An Update of a Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on the Role and Timing of Decompressive Surgery.

STUDY DESIGN: Clinical practice guideline development. OBJECTIVES: Acute spinal cord injury (SCI) can result in devastating motor, sensory, and autonomic impairment; loss of independence; and reduced quality of life. Preclinical evidence suggests that early decompression of the spinal cord may help to limit secondary injury, reduce damage to the neural tissue, and improve functional outcomes. Emerging evidence indicates that "early" surgical decompression completed within 24 hours of injury also improves neurological recovery in patients with acute SCI. The objective of this clinical practice guideline (CPG) is to update the 2017 recommendations on the timing of surgical decompression and to evaluate the evidence with respect to ultra-early surgery (in particular, but not limited to, <12 hours after acute SCI). METHODS: A multidisciplinary, international, guideline development group (GDG) was formed that consisted of spine surgeons, neurologists, critical care specialists, emergency medicine doctors, physical medicine and rehabilitation professionals, as well as individuals living with SCI. A systematic review was conducted based on accepted methodological standards to evaluate the impact of early (within 24 hours of acute SCI) or ultra-early (in particular, but not limited to, within 12 hours of acute SCI) surgery on neurological recovery, functional outcomes, administrative outcomes, safety, and cost-effectiveness. The GRADE approach was used to rate the overall strength of evidence across studies for each primary outcome. Using the "evidence-to-recommendation" framework, recommendations were then developed that considered the balance of benefits and harms, financial impact, patient values, acceptability, and feasibility. The guideline was internally appraised using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. RESULTS: The GDG recommended that early surgery (≤24 hours after injury) be offered as the preferred option for adult patients with acute SCI regardless of level. This recommendation was based on moderate evidence suggesting that patients were 2 times more likely to recover by ≥ 2 ASIA Impairment Score (AIS) grades 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, patients undergoing early surgery improved by an additional 4.50 (95% 1.70 to 7.29) points on the ASIA Motor Score compared to patients undergoing surgery after 24 hours post-injury. The GDG also agreed that a recommendation for ultra-early surgery could not be made on the basis of the current evidence because of the small sample sizes, variable definitions of what constituted ultra-early in the literature, and the inconsistency of the evidence. CONCLUSIONS: It is recommended that patients with an acute SCI, regardless of level, undergo surgery within 24 hours after injury when medically feasible. Future research is required to determine the differential effectiveness of early surgery in different subpopulations and the impact of ultra-early surgery on neurological recovery. Moreover, further work is required to define what constitutes effective spinal cord decompression and to individualize care. It is also recognized that a concerted international effort will be required to translate these recommendations into policy.

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 (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.

Interhospital Transfer Delays Care for Spinal Cord Injury Patients: A Report from the North American Clinical Trials Network for Spinal Cord Injury.

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.

Bulbocavernosus Reflex 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 (SCI) 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. A total of 769 registry patients with recorded BCRs were included in the study. The median age was 49 years (32-61 years), and the 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. 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 American Spinal Injury Association Impairment Scale 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.

Evolving Profile of Acute Spinal Cord Injury Demographics, Outcomes, and Surgical Treatment in North America: Analysis of a Prospective Multi-Center Dataset of 989 Patients.

Changes in demography and injury patterns have altered the profile and outcome of acute spinal cord injury (SCI) over time. This study sought to describe recent trends in epidemiology and early clinical outcomes using the multi-center North American Clinical Trial Network (NACTN) for Spinal Cord Injury Registry. All participants with blunt acute traumatic SCI (n = 782) were grouped into three five-year time intervals from 2005 to 2019 (2005-2009, 2010-2014, and 2015-2019). Baseline demographics, clinical scores, medical co-morbidities, as well as early clinical outcomes were extracted. Categorical and continuous variables were analyzed to determine between-group differences. Subgroup analysis was performed for participants <50 and ≥50 years of age. Over the duration of the study period, there was an increase in age at presentation (p = 0.0077) as well as a greater incidence of falls as the mechanism of injury. Participants who were ≥50 years of age were more likely to sustain incomplete SCI (<0.0003) and central cord syndrome (< 0.0001). In the most recent period (2015-2019), a greater proportion of NACTN participants underwent surgery within 24 h of injury (63% vs. 41% vs. 41%, p = 0.0001). There was a statistically significant increase in cardiac complications (p < 0.0001) and decrease in pulmonary complications (p < 0.0001) during the study period. Data from the NACTN registry shows that the age of participants with acute SCI is increasing, falls have become the major mechanism of injury, and central cord injury is becoming increasingly prevalent. While early surgical intervention for acute SCI is more common in recent years, cardiac complications are more prevalent while pulmonary complications are less prevalent.

