Epidemiology, patterns of care and outcomes of traumatic brain injury in deployed military settings: Implications for future military operations.

BACKGROUND: Traumatic brain injury (TBI) is prevalent and highly morbid among Service Members. A better understanding of TBI epidemiology, outcomes, and care patterns in deployed settings could inform potential approaches to improve TBI diagnosis and management. METHODS: A retrospective cohort analysis of Service Members who sustained a TBI in deployed settings between 2001 and 2018 was conducted. Among individuals hospitalized with TBI, we compared the demographic characteristics, mechanism of injury, injury type, and severity between combat and noncombat injuries. We compared diagnostic tests and procedures, evacuation patterns, return to duty rates and days in care between individuals with concussion and those with severe TBI. RESULTS: There were 46,309 service members with TBI and 9,412 who were hospitalized; of those hospitalized, 55% (4,343) had isolated concussion and 9% (796) had severe TBI, of whom 17% (132/796) had multiple injuries. Overall mortality was 2% and ranged from 0.1% for isolated concussion to 18% for severe TBI. The vast majority of TBI were evacuated by rotary wing to role 3 or higher, including those with isolated concussion. As compared with severe TBI, individuals with isolated concussion had fewer diagnostic or surgical procedures performed. Only 6% of service members with severe TBI were able to return to duty as compared with 54% of those with isolated concussion. Traumatic brain injury resulted in 123,677 lost duty days; individuals with isolated concussion spent a median of 2 days in care and those with severe TBI spent a median of 17 days in care and a median of 6 days in the intensive care unit. CONCLUSION: While most TBI in the deployed setting are mild, TBI is frequently associated with hospitalization and multiple injuries. Overtriage of mild TBI is common. Improved TBI capabilities applicable to forward settings will be critical to the success of future multidomain operations with limitations in air superiority. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level III.

Accuracy of a rapid glial fibrillary acidic protein/ubiquitin carboxyl-terminal hydrolase L1 test for the prediction of intracranial injuries on head computed tomography after mild traumatic brain injury.

OBJECTIVE: The objective was to determine the accuracy of a new, rapid blood test combining measurements of both glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) for predicting acute traumatic intracranial injury (TII) on head CT scan after mild traumatic brain injury (mTBI). METHODS: Analysis of banked venous plasma samples from subjects completing the Prospective Clinical Evaluation of Biomarkers of Traumatic Brain Injury (ALERT-TBI) trial, enrolled 2012-2014 at 22 investigational sites in the United States and Europe. All subjects were ≥18 years old, presented to an emergency department (ED) with a nonpenetrating head injury and Glasgow Coma Scale score (GCS) 9-15 (mild to moderate TBI), underwent head CT scanning as part of their clinical care, and had blood sampling within 12 h of injury. Plasma concentrations of GFAP and UCH-L1 were measured using i-STAT Alinity and TBI plasma cartridge and compared to acute TII on head CT scan. RESULTS: Of the 2011 subjects enrolled in ALERT-TBI, 1918 had valid CT scans and plasma specimens for testing and 1901 (99.1%) had GCS 13-15 (mTBI), for which the rapid test was intended. Among these subjects, the rapid test had a sensitivity of 0.958 (95% confidence interval [CI] = 0.906 to 0.982), specificity of 0.404 (95% CI = 0.382 to 0.427), negative predictive value of 0.993 (95% CI = 0.985 to 0.997), and positive predictive value of 0.098 (95% CI = 0.082 to 0.116) for acute TII. CONCLUSIONS: A rapid i-STAT-based test had high sensitivity for prediction of acute TII, comparable to lab-based platforms. The speed, portability, and high accuracy of this test may facilitate clinical adoption of brain biomarker testing as an aid to head CT decision making in EDs.

Comparison of GFAP and UCH-L1 Measurements from Two Prototype Assays: The Abbott i-STAT and ARCHITECT Assays.

Glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) may aid in the evaluation of traumatic brain injury (TBI). The objective of this analysis was to compare GFAP and UCH-L1 values measured using a handheld device compared with a core laboratory platform. We analyzed plasma samples from patients with TBI and healthy controls enrolled in the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) cohort study. GFAP and UCH-L1 were measured twice in each subject using prototype assays, first with the Abbott i-STAT™ handheld device, and second with the Abbott ARCHITECT® platform. We then quantified the agreement in biomarker values obtained using these two methods. GFAP and UCH-L1 were measured twice in 570 and 572 samples, respectively. GFAP values measured by the ARCHITECT platform (median 143.3 [interquartile range (IQR): 19.8-925.8] pg/mL) were higher than values measured by the i-STAT (median 116.0 [IQR: 9.2-856.5] pg/mL). GFAP values from the two platforms were strongly correlated (p = 0.985). Similarly, UCH-L1 values measured by the ARCHITECT platform (median 163.9 [IQR: 82.5-412.4] pg/mL) were higher than values measured by the i-STAT (median 122.5 [IQR: 63.0-297.3] pg/mL). UCH-L1 values from the two platforms were strongly correlated (p = 0.933). Passing-Bablok regression equations were developed to estimate the relationship between the two platforms, specifically to predict i-STAT values from the ARCHITECT platform. GFAP and UCH-L1 values measured using the prototype assays on the Abbott i-STAT and ARCHITECT platforms are strongly correlated and values from either platform may be converted to the other.

Cognitive Evaluation Using Morris Water Maze in Neurotrauma.

The Morris water maze (MWM) task is one of the most widely used and versatile tools in behavioral neuroscience for evaluating spatial learning and memory. With regard to detecting cognitive deficits following central nervous system (CNS) injuries, MWM has been commonly utilized in various animal models of neurotrauma, such as fluid percussion injury (FPI), cortical controlled impact (CCI) injury, weight-drop impact injury, and penetrating ballistic-like brain injury (PBBI). More importantly, it serves as a therapeutic index for assessing the efficacy of treatment interventions on cognitive performance following neurotrauma. Thus, it is critical to design an MWM testing paradigm that is sensitive yet discriminating for the purpose of evaluating potential therapeutic interventions. In this chapter, we discuss how multiple test manipulations, including the size of platform, numbers of trials per day, the frequency of retesting intervals, and the texture of platform surface, impact MWM's ability to detect cognitive deficits using a rat model of PBBI.

Neuroprotection and anti-seizure effects of levetiracetam in a rat model of penetrating ballistic-like brain injury.

PURPOSE: We assessed the therapeutic efficacy of FDA-approved anti-epileptic drug Levetiracetam (LEV) to reduce post-traumatic nonconvulsive seizure (NCS) activity and promote neurobehavioral recovery following 10% frontal penetrating ballistic-like brain injury (PBBI) in male Sprague-Dawley rats. METHODS: Experiment 1 anti-seizure study: 50 mg/kg LEV (25 mg/kg maintenance doses) was given twice daily for 3 days (LEV3D) following PBBI; outcome measures included seizures incidence, frequency, duration, and onset. Experiment 2 neuroprotection studies: 50 mg/kg LEV was given twice daily for either 3 (LEV3D) or 10 days (LEV10D) post-injury; outcome measures include motor (rotarod) and cognitive (water maze) functions. RESULTS: LEV3D treatment attenuated seizure activity with significant reductions in NCS incidence (54%), frequency, duration, and delayed latency to seizure onset compared to vehicle treatment. LEV3D treatment failed to improve cognitive or motor performance; however extending the dosing regimen through 10 days post-injury afforded significant neuroprotective benefit. Animals treated with the extended LEV10D dosing regimen showed a twofold improvement in rotarod task latency to fall as well as significantly improved spatial learning performance (24%) in the MWM task. CONCLUSIONS: These findings support the dual anti- seizure and neuroprotective role of LEV, but more importantly identify the importance of an extended dosing protocol which was specific to the therapeutic targets studied.

