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Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 10 12 (×2), and then consecutive infusions of 7.5 × 10 12 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.
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This paper provides an overview of the history, composition, organization, responsibilities, and regulatory requirements of Data Safety Monitoring Boards (DSMB), with particular reference to the context of clinical trials in spinal cord injury. It is intended to help potential members of such boards and those undertaking the design of new clinical trials to understand the important role of the DSMB in safeguarding the integrity of complex trials, promoting safety, and countering potential bias. An independent DSMB helps to protect research subjects by providing study oversight and serves as an additional step to assure that clinical trials are performed to existing and appropriate standards. The DSMB must meet on a regular schedule, diligently evaluate all the information it receives, and report in a timely and decisive manner. Members must be free of significant conflicts of interest throughout the study and be adequately trained and experienced to serve their roles within the group. DSMB service can be a valuable learning experience and a gratifying opportunity to participate in advancing medicine and helping to maintain and improve the standards of research.
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Comités de Monitoreo de Datos de Ensayos Clínicos , Traumatismos de la Médula Espinal , Humanos , Ensayos Clínicos como AsuntoRESUMEN
JOURNAL/nrgr/04.03/01300535-202412000-00032/figure1/v/2024-04-08T165401Z/r/image-tiff For patients with chronic spinal cord injury, the conventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection, pressure sores, osteoporosis, and deep vein thrombosis. Surgery is rarely performed on spinal cord injury in the chronic phase, and few treatments have been proven effective in chronic spinal cord injury patients. Development of effective therapies for chronic spinal cord injury patients is needed. We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal cord injury to compare intensive rehabilitation (weight-bearing walking training) alone with surgical intervention plus intensive rehabilitation. This clinical trial was registered at ClinicalTrials.gov (NCT02663310). The goal of surgical intervention was spinal cord detethering, restoration of cerebrospinal fluid flow, and elimination of residual spinal cord compression. We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement, reduced spasticity, and more rapid bowel and bladder functional recovery than weight-bearing walking training alone. Overall, the surgical procedures and intensive rehabilitation were safe. American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries. Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.
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Espasticidad Muscular , Recuperación de la Función , Traumatismos de la Médula Espinal , Humanos , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/complicaciones , Espasticidad Muscular/etiología , Espasticidad Muscular/fisiopatología , Recuperación de la Función/fisiología , Valor Predictivo de las PruebasRESUMEN
STUDY DESIGN: Systematic review update. OBJECTIVES: Interventions that aim to optimize spinal cord perfusion are thought to play an important role in minimizing secondary ischemic damage and improving outcomes in patients with acute traumatic spinal cord injuries (SCIs). However, exactly how to optimize spinal cord perfusion and enhance neurologic recovery remains controversial. We performed an update of a recent systematic review (Evaniew et al, J. Neurotrauma 2020) to evaluate the effects of Mean Arterial Pressure (MAP) support or Spinal Cord Perfusion Pressure (SCPP) support on neurological recovery and rates of adverse events among patients with acute traumatic SCI. METHODS: We searched PubMed/MEDLINE, EMBASE and ClinicalTrials.gov for new published reports. Two reviewers independently screened articles, extracted data, and evaluated risk of bias. We implemented the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach to rate confidence in the quality of the evidence. RESULTS: From 569 potentially relevant new citations since 2019, we identified 9 new studies for inclusion, which were combined with 19 studies from a prior review to give a total of 28 studies. According to low or very low quality evidence, the effect of MAP support on neurological recovery is uncertain, and increased SCPP may be associated with improved neurological recovery. Both approaches may involve risks for specific adverse events, but the importance of these adverse events to patients remains unclear. Very low quality evidence failed to yield reliable guidance about particular monitoring techniques, perfusion ranges, pharmacological agents, or durations of treatment. CONCLUSIONS: This update provides an evidence base to support the development of a new clinical practice guideline for the hemodynamic management of patients with acute traumatic SCI. While avoidance of hypotension and maintenance of spinal cord perfusion are important principles in the management of an acute SCI, the literature does not provide high quality evidence in support of a particular protocol. Further prospective, controlled research studies with objective validated outcome assessments are required to examine interventions to optimize spinal cord perfusion in this setting.
