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Open Access
A clinical prediction model for long-term functional outcome after traumatic spinal cord injury based on acute clinical and imaging factors.
(Journal of neurotrauma, 2012-09) Wilson, Jefferson R; Grossman, Robert G; Frankowski, Ralph F; Kiss, Alexander; Davis, Aileen M; Kulkarni, Abhaya V; Harrop, James S; Aarabi, Bizhan; Vaccaro, Alexander; Tator, Charles H; Dvorak, Marcel; Shaffrey, Christopher I; Harkema, Susan; Guest, James D; Fehlings, Michael G
To improve clinicians' ability to predict outcome after spinal cord injury (SCI) and to help classify patients within clinical trials, we have created a novel prediction model relating acute clinical and imaging information to functional outcome at 1 year. Data were obtained from two large prospective SCI datasets. Functional independence measure (FIM) motor score at 1 year follow-up was the primary outcome, and functional independence (score ≥ 6 for each FIM motor item) was the secondary outcome. A linear regression model was created with the primary outcome modeled relative to clinical and imaging predictors obtained within 3 days of injury. A logistic model was then created using the dichotomized secondary outcome and the same predictor variables. Model validation was performed using a bootstrap resampling procedure. Of 729 patients, 376 met the inclusion criteria. The mean FIM motor score at 1 year was 62.9 (±28.6). Better functional status was predicted by less severe initial American Spinal Injury Association (ASIA) Impairment Scale grade, and by an ASIA motor score >50 at admission. In contrast, older age and magnetic resonance imaging (MRI) signal characteristics consistent with spinal cord edema or hemorrhage predicted worse functional outcome. The linear model predicting FIM motor score demonstrated an R-square of 0.52 in the original dataset, and 0.52 (95% CI 0.52,0.53) across the 200 bootstraps. Functional independence was achieved by 148 patients (39.4%). For the logistic model, the area under the curve was 0.93 in the original dataset, and 0.92 (95% CI 0.92,0.93) across the bootstraps, indicating excellent predictive discrimination. These models will have important clinical impact to guide decision making and to counsel patients and families.
Open Access
A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury.
(Journal of neurotrauma, 2014-02) Grossman, Robert G; Fehlings, Michael G; Frankowski, Ralph F; Burau, Keith D; Chow, Diana SL; Tator, Charles; Teng, Angela; Toups, Elizabeth G; Harrop, James S; Aarabi, Bizhan; Shaffrey, Christopher I; Johnson, Michele M; Harkema, Susan J; Boakye, Maxwell; Guest, James D; Wilson, Jefferson R
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.
Open Access
Acute Adverse Events After Spinal Cord Injury and Their Relationship to Long-term Neurologic and Functional Outcomes: Analysis From the North American Clinical Trials Network for Spinal Cord Injury.
(Critical care medicine, 2019-11) Jiang, Fan; Jaja, Blessing NR; Kurpad, Shekar N; Badhiwala, Jetan H; Aarabi, Bizhan; Grossman, Robert G; Harrop, James S; Guest, Jim D; Schär, Ralph T; Shaffrey, Chris I; Boakye, Max; Toups, Elizabeth G; Wilson, Jefferson R; Fehlings, Michael G; North American Clinical Trials Network Collaborators
Objectives
There are few contemporary, prospective multicenter series on the spectrum of acute adverse events and their relationship to long-term outcomes after traumatic spinal cord injury. The goal of this study is to assess the prevalence of adverse events after traumatic spinal cord injury and to evaluate the effects on long-term clinical outcome.
Design
Multicenter prospective registry.
Setting
Consortium of 11 university-affiliated medical centers in the North American Clinical Trials Network.
Patients
Eight-hundred one spinal cord injury patients enrolled by participating centers.
Interventions
Appropriate spinal cord injury treatment at individual centers.
Measurements and main results
A total of 2,303 adverse events were recorded for 502 patients (63%). Penalized maximum logistic regression models were fitted to estimate the likelihood of neurologic recovery (ASIA Impairment Scale improvement ≥ 1 grade point) and functional outcomes in subjects who developed adverse events at 6 months postinjury. After accounting for potential confounders, the group that developed adverse events showed less neurologic recovery (odds ratio, 0.55; 95% CI, 0.32-0.96) and was more likely to require assisted breathing (odds ratio, 6.55; 95% CI, 1.17-36.67); dependent ambulation (odds ratio, 7.38; 95% CI, 4.35-13.06) and have impaired bladder (odds ratio, 9.63; 95% CI, 5.19-17.87) or bowel function (odds ratio, 7.86; 95% CI, 4.31-14.32) measured using the Spinal Cord Independence Measure subscores.
