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1.
Eur Spine J ; 29(Suppl 2): 162-170, 2020 12.
Article En | MEDLINE | ID: mdl-32296950

OBJECTIVE: The treatment of a retro-odontoid pseudotumor mass associated with severe spinal cord compression is challenging due to the complex regional anatomy. Here, we present an attractive treatment option involving a single-stage posterior transdural microsurgical resection followed by instrumented cervical reconstruction. METHODS: We describe three patients presenting with clinical signs of cervical myelopathy and an imaging finding of mucoid and fibrous soft or semi-soft retro-odontoid pseudotumor mass with significant spinal cord compression at the C1/C2 level. Given the severity of the symptoms, surgical decompression was planned and fusion was necessitated by the severe degenerative osteoarthritis seen at the C1/C2 level with signs of instability. Using a standard posterior approach to the spine, a suboccipital decompression by craniectomy and laminectomy of C1, C2 and C3 was performed. The masses were visualized and confirmed with ultrasound imaging, and intraoperative neurosurgical monitoring was applied. The dura was then opened from the level of C0-C2. Exiting C2-C3 nerve roots were identified and protected throughout the procedure, and the dentate ligament was cut to facilitate access. Incision of the anterior dura provided easy access to the lesion for resection without any spinal cord retraction. Multiple intraoperative samples were sent to pathology for tissue diagnosis. The dura was closed with sutures and an overlay of fibrin sealant with collagen matrix sponge. The fusion procedures were performed using a standard occipital cervical plate and screws technique with contoured titanium rods. CONCLUSIONS: The posterior cervical transdural approach is a safe alternative procedure for mucoid and fibrous soft or semi-soft retro-odontoid pseudotumor mass removal. Preoperative CT scan can evaluate tissue characteristics and distinguish between a soft or ossified mass in front of the spinal cord. Local anatomical conditions facilitate less bleeding and adhesions, together with less spinal cord traction, in the intradural space. Cranio-cervical and suboccipital stabilization can be easily and safely performed with this exposure.


Odontoid Process , Spinal Cord Compression , Cervical Vertebrae/diagnostic imaging , Cervical Vertebrae/surgery , Humans , Laminectomy , Magnetic Resonance Imaging , Odontoid Process/surgery
3.
Nat Commun ; 9(1): 3000, 2018 07 26.
Article En | MEDLINE | ID: mdl-30050138

The original version of this Article omitted a declaration from the competing interests statement, which should have included the following: 'R.D.S. is a cofounder, stock holder, and scientific advisory board member of Jounce Therapeutics and Neon Therapeutics, and a member of the scientific advisory boards of BioLegend, Constellation, Lytix, and NGM. He also received research funding from Janssen and Agios.'. This has now been corrected in both the PDF and HTML versions of the Article.

4.
J Immunol Methods ; 453: 30-36, 2018 02.
Article En | MEDLINE | ID: mdl-28974367

Antigen-specific T cells play a crucial role for the host protective immunity against viruses and other diseases. The use of mass cytometry together with a combinatorial multiplex tetramer staining has successfully been applied for probing and characterization of multiple antigen-specific CD8+ T cells in human blood samples. The present study shows that this approach can also be used to rapidly assess the magnitude of influenza-specific CD8+ T cell epitope dominance across lymph nodes and lungs in a murine model of a highly pathological influenza infection. Moreover, we show feasibility of extending this approach to include concurrent identification of virus-specific CD4+ T cells. By using a double coding approach, we probed for five influenza-specific MHCI-peptide complexes as well as one influenza-specific MHCII-peptide complex in the presence of irrelevant control peptides and show that this approach is capable of tracking antigen-specific T cells across individual lymph nodes and lungs. The simultaneous staining with 26 surface maker molecules further facilitated an in-depth characterization of T cells reacting with influenza epitopes and revealed tissue specific phenotypic differences between CD4+ T cells targeting the same pathogenic epitope. In conclusion, this approach provides the possibility for a rapid and comprehensive analysis of antigen-specific CD8+ and CD4+ T cells in different disease settings that might be advantageous for subsequent vaccine formulation strategies.


CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Influenza A virus/immunology , Mass Spectrometry/methods , Orthomyxoviridae Infections/diagnosis , Animals , Antigens, Viral/metabolism , Epitopes, T-Lymphocyte/metabolism , Histocompatibility Antigens/metabolism , Influenza Vaccines , Lymphocyte Activation , Mice , Peptides/metabolism , Protein Binding , Staining and Labeling
5.
Nat Commun ; 8(1): 562, 2017 09 15.
Article En | MEDLINE | ID: mdl-28916749

The analysis of neoantigen-specific CD8+ T cells in tumour-bearing individuals is challenging due to the small pool of tumour antigen-specific T cells. Here we show that mass cytometry with multiplex combinatorial tetramer staining can identify and characterize neoantigen-specific CD8+ T cells in mice bearing T3 methylcholanthrene-induced sarcomas that are susceptible to checkpoint blockade immunotherapy. Among 81 candidate antigens tested, we identify T cells restricted to two known neoantigens simultaneously in tumours, spleens and lymph nodes in tumour-bearing mice. High-dimensional phenotypic profiling reveals that antigen-specific, tumour-infiltrating T cells are highly heterogeneous. We further show that neoantigen-specific T cells display a different phenotypic profile in mice treated with anti-CTLA-4 or anti-PD-1 immunotherapy, whereas their peripheral counterparts are not affected by the treatments. Our results provide insights into the nature of neoantigen-specific T cells and the effects of checkpoint blockade immunotherapy.Immune checkpoint blockade (ICB) therapies can unleash anti-tumour T-cell responses. Here the authors show, by integrating MHC tetramer multiplexing, mass cytometry and high-dimensional analyses, that neoantigen-specific, tumour-infiltrating T cells are highly heterogeneous and are subjected to ICB modulations.


Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Sarcoma, Experimental/immunology , Animals , Antineoplastic Agents, Immunological/pharmacology , CD8-Positive T-Lymphocytes/drug effects , CTLA-4 Antigen/antagonists & inhibitors , Immunophenotyping , Immunotherapy , Lymphocytes, Tumor-Infiltrating/drug effects , Methylcholanthrene/toxicity , Mice , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Sarcoma, Experimental/chemically induced
6.
AJNR Am J Neuroradiol ; 38(6): 1266-1273, 2017 Jun.
Article En | MEDLINE | ID: mdl-28428212

BACKGROUND AND PURPOSE: T2*-weighted imaging provides sharp contrast between spinal cord GM and WM, allowing their segmentation and cross-sectional area measurement. Injured WM demonstrates T2*WI hyperintensity but requires normalization for quantitative use. We introduce T2*WI WM/GM signal-intensity ratio and compare it against cross-sectional area, the DTI metric fractional anisotropy, and magnetization transfer ratio in degenerative cervical myelopathy. MATERIALS AND METHODS: Fifty-eight patients with degenerative cervical myelopathy and 40 healthy subjects underwent 3T MR imaging, covering C1-C7. Metrics were automatically extracted at maximally compressed and uncompressed rostral/caudal levels. Normalized metrics were compared with t tests, area under the curve, and logistic regression. Relationships with clinical measures were analyzed by using Pearson correlation and multiple linear regression. RESULTS: The maximally compressed level cross-sectional area demonstrated superior differences (P = 1 × 10-13), diagnostic accuracy (area under the curve = 0.890), and univariate correlation with the modified Japanese Orthopedic Association score (0.66). T2*WI WM/GM showed strong differences (rostral: P = 8 × 10-7; maximally compressed level: P = 1 × 10-11; caudal: P = 1 × 10-4), correlations (modified Japanese Orthopedic Association score; rostral: -0.52; maximally compressed level: -0.59; caudal: -0.36), and diagnostic accuracy (rostral: 0.775; maximally compressed level: 0.860; caudal: 0.721), outperforming fractional anisotropy and magnetization transfer ratio in most comparisons and cross-sectional area at rostral/caudal levels. Rostral T2*WI WM/GM showed the strongest correlations with focal motor (-0.45) and sensory (-0.49) deficits and was the strongest independent predictor of the modified Japanese Orthopedic Association score (P = .01) and diagnosis (P = .02) in multivariate models (R2 = 0.59, P = 8 × 10-13; area under the curve = 0.954, respectively). CONCLUSIONS: T2*WI WM/GM shows promise as a novel biomarker of WM injury. It detects damage in compressed and uncompressed regions and contributes substantially to multivariate models for diagnosis and correlation with impairment. Our multiparametric approach overcomes limitations of individual measures, having the potential to improve diagnostics, monitor progression, and predict outcomes.