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STUDY DESIGN: Scoping Review. OBJECTIVE: To review the literature and summarize information on checklists and algorithms for responding to intraoperative neuromonitoring (IONM) alerts and management of intraoperative spinal cord injuries (ISCIs). METHODS: MEDLINE® was searched from inception through January 26, 2022 as were sources of grey literature. We attempted to obtain guidelines and/or consensus statements from the following sources: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), American Academy of Neurology (AAN), American Clinical Neurophysiology Society, NASS (North American Spine Society), and other spine surgery organizations. RESULTS: Of 16 studies reporting on management strategies for ISCIs, two were publications of consensus meetings which were conducted according to the Delphi method and eight were retrospective cohort studies. The remaining six studies were narrative reviews that proposed intraoperative checklists and management strategies for IONM alerts. Of note, 56% of included studies focused only on patients undergoing spinal deformity surgery. Intraoperative considerations and measures taken in the event of an ISCI are divided and reported in three categories of i) Anesthesiologic, ii) Neurophysiological/Technical, and iii) Surgical management strategies. CONCLUSION: There is a paucity of literature on comparative effectiveness and harms of management strategies in response to an IONM alert and possible ISCI. There is a pressing need to develop a standardized checklist and care pathway to avoid and minimize the risk of postoperative neurologic sequelae.
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STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: Surgical decompression is a cornerstone in the management of patients with traumatic spinal cord injury (SCI); however, the influence of the timing of surgery on neurological recovery after acute SCI remains controversial. This systematic review aims to summarize current evidence on the effectiveness, safety, and cost-effectiveness of early (≤24 hours) or late (>24 hours) surgery in patients with acute traumatic SCI for all levels of the spine. Furthermore, this systematic review aims to evaluate the evidence with respect to the impact of ultra-early surgery (earlier than 24 hours from injury) on these outcomes. METHODS: A systematic search of the literature was performed using the MEDLINE database (PubMed), Cochrane database, and EMBASE. Two reviewers independently screened the citations from the search to determine whether an article satisfied predefined inclusion and exclusion criteria. For all key questions, we focused on primary studies with the least potential for bias and those that controlled for baseline neurological status and specified time from injury to surgery. Risk of bias of each article was assessed using standardized tools based on study design. Finally, the overall strength of evidence for the primary outcomes was assessed using the GRADE approach. Data were synthesized both qualitatively and quantitively using meta-analyses. RESULTS: Twenty-one studies met inclusion and exclusion criteria and formed the evidence base for this review update. Seventeen studies compared outcomes between patients treated with early (≤24 hours from injury) compared to late (>24 hours) surgical decompression. An additional 4 studies evaluated even earlier time frames: <4, <5, <8 or <12 hours. Based on moderate evidence, patients were 2 times more likely to recover by ≥ 2 grades on the ASIA Impairment Score (AIS) at 6 months (RR: 2.76, 95% CI 1.60 to 4.98) and 12 months (RR: 1.95, 95% CI 1.26 to 3.18) if they were decompressed within 24 hours compared to after 24 hours. Furthermore, moderate evidence suggested that patients receiving early decompression had an additional 4.50 (95% CI 1.70 to 7.29) point improvement on the ASIA motor score. With respect to administrative outcomes, there was low evidence that early decompression may decrease acute hospital length of stay. In terms of safety, there was moderate evidence that suggested the rate of major complications does not differ between patients undergoing early compared to late surgery. Furthermore, there was no difference in rates of mortality, surgical device-related complications, sepsis/systemic infection or neurological deterioration based on timing of surgery. Firm conclusions were not possible with respect to the impact of ultra-early surgery on neurological, functional or safety outcomes given the poor-quality studies, imprecision and the overlap in the time frames examined. CONCLUSIONS: This review provides an evidence base to support the update on clinical practice guidelines related to the timing of surgical decompression in acute SCI. Overall, the strength of evidence was moderate that early surgery (≤24 hours from injury) compared to late (>24 hours) results in clinically meaningful improvements in neurological recovery. Further studies are required to delineate the role of ultra-early surgery in patients with acute SCI.