Conclusions
Results from this contemporary series demonstrate that acute adverse events are common and are associated with worsened long-term outcomes after traumatic spinal cord injury.
Open Access
Association of Pneumonia, Wound Infection, and Sepsis with Clinical Outcomes after Acute Traumatic Spinal Cord Injury.
(Journal of neurotrauma, 2019-11) Jaja, Blessing NR; Jiang, Fan; Badhiwala, Jetan H; Schär, Ralph; Kurpad, Shekar; Grossman, Robert G; Harrop, James S; Guest, Jim D; Toups, Elizabeth G; Shaffrey, Chris I; Aarabi, Bizhan; Boakye, Max; Fehlings, Michael G; Wilson, Jefferson R
Pneumonia, wound infections, and sepsis (PWS) are the leading causes of acute mortality after traumatic spinal cord injury (SCI). However, the impact of PWS on neurological and functional outcomes is largely unknown. The present study analyzed participants from the prospective North American Clinical Trials Network (NACTN) registry and the Surgical Timing in Acute SCI Study (STASCIS) for the association between PWS and functional outcome (assessed as Spinal Cord Independence Measure subscores for respiration and indoor ambulation) at 6 months post-injury. Neurological outcome was analyzed as a secondary end-point. Among 1299 participants studied, 180 (14%) developed PWS during the acute admission. Compared with those without PWS, participants with PWS were mostly male (76% vs. 86%; p = 0.007), or presented with mostly American Spinal Injury Association Impairment Scale (AIS) grade A injury (36% vs. 61%; p < 0.001). There were no statistical differences between participants with or without PWS with respect to time from injury to surgery, and administration of steroids. Dominance analysis showed injury level, baseline AIS grade, and subject pre-morbid medical status collectively accounted for 77.7% of the predicted variance of PWS. Regression analysis indicated subjects with PWS demonstrated higher odds for respiratory (odds ratio [OR] 3.91, 95% confidence interval [CI]: 1.42-10.79) and ambulatory (OR 3.94, 95% CI: 1.50-10.38) support at 6 month follow-up in adjusted analysis. This study has shown an association between PWS occurring during acute admission and poorer functional outcomes following SCI.
Open Access
Demographics, Mechanism of Injury and Outcomes for Acute Upper and Lower Cervical Spinal Cord Injuries - An Analysis of 470 Patients in the Prospective, Multicenter North American Clinical Trials Network (NACTN) Registry.
(Journal of neurotrauma, 2023-02) Futch, Brittany Grace; Kouam, Romaric Waguia; Ugiliweneza, Beatrice; Harrop, James; Kurpad, Shekar; Foster, Norah; Than, Khoi; Crutcher, Clifford; Goodwin, C Rory; Tator, Charles; Shaffrey, Christopher I; Aarabi, Bizhan; Fehlings, Michael; Neal, Chris J; Guest, James; Abd-El-Barr, Muhammad M
There is a paucity of data comparing the demographics, mechanism of injury, and outcomes of upper versus lower cervical spinal cord injuries (cSCI). The study objective was to define different clinical manifestations of cSCI. Data were collected prospectively through centers of the North American Clinical Trials Network (NACTN). Data was collected on 470 patients (21% women, mean age 50 years). Cervical vertebral level was analyzed as an ordinal variable to determine a natural demarcation to classify upper versus lower cSCI. For continuous variable analysis, falls were associated with C3 more than C4 vertebral level injuries (60% vs. 42%) (p=0.0126), while motor vehicle accidents (MVA) were associated with C4 more than C3 (40% vs. 29%) (p=0.0962). Motor ISNSCI scores also demonstrated a natural demarcation between C3 and C4, with C3 having higher median ASIA motor scores (40 [4 - 73] vs. 11 [3 - 59], p= 0.0227). There were no differences when comparing C2 to C3 nor C4 to C5. Given the significant differences seen between C3 and C4, but not C2 and C3 nor C4 and C5, upper cSCI was designated as C1-C3, and lower cSCI was designated as C4-C7. Compared to a lower cSCI, patients with an upper cSCI were more likely to have a fall as their mechanism of injury (54% vs. 36%, p= 0.0072). Patients with an ASIA C cSCI were likely to have an upper cervical injury: 23% vs. 11% (p= 0.0226). Additionally, patients with an upper cSCI were more likely to have diabetes prior to injury, 37% vs. 22% respectively (p= 0.0084). Lower cSCI were more likely injured through sports (19% vs. 8%, p= 0.0171) and present with ASIA A (42% vs. 25%, p= 0.0186) neurological grade. Patients with lower cSCI were also significantly more likely to have complications such as shock, pulmonary embolism, and pleural effusion. In conclusion, there appears to be a natural demarcation of injury type between C3 and C4. Upper cSCI (C1-C3) was more associated with falls and diabetes, whereas lower cSCI (C4-C7) was more associated with sports, worse ASIA scores, and more complications. Further research will be needed to understand the mechanistic and biological differences between these two groups and whether different treatments may be appropriate for each of these groups.
