An Integrated 3-Dimentional Navigation System Increases the Accuracy, Efficiency, and Safety of Percutaneous Thoracolumbar Pedicle Screw Placement in Minimally Invasive Approaches: A Randomized Cadaveric Study.

STUDY DESIGN: Cadaveric study. OBJECTIVES: The purpose of this study was to compare a novel, integrated 3D navigational system (NAV) and conventional fluoroscopy in the accuracy, efficiency, and radiation exposure of thoracolumbar percutaneous pedicle screw (PPS) placement. METHODS: Twelve skeletally mature cadaveric specimens were obtained for twelve individual surgeons. Each participant placed bilateral PS at 11 segments, from T8 to S1. Prior to insertion, surgeons were randomized to the sequence of techniques and the side (left or right). Following placement, a CT scan of the spine was obtained for each cadaver, and an independent reviewer assessed the accuracy of screw placement using the Gertzbein grading system. Outcome metrics of interest included a comparison of breach incidence/severity, screw placement time, total procedure time, and radiation exposure between the techniques. Bivariate statistics were employed to compare outcomes at each level. RESULTS: A total of 262 screws (131 using each technique) were placed. The incidence of cortical breaches was significantly lower with NAV compared to FG (9% vs 18%; P = .048). Of breaches with NAV, 25% were graded as moderate or severe compared to 39% in the FG subgroup (P = .034). Median time for screw placement was significantly lower with NAV (2.7 vs 4.1 min/screw; P = .012), exclusive of registration time. Cumulative radiation exposure to the surgeon was significantly lower for NAV-guided placement (9.4 vs 134 µGy, P = .02). CONCLUSIONS: The use of NAV significantly decreased the incidence of cortical breaches, the severity of screw breeches, screw placement time, and radiation exposure to the surgeon when compared to traditional FG.

Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent.

Riluzole, a benzothiazole sodium channel blocker that received US Food and Drug Administration approval to attenuate neurodegeneration in amyotrophic lateral sclerosis in 1995, was found to be safe and potentially efficacious in a spinal cord injury (SCI) population, as evident in a phase I clinical trial. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes can alter the pharmacokinetics of therapeutics. A 1-compartment with first-order elimination population pharmacokinetic model for riluzole incorporating time-dependent clearance and volume of distribution was developed from combined data of the phase 1 and the ongoing phase 2/3 trials. This change in therapeutic exposure may lead to a biased estimate of the exposure-response relationship when evaluating therapeutic effects. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification that preserves the required therapeutic exposure of riluzole.

ACR Appropriateness Criteria® Suspected Spine Trauma.

Injuries to the cervical and thoracolumbar spine are commonly encountered in trauma patients presenting for treatment. Cervical spine injuries occur in 3% to 4% and thoracolumbar fractures in 4% to 7% of blunt trauma patients presenting to the emergency department. Clear, validated criteria exist for screening the cervical spine in blunt trauma. Screening criteria for cervical vascular injury and thoracolumbar spine injury have less validation and widespread acceptance compared with cervical spine screening. No validated criteria exist for screening of neurologic injuries in the setting of spine trauma. CT is preferred to radiographs for initial assessment of spine trauma. CT angiography and MR angiography are both acceptable in assessment for cervical vascular injury. MRI is preferred to CT myelography for assessing neurologic injury in the setting of spine trauma. MRI is usually appropriate when there is concern for ligament injury or in screening obtunded patients for cervical spine instability. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Management of Vertebral Compression Fractures.

Vertebral compression fractures (VCFs) have various causes, including osteoporosis, neoplasms, and acute trauma. As painful VCFs may contribute to general physical deconditioning, management of painful VCFs has the potential for improving quality of life and preventing superimposed medical complications. Various imaging modalities can be used to evaluate a VCF to help determine the etiology and guide intervention. The first-line treatment of painful VCFs has been nonoperative or conservative management as most VCFs show gradual improvement in pain over 2 to 12 weeks, with variable return of function. There is evidence that vertebral augmentation (VA) is associated with better pain relief and improved functional outcomes compared to conservative therapy for osteoporotic VCFs. A multidisciplinary approach is necessary for the management of painful pathologic VCFs, with management strategies including medications to affect bone turnover, radiation therapy, and interventions such as VA and percutaneous thermal ablation to alleviate symptoms. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Penetrating Neck Injury.

In patients with penetrating neck injuries with clinical soft injury signs, and patients with hard signs of injury who do not require immediate surgery, CT angiography of the neck is the preferred imaging procedure to evaluate extent of injury. Other modalities, such as radiography and fluoroscopy, catheter-based angiography, ultrasound, and MR angiography have their place in the evaluation of the patient, depending on the specific clinical situation and question at hand. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury.

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group.

Predictors of pulmonary complications in blunt traumatic spinal cord injury.