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BACKGROUND: In the last decades, medical research fields studying rare conditions such as spinal cord injury (SCI) have made extensive efforts to collect large-scale data. However, most analysis methods rely on complete data. This is particularly troublesome when studying clinical data as they are prone to missingness. Often, researchers mitigate this problem by removing patients with missing data from the analyses. Less commonly, imputation methods to infer likely values are applied. OBJECTIVE: Our objective was to study how handling missing data influences the results reported, taking the example of SCI registries. We aimed to raise awareness on the effects of missing data and provide guidelines to be applied for future research projects, in SCI research and beyond. METHODS: Using the Sygen clinical trial data (n = 797), we analyzed the impact of the type of variable in which data is missing, the pattern according to which data is missing, and the imputation strategy (e.g. mean imputation, last observation carried forward, multiple imputation). RESULTS: Our simulations show that mean imputation may lead to results strongly deviating from the underlying expected results. For repeated measures missing at late stages (> = 6 months after injury in this simulation study), carrying the last observation forward seems the preferable option for the imputation. This simulation study could show that a one-size-fit-all imputation strategy falls short in SCI data sets. CONCLUSIONS: Data-tailored imputation strategies are required (e.g., characterisation of the missingness pattern, last observation carried forward for repeated measures evolving to a plateau over time). Therefore, systematically reporting the extent, kind and decisions made regarding missing data will be essential to improve the interpretation, transparency, and reproducibility of the research presented.
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Investigación Biomédica , Traumatismos de la Médula Espinal , Humanos , Reproducibilidad de los Resultados , Traumatismos de la Médula Espinal/epidemiología , Traumatismos de la Médula Espinal/terapia , Simulación por Computador , Enfermedades RarasRESUMEN
STUDY DESIGN: Literature Review. OBJECTIVE: Myelopathy affecting the thoracic spinal cord can arise secondary to several aetiologies which have similar presentation and management. Consequently, there are many uncertainties in this area, including optimal terminology and definitions. Recent collaborative cervical spinal research has led to the proposal and subsequent community adoption of the name degenerative cervical myelopathy(DCM), which has facilitated the establishment of internationally-agreed research priorities for DCM. We put forward the case for the introduction of the term degenerative thoracic myelopathy(DTM) and degenerative spinal myelopathy(DSM) as an umbrella term for both DCM and DTM. METHODS: Following PRISMA guidelines, a systematic literature search was performed to identify degenerative thoracic myelopathy literature in Embase and MEDLINE. RESULTS: Conditions encompassed within DTM include thoracic spondylotic myelopathy, ossification of the posterior longitudinal ligament, ossification of the ligamentum flavum, calcification of ligaments, hypertrophy of ligaments, degenerative disc disease, thoracic osteoarthritis, intervertebral disc herniation, and posterior osteophytosis. The classic presentation includes girdle pain, gait disturbance, leg weakness, sensory disturbance, and bladder or bowel dysfunction, often with associated back pain. Surgical management is typically favoured with post-surgical outcomes dependent on many factors, including the causative pathology, and presence of additional stenosis. CONCLUSION: The clinical entities encompassed by the term DTM are interrelated, can manifest concurrently, and present similarly. Building on the consensus adoption of DCM in the cervical spine and the recent proposal of degenerative cervical radiculopathy(DCR), extending this common nomenclature framework to the terms degenerative spinal myelopathy and degenerative thoracic myelopathy will help improve recognition and communication.
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PURPOSE OF REVIEW: High-cervical spinal cord stimulation can alter cortical activity and cerebral metabolism. These effects are potentially beneficial for disorders of consciousness. A better understanding of the effects of clinical application of stimulation is needed. We aimed to evaluate the existing literature to determine the state of available knowledge. We performed a literature review of clinical studies assessing cervical spinal cord epidural stimulation for disorders of consciousness. Only peer-reviewed articles reporting preoperative and postoperative clinical status were included. RECENT FINDINGS: Nineteen studies were included. A total of 532 cases were reported, and 255 patients were considered responsive (47.9%). Considering only studies published after the definition of minimally conscious state (MCS) as an entity, 402 individuals in unresponsive wakefulness syndrome (UWS) and 113 in MCS were reported. Responsiveness to SCS was reported in 170 UWS patients (42.3%) and in 78 MCS cases (69.0%), although the criteria for responsiveness and outcome measures varied among publications. SUMMARY: Cervical SCS yielded encouraging results in patients with disorders of consciousness and seems to be more effective in MCS. More extensive investigation is needed to understand its potential role in clinical practice.