Gray Matter/diagnostic imaging , Magnetic Resonance Imaging/methods , Spinal Cord Injuries/diagnostic imaging , Spinal Cord/diagnostic imaging , White Matter/diagnostic imaging , Adult , Aged , Anatomy, Cross-Sectional , Anisotropy , Diffusion Tensor Imaging , Disability Evaluation , Female , Humans , Image Processing, Computer-Assisted , Male , Middle Aged , Reproducibility of Results , Spinal Cord Compression/diagnostic imaging
7.
AJNR Am J Neuroradiol ; 38(6): 1257-1265, 2017 Jun.
Article En | MEDLINE | ID: mdl-28428213

BACKGROUND AND PURPOSE: DTI, magnetization transfer, T2*-weighted imaging, and cross-sectional area can quantify aspects of spinal cord microstructure. However, clinical adoption remains elusive due to complex acquisitions, cumbersome analysis, limited reliability, and wide ranges of normal values. We propose a simple multiparametric protocol with automated analysis and report normative data, analysis of confounding variables, and reliability. MATERIALS AND METHODS: Forty healthy subjects underwent T2WI, DTI, magnetization transfer, and T2*WI at 3T in <35 minutes using standard hardware and pulse sequences. Cross-sectional area, fractional anisotropy, magnetization transfer ratio, and T2*WI WM/GM signal intensity ratio were calculated. Relationships between MR imaging metrics and age, sex, height, weight, cervical cord length, and rostrocaudal level were analyzed. Test-retest coefficient of variation measured reliability in 24 DTI, 17 magnetization transfer, and 16 T2*WI datasets. DTI with and without cardiac triggering was compared in 10 subjects. RESULTS: T2*WI WM/GM showed lower intersubject coefficient of variation (3.5%) compared with magnetization transfer ratio (5.8%), fractional anisotropy (6.0%), and cross-sectional area (12.2%). Linear correction of cross-sectional area with cervical cord length, fractional anisotropy with age, and magnetization transfer ratio with age and height led to decreased coefficients of variation (4.8%, 5.4%, and 10.2%, respectively). Acceptable reliability was achieved for all metrics/levels (test-retest coefficient of variation < 5%), with T2*WI WM/GM comparing favorably with fractional anisotropy and magnetization transfer ratio. DTI with and without cardiac triggering showed no significant differences for fractional anisotropy and test-retest coefficient of variation. CONCLUSIONS: Reliable multiparametric assessment of spinal cord microstructure is possible by using clinically suitable methods. These results establish normalization procedures and pave the way for clinical studies, with the potential for improving diagnostics, objectively monitoring disease progression, and predicting outcomes in spinal pathologies.


Cervical Vertebrae/diagnostic imaging , Cervical Vertebrae/ultrastructure , Diffusion Tensor Imaging/methods , Magnetic Resonance Imaging/methods , Spinal Cord Injuries/diagnostic imaging , Spinal Cord/diagnostic imaging , Spinal Cord/ultrastructure , Adult , Aged , Anatomy, Cross-Sectional , Anisotropy , Feasibility Studies , Female , Healthy Volunteers , Heart/physiology , Humans , Image Processing, Computer-Assisted , Male , Middle Aged , Reference Values , Reproducibility of Results , Young Adult
8.
Spinal Cord ; 55(6): 618-623, 2017 Jun.
Article En | MEDLINE | ID: mdl-28418395

STUDY DESIGN: Retrospective analysis of a prospective registry and surgeon survey. OBJECTIVES: To identify surgeon opinion on ideal practice regarding the timing of decompression/stabilization for spinal cord injury and actual practice. Discrepancies in surgical timing and barriers to ideal timing of surgery were explored. SETTING: Canada. METHODS: Patients from the Rick Hansen Spinal Cord Registry (RHSCIR, 2004-2014) were reviewed to determine actual timing of surgical management. Following data collection, a survey was distributed to Canadian surgeons, asking for perceived to be the optimal and actual timings of surgery. Discrepancies between actual data and surgeon survey responses were then compared using χ2 tests and logistic regression. RESULTS: The majority of injury patterns identified in the registry were treated operatively. ASIA Impairment Scale (AIS) C/D injuries were treated surgically less frequently in the RHSCIR data and surgeon survey (odds ratio (OR)= 0.39 and 0.26). Significant disparities between what surgeons identified as ideal, actual current practice and RHSCIR data were demonstrated. A great majority of surgeons (93.0%) believed surgery under 24 h was ideal for cervical AIS A/B injuries and 91.0% for thoracic AIS A/B/C/D injuries. Definitive surgical management within 24 h was actually accomplished in 39.0% of cervical and 45.0% of thoracic cases. CONCLUSION: Ideal surgical timing for traumatic spinal cord injury (tSCI) within 24 h of injury was identified, but not accomplished. Discrepancies between the opinions on the optimal and actual timing of surgery in tSCI patients suggest the need for strategies for knowledge translation and reduction of administrative barriers to early surgery.