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

STUDY DESIGN: Literature Review (Narrative). OBJECTIVE: To contextualize AO Spine RECODE-DCM research priority number 5: What is the socio-economic impact of DCM? (The financial impact of living with DCM to the individual, their supporters, and society as a whole). METHODS: In this review, we introduce the methodology of health-economic investigation, including potential techniques and approaches. We summarize the current health-economic evidence within DCM, so far focused on surgical treatment. We also cover the first national estimate, in partnership with Myelopathy.org from the United Kingdom, of the cost of DCM to society. We then demonstrate the significance of this question to advancing care and outcomes in the field. RESULTS: DCM is a common and often disabling condition, with a significant lack of recognition. While evidence demonstrates the cost-effectives of surgery, even among higher income countries, health inequalities exist. Further the prevalent residual disability in myelopathy, despite treatment affects both the individual and society as a whole. A report from the United Kingdom provides the first cost-estimate to their society; an annual cost of ∼£681.6 million per year, but this is likely a significant underestimate. CONCLUSION: A clear quantification of the impact of DCM is needed to raise the profile of a common and disabling condition. Current evidence suggests this is likely to be globally substantial.

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

STUDY DESIGN: Literature Review (Narrative). OBJECTIVE: To introduce the number 10 research priority for Degenerative Cervical Myelopathy: Individualizing Surgery. METHODS: This article summarizes the current recommendations and indications for surgery, including how known prognostic factors such as injury time, age, disease severity, and associated comorbidities impact surgical outcome. It also considers key areas of uncertainty that should be the focus of future research. RESULTS: While a small proportion of conservatively managed patients may remain stable, the majority will deteriorate over time. To date, surgical decompression is the mainstay of treatment, able to halt disease progression and improve neurologic function and quality of life for most patients. Whilst this recognition has led to recommendations on when to offer surgery, there remain many uncertainties including the type of surgery, or timing in milder and/or asymptomatic cases. Their clarification has the potential to transform outcomes, by ensuring surgery offers each individual its maximum benefit. CONCLUSION: Developing the evidence to better guide surgical decision-making at the individual patient level is a research priority for Degenerative Cervical Myelopathy.

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

STUDY DESIGN: Literature Review (Narrative). OBJECTIVE: To introduce the number one research priority for Degenerative Cervical Myelopathy (DCM): Raising Awareness. METHODS: Raising awareness has been recognized by AO Spine RECODE-DCM as the number one research priority. This article reviews the evidence that awareness is low, the potential drivers, and why this must be addressed. Case studies of success from other diseases are also reviewed, drawing potential parallels and opportunities for DCM. RESULTS: DCM may affect as many as 1 in 50 adults, yet few will receive a diagnosis and those that do will wait many years for it. This leads to poorer outcomes from surgery and greater disability. DCM is rarely featured in healthcare professional training programs and has received relatively little research funding (<2% of Amyotrophic Lateral Sclerosis or Multiple Sclerosis over the last 25 years). The transformation of stroke and acute coronary syndrome services, from a position of best supportive care with occasional surgery over 50 years ago, to avoidable disability today, represents transferable examples of success and potential opportunities for DCM. Central to this is raising awareness. CONCLUSION: Despite the devastating burden on the patient, recognition across research, clinical practice, and healthcare policy are limited. DCM represents a significant unmet need that must become an international public health priority.

Are Lumbar Fusion Guidelines Followed? A Survey of North American Spine Surgeons.