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Estimulación de la Médula Espinal , Humanos , Trastornos de la Conciencia/terapia , Estado Vegetativo Persistente/metabolismo , Vigilia/fisiología , Evaluación de Resultado en la Atención de Salud , Estado de ConcienciaRESUMEN
The North American Clinical Trials Network (NACTN) has been established as a network of translational clinical research centers focused on traumatic spinal cord injury (SCI) with the goals of facilitating clinical translational research, promotion of enhanced clinical care protocols including the principle of early surgery for SCI, and improving outcomes for individuals with acute SCI. Since its foundation in 2004 by Dr. Robert Grossman, NACTN has evolved into a powerful multi-stakeholder consortium of eight neurosurgical department faculties at university-affiliated institutions in the United States and Canada, a data management center, and a pharmacological center. To date, high-quality data from more than 1000 patients have been prospectively collected, providing us with a strong body of evidence surrounding SCI epidemiology, the natural history, and complications of acute and subacute SCI management. Key accomplishments of NACTN are summarized in this Focus issue. They include the launch, in collaboration with AO Spine, of the international, multi-center, placebo-controlled, Phase III Riluzole in Acute Spinal Cord Injury Study (RISCIS) that recruited 192 patients. While the primary analyses did not achieve the predetermined endpoint of efficacy for Riluzole, likely related to insufficient power, pre-planned secondary analyses demonstrated that all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with Riluzole showed significant gains in functional recovery. The Focus Issue also includes a detailed analysis of the pharmacokinetics and pharmacodynamics of riluzole in the setting of acute SCI (RISCIS-PK study). Additional achievements include key contributions to the evidence supporting the role of early surgery in acute SCI, and a better understanding of the impact of complications on the outcomes of SCI. Future directions of NACTN will build on past accomplishments and focus on enhanced collaborations with other SCI networks, advanced analytics to examine large datasets, and a greater focus on chronic SCI.
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Riluzol , Traumatismos de la Médula Espinal , Humanos , Canadá , Recuperación de la Función , Traumatismos de la Médula Espinal/terapia , Ensayos Clínicos como AsuntoRESUMEN
OBJECTIVE: A motor complete spinal cord injury (SCI) results in the loss of voluntary motor control below the point of injury. Some of these patients can regain partial motor function through inpatient rehabilitation; however, there is currently no biomarker to easily identify which patients have this potential. Evidence indicates that spasticity could be that marker. Patients with motor complete SCI who exhibit spasticity show preservation of descending motor pathways, the pathways necessary for motor signals to be carried from the brain to the target muscle. We hypothesized that the presence of spasticity predicts motor recovery after subacute motor complete SCI. METHODS: Spasticity (Modified Ashworth Scale and pendulum test) and descending connectivity (motor evoked potentials) were tested in the rectus femoris muscle in patients with subacute motor complete (n = 36) and motor incomplete (n = 30) SCI. Motor recovery was assessed by using the International Standards for Neurological Classification of Spinal Cord Injury and the American Spinal Injury Association Impairment Scale (AIS). All measurements were taken at admission and discharge from inpatient rehabilitation. RESULTS: We found that motor complete SCI patients with spasticity improved in motor scores and showed AIS conversion to either motor or sensory incomplete. Conversely, patients without spasticity showed no changes in motor scores and AIS conversion. In incomplete SCI patients, motor scores improved and AIS conversion occurred regardless of spasticity. INTERPRETATION: These findings suggest that spasticity represents an easy-to-use clinical outcome that might help to predict motor recovery after severe SCI. This knowledge can improve inpatient rehabilitation effectiveness for motor complete SCI patients. ANN NEUROL 2023.
