Traumatic Brain Injury Events Research Articles

Self-reported Participation Restrictions Among Male and Female Veterans With Traumatic Brain Injury in Veterans Health Administration Outpatient Polytrauma Programs

ObjectivesTo identify areas of most restricted self-reported participation among veterans with traumatic brain injury (TBI), explore associations among participation restriction and clinical characteristics, and examine differences in participation restrictions by sex. DesignRetrospective cross-sectional design. SettingNational VA Polytrauma System of Care outpatient settings. ParticipantsVeterans with a confirmed TBI event (N=6065). InterventionsNot applicable. Main Outcome Measure(s)Mayo-Portland Participation Index (M2PI), a 5-point Likert-type scale with 8 items. Total score was converted to standardized T score for analysis. ResultsThe sample consisted of 5679 male and 386 female veterans with ≥1 clinically confirmed TBI events (69% white; 74% with blast exposure). The M2PI items with greatest perceived restrictions were social contact, leisure, and initiation. There were no significant differences between men and women on M2PI standardized T scores. Wilcoxon rank-sum analyses showed significant differences by sex on 4 items: leisure, residence, employment, and financial management (all P<.01). In multinomial logistic regression on each item controlling for demographics, injury characteristics, and comorbidities, female veterans had significantly greater relative risk for part-time work and unemployment on the employment item and significantly less risk for impairment on the residence and financial management item. ConclusionsThere was no significant difference between men and women. Veterans on M2PI standardized T scores, which masks differences in response patterns to individual items. Clinical teams should be encouraged to discuss perceived restrictions with patients and target these areas in treatment planning. Future work is needed to investigate the psychometric properties of the M2PI by biological sex.

Incidence of Antithrombin Deficiency and Anti-Cardiolipin Antibodies After Severe Traumatic Brain Injury: A Prospective Cohort Study.

Animal studies suggested that cerebral mitochondrial cardiolipin phospholipids were released after severe traumatic brain injury (TBI), contributing to the pathogenesis of thromboembolism. To determine the incidence of anti-cardiolipin antibodies after severe TBI and whether this was related to the severity of TBI and development of venous thromboembolism. Serial anti-cardiolipin antibodies, antithrombin levels, viscoelastic testing, and coagulation parameters were measured on admission, day-1, and between day-5 and day-7 in patients with severe TBI requiring intracranial pressure monitoring. Of the 40 patients included (85% male and median age 42years), 7 (18%) had a raised Ig-G or Ig-M anti-cardiolipin antibody titer after TBI. Antithrombin levels were below the normal level-especially on day-0 and day-1-in 15 patients (38%), and 14 patients (38%) developed an increase in maximum clot firmness on the viscoelastic test in conjunction with elevations in fibrinogen concentration and platelet count. Four patients (10%) developed deep vein thrombosis, and 10 patients (25%) died, both of which were not significantly related to the presence of anti-cardiolipin antibodies (P = 0.619 and P = 0.638, respectively). A reduction in antithrombin level and development of anti-cardiolipin antibodies were not rare immediately after severe TBI; these abnormalities were followed by an increase in in vitro clot strength due to elevations in fibrinogen concentration and platelet count. The quantitative relationships between the development of anti-cardiolipin antibodies and severity of TBI or clinical thromboembolic events deserve further investigation.

Data Mining to Understand How Health Status Preceding Traumatic Brain Injury Affects Functional Outcome: A Population-Based Sex-Stratified Study

ObjectivesTo understand how health status preceding traumatic brain injury (TBI) affects relative functional gain after inpatient rehabilitation using a data mining approach. DesignPopulation-based, sex-stratified, retrospective cohort study using health administrative data from Ontario, Canada (39% of the Canadian population). SettingInpatient rehabilitation. ParticipantsPatients 14 years or older (N=5802; 63.4% male) admitted to inpatient rehabilitation within 1 year of a TBI-related acute care discharge between April 1, 2008, and March 31, 2015. InterventionsNot applicable. Main Outcome MeasuresRelative functional gain (RFG) in percentage, calculated as ([discharge FIM−admission FIM]/[126−admission FIM]×100). Health status prior to TBI was identified and internally validated using a data mining approach that categorized all International Classification of Diseases, 10th revision, codes for each patient. ResultsThe average RFG was 52.8%±27.6% among male patients and 51.6%±27.1% among female patients. Sex-specific Bonferroni adjusted multivariable linear regressions identified 10 factors of preinjury health status related to neurology, emergency medicine, cardiology, psychiatry, geriatrics, and gastroenterology that were significantly associated with reduced RFG in FIM for male patients. Only 1 preinjury health status category, geriatrics, was significantly associated with RFG in female patients. ConclusionsComorbid health conditions present up to 5 years preceding the TBI event were significantly associated with RFG. These findings should be considered when planning and executing interventions to maximize functional gain and to support an interdisciplinary approach. Best practices guidelines and clinical interventions for older male and female patients with TBI should be developed given the increasingly aging population with TBI.