Neurosurgical Procedures , Spinal Cord Injuries/epidemiology , Spinal Cord Injuries/surgery , Time-to-Treatment , Adolescent , Adult , Aged , Aged, 80 and over , Canada/epidemiology , Cervical Vertebrae , Female , Humans , Male , Middle Aged , Neurosurgeons , Prospective Studies , Registries , Retrospective Studies , Surveys and Questionnaires , Thoracic Vertebrae , Young Adult
9.
Spine J ; 17(6): 759-767, 2017 06.
Article En | MEDLINE | ID: mdl-26239762

BACKGROUND: With recent advances in oncologic treatments, there has been an increase in patient survival rates and concurrently an increase in the number of incidence of symptomatic spinal metastases. Because elderly patients are a substantial part of the oncology population, their types of treatment as well as the possible impact their treatment will have on healthcare resources need to be further examined. PURPOSE: We studied whether age has a significant influence on quality of life and survival in surgical interventions for spinal metastases. STUDY DESIGN: We used data from a multicenter prospective study by the Global Spine Tumor Study Group (GSTSG). This GSTSG study involved 1,266 patients who were admitted for surgical treatments of symptomatic spinal metastases at 22 spinal centers from different countries and followed up for 2 years after surgery. PATIENT SAMPLE: There were 1,266 patients recruited between March 2001 and October 2014. OUTCOME MEASURES: Patient demographics were collected along with outcome measures, including European Quality of Life-5 Dimensions (EQ-5D), neurologic functions, complications, and survival rates. METHODS: We realized a multicenter prospective study of 1,266 patients admitted for surgical treatment of symptomatic spinal metastases. They were divided and studied into three different age groups: <70, 70-80, and >80 years. RESULTS: Despite a lack of statistical difference in American Society of Anesthesiologists (ASA) score, Frankel neurologic score, or Karnofsky functional score at presentation, patients >80 years were more likely to undergo emergency surgery and palliative procedures compared with younger patients. Postoperative complications were more common in the oldest age group (33.3% in the >80, 23.9% in the 70-80, and 17.9% for patients <70 years, p=.004). EQ-5D improved in all groups, but survival expectancy was significantly longer in patients <70 years old (p=.02). Furthermore, neurologic recovery after surgery was lower in patients >80 years old. CONCLUSIONS: Surgeons should not be biased against operating elderly patients. Although survival rates and neurologic improvements in the elderly patients are lower than for younger patients, operating the elderly is compounded by the fact that they undergo more emergency and palliative procedures, despite good ASA scores and functional status. Age in itself should not be a determinant of whether to operate or not, and operations should not be avoided in the elderly when indicated.


Neurosurgical Procedures/adverse effects , Postoperative Complications/epidemiology , Spinal Neoplasms/surgery , Adult , Age Factors , Aged , Aged, 80 and over , Contraindications, Procedure , Female , Humans , Male , Middle Aged , Neurosurgical Procedures/statistics & numerical data , Quality of Life , Spinal Neoplasms/secondary
10.
Z Orthop Unfall ; 154(1): 35-42, 2016 Feb.
Article De | MEDLINE | ID: mdl-27340713

Optimal treatment of injuries to the thoracolumbar spine is based on a detailed analysis of instability, as indicated by injury morphology and neurological status, together with significant modifying factors. A classification system helps to structure this analysis and should also provide guidance for treatment. Existing classification systems, such as the Magerl classification, are complex and do not include the neurological status, while the TLICS system has been accused of over-simplifying the influence of fracture morphology and instability. The AOSpine classification group has developed a new classification system, based mainly upon the Magerl and TLICS classifications, and with the aim of overcoming these drawbacks. This differentiates three main types of injury: Type A lesions are compression lesions to the anterior column; Type B lesions are distraction lesions of either the anterior or the posterior column; Type C lesions are translationally unstable lesions. Type A and B lesions are split into subgroups. The neurological damage is graded in 5 steps, ranging from a transient neurological deficit to complete spinal cord injury. Additional modifiers describe disorders which affect treatment strategy, such as osteoporosis or ankylosing diseases. Evaluations of intra- and inter-observer reliability have been very promising and encourage the introduction of this AOSpine classification of thoracolumbar injuries to the German speaking community.


