermore, the combined treatment led to recovery in key functional muscle groups including forelimb grip strength and measures of forelimb/hindlimb locomotion assessed by Catwalk. This represents important proof-of-concept data that the chronically injured spinal cord can be 'unlocked' by ChABC pretreatment to produce a microenvironment conducive to regenerative iPS-NSC therapy.

Generation of Oligodendrogenic Spinal Neural Progenitor Cells From Human Induced Pluripotent Stem Cells.

This unit describes protocols for the efficient generation of oligodendrogenic neural progenitor cells (o-NPCs) from human induced pluripotent stem cells (hiPSCs). Specifically, detailed methods are provided for the maintenance and differentiation of hiPSCs, human induced pluripotent stem cell-derived neural progenitor cells (hiPS-NPCs), and human induced pluripotent stem cell-oligodendrogenic neural progenitor cells (hiPSC-o-NPCs) with the final products being suitable for in vitro experimentation or in vivo transplantation. Throughout, cell exposure to growth factors and patterning morphogens has been optimized for both concentration and timing, based on the literature and empirical experience, resulting in a robust and highly efficient protocol. Using this derivation procedure, it is possible to obtain millions of oligodendrogenic-NPCs within 40 days of initial cell plating which is substantially shorter than other protocols for similar cell types. This protocol has also been optimized to use translationally relevant human iPSCs as the parent cell line. The resultant cells have been extensively characterized both in vitro and in vivo and express key markers of an oligodendrogenic lineage. © 2017 by John Wiley & Sons, Inc.

Spinal Cord Injury-What Are the Controversies?

Traumatic spinal cord injuries have a tremendous impact on individuals, families, and society as a whole. Substantial heterogeneity in the patient population, their presentation and underlying pathophysiology has sparked debates along the care spectrum from initial assessment to definitive treatment. This article reviews spinal cord injury (SCI) management followed by a discussion of the salient controversies in the field. Current care practices modeled on the American Association of Neurological Surgeons/Congress of Neurological Surgeons joint section guidelines are highlighted including key recommendations regarding immobilization, avoidance of hypotension, early International Standards for Neurological Classification of SCI examination and intensive care unit treatment. From a diagnostic perspective, the evolving roles of CT, MRI, and leading-edge microstructural MRI techniques are discussed with descriptions of the relevant clinical literature for each. Controversies in management relevant to clinicians including the timing of surgical decompression, methylprednisolone administration, blood pressure augmentation, intraoperative electrophysiological monitoring, and the role of surgery in central cord syndrome and pediatric SCI are also covered in detail. Finally, the article concludes with a reflection on clinical trial design tailored to the heterogeneous population of individuals with SCI.