Association of Cerebrovascular Injury and Secondary Vascular Insult With Poor Outcomes After Gunshot Wound to the Head in a Large Civilian Population.

BACKGROUND AND OBJECTIVES: Cerebrovascular injury (CVI) after civilian gunshot wound to the head (GSWH) likely contributes to poor outcomes, but little supporting evidence exists. The purpose of this study was to determine whether intracranial CVI from GSWH and secondary vascular insult (stroke or rehemorrhage) were associated with poor outcomes in a large civilian population. METHODS: This was a single-institution, retrospective cohort study on patients admitted between January 2014 and July 2022 at a large, metropolitan, level-1 trauma center. Multivariate regression models and propensity score matching were used. RESULTS: A total of 512 civilian patients presented with GSWH, and a cohort of 172 (33.5%) met inclusion criteria, with 143 (83.1%) males and a mean (SD) age of 34.3 (±14.2) years. The incidence of intracranial CVI was 50.6% (87/172 patients), and that of secondary vascular insult was 32.2% (28/172 patients). Bifrontal trajectories (adjusted odds ratio [aOR] 13.11; 95% CI 2.45-70.25; P = .003) and the number of lobes traversed by the projectile (aOR 3.18; CI 1.77-5.71; P < .001) were associated with increased odds of resultant CVI. Patients with CVI suffered higher rate of mortality (34% vs 20%; odds ratio [OR] 2.1; CI 0.78-5.85; P = .015) and were less likely to achieve a good functional outcome with a Glasgow Outcome Score of 4-5 (34% vs 68%; OR 0.24; CI 0.1-0.6; P = .004) at follow-up. Furthermore, patients with CVI and resultant secondary vascular insult had even worse functional outcomes (Glasgow Outcome Score 4-5, 16.7% vs 39.0%; aOR 0.012; CI 0.001-0.169, P = .001). CONCLUSION: Intracranial CVI from GSWH and associated secondary vascular insult are associated with poor outcomes. Given the high prevalence and potentially reversible nature of these secondary injuries, early screening with vascular imaging and treatment of underlying CVI may prove to be critical to improve outcomes by reducing stroke and rehemorrhage incidence.

Comparing Cortical Bone Trajectory and Traditional Pedicle Screws in Transforaminal Lumbar Interbody Fusion: A Retrospective Cohort Study of One-Year Outcomes.

INTRODUCTION: This is a retrospective study of consecutive patients undergoing transforaminal lumbar interbody fusion (TLIF) at a single institution. The objective of this study was to compare the long-term results associated with cortical bone trajectory (CBT) and traditional pedicle screw (TPS) via posterolateral approach in TLIF. METHODS: Consecutive patients treated from November 2014 to March 2019 were included in the CBT TLIF group, while consecutive patients treated from October 2010 to August 2017 were included in the TPS TLIF group. Inclusion criteria comprised single-level or two-level TLIF for degenerative spondylolisthesis with stenosis and at least one year of clinical and radiographic follow-up. Variables of interest included pertinent preoperative, perioperative, and postoperative data. Non-parametric evaluation was performed using the Wilcoxon test. Fisher's exact test was used to assess group differences for nominal data. RESULTS: Overall, 140 patients met the inclusion criteria; 69 patients had CBT instrumentation (mean follow-up 526 days) and 71 patients underwent instrumentation placement via TPS (mean follow-up 825 days). Examination of perioperative and postoperative outcomes demonstrate comparable results between the groups with perioperative complications, length of stay, discharge destination, surgical revision rate, and fusion rates all being similar between groups (p = 0.1; p = 0.53; p = 0.091; p = 0.61; p = 0.665, respectively). CONCLUSIONS: CBT in the setting of TLIF offer equivalent outcomes to TPS with TLIF at both short- and long-term intervals of care.

Tumor microenvironment in a minipig model of spinal cord glioma.