Lumbar Vertebrae/injuries , Spinal Cord Compression/diagnosis , Spinal Cord Injuries/diagnosis , Spinal Fractures/diagnosis , Thoracic Vertebrae/injuries , Trauma Severity Indices , Germany , Spinal Cord Compression/classification , Spinal Cord Compression/etiology , Spinal Cord Injuries/classification , Spinal Cord Injuries/etiology , Spinal Fractures/classification , Spinal Fractures/complications
11.
Spinal Cord ; 54(12): 1145-1151, 2016 Dec.
Article En | MEDLINE | ID: mdl-27241449

BACKGROUND: Automated sensor-based assessments of upper extremity (UE) function after cervical spinal cord injury (SCI) could provide more detailed tracking of individual recovery profiles than is possible with existing assessments, and optimize the delivery and assessment of new interventions. The design of reliable automated assessments requires identifying the key variables that need to be measured to meaningfully quantify UE function. An unanswered question is to what extent measures of sensorimotor impairment can quantitatively predict performance on functional tasks. OBJECTIVE: The objective was to define the predictive value of impairment measures for concurrent functional task performance in traumatic cervical SCI, as measured by the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP). SETTING: Retrospective analysis. METHODS: A data set of 138 GRASSP assessments was analyzed. The Strength and Sensation modules were used as measures of impairment, whereas the concurrent Prehension Performance module was used as the surrogate measure of function. Classifiers were trained to predict the scores on each of the six individual tasks in the Prehension Performance module. The six scores were added to obtain a total score. RESULTS: The Spearman's ρ between predicted and actual total Prehension Performance scores was 0.84. Predictions using both the Strength and Sensation scores were not found to be superior to predictions using the Strength scores alone. CONCLUSIONS: Measures of UE motor impairment are highly predictive of functional task performance after cervical SCI. Automated sensor-based assessments of UE motor function after SCI can rely on measuring only impairment and estimating functional performance accordingly.


Accelerometry/methods , Cervical Cord/injuries , Motor Activity/physiology , Spinal Cord Injuries/diagnosis , Spinal Cord Injuries/physiopathology , Upper Extremity/physiopathology , Accelerometry/instrumentation , Cervical Cord/physiopathology , Cross-Sectional Studies , Disability Evaluation , Humans , Longitudinal Studies , Machine Learning , Prognosis , Recovery of Function/physiology , Retrospective Studies
13.
Spinal Cord ; 54(10): 872-877, 2016 Oct.
Article En | MEDLINE | ID: mdl-26882491

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Although cardiac arrhythmias are relatively well recognized in the chronic stage after spinal cord injury (SCI), little is known regarding its occurrence during the early stage. The objective of this study was to examine electrocardiogram changes within the first 72 h after acute traumatic SCI. SETTING: Acute spine trauma center, Toronto, Ontario, CanadaMethods:This study included all consecutive patients with spine trauma admitted to our institution from January 1998 to June 2007 who had an electrocardiogram within the first 72 h post trauma. Patients were divided into four groups: (I) patients with motor complete SCI at T6 or above; (II) patients with motor incomplete SCI at T6 or above; (III) patients with spine trauma but no/minor SCI at T6 or above; and (IV) patients with SCI below T6. RESULTS: There were 69 men and 20 women with mean age of 53.8 years (16-88 years). All groups were comparable regarding age, sex, pre-existing comorbidities and cause of SCI. There were no significant differences among the groups regarding predominant rhythm, PR interval, atrial-ventricular conduction, ventricular rate, QRS axis and intraventricular conduction abnormalities. Nonetheless, patients in Group I had longer RR interval (P=0.016), longer QTc (P=0.025) and more prolonged duration of the longest QRS (P=0.017) in comparison with the other groups. CONCLUSIONS: Our results indicate that electrocardiogram abnormalities are more common within the first 72 h following acute traumatic, motor complete, cervical or high-thoracic SCI. This may represent early manifestations of autonomic dysfunction due to disruption of descending cardiovascular pathways in individuals with severe SCI at T6 or above.


Heart Diseases/etiology , Spinal Cord Injuries/complications , Adolescent , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , Cohort Studies , Electrocardiography , Female , Heart Diseases/diagnosis , Humans , Male , Middle Aged , Young Adult
14.
Spinal Cord ; 54(1): 29-33, 2016 Jan.
Article En | MEDLINE | ID: mdl-26055818