OBJECTIVE: To evaluate the use of guidelines for lumbar spine fusions among spine surgeons in North America. METHODS: An anonymous survey was electronically sent to all AO Spine North America members. Survey respondents were asked to indicate their opinion surrounding the suitability of instrumented fusion in a variety of clinical scenarios. Fusion indications in accordance with North America Spine Society (NASS) guidelines for lumbar fusion were considered NASS-concordant answers. Respondents were considered to have a NASS-concordant approach if ≥ 70% (13 of 18) of their answers were NASS-concordant answers. Comparisons were performed using bivariable statistics. RESULTS: A total of 105 responses were entered with complete data available on 70. Sixty percent of the respondents (n = 42) were considered compliant with NASS guidelines. NASS-discordant responses did not differ between surgeons who stated that they include the NASS guidelines in their decision-making algorithm (5.10 ± 1.96) and those that did not (4.68 ± 2.09) (p = 0.395). The greatest number of NASS-discordant answers in the United States. was in the South (5.75 ± 2.09), with the lowest number in the Northeast (3.84 ± 1.70) (p < 0.01). For 5 survey items, rates of NASS-discordant answers were ≥ 40%, with the greatest number of NASS-discordant responses observed in relation to indications for fusion in spinal deformity (80%). Spine surgeons utilizing a NASS-concordant approach had a significant lower number of NASS-discordant answers for synovial cysts (p = 0.03), axial low back pain (p < 0.01), adjacent level disease (p < 0.01), recurrent stenosis (p < 0.01), recurrent disc herniation (p = 0.01), and foraminal stenosis (p < 0.01). CONCLUSION: This study serves an important role in clarifying the rates of uptake of clinical practice guidelines in spine surgery as well as to identify barriers to their implementation.

AOSpine Global Survey: International Trends in Utilization of Magnetic Resonance Imaging/Computed Tomography for Spinal Trauma and Spinal Cord Injury across AO Regions.

The aim of this study was to determine the current trends in magnetic resonance imaging (MRI)/computed tomography (CT) utilization for spine trauma in various clinical scenarios. We conducted a survey across six AO regions and preformed pair-wise comparisons between responses obtained from different AO regions. The survey was sent to 5813 surgeons and had a 9.6% response rate with the majority being orthopedic followed by neurosurgeons. In a neurologically intact patient, the predominant imaging modality for all AO regions was CT. For patients with spinal cord injury (SCI), the predominant choice for all AO regions was CT + MRI + x-ray except North America, which was CT + MRI; pair-wise comparisons revealed significant differences involving LATAM (Latin America) versus (Asia-Pacific [APAC], Europe [EU], and Middle East [MEA]) and APAC versus (LATAM and North America [NA]). In a patient with incomplete SCI (ISCI) who presented within 4 h and had CT, the predominant choice for all AO regions was "forgo MRI and proceed to operating room (OR)." Similar to ISCI, in a patient with complete SCI, the predominant option for all AO regions was the same as ISCI, but the range was lower. Pair-wise comparisons noted significant differences between MEA and APAC, with both exhibiting differences compare to NA, LATAM, and EU for complete and ISCI. Most AO regions obtained post-operative MRI only if there was a new deficit. In summary, decisions about the use of a particular imaging modality across AO regions appears to be influenced by the neurological status of the patient upon admission and the presence of neurological deficits post-surgery. Type of residency training and fellowship training did not have an influence on choosing the appropriate imaging modality for both intact and impaired patients. Further study is needed to determine whether accessibility to MRI would change surgeons' attitude toward obtaining MRI in patients with SCI.

Great Hospitals in North America: The Medical College of Wisconsin Neurological Surgery.

The Medical College of Wisconsin Department of Neurosurgery delivers subspecialty adult and pediatric neurosurgical care that is patient-centered, evidence-informed, and value-based. Medical College of Wisconsin research advances the science of neurological disease with the goal of a positive translational effect on clinical care. The department supports an environment of education and scholarship for trainees, faculty, and staff alike. The journey to become a neurosurgical center of excellence was accomplished with the leadership and foresight of the men and women who turned their dreams into reality. The establishment and rise of the department as a national force for neurosurgery and spine is an elegant example of the combination of individual leadership and foresight with synergistic institutional support.

Clinical Outcomes from a Multi-Center Study of Human Neural Stem Cell Transplantation in Chronic Cervical Spinal Cord Injury.