Open Access
Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS).
(PloS one, 2012-01) Fehlings, Michael G; Vaccaro, Alexander; Wilson, Jefferson R; Singh, Anoushka; W Cadotte, David; Harrop, James S; Aarabi, Bizhan; Shaffrey, Christopher; Dvorak, Marcel; Fisher, Charles; Arnold, Paul; Massicotte, Eric M; Lewis, Stephen; Rampersaud, Raja
BACKGROUND:There is convincing preclinical evidence that early decompression in the setting of spinal cord injury (SCI) improves neurologic outcomes. However, the effect of early surgical decompression in patients with acute SCI remains uncertain. Our objective was to evaluate the relative effectiveness of early (<24 hours after injury) versus late (≥ 24 hours after injury) decompressive surgery after traumatic cervical SCI. METHODS:We performed a multicenter, international, prospective cohort study (Surgical Timing In Acute Spinal Cord Injury Study: STASCIS) in adults aged 16-80 with cervical SCI. Enrolment occurred between 2002 and 2009 at 6 North American centers. The primary outcome was ordinal change in ASIA Impairment Scale (AIS) grade at 6 months follow-up. Secondary outcomes included assessments of complications rates and mortality. FINDINGS:A total of 313 patients with acute cervical SCI were enrolled. Of these, 182 underwent early surgery, at a mean of 14.2(± 5.4) hours, with the remaining 131 having late surgery, at a mean of 48.3(± 29.3) hours. Of the 222 patients with follow-up available at 6 months post injury, 19.8% of patients undergoing early surgery showed a ≥ 2 grade improvement in AIS compared to 8.8% in the late decompression group (OR = 2.57, 95% CI:1.11,5.97). In the multivariate analysis, adjusted for preoperative neurological status and steroid administration, the odds of at least a 2 grade AIS improvement were 2.8 times higher amongst those who underwent early surgery as compared to those who underwent late surgery (OR = 2.83, 95% CI:1.10,7.28). During the 30 day post injury period, there was 1 mortality in both of the surgical groups. Complications occurred in 24.2% of early surgery patients and 30.5% of late surgery patients (p = 0.21). CONCLUSION:Decompression prior to 24 hours after SCI can be performed safely and is associated with improved neurologic outcome, defined as at least a 2 grade AIS improvement at 6 months follow-up.
Open Access
History and Accomplishments of the North American Clinical Trials Network (NACTN) for Spinal Cord Injury, 2004 to 2022.
