Time-Dependent Long-Term Effect of Memantine following Repetitive Mild Traumatic Brain Injury.

Repetitive mild traumatic brain injury (rmTBI, e.g., sports concussions) may be associated with both acute and chronic symptoms and neurological changes. Despite the common occurrence of these injuries, therapeutic strategies are limited. One potentially promising approach is N-methyl-D-aspartate receptor (NMDAR) blockade to alleviate the effects of post-injury glutamatergic excitotoxicity. Initial pre-clinical work using the NMDAR antagonist, memantine, suggests that immediate treatment following rmTBI improves a variety of acute outcomes. It remains unclear (1) whether acute memantine treatment has long-term benefits and (2) whether delayed treatment following rmTBI is beneficial, which are both clinically relevant concerns. To test this, animals were subjected to rmTBI via a weight drop model with rotational acceleration (five hits in 5 days) and randomized to memantine treatment immediately, 3 months, or 6 months post-injury, with a treatment duration of one month. Behavioral outcomes were assessed at 1, 4, and 7 months post-injury. Neuropathological outcomes were characterized at 7 months post-injury. We observed chronic changes in behavior (anxiety-like behavior, motor coordination, spatial learning, and memory), as well as neuroinflammation (microglia, astrocytes) and tau phosphorylation (T231). Memantine treatment, either immediately or 6 months post-injury, appears to confer greater rescue of neuroinflammatory changes (microglia) than vehicle or treatment at the 3-month time point. Although memantine is already being prescribed chronically to address persistent symptoms associated with rmTBI, this study represents the first evidence of which we are aware to suggest a small but durable effect of memantine treatment in mild, concussive injuries. This effect suggests that memantine, although potentially beneficial, is insufficient to treat all aspects of rmTBI alone and should be combined with other therapeutic agents in a multi-therapy approach, with attention given to the timing of treatment.

Nonoperative Management, Repair, or Reconstruction of the Medial Collateral Ligament in Combined Anterior Cruciate and Medial Collateral Ligament Injuries-Which Is Best? A Systematic Review and Meta-analysis.

BACKGROUND: Combined injury of the anterior cruciate ligament (ACL) and the medial collateral ligament (MCL) is a common injury pattern and accounts for 20% of all ligamentous knee injuries. Despite advancements in surgical technique, there is no up-to-date consensus regarding the superiority of nonoperative versus operative management in higher-grade MCL tears of combined ACL-MCL injuries. PURPOSE: To interpret recent literature on treatment options and to provide an updated evidence-based approach for management of combined ACL-MCL knee injuries. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: We performed a systematic review on outcomes following treatment of concomitant ACL and MCL injuries. A computerized search was conducted in PubMed, Embase.com, and Scopus.com. Authors independently assessed eligible studies and screened titles and abstracts. Articles reporting on patients with concomitant ACL and MCL injuries with or without concomitant procedures were included. Data regarding study design, sample size, patient age and sex, length of follow-up, timing of surgery, indications, surgical methods, concomitant procedures, outcomes, and complications were recorded. Patient-reported outcomes (PROs) and functional outcomes, including Knee injury and Osteoarthritis Outcome Score, International Knee Documentation Committee scores, Lysholm and Tegner scores, and range of motion, were estimated via meta-analysis and compared statistically by surgical approach. RESULTS: In total, 18 studies were included in the systematic review with level 1 to level 4 evidence, with a total of 1,534 cases, were included in the systematic review. Of these, 16 studies with sufficient statistical reporting including 997 cases with sufficient follow-up were included in meta-analysis. Three different approaches to combined ACL-MCL injuries were identified: ACL reconstruction with (1) nonoperative MCL, (2) MCL repair, and (3) MCL reconstruction. There was no statistical difference between nonoperative versus surgically managed MCL injuries for PROs, range of motion at final follow up, or quadriceps strength. CONCLUSION: Reconstruction of combined injury in a delayed fashion facilitates return of range of motion and may allow time for low-grade MCL tears to heal. If residual valgus or anteromedial rotatory laxity remains after a period of rehabilitation, then concomitant surgical management of ACL and MCL injuries is warranted. Avulsion MCL injuries and Stener-type lesions may benefit from early repair techniques.