Human neural stem cell transplantation (HuCNS-SC®) is a promising central nervous system (CNS) tissue repair strategy in patients with stable neurological deficits from chronic spinal cord injury (SCI). These immature human neural cells have been demonstrated to survive when transplanted in vivo, extend neural processes, form synaptic contacts, and improve functional outcomes after experimental SCI. A phase II single blind, randomized proof-of-concept study of the safety and efficacy of HuCNS-SC transplantation into the cervical spinal cord was undertaken in patients with chronic C5-7 tetraplegia, 4-24 months post-injury. In Cohort I (n = 6) dose escalation from 15,000,000 to 40,000,000 cells was performed to determine the optimum dose. In Cohort II an additional six participants were transplanted at target dose (40,000,000) and compared with four untreated controls. Within the transplant group, there were nine American Spinal Injury Association Impairment Scale (AIS) B and three AIS A participants with a median age at transplant of 28 years with an average time to transplant post-injury of 1 year. Immunosuppression was continued for 6 months post-transplant, and immunosuppressive blood levels of tacrolimus were achieved and well tolerated. At 1 year post-transplantation, there was no evidence of additional spinal cord damage, new lesions, or syrinx formation on magnetic resonance (MR) imaging. In summary, the incremental dose escalation design established surgical safety, tolerability, and feasibility in Cohort I. Interim analysis of Cohorts I and II demonstrated a trend toward Upper Extremity Motor Score (UEMS) and Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) motor gains in the treated participants, but at a magnitude below the required clinical efficacy threshold set by the sponsor to support further development resulting in early study termination.

Diffusion Tensor Imaging in a Large Longitudinal Series of Patients With Cervical Spondylotic Myelopathy Correlated With Long-Term Functional Outcome.

BACKGROUND: Fractional anisotropy (FA) of the high cervical cord correlates with upper limb function in acute cervical cord injury. We investigated the correlation between preoperative FA at the level of maximal compression and functional recovery in a group of patients after decompressive surgery for cervical spondylotic myelopathy (CSM). OBJECTIVE: To determine the usefulness of FA as a biomarker for severity of CSM and as a prognostic biomarker for improvement after surgery. METHODS: Patients received diffusion tensor imaging (DTI) scans preoperatively. FA values of the whole cord cross-section at the level of maximal compression and upper cervical cord (C1-2) were calculated. Functional status was measured using the modified Japanese Orthopedic Association (mJOA) scale preoperatively and at follow-up up to 2 yr. Regression analysis between FA and mJOA was performed. DTI at C4-7 was obtained in controls. RESULTS: Forty-four CSM patients enrolled prior to decompression were compared with 24 controls. FA at the level of maximal compression correlated positively with preoperative mJOA score. Preoperative FA correlated inversely with recovery throughout the postoperative period. This was statistically significant at 12 mo postoperation and nearly so at 6 and 24 mo. Patients with preoperative FA <0.55 had a statistically significant difference in outcome compared to FA >0.55. CONCLUSION: In the largest longitudinal study of this kind, FA promises a valid biomarker for severity of CSM and postoperative improvement. FA is an objective measure of function and could provide a basis for prognosis. FA is particularly useful if preoperative values are less than 0.55.

Imaging Evaluation of Degenerative Cervical Myelopathy: Current State of the Art and Future Directions.

Degenerative cervical myelopathy (DCM) is a common neurologic condition that is often treated with surgery. Imaging plays a central role in the management of DCM, including diagnosis, preoperative planning, postoperative assessment, and prognostication. Radiographs, CT, and MRI offer unique and complementary assessments, and all have important uses in current clinical practice. Emerging microstructural and functional MRI techniques have the potential to have a major impact, potentially transforming practice by offering earlier and more accurate diagnosis, monitoring for deterioration, and prediction of outcomes. In the future, it can be expected that imaging will play an even greater role in DCM management.

Emerging Safety of Intramedullary Transplantation of Human Neural Stem Cells in Chronic Cervical and Thoracic Spinal Cord Injury.