(Journal of neurotrauma, 2022-12) Tator, Charles H; Guest, James D; Neal, Chris J; Howley, Susan P; Toups, Elizabeth G; Harrop, James S; Aarabi, Bizhan; Shaffrey, Christopher I; Fehlings, Michael G
This is a historical account of the origin and accomplishments of the North American Clinical Trials Network (NACTN) for traumatic spinal cord injury (SCI), which was established in 2004 by Christopher Reeve and Dr. Robert Grossman. Christopher Reeve was an actor who became quadriplegic and started the Christopher and Dana Reeve Foundation, while Robert Grossman was a neurosurgeon experienced in neurotrauma and a university professor in Houston. NACTN has member investigators at university and military centers in North America and has contributed greatly to the improvement of care, primarily acute care, of patients sustaining traumatic SCI. Its accomplishments are a clinical registry database of more than 1000 acute SCI patients documenting the care pathways, including complications. NACTN determined the effectiveness of treatment, including pharmacotherapy and the role and timing of surgery, and barriers to early surgery with a focus on neurological recovery. NACTN has assessed the effectiveness of treatment, including pharmacotherapy and the role and timing of surgery, and has also identified barriers to early surgery. The principal focus has been on improving neurological recovery. It has trained many SCI practitioners and has collaborated with many other SCI networks and organizations internationally to promote the care of SCI patients.
Open Access
Incidence and severity of acute complications after spinal cord injury.
(Journal of neurosurgery. Spine, 2012-09) Grossman, Robert G; Frankowski, Ralph F; Burau, Keith D; Toups, Elizabeth G; Crommett, John W; Johnson, Michele M; Fehlings, Michael G; Tator, Charles H; Shaffrey, Christopher I; Harkema, Susan J; Hodes, Jonathan E; Aarabi, Bizhan; Rosner, Michael K; Guest, James D; Harrop, James S
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.
Open Access
Interhospital Transfer delays care for spinal cord injury patients: A Report from the North American Clinical Trials Network for Spinal Cord Injury.
(Journal of neurotrauma, 2023-04) Kelly-Hedrick, Margot; Ugiliweneza, Beatrice; Toups, Elizabeth G; Jimsheleishvili, George; Kurpad, Shekar N; Aarabi, Bizhan; Harrop, James S; Foster, Norah; Goodwin, Rory C; Shaffrey, Christopher I; Fehlings, Michael G; Tator, Charles H; Guest, James D; Neal, Chris J; Abd-El-Barr, Muhammad M; Williamson, Theresa
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.
Open Access
Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent.
(Journal of clinical pharmacology, 2021-09) Nguyen, Ashley; Chow, Diana S-L; Wu, Lei; Teng, Yang Angela; Sarkar, Mahua; Toups, Elizabeth G; Harrop, James S; Schmitt, Karl M; Johnson, Michele M; Guest, James D; Aarabi, Bizhan; Shaffrey, Christopher I; Boakye, Maxwell; Frankowski, Ralph F; Fehlings, Michael G; Grossman, Robert G
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.
Open Access
Natural History, Predictors of Outcome, and Effects of Treatment in Thoracic Spinal Cord Injury: A Multi-Center Cohort Study from the North American Clinical Trials Network.
(Journal of neurotrauma, 2018-11) Wilson, Jefferson R; Jaja, Blessing NR; Kwon, Brian K; Guest, James D; Harrop, James S; Aarabi, Bizhan; Shaffrey, Christopher I; Badhiwala, Jetan H; Toups, Elizabeth G; Grossman, Robert G; Fehlings, Michael G
The course, treatment response, and recovery potential after acute traumatic spinal cord injury (SCI) have been shown to differ depending on the neurological level of injury. There are limited data focused on thoracic-level injuries, however. A cohort of 86 patients from the prospectively maintained North American Clinical Trials Network SCI registry were identified and studied to characterize the patterns of neurological recovery and to determine rates of acute hospital death and pulmonary complications. Regression analyses were used to examine the relationship between timing of surgery and administration of methylprednisolone on neurologic and clinical outcomes. Neurological conversion (≥1 American Spinal Injury Association Impairment Scale [AIS] grade improvement) was poorest for AIS grade A patients; 14.3% converted at last available follow-up (mean eight months). While rates of conversion were more optimistic for AIS-B patients (54.5%) and AIS C injuries (77.8%) at the same time point, none of the AIS grade D patients converted to AIS E. At last available follow-up (mean eight months), the magnitudes of lower motor extremity score (LEMS) change were highest for AIS C injuries (21.9 points), then AIS B (17.7 points), AIS D (16.4 points), and finally AIS A (2.5 points) (p < 0.05). Early surgical intervention (<24 h post-injury) was independently associated with an additional seven points in motor recovery and a 60% decreased incidence of pulmonary events (p < 0.05). Methylprednisolone administration was not an independent predictor of neurological outcome or pulmonary complications. Evaluation of this cohort obtained from a modern multi-center SCI registry provides an update on the natural history, acute death, and incidence of pulmonary complications after traumatic thoracic SCI. Although small sample size limited the extent of analyses possible, early surgical treatment was associated with significantly larger motor recovery and lower rates of pulmonary complications.
