Publications by authors named "Michael G Fehlings"

866 Publications

Cell-based and stem-cell-based treatments for spinal cord injury: evidence from clinical trials.

Lancet Neurol 2022 May 12. Epub 2022 May 12.

Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich, Zurich, Switzerland. Electronic address:

Spinal cord injury is a severely disabling neurological condition leading to impaired mobility, pain, and autonomic dysfunction. Most often, a single traumatic event, such as a traffic or recreational accident, leads to primary spinal cord damage through compression and laceration, followed by secondary damage consisting of inflammation and ischaemia, and culminating in substantial tissue loss. Patients need appropriate timely surgical and critical care, followed by neurorehabilitation to facilitate neuronal reorganisation and functional compensation. Although some neurological function might be regained, most patients with initially complete lesions have severe, irreversible neurological impairment. Cell-based and stem-cell-based therapies are recognised as promising candidates to promote functional recovery. However, no trials of these therapies in patients have yet provided reproducible evidence for clinical efficacy, challenged by small effect sizes, low immune suppression, and low sensitivity study designs. Nevertheless, in the past decade, clinical trials have shown the feasibility and long-term safety of cell transplantation into the injured spinal cord. This crucial milestone has paved the way to consider refinements and combined therapies, such as the use of biomaterials to augment the effects of cell transplantation. In the future, emerging cell types, scaffolding, and cell engineering might improve cell survival, integration, and therapeutic efficiency.
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http://dx.doi.org/10.1016/S1474-4422(21)00464-6DOI Listing
May 2022

Commentary: Acute Implantation of a Bioresorbable Polymer Scaffold in Patients With Complete Thoracic Spinal Cord Injury: 24-Month Follow-up From the INSPIRE Study.

Neurosurgery 2022 Jun 22;90(6):e140-e141. Epub 2022 Apr 22.

Division of Neurosurgery and Spine Program, Krembil Brain Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1227/neu.0000000000001945DOI Listing
June 2022

The Impact of Spinal Cord Neuromodulation on Restoration of Walking Ability After Spinal Cord Injury.

Neurospine 2022 Mar 31;19(1):244-245. Epub 2022 Mar 31.

Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON, Canada.

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http://dx.doi.org/10.14245/ns.2244212.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987563PMC
March 2022

Clinical outcomes and revision rates following four-level anterior cervical discectomy and fusion.

Sci Rep 2022 03 29;12(1):5339. Epub 2022 Mar 29.

Division of Neurosurgery, Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, University of Toronto, 399 Bathurst St, Toronto, ON, M5T2S8, Canada.

Studies on outcomes after four-level anterior cervical discectomy and fusion (ACDF) are limited in the literature. The purpose of this study was to report on clinical outcomes and revision rates following four-level ACDF. Patients operated with four-level ACDF were identified in a prospectively accrued single institution database. Outcome scores included the Neck Disability Index (NDI) and Visual Analogue Scale (VAS) for neck and arm pain. Reoperation rates were determined. Any complications were identified from a review of the medical records. Twenty-eight patients with a minimum of 12 months follow up were included in the analysis. The mean age at surgery was 58.5 years. The median radiographic follow up time was 23 (IQR = 16-31.25) months. Cervical lordosis was significantly improved postoperatively (- 1 to - 13, p < 0.001). At the median 24 (IQR = 17.75-39.50) months clinical follow up time, there was a significant improvement in the NDI (38 to 28, p = 0.046) and VAS for neck pain scores (5.1 to 3, p = 0.012). The most common perioperative complication was transient dysphagia (32%) followed by hoarseness (14%). Four (14%) patients required revision surgery at a median 11.5 (IQR = 2-51) months postoperatively. The results of this study indicate that patients who undergo four-level ACDF have a significant improvement in clinical outcomes at median 24 months follow up. Stand-alone four-level ACDF is a valid option for the management of complex cervical degenerative conditions.
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http://dx.doi.org/10.1038/s41598-022-09389-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964822PMC
March 2022

Prevention of Surgical Site Infections in Spine Surgery: An International Survey of Clinical Practices Among Expert Spine Surgeons.

Global Spine J 2022 Feb 25:21925682211068414. Epub 2022 Feb 25.

Department of Neurosurgery, 14903Charité - Universitätsmedizin Berlin, Berlin, Germany.

Study Design: Questionnaire-based survey.

Objectives: Surgical site infection (SSI) is a common complication in spine surgery but universal guidelines for SSI prevention are lacking. The objectives of this study are to depict a global status quo on implemented prevention strategies in spine surgery, common themes of practice and determine key areas for future research.