Initial Validation of the Mid-Atlantic Mental Illness Research, Education, and Clinical Center Assessment of Traumatic Brain Injury.

With the increasing prevalence of traumatic brain injury (TBI), the need for reliable and valid methods to evaluate TBI has also increased. The purpose of this study was to establish the validity and reliability of a new comprehensive assessment of TBI, the Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC) Assessment of TBI (MMA-TBI). The participants in this study were post-deployment, combat exposed veterans. First, MMA-TBI outcomes were compared with those of independently conducted clinical TBI assessments. Next, MMA-TBI outcomes were compared with those of a different validated TBI measure (the Ohio State University TBI Identification method [OSU-TBI-ID]). Next, four TBI subject matter experts independently evaluated 64 potential TBI events based on both clinical judgment and Veterans Administration/Department of Defense (VA/DoD) Clinical Practice Guidelines. Results of the MMA-TBI algorithm (based on VA/DoD clinical guideline) were compared with those of the subject matter experts. Diagnostic correspondence with independently conducted expert clinical evaluation was 96% for lifetime TBI and 92% for deployment-acquired TBI. Consistency between the MMA-TBI and the OSU-TBI-ID was high (κ = 0.90; Kendall Tau = 0.94). Comparison of MMA-TBI algorithm results with those of subject matter experts was high (κ = 0.97-1.00). The MMA-TBI is the first TBI interview to be validated against an independently conducted clinical TBI assessment. Overall, results demonstrate the MMA-TBI is a highly valid and reliable instrument for determining TBI based on VA/DoD clinical guidelines. These results support the need for application of standardized TBI criteria across all diagnostic contexts.

Dendrimer mediated targeted delivery of sinomenine for the treatment of acute neuroinflammation in traumatic brain injury

Traumatic brain injury (TBI) is a significant medical problem with limited treatment options and is one of the main causes of life-long disability. Neuroinflammation orchestrated by activated microglia/macrophages at the site of injury plays a critical role in the onset of many pathological events following TBI, leading to blood brain barrier (BBB) dysfunction, neuronal damage and long term neuronal and behavioral deficits. Current treatment involves intravenous administration of anti-inflammatory drugs which have limited clinical outcomes only when dosed within the early time window after injury. Hence there is an urgent need to develop improved drug delivery systems which have potential to cross impaired BBB, target and deliver drugs selectively to activated microglia/macrophages at the sites of injury, and suppress the detrimental effects of acute inflammation. In this study, we have used Sinomenine (Sino), a potent anti-inflammatory and antioxidant drug conjugated to hydroxyl terminated generation-4 PAMAM dendrimer (D-Sino) as a potential therapy for attenuating early inflammation in TBI. D-Sino conjugates were synthesized using highly robust copper-catalyzed click reaction with high purity. D-Sino conjugates enhanced the intracellular availability of Sino due to their rapid cellular uptake, significantly attenuated early/acute inflammation by suppressing pro-inflammatory cytokines (TNF-α, IL-1β, CCL-3 and IL-6), and reduced oxidative stress (iNOS and NO) in LPS activated murine macrophages (RAW 264.7) by inhibiting NF-κB activation and its nuclear translocation (the root cause for inflammation inception) significantly more as compared to the free drug. Upon systemic administration in a rabbit model of pediatric TBI, D-Sino conjugates specifically targeted activated microglia/macrophages at the site of injury in the brain. Single dose of D-Sino attenuated inflammation in the injured brain areas by suppressing inflammatory cytokines expression whereas free Sino treatment did not demonstrate a significant effect. Together, these results suggest that D-Sino conjugate may open up new avenues for increasing the therapeutic window in the treatment of early inflammation and for improving the efficacy of the drug in TBI. Moreover, this treatment can work in conjunction with current clinical practices such as therapeutic hypothermia and pharmacologically induced coma for many indications associated with TBI, where acute inflammation plays a critical role in disease progression.