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OBJECTIVES: To explore whether a James Lind Alliance Priority Setting Partnership could provide insights on knowledge translation within the field of degenerative cervical myelopathy (DCM). DESIGN: Secondary analysis of a James Lind Alliance Priority Setting Partnership process for DCM. PARTICIPANTS AND SETTING: DCM stake holders, including spinal surgeons, people with myelopathy and other healthcare professionals, were surveyed internationally. Research suggestions submitted by stakeholders but considered answered were identified. Sampling characteristics of respondents were compared with the overall cohort to identify subgroups underserved by current knowledge translation. RESULTS: The survey was completed by 423 individuals from 68 different countries. A total of 22% of participants submitted research suggestions that were considered 'answered'. There was a significant difference between responses from different stakeholder groups (p<0.005). Spinal surgeons were the group which was most likely to submit an 'answered' research question. Respondents from South America were also most likely to submit 'answered' questions, when compared with other regions. However, there was no significant difference between responses from different stakeholder regions (p=0.4). CONCLUSIONS: Knowledge translation challenges exist within DCM. This practical approach to measuring knowledge translation may offer a more responsive assessment to guide interventions, complementing existing metrics.
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Investigación Biomédica , Enfermedades de la Médula Espinal , Humanos , Ciencia Traslacional Biomédica , Personal de Salud , Encuestas y Cuestionarios , Participación de los Interesados , Enfermedades de la Médula Espinal/terapia , Prioridades en SaludRESUMEN
Rarely, penetrating injuries to the spinal cord result from wooden objects, creating unique challenges to mitigate neurological injury and high rates of infection and foreign body reactions. We report a man who sustained a penetrating cervical spinal cord injury from a sharpened stick. While initially tetraparetic, he rapidly recovered function. The risks of neurological deterioration during surgical removal made the patient reluctant to consent to surgery despite the impalement of the spinal cord. A repeat MRI on day 3 showed an extension of edema indicating progressive inflammation. On the 7th day after injury, fever and paresthesias occurred with a large increase in serum inflammatory indicators, and the patient agreed to undergo surgical removal of the wooden object. We discuss the management nuances related to wood, the longitudinal evolution of MRI findings, infection risk, surgical risk mitigation and technique, an inflammatory marker profile, long-term recovery, and the surprisingly minimal neurological deficits associated with low-velocity midline spinal cord injuries. The patient had an excellent clinical outcome. The main lessons are that a wooden penetrating central nervous system injury has a high risk for infection, and that surgical removal from the spinal cord should be performed soon after injury and under direct visualization.
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Odontoid fractures are common, often presenting in the elderly after a fall and infrequently associated with traumatic spinal cord injury (tSCI). The goal of this study was to analyze predictors of mortality and neurological outcome when odontoid fractures were associated with signal change on magnetic resonance imaging (MRI) at admission. Over an 18-year period (2001-2019), 33 patients with odontoid fractures and documented tSCI on MRI were identified. Mean age was 65.3 years (standard deviation [SD] = 17.2), and 21 patients were male. The mechanism of injury was falls in 25 patients, motor vehicle accidents in 5, and other causes in 3. Mean Injury Severity Score (ISS) was 40.5 (SD = 30.2), Glasgow Coma Scale (GCS) score was 13 (SD = 3.4), and American Spinal Injury Association (ASIA) motor score (AMS) was 51.6 (SD = 42.7). ASIA Impairment Scale (AIS) grade was A, B, C, and D in 9, 2, 3, and 19 patients, respectively. Mean intramedullary lesion length was 32.3 mm (SD = 18.6). The odontoid peg was displaced ventral or dorsal in 15 patients. Twenty patients had surgical intervention: anterior odontoid screw fixation in 7 and posterior spinal fusion in 13. Eleven (33.3%) patients died in this series: withdrawal of medical care in 5; anoxic brain injury in 4; and failure of critical care management in 2. Univariate logistic regression indicated that GCS score (p < 0.014), AMS (p < 0.002), AIS grade (p < 0.002), and ISS (p < 0.009) were risk factors for mortality. Multi-variate regression analysis indicated that only AMS (p < 0.002) had a significant relationship with mortality when odontoid fracture was associated with tSCI (odds ratio, 0.963; 95% confidence interval, 0.941-0.986).