Methods: An 80-item survey was distributed among spine surgeons worldwide via email. The questionnaire was designed and approved by an International Consensus Group on spine SSI. Consensus was defined as more than 60% of participants agreeing to a specific prevention strategy.

Results: Four hundred seventy-two surgeons participated in the survey. Screening for (SA) is not common, whereas preoperative decolonization is performed in almost half of all hospitals. Body mass index (BMI) was not important for surgery planning. In contrast, elevated HbA1c level and hypoalbuminemia were often considered as reasons to postpone surgery. Cefazoline is the common drug for antimicrobial prophylaxis. Alcohol-based chlorhexidine is mainly used for skin disinfection. Double-gloving, wound irrigation, and tissue-conserving surgical techniques are routine in the operating room (OR). Local antibiotic administration is not common. Wound closure techniques and postoperative wound dressing routines vary greatly between the participating institutions.

Conclusions: With this study we provide an international overview on the heterogeneity of SSI prevention strategies in spine surgery. We demonstrated a large heterogeneity for pre-, peri- and postoperative measures to prevent SSI. Our data illustrated the need for developing universal guidelines and for testing areas of controversy in prospective clinical trials.
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http://dx.doi.org/10.1177/21925682211068414DOI Listing
February 2022

Administration of C5a Receptor Antagonist Improves the Efficacy of Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in the Acute Phase of Spinal Cord Injury.

J Neurotrauma 2022 May;39(9-10):667-682

Department of Physiology, Keio University School of Medicine, Tokyo, Japan.

Human-induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation during the acute phase of spinal cord injury (SCI) is not effective due to the inflammatory response occurring immediately after SCI, which negatively impacts transplanted cell survival. Therefore, we chose to study the powerful chemoattractant complement C5a as a method to generate a more favorable transplantation environment. We hypothesized that suppression of the inflammatory response immediately after SCI by C5a receptor antagonist (C5aRA) would improve the efficacy of hiPSC-NS/PCs transplantation for acute phase SCI. Here, we evaluated the influence of C5aRA on the inflammatory reaction during the acute phase after SCI, and observed significant reductions in several inflammatory cytokines, macrophages, neutrophils, and apoptotic markers. Next, we divided the SCI mice into four groups: 1) phosphate-buffered saline (PBS) only; 2) C5aRA only; 3) PBS + transplantation (PBS+TP); and 4) C5aRA + transplantation (C5aRA+TP). Immediately after SCI, C5aRA or PBS was injected once a day for 4 consecutive days, followed by hiPSC-NS/PC transplantation or PBS into the lesion epicenter on Day 4. The C5aRA+TP group had better functional improvement compared with the PBS only group. The C5aRA+TP group also had a significantly higher cell survival rate compared with the PBS+TP group. This study demonstrates that administration of C5aRA can suppress the inflammatory response during the acute phase of SCI, while improving the survival rate of transplanted hiPSC-NS/PCs, as well as enhancing motor functional restoration. Human-induced pluripotent stem cell-derived neural stem/progenitor cell transplantation with C5aRA is a promising treatment during the acute injury phase for SCI patients.
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http://dx.doi.org/10.1089/neu.2021.0225DOI Listing
May 2022

Craniocervical Instability in Ehlers-Danlos Syndrome-A Systematic Review of Diagnostic and Surgical Treatment Criteria.

Global Spine J 2022 Feb 23:21925682211068520. Epub 2022 Feb 23.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.

Study Design: Systematic review.

Objective: Ehlers-Danlos Syndrome (EDS) comprises a spectrum of connective tissue disorders, which may be associated with cranio-cervical instability (CCI). There is a lack of consensus on diagnostic imaging parameters, indications, and outcomes of surgical treatment.

Methods: This systematic review analyses the literature on diagnostic methods and/or criteria for CCI, screening the databases Ovid Medline, Embase, Cochrane Library, and PubMed. Articles were included based on the PRISMA guidelines and assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS) and according to their evidence level.

Results: Sixteen articles, including 78 surgical patients, met the inclusion criteria. The main diagnostic measures for CCI were dynamic x-rays and CT imaging. Ten different radiographic parameters were reported, of which 4 were the most frequently applied for surgical decision-making: the clivo-axial angle (CXA), the Harris measurement, the Grabb-Mapstone-Oakes measurement, and the angular displacement of C1 to C2. The evidence level ranged between III and V and the article quality between 4 and 8 out of 9 stars on the NOS Scale.