BACKGROUND: Human central nervous system stem cells (HuCNS-SC) are multipotent adult stem cells with successful engraftment, migration, and region-appropriate differentiation after spinal cord injury (SCI). OBJECTIVE: To present data on the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after SCI. METHODS: Intramedullary free-hand (manual) transplantation of HuCNS-SC cells was performed in subjects with thoracic (n = 12) and cervical (n = 17) complete and sensory incomplete chronic traumatic SCI. RESULTS: Intramedullary stem cell transplantation needle times in the thoracic cohort (20 M HuCNS-SC) were 19:30 min and total injection time was 42:15 min. The cervical cohort I (n = 6), demonstrated that escalating doses of HuCNS-SC up to 40 M range were well tolerated. In cohort II (40 M, n = 11), the intramedullary stem cell transplantation needle times and total injection time was 26:05 ± 1:08 and 58:14 ± 4:06 min, respectively. In the first year after injection, there were 4 serious adverse events in 4 of the 12 thoracic subjects and 15 serious adverse events in 9 of the 17 cervical patients. No safety concerns were considered related to the cells or the manual intramedullary injection. Cervical magnetic resonance images demonstrated mild increased T2 signal change in 8 of 17 transplanted subjects without motor decrements or emerging neuropathic pain. All T2 signal change resolved by 6 to 12 mo post-transplant. CONCLUSION: A total cell dose of 20 M cells via 4 and up to 40 M cells via 8 perilesional intramedullary injections after thoracic and cervical SCI respectively proved safe and feasible using a manual injection technique.

Diffusion Tensor Imaging Correlates with Short-Term Myelopathy Outcome in Patients with Cervical Spondylotic Myelopathy.

OBJECTIVE: To determine if spinal cord diffusion tensor imaging indexes correlate with short-term clinical outcome in patients undergoing elective cervical spine surgery for cervical spondylotic myelopathy (CSM). METHODS: A prospective consecutive cohort study was performed in patients undergoing elective cervical spine surgery for CSM. After obtaining informed consent, patients with CSM underwent preoperative T2-weighted magnetic resonance imaging and diffusion tensor imaging of the cervical spine. Fractional anisotropy (FA) values at the level of maximum cord compression and at the noncompressed C1-2 level were calculated on axial images. We recorded the modified Japanese Orthopaedic Association (mJOA) scale, Neck Disability Index, and Short Form-36 physical functioning subscale scores for all patients preoperatively and 3 months postoperatively. Statistical analysis was performed to identify correlations between FA and clinical outcome scores. RESULTS: The study included 27 patients (mean age 54.5 years ± 1.9, 12 men). The mean postoperative changes in mJOA scale, Neck Disability Index, and Short Form-36 physical functioning subscale scores were 0.9 ± 0.3, -6.0 ± 1.9, and 3.4 ± 1.9. The mean FA at the level of maximum compression was significantly lower than the mean FA at the C1-2 level (0.5 vs. 0.55, P = 0.01). FA was significantly correlated with change in mJOA scale score (Pearson r = -0.42, P = 0.02). FA was significantly correlated with the preoperative mJOA scale score (Pearson r = 0.65, P < 0.001). CONCLUSIONS: Preoperative FA at the level of maximum cord compression significantly correlates with the 3-month change in mJOA scale score among patients with CSM. FA was also significantly associated with preoperative mJOA scale score and is a potential biomarker for spinal cord dysfunction in CSM.

Diffusion tensor imaging as a biomarker for assessing neuronal stem cell treatments affecting areas distal to the site of spinal cord injury.

OBJECTIVE The aims of this study were to determine if the morphological and functional changes induced by neural stem cell (NSC) grafts after transplantation into the rodent spinal cord can be detected using MR diffusion tensor imaging (DTI) and, furthermore, if the DTI-derived mean diffusivity (MD) metric could be a biomarker for cell transplantation in spinal cord injury (SCI). METHODS A spinal contusion was produced at the T-8 vertebral level in 40 Sprague Dawley rats that were separated into 4 groups, including a sham group (injury without NSC injection), NSC control group (injury with saline injection), co-injection control group (injury with Prograf), and the experimental group (injury with NSC and Prograf injection). The NSC injection was completed 1 week after injury into the site of injury and the rats in the experimental group were compared to the rats from the sham, NSC control, and co-injection groups. The DTI index, MD, was assessed in vivo at 2, 5, and 10 weeks and ex vivo at 10 weeks postinjury on a 9.4-T Bruker scanner using a spin-echo imaging sequence. DTI data of the cervical spinal cord from the sham surgery, injury with saline injection, injury with injection of Prograf only, and injury with C17.2 NSC and Prograf injection were examined to evaluate if cellular proliferation induced by intrathoracic C17.2 engraftment was detectable in a noninvasive manner. RESULTS At 5 weeks after injury, the average fractional anisotropy, longitudinal diffusion (LD) and radial diffusion (RD) coefficients, and MD of water (average of the RD and LD eigenvalues in the stem cell line-treated group) increased to an average of 1.44 × 10-3 sec/mm2 in the cervical segments, while the control groups averaged 0.98 × 10-3 s/mm2. Post hoc Tukey's honest significant difference tests demonstrated that the transplanted stem cells had significantly higher MD values than the other groups (p = 0.032 at 5 weeks). In vivo and ex vivo findings at 10 weeks displayed similar results. This statistical difference between the stem cell line and the other groups was maintained at the 10-week postinjury in vivo and ex vivo time points. CONCLUSIONS These results indicate that the DTI-derived MD metric collected from noninvasive imaging techniques may provide useful biomarker indices for transplantation interventions that produce changes in the spinal cord structure and function. Though promising, the results demonstrated here suggest additional work is needed before implementation in a clinical setting.

