Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial.

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.

Oligometastatic Parathyroid Carcinoma Presenting as Neck Pain: A Case Report.

BACKGROUND: Parathyroid carcinoma (PC) is an exceedingly rare, slow-growing but progressive endocrine malignancy that represents a diagnostic and therapeutic challenge. Vertebral metastasis of PC is remarkable, with only 3 prior cases of spinal metastasis reported in the literature. CASE DESCRIPTION: A 62-year-old woman presented with 1 week of neck pain radiating down her right arm. Cervical x-ray revealed a lytic lesion of the C4 vertebral body. Lab work revealed hypercalcemia with an elevated parathyroid hormone level. Computed tomography and magnetic resonance imaging revealed frank destruction of the C4 vertebral body and pedicles by PC. She was treated with corpectomy, mass excision, anterior cervical discectomy and fusion, postoperative radiotherapy, and nonspecific inhibitors of active tumor pathways. Her symptoms resolved postoperatively, and she has remained negative for reoccurrence at 15-month follow-up. CONCLUSIONS: To the authors' knowledge, we report the first described cervical spine metastasis of PC. Additionally, we review the treatment of this rare neoplasm in an extremely rare location in the age of tumor sequencing and morphoproteomic analysis.

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.

Atlanto-occipital distraction injuries in survivors: craniometrics and associated ligamentous, spinal cord, and blunt cerebrovascular injury.

PURPOSE: Newer classification systems for upper cervical spine trauma now include ligamentous injury in addition to fracture and dislocation patterns. Assessment of associated ligamentous injury, spinal cord injury (SCI), and blunt cerebrovascular injuries (BCVI) in patients with atlanto-occipital distraction injuries (AODI) are critical for management. We aim to determine the incidence of ligamentous injury, SCI, and BCVI in patients with AODI and assess how craniometrics perform in diagnosis of AODI. MATERIALS AND METHODS: We performed an IRB-approved retrospective analysis of 35 cases of diagnosed AODI over a period of 8 years. Imaging was analyzed by two experienced neuroradiologists for craniometric measurements, ligamentous injury, SCI, and BCVI. Craniometric measurements were compared to 35 age-matched controls with normal atlanto-occipital joint. RESULTS: Out of 35 patients diagnosed with AODI, 27 were adults and 8 belonged to pediatric age group. The mean age of presentation was 29.4 years with a male/female ratio of 22:13. The basion-dental interval (70.4%) and the combined condylar sum (74.1%) were the most sensitive craniometric measurements for diagnosis of AODI. Alar ligament (83%) and the tectorial membrane (89%) injuries were most commonly injured ligaments. Three adult patients sustained SCI and 10 patients had BCVI. Majority of BCVI involved the internal carotid artery followed by the vertebral artery. CONCLUSIONS: The combination of craniometric indices with assessment of ligamentous injuries provides higher diagnostic accuracy for AODI. Alar ligament and tectorial membrane injuries have high association with AODI. There is high association of SCI and BCVI in AODI survivors.

Early chemoprophylaxis is associated with decreased venous thromboembolism risk without concomitant increase in intraspinal hematoma expansion after traumatic spinal cord injury.