Conclusions: There is a lack of high quality, prospective evidence regarding the evaluation of suspected CCI in patients with EDS. Based on our systematic review, we recommend that the CXA, Harris measurement, Grabb-Mapstone-Oakes measurement, and the angular displacement of C1 to C2 be used to evaluate suspected CCI in EDS patients. Surgical fixation of suspected CCI should only be performed in cases with clear radiographic presence of instability and concordant symptoms/signs. Consensus-based guidelines and care pathways are required.
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http://dx.doi.org/10.1177/21925682211068520DOI Listing
February 2022

Developing Peri-Operative Rehabilitation in Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 6]: An Unexplored Opportunity?

Global Spine J 2022 Feb;12(1_suppl):97S-108S

Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, 25809The University of Hong Kong, Hong Kong, China.

Study Design: Narrative review.

Objective: Degenerative cervical myelopathy is one of the most frequent impairments of the spinal cord encountered internationally in adults. Currently, surgical decompression is the recommended treatment for people with DCM (PwCM) presenting with moderate to severe symptoms or neurological deficits. However, despite surgical intervention, not all patients make a complete recovery due to the irreversible tissue damage within the spinal cord. The objective of this review is to describe the state and gaps in the current literature on rehabilitation for PwCM and possible innovative rehabilitation strategies.

Methods: Literature search.

Results: In other neurological disorders such as stroke and acute traumatic spinal cord injury (SCI), timely and strategic rehabilitation has been shown to be indispensable for maximizing functional outcomes, and it is imperative that appropriate perioperative rehabilitative interventions accompany surgical approaches in order to enable the best outcomes. In this review, the current state of knowledge regarding rehabilitation for PwCM is described. Additionally, various therapies that have shown to improve outcomes in comparable neurological conditions such as stroke and SCI which may be translated to DCM will be reviewed.

Conclusions: We conclude that locomotor training and arm/hand therapy may benefit PwCM. Further, we conclude that body weight support, robotic assistance, and virtual/augmented reality therapies may be beneficial therapeutic analogs to locomotor and hand therapies.
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http://dx.doi.org/10.1177/21925682211050925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859699PMC
February 2022

Improving Awareness Could Transform Outcomes in Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 1].

Global Spine J 2022 Feb;12(1_suppl):28S-38S

Department of Surgery, Division of Neurosurgery, 7938University of Toronto, Toronto, ON, Canada.

Study Design: Literature Review (Narrative).

Objective: To introduce the number one research priority for Degenerative Cervical Myelopathy (DCM): Raising Awareness.

Methods: Raising awareness has been recognized by AO Spine RECODE-DCM as the number one research priority. This article reviews the evidence that awareness is low, the potential drivers, and why this must be addressed. Case studies of success from other diseases are also reviewed, drawing potential parallels and opportunities for DCM.

Results: DCM may affect as many as 1 in 50 adults, yet few will receive a diagnosis and those that do will wait many years for it. This leads to poorer outcomes from surgery and greater disability. DCM is rarely featured in healthcare professional training programs and has received relatively little research funding (<2% of Amyotrophic Lateral Sclerosis or Multiple Sclerosis over the last 25 years). The transformation of stroke and acute coronary syndrome services, from a position of best supportive care with occasional surgery over 50 years ago, to avoidable disability today, represents transferable examples of success and potential opportunities for DCM. Central to this is raising awareness.

Conclusion: Despite the devastating burden on the patient, recognition across research, clinical practice, and healthcare policy are limited. DCM represents a significant unmet need that must become an international public health priority.
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http://dx.doi.org/10.1177/21925682211050927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859708PMC
February 2022

Optimizing the Application of Surgery for Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 10].

Global Spine J 2022 Feb;12(1_suppl):147S-158S

Department of Neurological Surgery, 6529Thomas Jefferson University, Philadelphia, PA, USA.

Study Design: Literature Review (Narrative).

Objective: To introduce the number 10 research priority for Degenerative Cervical Myelopathy: Individualizing Surgery.

Methods: This article summarizes the current recommendations and indications for surgery, including how known prognostic factors such as injury time, age, disease severity, and associated comorbidities impact surgical outcome. It also considers key areas of uncertainty that should be the focus of future research.

Results: While a small proportion of conservatively managed patients may remain stable, the majority will deteriorate over time. To date, surgical decompression is the mainstay of treatment, able to halt disease progression and improve neurologic function and quality of life for most patients. Whilst this recognition has led to recommendations on when to offer surgery, there remain many uncertainties including the type of surgery, or timing in milder and/or asymptomatic cases. Their clarification has the potential to transform outcomes, by ensuring surgery offers each individual its maximum benefit.