Peripheral Nerve Block Delays Mobility and Increases Length of Stay in Patients With Geriatric Hip Fracture.

INTRODUCTION: Peripheral nerve blocks (PNB) has been increasingly used in the care of patients with geriatric hip fracture to reduce perioperative opiate use and the need for general anesthesia. However, the associated motor palsy may impair patients' ability to mobilize effectively after surgery and subsequently may increase latency to key mobility milestones postoperatively, as well as increase inpatient length of stay (LOS). The aim of this study was to investigate time-to-mobility milestones and length of hospital stay between peripheral, epidural, and general anesthesia. METHODS: A retrospective review identified 1,351 patients aged 65 years or older who underwent surgery for hip fracture between 2012 and 2018 at a single academic health system. Patients were excluded if baseline nonambulatory, restricted weight-bearing postoperatively, or sustained concomitant injuries precluding mobilization, with a final cohort of 1,013 patients. Time-to-event analyses for discharge and mobility milestones were assessed using univariate Kaplan-Meier and multivariate Cox proportional hazard regression analyses. RESULTS: PNB was associated with delayed postoperative time to ambulation ( P < 0.001) and time to out-of-bed ( P = 0.029), along with increased LOS ( P < 0.001). Epidural anesthesia was associated with less delay to first out-of-bed ( P = 0.002), less delay to ambulation ( P = 0.001), and overall reduced length of stay ( P < 0.001). DISCUSSION: PNB was associated with slower mobilization and longer hospitalization while epidural anesthesia was associated with quicker mobilization and shorter hospital stays. Epidural anesthesia may be a preferable anesthesia choice in patients with geriatric hip fracture when possible. LEVEL OF EVIDENCE: Level III.

Association Between Preoperative Multidimensional Psychological Distress and Physical Function After Surgery for Sports-Related Injury.

Background: Psychological distress after orthopaedic surgery can lead to worse outcomes, including higher levels of disability and pain and lower quality of life. The 10-item Optimal Screening for Prediction for Referral and Outcome-Yellow Flag (OSPRO-YF) survey screens for multiple psychological constructs relevant to recovery from orthopaedic injury and may be useful to preoperatively identify patients who may require further psychological assessment and possible intervention after surgery. Purpose/Hypothesis: To determine the association between the OSPRO-YF and physiological patient-reported outcomes (PROs). It was hypothesized that higher OSPRO-YF scores (indicating worse psychological distress) would be associated with worse PRO scores at time of return to sport. Study Design: Case series; Level of evidence, 4. Methods: This study evaluated 107 patients at a single, academic health center who were assessed at a sports orthopaedics clinic and ultimately treated surgically for injuries to the knee, shoulder, foot, or ankle. Preoperatively, patients completed the OSPRO-YF survey as well as the following PRO measures: Patient-Reported Outcomes Measurement Information System (PROMIS), Single Assessment Numeric Evaluation, numeric rating scale for pain; American Shoulder and Elbow Surgeons standardized shoulder assessment form for patients with shoulder injuries, the International Knee Documentation Committee score (for patients with knee injuries), and the Foot and Ankle Ability Measure (FAAM; for patients with foot or ankle injuries). At the time of anticipated full recovery and/or return to sport, patients again completed the same PRO surveys. Multivariable regression was used to evaluate the association between total OSPRO-YF score at baseline and PRO scores at the time of functional recovery. Results: The baseline OSPRO-YF score predicted postoperative PROMIS Physical Function and FAAM Sports scores only. A 1-unit increase in the OSPRO-YF was associated with a 0.55-point reduction in PROMIS Physical Function (95% CI, -1.05 to -0.04; P = .033) indicating worse outcomes. Among patients who underwent ankle surgery, a 1-unit increase in OSPRO-YF was associated with a 6.45-point reduction in FAAM Sports (95% CI, -12.0 to -0.87; P = .023). Conclusion: The study findings demonstrated that the OSPRO-YF survey predicts certain long-term PRO scores at the time of expected return to sport, independent of baseline scores.