Open Access
Pharmacology of riluzole in acute spinal cord injury.
(Journal of neurosurgery. Spine, 2012-09) Chow, Diana SL; Teng, Yang; Toups, Elizabeth G; Aarabi, Bizhan; Harrop, James S; Shaffrey, Christopher I; Johnson, Michele M; Boakye, Maxwell; Frankowski, Ralph F; Fehlings, Michael G; Grossman, Robert G
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.
Open Access
Predictors of pulmonary complications in blunt traumatic spinal cord injury.
(Journal of neurosurgery. Spine, 2012-09) Aarabi, Bizhan; Harrop, James S; Tator, Charles H; Alexander, Melvin; Dettori, Joseph R; Grossman, Robert G; Fehlings, Michael G; Mirvis, Stuart E; Shanmuganathan, Kathirkamanathan; Zacherl, Katie M; Burau, Keith D; Frankowski, Ralph F; Toups, Elizabeth; Shaffrey, Christopher I; Guest, James D; Harkema, Susan J; Habashi, Nader M; Andrews, Penny; Johnson, Michele M; Rosner, Michael K
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.
Open Access
Reliability and reproducibility of subaxial cervical injury description system: a standardized nomenclature schema.
(Spine, 2011-08) Bono, Christopher M; Schoenfeld, Andrew; Gupta, Giri; Harrop, James S; Anderson, Paul; Patel, Alpesh A; Dimar, John; Aarabi, Bizhan; Dailey, Andrew; Vaccaro, Alexander R; Gahr, Ralf; Shaffrey, Christopher; Anderson, David G; Rampersaud, Raj
Study design
Radiographic measurement study.
Objective
To develop a standardized cervical injury nomenclature system to facilitate description, communication, and classification among health care providers. The reliability and reproducibility of this system was then examined.
Summary of background data
Description of subaxial cervical injuries is critical for treatment decision making and comparing scientific reports of outcomes. Despite a number of available classification systems, surgeons, and researchers continue to use descriptive nomenclature, such as "burst" and "teardrop" fractures, to describe injuries. However, there is considerable inconsistency with use of such terms in the literature.
Methods
Eleven distinct injury types and associated definitions were established for the subaxial cervical spine and subsequently refined by members of the Spine Trauma Study Group. A series of 18 cases of patients with a broad spectrum of subaxial cervical spine injuries was prepared and distributed to surgeon raters. Each rater was provided with the full nomenclature document and asked to select primary and secondary injury types for each case. After receipt of the raters' first round of classifications, the cases were resorted and returned to the raters for a second round of review. Interrater and intrarater reliabilities were calculated as percent agreement and Cohen kappa (κ) values. Intrarater reliability was assessed by comparing a given rater's diagnosis from the first and second rounds.
Results
Nineteen surgeons completed the first and second rounds of the study. Overall, the system demonstrated 56.4% interrater agreement and 72.8% intrarater agreement. Overall, interrater κ values demonstrated moderate agreement while intrarater κ values showed substantial agreement. Analyzed by injury types, only four (burst fractures, lateral mass fractures, flexion teardrop fractures, and anterior distraction injuries) demonstrated greater than 50% interrater agreement.
Conclusion
This study demonstrated that, even in ideal circumstances, there is only moderate agreement among raters regarding cervical injury nomenclature. It is hoped that more familiarity with the proposed system will increase reproducibility in the future. Additional research is required to establish the clinical utility of this novel nomenclature schema.
Open Access
Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial.