Conclusion: Developing the evidence to better guide surgical decision-making at the individual patient level is a research priority for Degenerative Cervical Myelopathy.
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http://dx.doi.org/10.1177/21925682211062494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859702PMC
February 2022

AO Spine RECODE-DCM: Why Prioritize Research in Degenerative Cervical Myelopathy?

Global Spine J 2022 Feb;12(1_suppl):5S-7S

Academic Neurosurgery Unit, Department of Clinical Neurosurgery, University of Cambridge, Cambridge, United Kingdom.

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http://dx.doi.org/10.1177/21925682211035379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859707PMC
February 2022

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.

Global Spine J 2022 Feb;12(1_suppl):19S-27S

Division of Neurosurgery, Department of Clinical Neurosciences, 2152University of Cambridge, Cambridge, UK.

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.
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http://dx.doi.org/10.1177/21925682211062501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859709PMC
February 2022

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

Global Spine J 2022 Feb;12(1_suppl):122S-129S

Department of Neurosurgery, University of Cambridge, Cambridge, United Kingdom.

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.
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http://dx.doi.org/10.1177/21925682211039835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859704PMC
February 2022

Establishing Diagnostic Criteria for Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 3].

Global Spine J 2022 Feb;12(1_suppl):55S-63S

Department of Orthopaedics, University of British Columbia, Blusson Spinal Cord Center, Vancouver, British Columbia, Canada.

Study Design: Narrative review.

Objectives: To discuss the importance of establishing diagnostic criteria in Degenerative Cervical Myelopathy (DCM), including factors that must be taken into account and challenges that must be overcome in this process.

Methods: Literature review summarising current evidence of establishing diagnostic criteria for DCM.

Results: Degenerative Cervical Myelopathy (DCM) is characterised by a degenerative process of the cervical spine resulting in chronic spinal cord dysfunction and subsequent neurological disability. Diagnostic delays lead to progressive neurological decline with associated reduction in quality of life for patients. Surgical decompression may halt neurologic worsening and, in many cases, improves function. Therefore, making a prompt diagnosis of DCM in order to facilitate early surgical intervention is a clinical priority in DCM.

Conclusion: There are often extensive delays in the diagnosis of DCM. Presently, no single set of diagnostic criteria exists for DCM, making it challenging for clinicians to make the diagnosis. Earlier diagnosis and subsequent specialist referral could lead to improved patient outcomes using existing treatment modalities.
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http://dx.doi.org/10.1177/21925682211030871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859706PMC
February 2022

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.

Global Spine J 2022 Feb;12(1_suppl):78S-96S

Department of Neurosurgery, 2152University of Cambridge, Cambridge, UK.

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.
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http://dx.doi.org/10.1177/21925682211057546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859710PMC
February 2022

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

Global Spine J 2022 Feb;12(1_suppl):39S-54S

Division of Neurosurgery and Spine Program, University of Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1177/21925682211036071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859703PMC
February 2022

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

Global Spine J 2022 Feb;12(1_suppl):109S-121S

Department of Neurosurgery and The Miami Project to Cure Paralysis, The Miller School of Medicine, 12235University of Miami, Miami, FL, USA.

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.
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http://dx.doi.org/10.1177/21925682211052920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859698PMC
February 2022

Steroids in the Management of Preoperative Neurological Deficits in Metastatic Spine Disease: Results From the EPOSO Study.

Neurospine 2022 Mar 30;19(1):43-50. Epub 2022 Jan 30.

Department of Surgery, McGill University, Montreal, QC, Canada.

Objective: Patients presenting with neurological deficit secondary to metastatic epidural spinal cord compression (MESCC) are often treated with surgery in combination with high-dose corticosteroids. Despite steroids being commonly used, the evidence regarding the effect of corticosteroids on patient outcomes is limited. The objective of this study was to describe the effect of corticosteroid use on preoperative neurological function in patients with MESCC.

Methods: Patients who underwent surgery between August 2013 and February 2017 for the treatment of spinal metastases and received steroids to prevent neurologic deficits were included. Data regarding demographics, diagnosis, treatment, neurological function, adverse events, health-related quality of life, and survival were extracted from an international multicenter prospective cohort.