BACKGROUND: Spinal cord glioma (SCG) is considered an orphan disease that lacks effective treatment options with margins that are surgically inaccessible and an overall paucity of literature on the topic. The tumor microenvironment is a critical factor to consider in treatment and modeling design, especially with respect to the unresectable tumor edge. Recently, our group developed a high-grade spinal cord glioma (SCG) model in Göttingen minipigs. METHODS: Immunofluorescence and ELISA were performed to explore the microenvironmental features and inflammation cytokines in this minipig SCG model. Protein carbonyl assay and GSH/GSSG assay were analyzed in the core and edge lesions in the minipig SCG model. The primary core and edge cells proliferation rate were shown in vitro, and the xenograft model in vivo. RESULTS: We identified an elevated Ki-67 proliferative index, vascular and pericyte markers, CD31 and desmin in the tumor edge as compared to the tumor core. In addition, we found that the tumor edge demonstrated increased pro-inflammatory and gliomagenic cytokines including TNF-α, IL-1ß, and IL-6. Furthermore, the mediation of oxidative stress is upregulated in the tumor edge. Hypoxic markers had statistically significant increased staining in the tumor core, but were notably still present in the tumor edge. The edge cells cultures derived from SCG biopsy also demonstrated an increased proliferative rate compared to core cell cultures in a xenotransplantation model. CONCLUSIONS: Our study demonstrates heterogeneity in microenvironmental features in our minipig model of high-grade SCG, with a phenotype at the edge showing increased oxidative stress, proliferation, inflammatory cytokines, neovascularization, and decreased but present staining for hypoxic markers. These findings support the utility of this model as a means for investigating therapeutic approaches targeting the more aggressive and surgically unresectable tumor border.

Spinal cord and brain concentrations of riluzole after oral and intrathecal administration: A potential new treatment route for amyotrophic lateral sclerosis.

Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."

Keyhole Supraorbital-Eyebrow Approach for Resection of an Olfactory Groove Meningioma with Intraoperative Endoscopic Assistance.

The authors present the case of a 52-year-old male with a history of new-onset seizures who presented in status epilepticus. Computed tomography and magnetic resonance imaging demonstrated an olfactory groove mass. A keyhole supraorbital-eyebrow approach assisted with a microinspection tool was performed for tumor resection.1-5 A Simpson grade 2 tumor resection was achieved, and histopathology revealed a World Health Organization grade I olfactory groove meningioma. Postoperative and follow-up course has been unremarkable, with early postoperative imaging demonstrating no residual tumoral mass. The operative video highlights the advantages of using the microinspection tool for the visualization of deep lesions.

Peripheral blood detection of systemic graft-specific xeno-antibodies following transplantation of human neural progenitor cells into the porcine spinal cord.

Extensive pre-clinical and clinical studies have searched for therapeutic efficacy of cell-based therapeutics in diseases of the Central Nervous System (CNS) with no other viable options. Allogeneic cells represent the primary source of these therapies and immunosuppressive regimens have been empirically employed based on experience with solid organ transplantation, attempting to avoid immune mediated graft rejection. In this study, we aimed to 1) characterize the host immune response to stem cells transplanted into the CNS and 2) develop a non-invasive method for detecting immune response to transplanted cell grafts. Human neural progenitor cells were transplanted into the spinal cord of 10 Göttingen minipigs, of which 5 received no immunosuppression and 5 received Tacrolimus. Peripheral blood samples were collected longitudinally for flow cytometry cross match studies. Necropsy was performed at day 21 and spinal cord tissue analysis. We observed a transient increase in xeno-reactive antibodies was detected on post-operative day 7 and 14 in pigs that did not receive immunosuppression. This response was not detected in pigs that received Tacrolimus immunosuppression. No difference in graft survival was observed between the groups. Infiltration of numerous immune mediators including granulocytes, T lymphocytes, and activated microglia, and complement deposition were detected. In summary, a systemic immunologic response to stem cell grafts was detected for two weeks after transplantation using peripheral blood. This could be used as a non-invasive biomarker by investigators for detection of immunologic rejection. However, the absence of a detectable response in peripheral blood does not rule out a parenchymal immune response.

Ferumoxytol Labeling of Human Neural Progenitor Cells for Diagnostic Cellular Tracking in the Porcine Spinal Cord with Magnetic Resonance Imaging.