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Traumatic spinal cord injury (SCI) causes a sudden onset multi-system disease, permanently altering homeostasis with multiple complications. Consequences include aberrant neuronal circuits, multiple organ system dysfunctions, and chronic phenotypes such as neuropathic pain and metabolic syndrome. Reductionist approaches are used to classify SCI patients based on residual neurological function. Still, recovery varies due to interacting variables, including individual biology, comorbidities, complications, therapeutic side effects, and socioeconomic influences for which data integration methods are lacking. Infections, pressure sores, and heterotopic ossification are known recovery modifiers. However, the molecular pathobiology of the disease-modifying factors altering the neurological recovery-chronic syndrome trajectory is mainly unknown, with significant data gaps between intensive early treatment and chronic phases. Changes in organ function such as gut dysbiosis, adrenal dysregulation, fatty liver, muscle loss, and autonomic dysregulation disrupt homeostasis, generating progression-driving allostatic load. Interactions between interdependent systems produce emergent effects, such as resilience, that preclude single mechanism interpretations. Due to many interacting variables in individuals, substantiating the effects of treatments to improve neurological outcomes is difficult. Acute injury outcome predictors, including blood and cerebrospinal fluid biomarkers, neuroimaging signal changes, and autonomic system abnormalities, often do not predict chronic SCI syndrome phenotypes. In systems medicine, network analysis of bioinformatics data is used to derive molecular control modules. To better understand the evolution from acute SCI to chronic SCI multi-system states, we propose a topological phenotype framework integrating bioinformatics, physiological data, and allostatic load tested against accepted established recovery metrics. This form of correlational phenotyping may reveal critical nodal points for intervention to improve recovery trajectories. This study examines the limitations of current classifications of SCI and how these can evolve through systems medicine.
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Traumatismos de la Médula Espinal , Humanos , Traumatismos de la Médula Espinal/complicaciones , Biomarcadores , Fenotipo , Médula Espinal , Recuperación de la Función/fisiologíaRESUMEN
Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.
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COVID-19 , Fármacos Neuroprotectores , Traumatismos de la Médula Espinal , Humanos , Riluzol/efectos adversos , Fármacos Neuroprotectores/efectos adversos , Pandemias , Estudios Prospectivos , Resultado del Tratamiento , Método Doble Ciego , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/inducido químicamenteRESUMEN
The North American Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of neurosurgery departments at university affiliated hospitals with medical, nursing, and rehabilitation personnel who are skilled in the assessment, evaluation, and management of SCI. NACTN was established with the goal of consistently advancing the quality of life of people with SCI through clinical trials of new therapies that provide robust evidence of safety and effectiveness. A prospective multi-center Registry was created to collect the natural course of the acute traumatic SCI patient from time of injury to 12 months follow-up. NACTN's network of hospitals enrolls a significant number of patients, defines and adheres to standard protocols, and provides the infrastructure and highly skilled personnel to conduct trials of therapy for SCI. Registry data have been used by academic institutions and by the biotechnology and pharmaceutical sectors to create comparison datasets for Phase I clinical trials of new therapies.