Results: A total of 30 patients treated surgically and receiving steroids at baseline were identified. Patients had a mean age of 58.2 years (standard deviation, 11.2 years) at time of surgery. Preoperatively, 50% of the patients experienced deterioration of neurological function, while in 30% neurological function was stable and 20% improved in neurological function. Lengthier steroid use did not correlate with improved or stabilized neurological function. Postoperative adverse events were observed in 18 patients (60%). Patients that stabilized or improved neurologically after steroid use showed a trend towards improved survival at 3- and 24-month postsurgery.

Conclusion: This study described the effect of steroids on preoperative neurological function in patients with MESCC. Stabilization or improvement of preoperative neurological function occurred in 50% of the patients.
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http://dx.doi.org/10.14245/ns.2142768.384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987562PMC
March 2022

History of the Department of Surgery at the University of Toronto: celebrating a centennial of progress and innovation.

Can J Surg 2022 Jan-Feb;65(1):E56-E65. Epub 2022 Feb 3.

From the Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ont.

Now in its centennial year since inauguration, the Department of Surgery at the University of Toronto lays claim to more than 500 faculty, 270 residents, and 250 clinical fellows. There are 7 direct entry residency training programs, and 4 subspecialty programs accredited by the Royal College of Physicians and Surgeons of Canada. There have been 10 chairs of the department since 1921. This article chronicles the life and times of the previous chairs in sequence; the success of the department originates from its many talented and luminary surgeons who have innovated and shaped their fields of surgery. In recent years, the department's academic productivity has been characterized by more than 1400 peer-reviewed publications per year, and annual research grant capture in excess of $90 million. Since the time of William Gallie, surgical trainees have been enabled to develop careers in surgery and science through the Gallie Program and, more recently, the Surgeon Scientist Training Program (SSTP) to attain higher graduate degrees. Providing quaternary surgical care at multiple hospital sites in Toronto, the Department of Surgery takes great pride in its robust clinical fellowship programs across all specialties that continue to attract trainees from around the world.
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http://dx.doi.org/10.1503/cjs.013621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820838PMC
March 2022

Clinical outcome measures and their evidence base in degenerative cervical myelopathy: a systematic review to inform a core measurement set (AO Spine RECODE-DCM).

BMJ Open 2022 Jan 19;12(1):e057650. Epub 2022 Jan 19.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

Objectives: To evaluate the measurement properties of outcome measures currently used in the assessment of degenerative cervical myelopathy (DCM) for clinical research.

Design: Systematic review DATA SOURCES: MEDLINE and EMBASE were searched through 4 August 2020.

Eligibility Criteria: Primary clinical research published in English and whose primary purpose was to evaluate the measurement properties or clinically important differences of instruments used in DCM.

Data Extraction And Synthesis: Psychometric properties and clinically important differences were both extracted from each study, assessed for risk of bias and presented in accordance with the Consensus-based Standards for the selection of health Measurement Instruments criteria.

Results: Twenty-nine outcome instruments were identified from 52 studies published between 1999 and 2020. They measured neuromuscular function (16 instruments), life impact (five instruments), pain (five instruments) and radiological scoring (five instruments). No instrument had evaluations for all 10 measurement properties and <50% had assessments for all three domains (ie, reliability, validity and responsiveness). There was a paucity of high-quality evidence. Notably, there were no studies that reported on structural validity and no high-quality evidence that discussed content validity. In this context, we identified nine instruments that are interpretable by clinicians: the arm and neck pain scores; the 12-item and 36-item short form health surveys; the Japanese Orthopaedic Association (JOA) score, modified JOA and JOA Cervical Myelopathy Evaluation Questionnaire; the neck disability index; and the visual analogue scale for pain. These include six scores with barriers to application and one score with insufficient criterion and construct validity.

Conclusions: This review aggregates studies evaluating outcome measures used to assess patients with DCM. Overall, there is a need for a set of agreed tools to measure outcomes in DCM. These findings will be used to inform the development of a core measurement set as part of AO Spine RECODE-DCM.
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http://dx.doi.org/10.1136/bmjopen-2021-057650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8772430PMC
January 2022

Degenerative Cervical Myelopathy: A Practical Approach to Diagnosis.

Global Spine J 2022 Jan 19:21925682211072847. Epub 2022 Jan 19.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.

Study Design: Narrative Review.

Objectives: The objective of this review is to provide a stepwise approach to the assessment of patients with potential symptoms of degenerative cervical myelopathy (DCM).

Methods: N/A.