Optimizing Choice and Timing of Behavioral Outcome Tests After Repetitive Mild Traumatic Brain Injury: A Machine Learning-Based Approach on Multiple Pre-Clinical Experiments.

Repetitive mild traumatic brain injury (rmTBI) is a potentially debilitating condition with long-term sequelae. Animal models are used to study rmTBI in a controlled environment, but there is currently no established standard battery of behavioral tests used. Primarily, we aimed to identify the best combination and timing of behavioral tests to distinguish injured from uninjured animals in rmTBI studies, and secondarily, to determine whether combinations of independent experiments have better behavioral outcome prediction accuracy than individual experiments. Data from 1203 mice from 58 rmTBI experiments, some of which have already been published, were used. In total, 11 types of behavioral tests were measured by 37 parameters at 13 time points during the first 6 months after injury. Univariate regression analyses were used to identify optimal combinations of behavioral tests and whether the inclusion of multiple heterogenous experiments improved accuracy. k-means clustering was used to determine whether a combination of multiple tests could distinguish mice with rmTBI from uninjured mice. We found that a combination of behavioral tests outperformed individual tests alone when distinguishing animals with rmTBI from uninjured animals. The best timing for most individual behavioral tests was 3-4 months after first injury. Overall, Morris water maze (MWM; hidden and probe frequency) was the behavioral test with the best capability of detecting injury effects (area under the curve [AUC] = 0.98). Combinations of open field tests and elevated plus mazes also performed well (AUC = 0.92), as did the forced swim test alone (AUC = 0.90). In summary, multiple heterogeneous experiments tended to predict outcome better than individual experiments, and MWM 3-4 months after injury was the optimal test, also several combinations also performed well. In order to design future pre-clinical rmTBI trials, we have included an interactive application available online utilizing the data from the study via the Supplementary URL.

Psychological resilience as a predictor of opioid consumption after orthopaedic trauma.

INTRODUCTION: Psychological distress after orthopaedic trauma negatively affects patient outcomes. Resilience may mediate distress and therefore be associated with post-operative outcomes, including opioid use. The purpose of this study is to evaluate the relationship between resilience and post-operative opioid demand with the hypothesis that low levels of resilience are associated with increased opioid consumption. MATERIALS AND METHODS: Patients age 18 - 65 at a single, tertiary care level 1 trauma center who underwent operative treatment of pelvic and/ or extremity fractures between 3/2017 - 6/2018 were contacted by phone to complete the OSPRO-YF, a ten-item screening tool that assesses psychological distress. Participants were screened for scores in the worst quartile (i.e., yellow flag) for resilience. Baseline patient and injury characteristics and opioid demand were compared between patients with and without positive yellow flags for resilience using Wilcoxon rank-sum for continuous variables and Fisher exact test for categorical variables. RESULTS: A total of 117 patients were surveyed. Patients with positive yellow flag screening scores for resilience had significantly higher opioid demand, number of opioid prescriptions filled, and were more likely to refill prescriptions long-term (3-months post-discharge to one-year post-discharge). Patients with a positive yellow flag for resilience had a significantly higher number of opioid prescriptions filled in the cumulative (one-month pre-op to one-year post-discharge) time period. DISCUSSION/ CONCLUSION: Lower long-term resilience scores were associated with higher postoperative opioid consumption, fill and refill rates. These results suggest low resilience may be a risk factor for increased long-term opioid consumption following surgical treatment for orthopaedic trauma.

Visual Dysfunction after Repetitive Mild Traumatic Brain Injury in a Mouse Model and Ramifications on Behavioral Metrics.