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Calidad de Vida , Traumatismos de la Médula Espinal , Humanos , América del Norte , Estudios Prospectivos , Sistema de Registros , Traumatismos de la Médula Espinal/tratamiento farmacológico , Ensayos Clínicos como AsuntoRESUMEN
Data supporting the benefits of early surgical intervention in acute spinal cord injury (SCI) is growing. For early surgery to be accomplished, understanding the causes of variabilities that effect the timing of surgery is needed to achieve this goal. The purpose of this analysis is to determine factors that affect the timing of surgery for acute cervical SCI within the North American Clinical Trials Network (NACTN) for SCI registry. Patients in the NACTN SCI registry from 2005 to 2019 with a cervical SCI, excluding acute traumatic central cord syndrome, were analyzed for time elapsed from injury to arrival to the hospital, and time to surgery. Two categories were defined: 1) Early Arrival with Early Surgery (EAES) commenced within 24 h of injury, and 2) Early Arrival but Delayed Surgery (EADS), with surgery occurring between 24 to 72 h post-injury. Patients' demographic features, initial clinical evaluation, medical comorbidities, neurological status, surgical intervention, complications, and outcome data were correlated with respect to the two arrival groups. Of the 222 acute cervical SCI patients undergoing surgery, 163 (73.4%) were EAES, and 59 (26.6%) were EADS. There was no statistical difference in arrival time between the EAES and EADS groups. There was a statistical difference in the median arrival time to surgery between the EAES group (9 h) compared with the EADS group (31 h; p < 0.05). There was no statistical difference in race, sex, age, mechanism of injury, Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores, or medical comorbidities between the two groups, but the EAES group did present with a significantly lower systolic blood pressure (p < 0.05). EADS patients were more likely to present as an American Spinal Injury Association Impairment Scale (AIS) D than EAES (p < 0.05). Early surgery was statistically more likely to occur if the injury occurred over the weekend (p < 0.05). There were variations in the rates of early surgery between the eight NACTN sites within the study, ranging from 57 to 100%. Of the 114 patients with 6-month outcome data, there was no significant change between the two groups regarding AIS grade change and motor/pin prick/light touch score recovery. A trend towards improved motor scores with early surgery was not statistically significant (p = 0.21). Although there is data that surgery within 24 h of injury improves outcomes and can be performed safely, there remain variations in care outside of clinical trials. In the present study of cervical SCI, NACTN achieved its goal of early surgery in 73.4% of patients from 2005-2019 who arrived within 24 h of their injury. Variability in achieving this goal was related to severity of neurological injury, the day of the week, and the treating NACTN center. Evaluating variations within our network improves understanding of potential systemic limitations and our decision-making process to accomplish the goal of early surgery.
Asunto(s)
Médula Cervical , Traumatismos de la Médula Espinal , Humanos , Médula Cervical/cirugía , Resultado del Tratamiento , Cuello/cirugía , Descompresión Quirúrgica/métodosRESUMEN
Abstract The North America Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of tertiary medical centers that has maintained a prospective SCI registry since 2004, and it has espoused that early surgical intervention is associated with improved outcome. It has previously been shown that initial presentation to a lower acuity center and necessity of transfer to a higher acuity center reduce rates of early surgery. The NACTN database was evaluated to examine the association between interhospital transfer (IHT), early surgery, and outcome, taking into account distance traveled and site of origin for the patient. Data from a 15-year period of the NACTN SCI Registry were analyzed (years 2005-2019). Patients were stratified into transfers directly from the scene to a Level 1 trauma center (NACTN site) versus IHT from a Level 2 or 3 trauma facility. The main outcome was surgery within 24 hours of injury (yes/no), whereas secondary outcomes were length of stay, death, discharge disposition, and 6-month American Spinal Injury Association Impairment Scale (AIS) grade conversion. For the IHT patients, distance traveled for transfer was calculated by measuring the shortest distance between origin and NACTN hospital. Analysis was performed with Brown-Mood test and chi-square tests. Of 724 patients with transfer data, 295 (40%) underwent IHT and 429 (60%) were admitted directly from the scene of injury. Patients who underwent IHT were more likely to have a less severe SCI (AIS D; p = 0.002), have a central cord injury (p = 0.004), and have a fall as their mechanism of injury (p < 0.0001) than those directly admitted to an NACTN center. Of the 634 patients who had surgery, direct admission to an NACTN site was more likely to result in surgery within 24 hours compared with IHT patients (52% vs. 38%) (p < 0.0003). Median IHT distance was 28 miles (interquartile range [IQR] = 13-62 miles). There was no significant difference in death, length of stay, discharge to a rehab facility versus home, or 6-month AIS grade conversion rates between the two groups. Patients who underwent IHT to an NACTN site were less likely to have surgery within 24 hours of injury, compared with those directly admitted to the Level 1 trauma facility. Although there was no difference in mortality rates, length of stay, or 6-month AIS conversion between groups, patients with IHT were more likely be older with a less severe level of injury (AIS D). This study suggests there are barriers to timely recognition of SCI in the field, appropriate admission to a higher level of care after recognition, and challenges related to the management of individuals with less severe SCI.