Results: DCM is an overarching term used to describe progressive compression of the cervical spinal cord by age-related changes to the spinal axis. These alterations to normal anatomy narrow the spinal canal, reduce the space available for the spinal cord, and may ultimately compress the ascending and descending neural tracts. Patients with DCM present with a wide range of symptoms that can significantly impact quality of life, including bilateral hand numbness and paresthesia, gait impairment, motor weakness of the upper and lower extremities, and bladder and bowel dysfunction. Unfortunately, DCM is often misdiagnosed, resulting in delayed assessment and management by the appropriate specialist. The proper evaluation of a patient with suspected DCM includes obtaining a detailed patient history, conducting a comprehensive neurological examination, and ordering appropriate tests to rule in or out other diagnoses.

Conclusion: This review summarizes a stepwise approach to the diagnosis of patients with DCM.
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http://dx.doi.org/10.1177/21925682211072847DOI Listing
January 2022

The biology of ependymomas and emerging novel therapies.

Nat Rev Cancer 2022 Apr 14;22(4):208-222. Epub 2022 Jan 14.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.

Ependymomas are rare central nervous system tumours that can arise in the brain's supratentorial region or posterior fossa, or in the spinal cord. In 1924, Percival Bailey published the first comprehensive study of ependymomas. Since then, and especially over the past 10 years, our understanding of ependymomas has grown exponentially. In this Review, we discuss the evolution in knowledge regarding ependymoma subgroups and the resultant clinical implications. We also discuss key oncogenic and tumour suppressor signalling pathways that regulate tumour growth, the role of epigenetic dysregulation in the biology of ependymomas, and the various biological features of ependymoma tumorigenesis, including cell immortalization, stem cell-like properties, the tumour microenvironment and metastasis. We further review the limitations of current therapies such as relapse, radiation-induced cognitive deficits and chemotherapy resistance. Finally, we highlight next-generation therapies that are actively being explored, including tyrosine kinase inhibitors, telomerase inhibitors, anti-angiogenesis agents and immunotherapy.
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http://dx.doi.org/10.1038/s41568-021-00433-2DOI Listing
April 2022

Impact of Surgical Timing on Motor Level Lowering in Motor Complete Traumatic Spinal Cord Injury Patients.

J Neurotrauma 2022 May 21;39(9-10):651-657. Epub 2022 Feb 21.

Department of Neurosurgery, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Patients with complete traumatic spinal cord injury (tSCI) have a low potential to recover ambulation. Motor level recovery, adjacent to the level of injury, could influence functional independency. This study addresses whether surgical timing influences motor level recovery in patients with motor complete (American Spinal Injury Association [ASIA] Impairment Scale A [AIS A]) and motor incomplete (AIS B) tSCI. A retrospective cohort study was performed in the Netherlands in patients with AIS A/B tSCI (C2-L2), who consecutively underwent surgery between January 2010 and April 2020. Neurological examination was performed directly at presentation to the emergency room and at discharge from the rehabilitation facility. Motor level lowering, AIS grade, and upper and lower extremity motor score recovery were calculated for patients who underwent early (< 24 h) and late (24 h+) surgery. A total of 96 patients met the inclusion criteria. In the multi-variate analysis, late surgical decompression (24 h+) was negatively associated with ≥1 motor level lowering and ≥2 AIS grade improvement [odds ratio (OR) 0.11 [95% confidence interval (CI): 0.01, 0.67],  = 0.046, and OR 0.06 [95% CI: 0.00, 047],  = 0.030. respectively). The presence of sacral sparing (AIS B) at initial examination, and cervical level of the tSCI were associated with ≥1 motor level lowering. In addition, AO Spine C-type injuries were negatively associated with any type of neurological recovery, except motor level lowering. Although sensorimotor complete injuries as well as thoracolumbar injuries negatively influence neurological recovery, early surgical decompression (< 24 h) appears independently associated with enhanced neurological recovery in patients with traumatic spinal cord injury despite level and severity of injury.
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http://dx.doi.org/10.1089/neu.2021.0428DOI Listing
May 2022

Improving Assessment of Disease Severity and Strategies for Monitoring Progression in Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 4].

Global Spine J 2022 Feb 31;12(1_suppl):64S-77S. Epub 2021 Dec 31.

Department of Neurosurgery, 151895University of Cambridge, Cambridge, UK.

Study Design: Narrative Review.

Objective: To (i) discuss why assessment and monitoring of disease progression is critical in Degenerative cervical myelopathy (DCM); (ii) outline the important features of an ideal assessment tool and (iii) discuss current and novel strategies for detecting subtle deterioration in DCM.

Methods: Literature review.