Mild traumatic brain injury (mTBI) is a major cause of morbidity and mortality with a poorly understood pathophysiology. Animal models have been increasingly utilized to better understand mTBI and recent research has identified visual deficits in these models that correspond to human literature. While visual impairment is being further characterized within TBI, the implications of impaired vision on behavioral tasks commonly utilized in animal models has not been well described thus far. Visual deficits may well confound behavioral tests that are believed to be isolated to cognitive functioning such as learning and memory. We utilized a mouse model of repetitive mTBI (rmTBI) to further characterize visual deficits using an optomotor task, electroretinogram, and visually evoked potential, and located likely areas of damage to the visual pathway. Mice were tested on multiple behavioral metrics, including a touchscreen conditional learning task to better identify the contribution of visual dysfunction to behavioral alterations. We found that rmTBI caused visual dysfunction resulting from damage distal to the retina that likely involves pathology within the optic nerve. Moreover, loss of vision led to poorer performance of rmTBI animals on classic behavioral tests such as the Morris water maze that would otherwise be attributed solely to learning and memory deficits. The touchscreen conditional learning task was able to differentiate rmTBI induced learning and memory dysfunction from visual impairment and is a valuable tool for elucidating subtle changes resulting from TBI.

Internal Jugular Vein Compression Collar Mitigates Histopathological Alterations after Closed Head Rotational Head Impact in Swine: A Pilot Study.

Recently, there has been increased concern about microstructural brain changes after head trauma. Clinical studies have investigated a neck collar that applies gentle bilateral jugular vein compression, designed to increase intracranial blood volume and brain stiffness during head trauma, which neuroimaging has shown to result in a reduction in brain microstructural alterations after a season of American football and soccer. Here, we utilized a swine model of mild traumatic brain injury to investigate the effects of internal jugular vein (IJV) compression on histopathological outcomes after injury. Animals were randomized to collar treatment (n = 8) or non-collar treatment (n = 6), anesthetized and suspended such that the head was supported by breakable tape. A custom-built device was used to impact the head, thus allowing the head to break the tape and rotate along the sagittal plane. Accelerometer data were collected for each group. Sham injured animals (n = 2) were exposed to anesthesia only. Following single head trauma, animals were euthanized and brains collected for histology. Whole slide immunohistochemistry was analyzed using Qupath software. There was no difference in linear or rotational acceleration between injured collar and non-collar animals (p > 0.05). Injured animals demonstrated higher levels of the phosphorylated tau epitope AT8 (p < 0.05) and the inflammatory microglial marker IBA1 (p < 0.05) across the entire brain, but the effect of injury was markedly reduced by collar treatment (p < 0.05) The current results indicate that internal jugular venous compression protects against histopathological alterations related to closed head trauma exposure.

Automated Quantification of Immunohistochemical Staining of Large Animal Brain Tissue Using QuPath Software.

Large scale unbiased quantification of immunohistochemistry (IHC) is time consuming, expensive, and/or limited in scope. Heterogeneous tissue types such as brain tissue have presented a further challenge to the development of automated analysis, as differing cellular morphologies result in either limited applicability or require large amounts of training tissue for machine-learning methods. Here we present the use of QuPath, a free and open source software, to quantify whole-brain sections stained with the immunohistochemical markers IBA1 and AT8, for microglia and phosphorylated tau respectively. The pixel-based method of analysis herein allows for statistical comparison of global protein expression between brains and generates heat-maps of stain intensity, visualizing stain signal across whole sections and permitting more specific investigation of regions of interest. This method is fast, automated, unbiased, and easily replicable. We compared swine brains that had undergone a closed head traumatic brain injury with brains of sham animals, and found a global increase in both microglial signal expression and phosphorylated tau. We discuss the IHC methods necessary to utilize this analysis and provide detailed instruction on the use of QuPath in the pixel-based analysis of whole-slide images.