BACKGROUND: After traumatic spinal cord injury (SCI), there is increased risk of venous thromboembolism (VTE), but chemoprophylaxis (PPX) may cause expansion of intraspinal hematoma (ISH). METHODS: Single-center retrospective study of adult trauma patients from 2012 to 2015 with SCI. EXCLUSION CRITERIA: VTE diagnosis, death, or discharge within 48 hours. Patients were dichotomized based on early (≤48 hours) heparinoid and/or aspirin PPX. Intraspinal hematoma expansion was diagnosed intraoperatively or by follow-up radiology. We used multivariable Cox proportional hazards to estimate the effect of PPX on risk of VTE and ISH expansion controlling for age, injury severity score (ISS), complete SCI, and mechanism as static covariates and operative spine procedure as a time-varying covariate. RESULTS: Five hundred one patients with SCI were dichotomized into early PPX (n = 260 [52%]) and no early PPX (n = 241 [48%]). Early PPX patients were less likely blunt injured (91% vs 97%) and had fewer operative spine interventions (65% vs 80%), but age (median, 43 vs 49 years), ISS (median 24 vs 21), admission ISH (47% vs 44%), and VTE (5% vs 9%) were similar. Cox analysis found that early heparinoids was associated with reduced VTE (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.16-0.84) and reduced pulmonary embolism (PE) (HR, 0.20; 95% CI, 0.06-0.69). The estimated number needed to treat with heparinoids was 10 to prevent one VTE and 13 to prevent one PE at 30 days. Early aspirin was not associated with reduced VTE or PE. Seven patients (1%) had ISH expansion, of which four were on PPX at the time of expansion. Using heparinoid and aspirin as time-varying covariates, neither heparinoids (HR, 1.90; 95% CI, 0.32-11.41) nor aspirin (HR, 3.67; 95% CI, 0.64-20.88) was associated with ISH expansion. CONCLUSION: Early heparinoid therapy was associated with decreased VTE and PE risk in SCI patients without concomitant increase in ISH expansion. LEVEL OF EVIDENCE: Therapeutic, level IV.

Communicating Hydrocephalus Due to Traumatic Lumbar Spine Injury: Case Report and Literature Review.

: Hydrocephalus is a rare complication of traumatic spine injury. A literature review reflects the rare occurrence with cervical spine injury. We present a case of traumatic injury to the lumbar spine from a gunshot wound, which caused communicating hydrocephalus. The patient sustained a gunshot wound to the lumbar spine and had an L4-5 laminectomy with exploration and removal of foreign bodies. At the time of surgery, the patient was found to have dense subarachnoid hemorrhage in the spinal column. He subsequently had intermittent headaches and altered mental status that resolved without intervention. The headaches worsened, so a computed tomography scan of the brain was obtained, which revealed hydrocephalus. A ventriculoperitoneal shunt was placed, and subsequent computed tomography scan of the brain showed reduced ventricle size. The patient returned to rehabilitation with complete resolution of hydrocephalus symptoms. Intrathecal hemorrhage with subsequent obstruction or decreased absorption of cerebrospinal fluid at the distal spinal cord was thought to lead to communicating hydrocephalus in this case of lumbar penetrating trauma. In patients with a history of hemorrhagic, traumatic spinal injury who subsequently experience headaches or altered mental status, hydrocephalus should be included in the differential diagnosis and adequately investigated.

Identification of autoantibodies to glial fibrillary acidic protein in spinal cord injury patients.

Traumatic spinal cord injury (SCI) is a devastating injury causing significant morbidity and mortality. Experimental studies have demonstrated that SCI induced cellular damage and disruption of the blood-spinal cord barrier can initiate an autoimmune response. This response is thought to be pathogenic and contribute to poor outcome. The objective of this research was to investigate whether human SCI mounts an autoimmune response to self-antigens. Plasma samples were collected longitudinally from SCI patients (n=18) at acute (T1, <48 h) and subacute (T2, 2-4 weeks) time points to probe western blots of human brain homogenates in order to screen patients for the presence of putative autoantibodies. To identify the corresponding antigens, two-dimensional gel electrophoresis, western blot and liquid chromatography coupled with mass spectrometry (LC-MS/MS) analyses were performed. We found that four of 18 patients (22%) had novel immunoreactive bands ranging in size from 36 to 42 kDa present in subacute, but not in acute, plasma samples suggesting postinjury production. To identify the cross-reacting antigens, we separated brain proteins by two-dimensional gel electrophoresis and identified nine immunoreactive spots. Amino acid sequence analysis of these spots identified peptides that mapped to glial fibrillary acidic protein. Our results suggest that ∼ 22% of SCI patients generated autoantibodies to glial fibrillary acidic protein. Future studies will be required to determine whether these autoantibodies contribute to the pathogenic sequelae of SCI.