Pathophysiology, Classification and Comorbidities after Traumatic Spinal Cord Injury

The spinal cord is a conduit within the central nervous system (CNS) that provides ongoing communication between the brain and the rest of the body, conveying complex sensory and motor information necessary for safety, movement, reflexes, and optimization of autonomic function. After a spinal cord injury (SCI), supraspinal influences on the spinal segmental control system and autonomic nervous system (ANS) are disrupted, leading to spastic paralysis, pain and dysesthesia, sympathetic blunting and parasympathetic dominance resulting in cardiac dysrhythmias, systemic hypotension, bronchoconstriction, copious respiratory secretions and uncontrolled bowel, bladder, and sexual dysfunction. This article outlines the pathophysiology of traumatic SCI, current and emerging methods of classification, and its influence on sensory/motor function, and introduces the probable comorbidities associated with SCI that will be discussed in more detail in the accompanying manuscripts of this special issue

A prospective multi-center study comparing the complication profile of modest systemic hypothermia versus normothermia for acute cervical spinal cord injury

STUDY DESIGN: Prospective multi-center trial. OBJECTIVES: To characterize the complication profile associated with modest systemic hypothermia after acute cervical SCI in a prospective multi-center study. SETTING: Five trauma centers in the United States. METHODS: We analyzed data from a prospective, multi-center trial on the use of modest systemic hypothermia for acute cervical SCI. Patients with acute cervical SCI were assigned to receive modest systemic hypothermia (33 C) or standard of care medical treatment. Patients in the hypothermia group were cooled to 33 C and maintained at the target temperature for 48 h. Complication profile and the rate of complications within the first 6 weeks after injury were compared between the two groups. Multiple regression analysis was performed to determine risk factors for complications after injury. RESULTS: Fifty patients (hypothermia: 27, control: 23) were analyzed for this study. Median age was significantly lower in the hypothermia arm (39 vs 59 years, p = 0.02). Respiratory complications were the most common (hypothermia: 55.6% vs control: 52.2%, p = 0.81). The rate of deep vein thrombosis was not significantly different between the two groups (hypothermia: 14.8% vs control 17.4%, p = 0.71). The rate of complications was not statistically different between the two groups. CONCLUSION: In this prospective multi-center controlled trial, preliminary data show that modest systemic hypothermia was not associated with increased risk of complications within the first 6 weeks after acute cervical SCI. TRIAL INFORMATION: The study is registered on clinicaltrials.gov NCT02991690. University of Miami IRB (Central IRB) approval No.: 20160758. Emory University IRB #IRB00093786

Stimulated Raman histology for rapid and accurate intraoperative diagnosis of CNS tumors: prospective blinded study

OBJECTIVEIn some centers where brain tumor surgery is performed, the opportunity for expert intraoperative neuropathology consultation is lacking. Consequently, surgeons may not have access to the highest quality diagnostic histological data to inform surgical decision-making. Stimulated Raman histology (SRH) is a novel technology that allows for rapid acquisition of diagnostic histological images at the bedside.METHODSThe authors performed a prospective blinded cohort study of 82 consecutive patients undergoing resection of CNS tumors to compare diagnostic time and accuracy of SRH simulation to the gold standard, i.e., frozen and permanent section diagnosis. Diagnostic accuracy was determined by concordance of SRH-simulated intraoperative pathology consultation with a blinded board-certified neuropathologist, with official frozen section and permanent section results.RESULTSOverall, the mean time to diagnosis was 30.5 ± 13.2 minutes faster (p < 0.0001) for SRH simulation than for frozen section, with similar diagnostic correlation: 91.5% (κ = 0.834, p < 0.0001) between SRH simulation and permanent section, and 91.5% between frozen and permanent section (κ = 0.894, p < 0.0001).CONCLUSIONSSRH-simulated intraoperative pathology consultation was significantly faster and equally accurate as frozen section

Treating amyotrophic lateral sclerosis with allogeneic Schwann cell–derived exosomal vesicles: a case report

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 × 1012 (×2), and then consecutive infusions of 7.5 × 1012 (×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

Variability in Early Surgery for Acute Cervical Spinal Cord Injury Patients: An Opportunity for Enhanced Care Delivery