STUDY DESIGN: Cross-sectional survey. OBJECTIVE: To examine the association between psychological characteristics in self-management and probable depression status in individuals with a traumatic spinal cord injury (SCI). SETTING: Community-dwelling individuals with traumatic SCI living across Canada. METHODS: Individuals with SCI were recruited by email via the Rick Hansen Institute as well as an outpatient hospital spinal clinic. Data were collected by self-report using an online survey. Standardized questionnaires were embedded within a larger survey and included the Hospital Anxiety and Depression Scale (HADS), the short version of the Patient Activation Measure (PAM), the Moorong Self-Efficacy Scale (MSES) and the Pearlin-Schooler Mastery Scale (PMS). RESULTS: Individuals with probable depression (n=25) had lower self-efficacy (67.9 vs 94.2, P<0.0001), mastery (18.9 vs 22.9, P<0.0001) and patient activation (60.4 vs 71.6, P<0.0001) as well as higher anxiety (9.0 vs 5.5, P<0.0001), compared with their non-depressed counterparts (n=75). A logistic regression determined that lower self-efficacy and mastery scores as well as less time since injury were associated with depression status (P=0.002; P=0.02 and P=0.02, respectively). Individuals with higher anxiety scores were almost 1.5 times more likely to be depressed, while older age was positively associated with depression status (P=0.016 and P=0.024, respectively). CONCLUSION: Interventions for depression in SCI, including a self-management program, should target factors such as self-efficacy and mastery, which could improve secondary medical complications and overall quality of life.


Depression/etiology , Self Care/methods , Spinal Cord Injuries/psychology , Adult , Aged , Cross-Sectional Studies , Female , Health Surveys , Humans , Logistic Models , Male , Middle Aged , Psychiatric Status Rating Scales , Self Efficacy , Spinal Cord Injuries/complications , Spinal Cord Injuries/therapy , Statistics, Nonparametric
15.
Exp Neurol ; 276: 59-71, 2016 Feb.
Article En | MEDLINE | ID: mdl-26394202

Cervical spinal cord injury (SCI) can result in devastating functional deficits that involve the respiratory and hand function. The mammalian spinal cord has limited ability to regenerate and restore meaningful functional recovery following SCI. Riluzole, 2-amino-6-trifluoromethoxybenzothiazole, an anti-glutamatergic drug has been shown to reduce excitotoxicity and confer neuroprotection at the site of injury following experimental SCI. Based on promising preclinical studies, riluzole is currently under Phase III clinical trial for the treatment of SCI (ClinicalTrials.gov: NCT01597518). Riluzole's anti-glutamatergic role has the potential to regulate neuronal function and provide neuroprotection and influence glutamatergic connections distal to the initial injury leading to enhanced functional recovery following SCI. In order to investigate this novel role of riluzole we used a high cervical hemisection model of SCI, which interrupts all descending input to motoneurons innervating the ipsilateral forelimb and diaphragm muscles. Following C2 spinal cord hemisection, animals were placed into one of two groups: one group received riluzole (8 mg/kg) 1 h after injury and every 12 h thereafter for 7 days at 6 mg/kg, while the second group of injured rats received vehicle solution for the same duration of time. A third group of sham injured rats underwent a C2 laminectomy without hemisection and served as uninjured control rats. Interestingly, this study reports a significant loss of motoneurons within the cervical spinal cord caudal to C2 hemisection injury. Disruption of descending input led to a decrease in glutamatergic synapses and motoneurons caudal to the injury while riluzole treatment significantly limited this decline. Functionally, Hoffmann reflex recordings revealed an increase in the excitability of the remaining ipsilateral cervical motoneurons and significant improvements in skilled and unskilled forelimb function and respiratory motor function in the riluzole-treated animals. In conclusion, using a C2 hemisection injury model, this study provides novel evidence of motoneuron loss caudal to the injury and supports riluzole's capacity to promote neuronal preservation and function of neural network caudal to the SCI resulting in early and sustained functional improvements.


Motor Neurons/drug effects , Neurons/drug effects , Recovery of Function/drug effects , Respiratory Mechanics/drug effects , Riluzole/therapeutic use , Spinal Cord Injuries/drug therapy , Animals , Cell Survival/drug effects , Cervical Cord , Male , Motor Neurons/physiology , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Neurons/physiology , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Rats , Rats, Wistar , Recovery of Function/physiology , Respiratory Mechanics/physiology , Riluzole/pharmacology , Spinal Cord Injuries/pathology
16.
Spinal Cord ; 54(1): 8-15, 2016 Jan.
Article En | MEDLINE | ID: mdl-26099215