Simvastatin Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Simvastatin, the fourth drug selected for testing by Operation Brain Trauma Therapy (OBTT), is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor used clinically to reduce serum cholesterol. In addition, simvastatin has demonstrated potent antineuroinflammatory and brain edema reducing effects and has shown promise in promoting functional recovery in pre-clinical models of traumatic brain injury (TBI). The purpose of this study was to assess the potential neuroprotective effects of oral administration of simvastatin on neurobehavioral, biomarker, and histopathological outcome measures compared across three pre-clinical TBI animal models. Adult male Sprague-Dawley rats were exposed to either moderate fluid percussion injury (FPI), controlled cortical impact injury (CCI), or penetrating ballistic-like brain injury (PBBI). Simvastatin (1 or 5 mg/kg) was delivered via oral gavage at 3 h post-injury and continued once daily out to 14 days post-injury. Results indicated an intermediate beneficial effect of simvastatin on motor performance on the gridwalk (FPI), balance beam (CCI), and rotarod tasks (PBBI). No significant therapeutic benefit was detected, however, on cognitive outcome across the OBTT TBI models. In fact, Morris water maze (MWM) performance was actually worsened by treatment in the FPI model and scored full negative points for low dose in the MWM latency and swim distance to locate the hidden platform. A detrimental effect on cortical tissue loss was also seen in the FPI model, and there were no benefits on histology across the other models. Simvastatin also produced negative effects on circulating glial fibrillary acidic protein biomarker outcomes that were evident in the FPI and PBBI models. Overall, the current findings do not support the beneficial effects of simvastatin administration over 2 weeks post-TBI using the oral route of administration and, as such, it will not be further pursued by OBTT.

Hindlimb stretching alters locomotor function after spinal cord injury in the adult rat.

BACKGROUND: Stretching is a widely accepted standard-of-care therapy following spinal cord injury (SCI) that has not been systematically studied in animal models. OBJECTIVE: To investigate the influence of a daily stretch-based physical therapy program on locomotor recovery in adult rats with moderate T9 contusive SCI. METHODS: A randomized treatment and control study of stretching in an animal model of acute SCI. Moderate SCIs were delivered with the NYU Impactor. Daily stretching (30 min/day, 5 days/wk for 8 weeks) was provided by a team of animal handlers. Hindlimb function was assessed using the BBB Open Field Locomotor Scale and kinematically. Passive range-of-motion for each joint was determined weekly using a goniometer. RESULTS: Declines in hindlimb function during overground stepping were observed for the first 4 weeks for stretched animals. BBB scores improved weeks 5 to 10 but remained below the control group. Stretched animals had significant deficits in knee passive range of motion starting at week 4 and for the duration of the study. Kinematic assessment showed decreased joint excursion during stepping that partially recovered beginning at week 5. CONCLUSION: Stretch-based therapy significantly impaired functional recovery in adult rats with a moderate contusive SCI at T10. The negative impact on function was greatest acutely but persisted even after the stretching ceased at 8 weeks postinjury.

Hindlimb immobilization in a wheelchair alters functional recovery following contusive spinal cord injury in the adult rat.

BACKGROUND: Locomotor training of rats with thoracic contusion spinal cord injuries can induce task-specific changes in stepping but rarely results in improved overground locomotion, possibly due to a ceiling effect. Thus, the authors hypothesize that incompletely injured rats maximally retrain themselves while moving about in their cages over the first few weeks postinjury. OBJECTIVE: To test the hypothesis using hindlimb immobilization after mild thoracic contusion spinal cord injury in adult female rats. A passive stretch protocol was included as an independent treatment. METHODS: Wheelchairs were used to hold the hindlimbs stationary in an extended position leaving the forelimbs free. The wheelchairs were used for 15 to 18 hours per day, 5 days per week for 8 weeks, beginning at 4 days postinjury. A 20-minute passive hindlimb stretch therapy was applied to half of the animals. RESULTS: Hindlimb locomotor function of the wheelchair group was not different from controls at 1 week postinjury but declined significantly over the next 4 weeks. Passive stretch had no influence on wheelchair animals but limited functional recovery of normally housed animals, preventing them from regaining forelimb-hindlimb coordination. Following 8 weeks of wheelchair immobilization and stretch therapy, only the wheelchair group displayed an improvement in function when returned to normal housing but retained significant deficits in stepping and coordination out to 16 weeks. CONCLUSION: Hindlimb immobilization and passive stretch may hinder or conceal the normal course of functional recovery of spinal cord injured rats. These observations have implications for the management of acute clinical spinal cord injuries.