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 commenced within 24 hours of injury (EAES) and 2) Early Arrival but Delayed Surgery (EADS) with surgery occurring between 24 to 72 hours 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 hours) compared to the EADS group (31 hours) (p<0.05). There was no statistical difference in race, sex, age, mechanism of injury, 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 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 8 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 hours 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 hours 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

Interhospital Transfer delays care for spinal cord injury patients: A Report from the North American Clinical Trials Network for Spinal Cord Injury

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 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 I trauma center (NACTN site) versus IHT from a level II or III trauma facility. The main outcome was surgery within 24 hours of injury (yes/no) while secondary outcomes were length of stay, death, discharge disposition, and 6-month 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 accident. Patients who underwent IHT were more likely to have a less severe SCI (AIS D) (p=.002), have a central cord injury (p=.004), and have a fall as their mechanism of injury (p<.0001) than those directly admitted to a NACTN center. Of the 634 patients who had surgery, direct admission to a NACTN site was more likely to result in surgery within 24 hours compared to IHT patients (52% vs. 38%) (p< .0003). Median IHT distance was 28 miles (interquartile range=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 a NACTN site were less likely to have surgery within 24 hours of injury, compared to those directly admitted to the level I trauma facility. While 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 work 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

The bulbocavernosus reflex (BCR) has no prognostic features during the acute evaluation of spinal cord injuries

The bulbocavernosus reflex (BCR) has been used during the initial evaluation of a spinal cord injury patient as a metric to determine prognosis and whether the patient is in "spinal shock". This reflex has been less utilized over the last decade and therefore, a review was performed to assess the value of BCR in patient prognosis. The North American Clinical Trials Network (NACTN) for Spinal Cord Injury is a consortium of tertiary medical centers that includes a prospective SCI registry. The NACTN registry data was analyzed to evaluate the prognostic implication of the BCR during the initial evaluation of a spinal cord injury patient. SCI patients were divided into those with an intact or absent BCR during their initial evaluation. Associations of participants' descriptors and neurological status on follow up were performed followed by associations with the presence of a BCR. 769 registry patients with recorded BCRs were included in the study. The median age was 49 years (32-61 years), majority were male (n=566, 77%), and white (n=519, 73%). Among included patients, high blood pressure was the most common comorbidity (n=230, 31%). Cervical spinal cord injury was the most common (n=470, 76%) with fall (n=320, 43%) being the most frequent mechanism of injury. BCR was present in 311 patients (40.4%), while 458 (59.6%) had a negative BCR within 7 days of injury or before surgery. At 6 months post-injury, 230 patients (29.9%) followed up, of which, 145 had a positive BCR while 85 had a negative BCR, respectively. The presence/absence of BCR was significantly different in patients with cervical (p=0.0015) or thoracic SCI (p=0.0089), or conus medullaris syndrome (p=0.0035), and in those who were AIS grade A (p=0.0313). No significant relationship was observed between BCR results and demographics, AIS grade conversion, motor score changes (p=0.1669), and changes in pin prick (p=0.3795) and light touch scores (p=0.8178). In addition, cohorts were not different in surgery decision (p=0.7762) and injury to surgery time (p=0.0681). In our review of the NACTN spinal cord registry, the BCR did not provide prognostic utility in the acute evaluation of spinal cord injury patients. Therefore, it should not be used as a reliable marker for predicting neurological outcomes post-injury

Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury

A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery. Participants underwent sural nerve harvest, and ahSCs were isolated and propagated in culture. The dose of culture-expanded ahSCs injected into the chronic spinal cord lesion of each individual followed a cavity-filling volume approach. Primary outcome measures for safety and trend-toward efficacy were assessed. Two participants with American Spinal Injury Association Impairment Scale (AIS) A and two participants with incomplete chronic SCI (AIS B, C) were each enrolled in cervical and thoracic SCI cohorts (  = 8 total). All participants completed the study per protocol, and no serious adverse events related to sural nerve harvest or ahSC transplantation were reported. Urinary tract infections and skin abrasions were the most common adverse events reported. One participant experienced a 4-point improvement in motor function, a 6-point improvement in sensory function, and a 1-level improvement in neurological level of injury. Follow-up MRI in the cervical (6 months) and thoracic (24 months) cohorts revealed a reduction in cyst volume after transplantation with reduced effect over time. This phase 1 trial demonstrated the feasibility and safety of ahSC transplantation combined with a multi-modal rehabilitation protocol for participants with chronic SCI