Results: Degenerative cervical myelopathy is an overarching term used to describe progressive injury to the cervical spinal cord by age-related changes of the spinal axis. Based on a study by Smith et al (2020), the prevalence of DCM is approximately 2.3% and is expected to rise as the global population ages. Given the global impact of this disease, it is essential to address important knowledge gaps and prioritize areas for future investigation. As part of the AO Spine RECODE-DCM (Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy) project, a priority setting partnership was initiated to increase research efficiency by identifying the top ten research priorities for DCM. One of the top ten priorities for future DCM research was: What assessment tools can be used to evaluate functional impairment, disability and quality of life in people with DCM? What instruments, tools or methods can be used or developed to monitor people with DCM for disease progression or improvement either before or after surgical treatment?

Conclusions: With the increasing prevalence of DCM, effective surveillance of this population will require both the implementation of a monitoring framework as well as the development of new assessment tools.
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http://dx.doi.org/10.1177/21925682211063854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859700PMC
February 2022

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

Front Cell Neurosci 2021 9;15:741681. Epub 2021 Dec 9.

Department of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada.

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 . 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. , 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.
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http://dx.doi.org/10.3389/fncel.2021.741681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8695970PMC
December 2021

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

Front Cell Neurosci 2021 6;15:638021. Epub 2021 Dec 6.

Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada.

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 toxicity, has yet to be investigated for NPC ablation. In this study, we demonstrate successful generation and 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 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.
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http://dx.doi.org/10.3389/fncel.2021.638021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8685296PMC
December 2021

The MAPK Signaling Pathway Presents Novel Molecular Targets for Therapeutic Intervention after Traumatic Spinal Cord Injury: A Comparative Cross-Species Transcriptional Analysis.

Int J Mol Sci 2021 Nov 29;22(23). Epub 2021 Nov 29.

Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON M5T 2S8, Canada.

Despite the debilitating consequences following traumatic spinal cord injury (SCI), there is a lack of safe and effective therapeutics in the clinic. The species-specific responses to SCI present major challenges and opportunities for the clinical translation of biomolecular and pharmacological interventions. Recent transcriptional analyses in preclinical SCI studies have provided a snapshot of the local SCI-induced molecular responses in different animal models. However, the variation in the pathogenesis of traumatic SCI across species is yet to be explored. This study aims to identify and characterize the common and inconsistent SCI-induced differentially expressed genes across species to identify potential therapeutic targets of translational relevance. A comprehensive search of open-source transcriptome datasets identified four cross-compatible microarray experiments in rats, mice, and salamanders. We observed consistent expressional changes in extracellular matrix components across the species. Conversely, salamanders showed downregulation of intracellular MAPK signaling compared to rodents. Additionally, sequence conservation and interactome analyses highlighted the well-preserved sequences of and with extensive protein-protein interaction networks. Lastly, in vivo immunohistochemical staining for fibronectin was used to validate the observed expressional pattern. These transcriptional changes in extracellular and MAPK pathways present potential therapeutic targets for traumatic SCI with promising translational relevance.
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http://dx.doi.org/10.3390/ijms222312934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657729PMC
November 2021

Gathering Global Perspectives to Establish the Research Priorities and Minimum Data Sets for Degenerative Cervical Myelopathy: Sampling Strategy of the First Round Consensus Surveys of AO Spine RECODE-DCM.

Global Spine J 2022 Feb 8;12(1_suppl):8S-18S. Epub 2021 Dec 8.

Division of Neurosurgery, Department of Surgery, 7938University of Toronto, Canada.

Study Design: Survey.

Introduction: AO Spine Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy (AO Spine RECODE-DCM) is an international initiative that aims to accelerate knowledge discovery and improve outcomes by developing a consensus framework for research. This includes defining the top research priorities, an index term and a minimum data set (core outcome set and core data elements set - core outcome set (COS)/core data elements (CDE)).

Objective: To describe how perspectives were gathered and report the detailed sampling characteristics.

Methods: A two-stage, electronic survey was used to gather and seek initial consensus. Perspectives were sought from spinal surgeons, other healthcare professionals and people with degenerative cervical myelopathy (DCM). Participants were allocated to one of two parallel streams: (1) priority setting or (2) minimum dataset. An email campaign was developed to advertise the survey to relevant global stakeholder individuals and organisations. People with DCM were recruited using the international DCM charity Myelopathy.org and its social media channels. A network of global partners was recruited to act as project ambassadors. Data from Google Analytics, MailChimp and Calibrum helped optimise survey dissemination.