BACKGROUND: Riluzole is a sodium channel-blocking agent used in treating amyotrophic lateral sclerosis. It has been approved by the U.S. Food and Drug Administration, Canadian and Australian authorities, and in many other countries. A phase I trial of riluzole for acute spinal cord injury (SCI) provided safety and pharmacokinetic data and suggested neuroprotective benefits. A phase IIB/III double-blinded randomized controlled trial (RCT) started in January 2014 (https://clinicaltrials.gov, NCT01597518). This article describes the pathophysiological rationale, preclinical experience and design of the phase IIB/III RCT of Riluzole in Acute Spinal Cord Injury Study (RISCIS). OBJECTIVES: The primary objective of the trial is to evaluate the superiority of riluzole, at a dose of 100 mg BID in the first 24 h followed by 50 mg BID for the following 13 days post injury, compared with placebo in improving neurological motor outcomes in patients with C4-C8 level, International Standards for Neurological Classification of Spinal Cord Injury Examination (ISNCSCI) grade A, B or C acute (within 12 h post injury) SCI. SETTING: Acute trauma centers worldwideMethods:A double-blind, multi-center, placebo-controlled RCT will enroll 351 participants randomized 1:1 to riluzole and placebo. The primary end point is the change between 180 days and baseline in ISNCSCI Motor Score. This study has 90% power to detect a change of nine points in ISNCSCI Motor Score at one-sided α=0.025. RESULTS: Currently enrolling in 11 centers. CONCLUSION: This study will provide class I evidence regarding the safety and neuroprotective efficacy of riluzole in patients with acute cervical SCI.


Neuroprotective Agents/therapeutic use , Riluzole/therapeutic use , Spinal Cord Injuries/drug therapy , Acute Disease , Adolescent , Adult , Aged , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Severity of Illness Index , Time Factors , Treatment Outcome , Young Adult
17.
Spinal Cord ; 53(8): 574-80, 2015 Aug.
Article En | MEDLINE | ID: mdl-25800695

STUDY DESIGN: This is a narrative review of the literature. OBJECTIVES: The objectives of this study were to review the current concepts underlying the pathobiology of radiation-induced spinal cord injury; to discuss potential biologic strategies to mitigate spinal cord injury following radiation; and to provide an update on the clinical guidelines to prevent injury in the era of image-guided stereotactic body radiotherapy (SBRT). SETTING: This study was conducted in Toronto, Canada. METHODS: A MEDLINE search was performed using the following terms: radiation injury; radiation myelopathy; CNS radiation injury; brain necrosis, radiation; demyelination, radiation; blood-brain barrier, radiation; white matter necrosis; and SBRT. RESULTS AND CONCLUSION: The biologic response of the spinal cord after radiation is a continuously evolving process. Death of vascular endothelial cells and disruption of the blood-spinal cord barrier leads to a complex injury response, resulting in demyelination and tissue necrosis. At present, there is no evidence that the pathobiology of cord injury after SBRT is different from that after standard fractionation. Although permanent myelopathy has become a rare complication following conventional fractionated radiation treatment, cases of radiation myelopathy have re-emerged with the increasing role of spine stereotactic body radiation therapy and reirradiation. Experimental biologic strategies targeting the injury response pathways hold promise in mitigating this dreaded late effect of radiation treatment.


Guidelines as Topic , Radiotherapy/adverse effects , Radiotherapy/standards , Spinal Cord Injuries/etiology , Spinal Cord Injuries/therapy , Animals , Humans , MEDLINE/statistics & numerical data , Neuroimaging/methods , Neuroimaging/standards , Spinal Cord/pathology , Spinal Cord/physiopathology
18.
Spinal Cord ; 53(2): 155-65, 2015 Feb.
Article En | MEDLINE | ID: mdl-25420492

STUDY DESIGN: Survey of expert opinion, feedback and final consensus. OBJECTIVE: To describe the development and the variables included in the International Spinal Cord Injury (SCI) Spinal Interventions and Surgical Procedures Basic Data set. SETTING: International working group. METHODS: A committee of experts was established to select and define data elements. The data set was then disseminated to the appropriate committees and organizations for comments. All suggested revisions were considered and both the International Spinal Cord Society and the American Spinal Injury Association endorsed the final version. RESULTS: The data set consists of nine variables: (1) Intervention/Procedure Date and start time (2) Non-surgical bed rest and external immobilization, (3) Spinal intervention-closed manipulation and/or reduction of spinal elements, (4) Surgical procedure-approach, (5) Date and time of the completion of the intervention or surgical closure; (6) Surgical procedure-open reduction, (7) Surgical procedure-direct decompression of neural elements, and (8 and 9) Surgical procedure-stabilization and fusion (spinal segment number and level). All variables are coded using numbers or characters. Each spinal intervention and procedure is coded (variables 1 through 7) and the spinal segment level is described (variables 8 and 9). Sample clinical cases were developed to illustrate how to complete it. CONCLUSION: The International SCI Spinal Interventions and Surgical Procedures Basic Data Set was developed to facilitate comparisons of spinal interventions and surgical procedures among studies, centers and countries.