We report on the diagnostic capability of magnetic resonance imaging (MRI)-based tracking of ferumoxytol-labeled human neural progenitor cells (hNPCs) transplanted into the porcine spinal cord. hNPCs prelabeled with two doses of ferumoxytol nanoparticles (hNPC-FLow and hNPC-FHigh ) were injected into the ventral horn of the spinal cord in healthy minipigs. Ferumoxytol-labeled grafts were tracked in vivo up to 105 days after transplantation with MRI. Injection accuracy was assessed in vivo at day 14 and was predictive of "on" or "off" target cell graft location assessed by histology. No difference in long-term cell survival, assessed by quantitative stereology, was observed among hNPC-FLow , hNPC-FHigh , or control grafts. Histological iron colocalized with MRI signal and engrafted human nuclei. Furthermore, the ferumoxytol-labeled cells retained nanoparticles and function in vivo. This approach represents an important leap forward toward facilitating translation of cell-tracking technologies to clinical trials by providing a method of assessing transplantation accuracy, delivered dose, and potentially cell survival. Stem Cells Translational Medicine 2017;6:139-150.

Magnetic Resonance Imaging-Guided Transplantation of Neural Stem Cells into the Porcine Spinal Cord.

BACKGROUND: Cell-based therapies are a promising treatment option for traumatic, tumorigenic and degenerative diseases of the spinal cord. Transplantation into the spinal cord is achieved with intravascular, intrathecal, or direct intraparenchymal injection. The current standard for direct injection is limited by surgical invasiveness, difficulty in reinjection, and the inability to directly target anatomical or pathological landmarks. The objective of this study was to present the proof of principle for minimally invasive, percutaneous transplantation of stem cells into the spinal cord parenchyma of live minipigs under MR guidance. METHODS: An MR-compatible spine injection platform was developed to work with the ClearPoint SmartFrame system (MRI Interventions Inc.). The system was attached to the spine of 2 live minipigs, a percutaneous injection cannula was advanced into the spinal cord under MR guidance, and cells were delivered to the cord. RESULTS: A graft of 2.5 × 106 human (n = 1) or porcine (n = 1) neural stem cells labeled with ferumoxytol nanoparticles was transplanted into the ventral horn of the spinal cord with MR guidance in 2 animals. Graft delivery was visualized with postprocedure MRI, and characteristic iron precipitates were identified in the spinal cord by Prussian blue histochemistry. Grafted stem cells were observed in the spinal cord of the pig injected with porcine neural stem cells. No postoperative morbidity was observed in either animal. CONCLUSION: This report supports the proof of principle for transplantation and visualization of pharmacological or biological agents into the spinal cord of a large animal under the guidance of MRI.

Preclinical Validation of Multilevel Intraparenchymal Stem Cell Therapy in the Porcine Spinal Cord.

BACKGROUND: Although multiple clinical trials are currently testing different stem cell therapies as treatment alternatives for many neurodegenerative diseases and spinal cord injury, the optimal injection parameters have not yet been defined. OBJECTIVE: To test the spinal cord's tolerance to increasing volumes and numbers of stem cell injections in the pig. METHODS: Twenty-seven female Göttingen minipigs received human neural progenitor cell injections using a stereotactic platform device. Cell transplantation in groups 1 to 5 (5-7 pigs in each) was undertaken with the intent of assessing the safety of an injection volume escalation (10, 25, and 50 µL) and an injection number escalation (20, 30, and 40 injections). Motor function and general morbidity were assessed for 21 days. Full necropsy was performed; spinal cords were analyzed for graft survival and microscopic tissue damage. RESULTS: No mortality or permanent surgical complications were observed during the 21-day study period. All animals returned to preoperative baseline within 14 days, showing complete motor function recovery. The histological analysis showed that there was no significant decrease in neuronal density between groups, and cell engraftment ranged from 12% to 31% depending on the injection paradigm. However, tissue damage was identified when injecting large volumes into the spinal cord (50 µL). CONCLUSION: This series supports the functional safety of various injection volumes and numbers in the spinal cord and gives critical insight into important safety thresholds. These results are relevant to all translational programs delivering cell therapeutics to the spinal cord.

Introduction to neuropathic pain syndromes.

Chronic pain impairs the quality of life for millions of individuals and therefore presents a serious ongoing challenge to clinicians and researchers. Debilitating chronic pain syndromes cost the US economy more than $600 billion per year. This article provides an overview of the epidemiology, clinical presentation, and treatment outcomes for craniofacial, spinal, and peripheral neurologic pain syndromes. Although the authors recognize that the diagnosis and treatment of the chronic forms of neuropathic pain syndromes represent a clinical challenge, there is an urgent need for standardized classification systems, improved epidemiologic data, and reliable treatment outcomes data.