(Journal of neurosurgery. Spine, 2012-09) Fehlings, Michael G; Wilson, Jefferson R; Frankowski, Ralph F; Toups, Elizabeth G; Aarabi, Bizhan; Harrop, James S; Shaffrey, Christopher I; Harkema, Susan J; Guest, James D; Tator, Charles H; Burau, Keith D; Johnson, Michele W; Grossman, Robert G
In the immediate period after traumatic spinal cord injury (SCI) a variety of secondary injury mechanisms combine to gradually expand the initial lesion size, potentially leading to diminished neurological outcomes at long-term follow-up. Riluzole, a benzothiazole drug, which has neuroprotective properties based on sodium channel blockade and mitigation of glutamatergic toxicity, is currently an approved drug that attenuates the extent of neuronal degeneration in patients with amyotrophic lateral sclerosis. Moreover, several preclinical SCI studies have associated riluzole administration with improved functional outcomes and increased neural tissue preservation. Based on these findings, riluzole has attracted considerable interest as a potential neuroprotective drug for the treatment of SCI. Currently, a Phase I trial evaluating the safety and pharmacokinetic profile of riluzole in human SCI patients is being conducted by the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The current review summarizes the existing preclinical and clinical literature on riluzole, provides a detailed description of the Phase I trial, and suggests potential opportunities for future investigation. Clinical trial registration no.: NCT00876889.
Open Access
The bulbocavernosus reflex (BCR) has no prognostic features during the acute evaluation of spinal cord injuries.
(Journal of neurotrauma, 2023-03) Mansoor Ali, Daniyal; Sivaganesan, Ahilan; Neal, Chris J; Thalheimer, Sara; Ugiliweneza, Beatrice; Toups, Elizabeth G; Abd-El-Barr, Muhammad; Jimsheleishvili, George; Kurpad, Shekar N; Aarabi, Bizhan; Shaffrey, Christopher I; Fehlings, Michael G; Tator, Charles H; Grossman, Robert G; Guest, James D; Harrop, James S
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.
Open Access
THE EFFECT OF RILUZOLE ON INTRAMEDULLARY LESION LENGTH AND DTI, RATIONALE AND DESIGN OF RISCIS MRI-SUBSTUDY
(JOURNAL OF NEUROTRAUMA, 2018-08-01) Aarabi, Bizhan; Fehlings, Michael G; Robertson, Claudia S; Shaffrey, Christopher; Kurpad, Shekar; Ray, Wilson Z
Open Access
The impact of facet dislocation on clinical outcomes after cervical spinal cord injury: results of a multicenter North American prospective cohort study.
(Spine, 2013-01) Wilson, Jefferson R; Vaccaro, Alexander; Harrop, James S; Aarabi, Bizhan; Shaffrey, Christopher; Dvorak, Marcel; Fisher, Charles; Arnold, Paul; Massicotte, Eric M; Lewis, Stephen; Rampersaud, Raja; Okonkwo, David O; Fehlings, Michael G
Study design
A multicenter prospective cohort study.
Objective
To define differences in baseline characteristics and long-term clinical outcomes in patients with cervical spinal cord injury (SCI) with and without facet dislocation (FD).
Summary of background data
Reports of dramatic neurological improvement in patients with FD and cervical SCI, treated with rapid reduction have led to the hypothesis that this represents a subgroup of patients with significant recovery potential. However, without a large systematic comparative analysis, this hypothesis remains untested.
Methods
Patients were classified into FD and non-FD groups based on imaging investigations at admission. The primary outcome was change in American Spinal Injury Association (ASIA) motor score (AMS) at 1-year follow-up. Secondary outcome measures included ASIA impairment scale (AIS) grade conversion and functional independence measure score at 1-year postinjury, as well as length of acute hospitalization. Baseline characteristics and long-term outcomes were also compared for patients with unilateral and bilateral FD.
Results
Of 421 patients who enrolled, 135 (32.1%) had FD and 286 (67.9%) had no FD. Patients in the FD group presented with a significantly worse AIS grade and higher energy injury mechanisms (P < 0.01). Patients with bilateral FD had a greater severity of baseline neurological deficit compared with those with unilateral FD, measured by AIS grade and AMS. The mean length of acute hospitalization was 41.2 days among patients with FD and 30 days among patients without FD (P = 0.04). At 1-year follow-up, patients with FD experienced a mean AMS improvement of 18.0 points, whereas patients without FD experienced an improvement of 27.9 points (P < 0.01). In the adjusted analysis, patients with FD continued to demonstrate less AMS recovery compared with the patients without FD (P = 0.04).
Conclusion
Compared with patients without FD, cervical SCI patients with FD tended to present with a more severe degree of initial injury and displayed less potential for motor recovery at 1-year follow-up.