Evaluation of combined bevacizumab plus irinotecan therapy in brain tumors using magnetic resonance imaging measures of relative cerebral blood volume.

Frequently, bevacizumab is combined with chemotherapeutics such as irinotecan, motivated by studies showing improved clinical outcomes compared with historical controls. However, no systematic studies have been performed to determine if and how these drugs should be combined for optimal therapeutic response. The purpose of this study was to characterize the temporal combinations of bevacizumab and irinotecan by measuring the contrast-agent enhanced tumor volumes and relative cerebral blood volume using dynamic susceptibility contrast imaging. The studies, performed in the U87 brain tumor model, show a vascular normalization window with bevacizumab monotherapy and are consistent with clinical indications of no additional benefit in the addition of irinotecan to bevacizumab therapy.

Feline bone marrow-derived mesenchymal stem cells express several pluripotent and neural markers and easily turn into neural-like cells by manipulation with chromatin modifying agents and neural inducing factors.

Recent studies suggest that cellular therapies that utilize mesenchymal stem cells (MSCs), especially ones that have been neurally induced (NI), may provide a functional benefit in a wide range of neurological disorders. Recently, we developed a new method for the efficient generation of neural cells from human bone marrow (BM)-derived MSCs (hMSC). Neural induction was achieved by exposing cells simultaneously to chromatin-modifying agents and neural-inducing factors. When transplanted into injured spinal cords, these NI-hMSCs survived, differentiated, promoted tissue preservation, and significantly improved locomotor recovery of injured animals. In the current study, we sought to determine whether this methodological approach would be equally effective in generating neural-like cells from feline BM-derived MSCs (fMSC). Our long-term goal is to develop an autologous source of neural stem cells that can be used in cellular replacement therapies in large animal (feline) models of neurological disorders. Our results showed that fMSCs exhibited a neural morphology after 48-72 h of neural induction. Immunocytochemistry, ELISA, Western blot, and real-time RT-PCR studies revealed a higher level of expression of several pluripotent and neural genes in NI-fMSCs, the majority of which were expressed in untreated fMSCs at relatively low levels. We concluded that the expression of pluripotency- and neural-associated genes in unmodified fMSCs make them more pliable for reprogramming into a neural fate by manipulation with chromatin modifying agents and neural inducing factors.

Characterization of bevacizumab dose response relationship in U87 brain tumors using magnetic resonance imaging measures of enhancing tumor volume and relative cerebral blood volume.

Despite the early promising results with the anti-angiogenic agent, bevacizumab, to prolong time to progression in patients with brain tumors, the optimal dose and drug combinations have not yet been defined. The purpose of this study was to characterize the bevacizumab dose-response relationship for brain tumors by measuring the contrast-agent enhanced tumor volumes and relative cerebral blood volume (rCBV) using dynamic susceptibility contrast (DSC) imaging. The studies, performed in the U87 brain tumor model using doses of bevacizumab ranging from 0 to 10 mg/kg, demonstrate that tumor growth and vascularity are inhibited at all doses used, compared to untreated controls. However, only the maximum dose showed a statistically significant difference in growth rate. Conversely tumor vascularity, as measured with rCBV, was inhibited equally well for all doses used with no clear indication that higher doses are more effective.