Results: Survey engagement was high amongst the three stakeholder groups: 208 people with DCM, 389 spinal surgeons and 157 other healthcare professionals. Individuals from 76 different countries participated; the United States, United Kingdom and Canada were the most common countries of participants.

Conclusion: AO Spine RECODE-DCM recruited a diverse and sufficient number of participants for an international PSP and COS/CDE process. Whilst PSP and COS/CDE have been undertaken in other fields, to our knowledge, this is the first time they have been combined in one process.
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http://dx.doi.org/10.1177/21925682211047546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859701PMC
February 2022

Long-term functional outcome of surgical treatment for degenerative cervical myelopathy.

J Neurosurg Spine 2021 Nov 26:1-11. Epub 2021 Nov 26.

1Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands.

Objective: Degenerative cervical myelopathy (DCM) is a major global cause of spinal cord dysfunction. Surgical treatment is considered a safe and effective way to improve functional outcome, although information about long-term functional outcome remains scarce despite increasing longevity. The objective of this study was to describe functional outcome 10 years after surgery for DCM.

Methods: A prospective observational cohort study was undertaken in a university-affiliated neurosurgery department. All patients who underwent surgery for DCM between 2008 and 2010 as part of the multicenter Cervical Spondylotic Myelopathy International trial were included. Participants were approached for additional virtual assessment 10 years after surgery. Functional outcome was assessed according to the modified Japanese Orthopaedic Association (mJOA; scores 0-18) score at baseline and 1, 2, and 10 years after surgery. The minimal clinically important difference was defined as 1-, 2-, or 3-point improvement for mild, moderate, and severe myelopathy, respectively. Outcome was considered durable when stabilization or improvement after 2 years was maintained at 10 years. Self-evaluated effect of surgery was assessed using a 4-point Likert-like scale. Demographic, clinical, and surgical data were compared between groups that worsened and improved or remained stable using descriptive statistics. Functional outcome was compared between various time points during follow-up with linear mixed models.

Results: Of the 42 originally included patients, 37 participated at follow-up (11.9% loss to follow-up, 100% response rate). The mean patient age was 56.1 years, and 42.9% of patients were female. Surgical approaches were anterior (76.2%), posterior (21.4%), or posterior with fusion (2.4%). The mean follow-up was 10.8 years (range 10-12 years). The mean mJOA score increased significantly from 13.1 (SD 2.3) at baseline to 14.2 (SD 3.3) at 10 years (p = 0.01). A minimal clinically important difference was achieved in 54.1%, and stabilization of functional status was maintained in 75.0% in the long term. Patients who worsened were older (median 63 vs 52 years, p < 0.01) and had more comorbidities (70.0% vs 25.9%, p < 0.01). A beneficial effect of surgery was self-reported by 78.3% of patients.

Conclusions: Surgical treatment for DCM results in satisfactory improvement of functional outcome that is maintained at 10-year follow-up.
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http://dx.doi.org/10.3171/2021.8.SPINE21651DOI Listing
November 2021

Imaging and Electrophysiology for Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 9].

Global Spine J 2022 Feb 19;12(1_suppl):130S-146S. Epub 2021 Nov 19.

Department of Neurosurgery, 5506Medical College of Wisconsin, Wauwatosa, WI, USA.

Study Design: Narrative review.

Objective: The current review aimed to describe the role of existing techniques and emerging methods of imaging and electrophysiology for the management of degenerative cervical myelopathy (DCM), a common and often progressive condition that causes spinal cord dysfunction and significant morbidity globally.

Methods: A narrative review was conducted to summarize the existing literature and highlight future directions.

Results: Anatomical magnetic resonance imaging (MRI) is well established in the literature as the key imaging tool to identify spinal cord compression, disc herniation/bulging, and inbuckling of the ligamentum flavum, thus facilitating surgical planning, while radiographs and computed tomography (CT) provide complimentary information. Electrophysiology techniques are primarily used to rule out competing diagnoses. However, signal change and measures of cord compression on conventional MRI have limited utility to characterize the degree of tissue injury, which may be helpful for diagnosis, prognostication, and repeated assessments to identify deterioration. Early translational studies of quantitative imaging and electrophysiology techniques show potential of these methods to more accurately reflect changes in spinal cord microstructure and function.

Conclusion: Currently, clinical management of DCM relies heavily on anatomical MRI, with additional contributions from radiographs, CT, and electrophysiology. Novel quantitative assessments of microstructure, perfusion, and function have the potential to transform clinical practice, but require robust validation, automation, and standardization prior to uptake.
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http://dx.doi.org/10.1177/21925682211057484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859711PMC
February 2022
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