Open Access
Trajectory-Based Classification of Recovery in Sensorimotor Complete Traumatic Cervical Spinal Cord Injury.
(Neurology, 2021-04) Jaja, Blessing NR; Badhiwala, Jetan; Guest, James; Harrop, James; Shaffrey, Chris; Boakye, Max; Kurpad, Shekar; Grossman, Robert; Toups, Elizabeth; Geisler, Fred; Kwon, Brian; Aarabi, Bizhan; Kotter, Mark; Fehlings, Michael G; Wilson, Jefferson R
To test the hypothesis that sensorimotor complete traumatic cervical spinal cord injury is a heterogenous clinical entity comprising several subpopulations that follow fundamentally different trajectories of neurologic recovery. We analyzed demographic and injury data from 655 patients who were pooled from 4 prospective longitudinal multicenter studies. Group based trajectory modeling was applied to model neurologic recovery trajectories over the initial 12-months postinjury and to identify predictors of recovery trajectories. Neurologic outcomes included: Upper Extremity Motor Score, Total Motor Scores and AIS grade improvement. The analysis identified 3 distinct trajectories of neurologic recovery. These clinical courses included: (1) Marginal recovery trajectory: characterized by minimal or no improvement in motor strength or change in AIS grade status (remained grade A); (2) Moderate recovery trajectory: characterized by low baseline motor scores that improved approximately 13 points; or AIS conversion of one grade point; (3) Good recovery trajectory: characterized by baseline motor scores in the upper quartile that improved to near maximum values within 3 months of injury. Patients following the moderate or good recovery trajectories were of younger age, had more caudally located injuries, a higher degree of preserved motor and sensory function at baseline examination and exhibited a greater extent of motor and sensory function in the zone of partial preservation. Cervical complete SCI can be classified into one of 3 distinct subpopulations with fundamentally different trajectories of neurologic recovery. This study defines unique clinical phenotypes based on potential for recovery, rather than baseline severity of injury alone. This approach may prove beneficial in clinical prognostication and in the design and interpretation of clinical trials in SCI.
Open Access
Treatment of Axis Body Fractures: A Systematic Review.
(Clinical spine surgery, 2017-12) Kepler, Christopher K; Vaccaro, Alexander R; Fleischman, Andrew N; Traynelis, Vincent C; Patel, Alpesh A; Dekutoski, Mark B; Harrop, James; Wood, Kirkham B; Schroeder, Gregory D; Bransford, Richard; Aarabi, Bizhan; Okonkwo, David O; Arnold, Paul M; Fehlings, Michael G; Nassr, Ahmad; Shaffrey, Christopher; Yoon, S Tim; Kwon, Brian
Study design
Evidence-based systematic review.
Objectives
To define the optimal treatment of fractures involving the C2 body, including those with concomitant injuries, based upon a systematic review of the literature.
Summary of background data
Axis body fractures have customarily been treated nonoperatively, but there are some injuries that may require operative intervention. High-quality literature is sparse and there are few class I or class II studies to guide treatment decisions.
Materials and methods
A literature search was conducted using PubMed (MEDLINE), Cochrane Central Register of Controlled Trials, and Scopus (EMBASE, MEDLINE, COMPENDEX). The quality of literature was rated according to a grading tool developed by the Center for Evidence-based Medicine. Operative and nonoperative treatment of axis body fractures were compared using fracture bony union as the primary outcome measure. As risk factors for nonunion were not consistently reported, cases were analyzed individually.
Results
The literature search identified 62 studies, of which 10 were case reports which were excluded from the analysis. A total of 920 patients from 52 studies were included. The overall bony union rate for all axis body fractures was 91%. Although the majority of fractures were treated nonoperatively, there has been an increasing trend toward operative intervention for Benzel type III (transverse) axis body fractures. Nearly 76% of axis body fractures were classified as type III fractures, of which 88% united successfully. Nearly all Benzel type I and type II axis body fractures were successfully treated nonoperatively. The risk factors for nonunion included: a higher degree of subluxation, fracture displacement, comminution, concurrent injuries, delay in treatment, and older age.
Conclusions
High rates for fracture union are reported in the literature for axis body fractures with nonoperative treatment. High-quality prospective studies are required to develop consensus as to which C2 body fractures require operative fixation.