Spinal Cord Injuries/rehabilitation , Spinal Cord Injuries/surgery , Humans , Internationality , Internet , Radiography , Spinal Cord Injuries/diagnostic imaging
19.
AJNR Am J Neuroradiol ; 36(4): 803-10, 2015 Apr.
Article En | MEDLINE | ID: mdl-25523587

BACKGROUND AND PURPOSE: Advanced MR imaging techniques are critical to understanding the pathophysiology of conditions involving the spinal cord. We provide a novel, quantitative solution to map vertebral and spinal cord levels accounting for anatomic variability within the human spinal cord. For the first time, we report a population distribution of the segmental anatomy of the cervical spinal cord that has direct implications for the interpretation of advanced imaging studies most often conducted across groups of subjects. MATERIALS AND METHODS: Twenty healthy volunteers underwent a T2-weighted, 3T MRI of the cervical spinal cord. Two experts marked the C3-C8 cervical nerve rootlets, C3-C7 vertebral bodies, and pontomedullary junction. A semiautomated algorithm was used to locate the centerline of the spinal cord and measure rostral-caudal distances from a fixed point in the brain stem, the pontomedullary junction, to each of the spinal rootlets and vertebral bodies. Distances to each location were compared across subjects. Six volunteers had 2 additional scans in neck flexion and extension to measure the effects of patient positioning in the scanner. RESULTS: We demonstrated that substantial variation exists in the rostral-caudal position of spinal cord segments among individuals and that prior methods of predicting spinal segments are imprecise. We also show that neck flexion or extension has little effect on the relative location of vertebral-versus-spinal levels. CONCLUSIONS: Accounting for spinal level variation is lacking in existing imaging studies. Future studies should account for this variation for accurate interpretation of the neuroanatomic origin of acquired MR signals.


Cervical Cord/anatomy & histology , Cervical Vertebrae/anatomy & histology , Magnetic Resonance Imaging/methods , Adult , Female , Humans , Male , Patient Positioning , Young Adult
20.
Neuroscience ; 265: 302-12, 2014 Apr 18.
Article En | MEDLINE | ID: mdl-24508749

The spinal cord is vulnerable to ischemic injury due to trauma, vascular malformations and correction of thoracic aortic lesions. Riluzole, a sodium channel blocker and anti-glutamate drug has been shown to be neuroprotective in a model of ischemic spinal cord injury, although the effects in clinically relevant ischemia/reperfusion models are unknown. Here, we examine the effect of riluzole following ischemia-reperfusion injury to the spinal cord. Female rats underwent high thoracic aortic balloon occlusion to produce an ischemia/reperfusion injury. Tolerance to ischemia was evaluated by varying the duration of occlusion. Riluzole (8mg/kg) was injected intraperitoneally 4h after injury. Locomotor function (Basso, Beattie and Bresnahan (BBB) scale) was assessed at 4h, 1day, and 5days post-ischemia. Spinal cords were extracted and evaluated for neuronal loss using immunohistology (choline acetyltransferase (ChAT) and neuronal nuclei (NeuN)), inflammation (CD11b), astrogliosis (glial fibrillary acidic protein - GFAP) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Ischemic injury lasting between 5.5 and 6.75min resulted in delayed paraplegia, whereas longer ischemia induced immediate paraplegia. When riluzole was administered to rats that underwent 6min of occlusion, delayed paraplegia was prevented. The BBB score of riluzole-treated rats was 11.14±4.85 compared with 1.86±1.07 in control animals. Riluzole also reduced neuronal loss, infiltration of microglia/macrophages and astrogliosis in the ventral horn and intermediate zone of the gray matter. In addition, riluzole reduced apoptosis of neurons in the dorsal horn of the gray matter. Riluzole has a neuroprotective effect in a rat model of spinal cord injury/reperfusion when administered up to 4h post-injury, a clinically relevant therapeutic time window.


Neuroprotective Agents/therapeutic use , Paraplegia/prevention & control , Reperfusion Injury/drug therapy , Riluzole/therapeutic use , Spinal Cord Injuries/drug therapy , Animals , Female , Paraplegia/etiology , Rats , Spinal Cord Injuries/complications , Spinal Cord Injuries/pathology , Treatment Outcome
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