OBJECT: Pulmonary complications are the most common acute systemic adverse events following spinal cord injury (SCI), and contribute to morbidity, mortality, and increased length of hospital stay (LOS). Identification of factors associated with pulmonary complications would be of value in prevention and acute care management. Predictors of pulmonary complications after SCI and their effect on neurological recovery were prospectively studied between 2005 and 2009 at the 9 hospitals in the North American Clinical Trials Network (NACTN). METHODS: The authors sought to address 2 specific aims: 1) define and analyze the predictors of moderate and severe pulmonary complications following SCI; and 2) investigate whether pulmonary complications negatively affected the American Spinal Injury Association (ASIA) Impairment Scale conversion rate of patients with SCI. The NACTN registry of the demographic data, neurological findings, imaging studies, and acute hospitalization duration of patients with SCI was used to analyze the incidence and severity of pulmonary complications in 109 patients with early MR imaging and long-term follow-up (mean 9.5 months). Univariate and Bayesian logistic regression analyses were used to analyze the data. RESULTS: In this study, 86 patients were male, and the mean age was 43 years. The causes of injury were motor vehicle accidents and falls in 80 patients. The SCI segmental level was in the cervical, thoracic, and conus medullaris regions in 87, 14, and 8 patients, respectively. Sixty-four patients were neurologically motor complete at the time of admission. The authors encountered 87 complications in 51 patients: ventilator-dependent respiratory failure (26); pneumonia (25); pleural effusion (17); acute lung injury (6); lobar collapse (4); pneumothorax (4); pulmonary embolism (2); hemothorax (2), and mucus plug (1). Univariate analysis indicated associations between pulmonary complications and younger age, sports injuries, ASIA Impairment Scale grade, ascending neurological level, and lesion length on the MRI studies at admission. Bayesian logistic regression indicated a significant relationship between pulmonary complications and ASIA Impairment Scale Grades A (p = 0.0002) and B (p = 0.04) at admission. Pulmonary complications did not affect long-term conversion of ASIA Impairment Scale grades. CONCLUSIONS: The ASIA Impairment Scale grade was the fundamental clinical entity predicting pulmonary complications. Although pulmonary complications significantly increased LOS, they did not increase mortality rates and did not adversely affect the rate of conversion to a better ASIA Impairment Scale grade in patients with SCI. Maximum canal compromise, maximum spinal cord compression, and Acute Physiology and Chronic Health Evaluation-II score had no relationship to pulmonary complications.

Incidence and severity of acute complications after spinal cord injury.

OBJECT: The aim of this multicenter, prospective study was to determine the spectrum, incidence, and severity of complications during the initial hospitalization of patients with spinal cord injury. METHODS: The study was conducted at 9 university-affiliated hospitals that comprise the clinical centers of the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The study population comprised 315 patients admitted to NACTN clinical centers between June 25, 2005, and November 2, 2010, who had American Spinal Injury Association (ASIA) Impairment Scale grades of A-D and were 18 years of age or older. Patients were managed according to a standardized protocol. RESULTS: The study population was 79% male with a median age of 44 years. The leading causes of injury were falls (37%) and motor vehicle accidents (28%). The distribution of initial ASIA grades were A (40%), B (16%), C (15%), and D (29%). Fifty-eight percent of patients sustained 1 or more severe, moderate, or mild complications. Complications were associated with more severe ASIA grade: 84% of patients with Grade A and 25% of patients with Grade D had at least 1 complication. Seventy-eight percent of complications occurred within 14 days of injury. The most frequent types of severe and moderate complications were respiratory failure, pneumonia, pleural effusion, anemia, cardiac dysrhythmia, and severe bradycardia. The mortality rate was 3.5% and was associated with increased age and preexisting morbidity. CONCLUSIONS: Knowledge of the type, frequency, time of occurrence, and severity of specific complications that occur after spinal cord injury can aid in their early detection, treatment, and prevention. The data are of importance in evaluating and selecting therapy for clinical trials.

Pharmacology of riluzole in acute spinal cord injury.

OBJECT: The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18-70 years old with acute spinal cord injury (SCI). METHODS: Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A-C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (C(max)), trough concentration (C(min)), systemic exposure (AUC(0-12)), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F). RESULTS: The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (C(max), C(min), AUC(0-12), CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that C(max), C(min), and AUC(0-12) (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed. CONCLUSIONS: This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.

T cell receptor transgenic mice recognizing the immunodominant epitope of the Torpedo californica acetylcholine receptor.

Myasthenia gravis (MG) is an autoimmune disease caused by T cell-dependent antibody-mediated reduction of acetylcholine receptors (AChR) at the neuromuscular junction. Immunization of animals with Torpedo californica AChR (TAChR) results in an experimental model of MG. We used the variable regions of alpha and beta T cell receptor (TCR) genes recognizing an immunodominant peptide containing amino acids 146-162 from the alpha subunit of TAChR presented in the context of I-A(b) to generate TCR-transgenic mice. We found that the transgenic TCR was strongly positively selected and that transgenic T cells proliferated robustly to the immunodominant peptide and TAChR. Unexpectedly, there was a variable paucity of B cells in the blood and spleen from transgenic mice, which averaged about 16% of peripheral blood lymphocytes, compared to 55% in wild-type B6 mice. Unselected transgenic mice immunized with TAChR exhibited weak anti-TAChR antibody responses. However, transgenic mice selected to have relatively higher B cell numbers produced anti-TAChR titers equal to B6 mice and a predominance of Th1-induced antibody isotypes were observed in certain experiments. The incidence and severity of clinical disease was variable following immunizations. These mice should be useful for studying the pathogenesis and treatment of MG.