Long-term negative emotional outcomes of warzone TBI

Objective Many veterans of the Iraq and Afghanistan Wars have experienced traumatic brain injury (TBI). Although prior work has examined associations between TBI and development of psychiatric syndromes, less is known about associations between TBI and component emotions constituting these syndromes, especially in the long term. The purpose of this study was to examine the long-term emotional consequences of deployment-related TBI. Methods As part of VA Cooperative Studies Program #566, we assessed a sample of n = 456 US Army soldiers prior to an index deployment to Iraq, and again an average of 8.3 years (SD = 2.4 years) after their deployment for a long-term follow-up assessment. In this report, we used adjusted regression analyses to examine the relationship of deployment TBI to depression, anxiety, and stress symptom severity measured at the long-term follow-up assessment. A structured interview was used to determine TBI history; the Depression, Anxiety, and Stress Scale, 21-item version (DASS-21) was used to determine emotional status at the follow-up evaluation. Results Warzone TBI events, particularly when greater than mild in severity, were independently associated with depression, anxiety, and stress severity at long-term follow-up, even after taking into account variance attributable to pre-deployment emotional distress and war-zone stress. Post-hoc analyses did not detect independent associations of either number of events or injury mechanism with outcomes. Conclusions These findings highlight the potentially enduring and multi-faceted emotional effects of deployment TBI, underscoring the need for early assessment of negative affectivity in warzone veterans reporting TBI.

Tranexamic acid is associated with reduced mortality, hemorrhagic expansion, and vascular occlusive events in traumatic brain injury \u2013 meta-analysis of randomized controlled trials

BackgroundThis systematic review and meta-analysis aimed to synthesize the latest evidence on the efficacy and safety of tranexamic acid (TXA) on traumatic brain injury (TBI).MethodsWe performed a systematic literature search on topics that compared intravenous TXA to placebo in patients with TBI up until January 2020 from several electronic databases.ResultsThere were 30.522 patients from 7 studies. Meta-analysis showed that TXA was associated with reduced mortality (RR 0.92 [0.88, 0.97], p = 0.002; I2: 0%) and hemorrhagic expansion (RR 0.79 [0.64, 0.97], p = 0.03; I2: 0%). Both TXA and control group has a similar need for neurosurgical intervention (p = 0.87) and unfavourable Glasgow Outcome Scale (GOS) (p = 0.59). The rate for vascular occlusive events (p = 0.09), and its deep vein thrombosis subgroup (p = 0.23), pulmonary embolism subgroup (p = 1), stroke subgroup (p = 0.38), and myocardial infarction subgroup (p = 0.15) were similar in both groups. Subgroup analysis on RCTs with low risk of bias showed that TXA was associated with reduced mortality and hemorrhagic expansion. TXA was associated with reduced vascular occlusive events (RR 0.85 [0.73, 0.99], p = 0.04; I2: 4%). GRADE was performed for the RCT with low risk of bias subgroup, it showed a high certainty of evidence for lower mortality, less hemorrhage expansion, and similar need for neurosurgical intervention in TXA group compared to placebo group.ConclusionTXA was associated with reduced mortality and hemorrhagic expansion but similar need for neurosurgical intervention and unfavorable GOS. Vascular occlusive events were slightly lower in TXA group on subgroup analysis of RCTs with low risk of bias.

Role of Intracellular Toll Like Receptors (TLRs) in the Secondary Events of Traumatic Brain Injury

The mechanisms underlying secondary brain damage following traumatic brain injury (TBI) is still unclear. Many studies demonstrated that inflammatory cascades contribute to brain damage through the activation of immune/inflammatory responses, including the increased release of cytokines and chemokines as well as the recruitment of leukocytes. The cells and tissues damaged by primary mechanical injury released a number of endogenous factors acting as damage‐associated molecular patterns (DAMPs), which initiate and perpetuate noninfectious inflammatory responses through transduction signaling pathways. Toll‐like receptors (TLRs) are a transmembrane receptor family that can recognize the specific DAMPs released from damaged cells and recruit a set of adaptors leading to the activation of downstream kinases and nuclear factors which regulate the expression of inflammatory genes. The activation of inflammatory responses mediated by TLR signaling is closely associated with brain tissue damage and neurological dysfunction following TBI. Since the role of intracellular TLRs such as 7, 8 and 9 after TBI is still unclear, we decided to evaluate the outcome and the secondary brain damage after TBI in TLR 7/8−/−and TLR 7/9−/−double KO mice. We performed a TBI, using a validate experimental model of controlled cortical impact injury (CCI), both TLR 7/8−/−and TLR 7/9−/−and in wild type (WT) mice. 24h thereafter we evaluated the contusion volume, the brain edema formation, the expression of pro‐inflammatory cytokines as well as the activation of immune response.Thus the obtained results demonstrated that modulation of intracellular TLR‐mediated signaling may attenuate brain damage and improve TBI outcome. Therefore, the intracellular TLRs and their downstream protein kinases may be potential targets for the treatment of TBI.

Clinical and Biochemical Predictors of Fatality in Traumatic Brain Injury

Traumatic brain injury is a global health problem, it is a major cause of devastating neurological sequelae and significant mortality. The underlying physiological events in traumatic brain injury are responsible for the poor clinical outcomes seen in patients. Inflammatory and oxidative stress changes in traumatic brain injury result in the release of inflammatory biomarkers, a reduction in the endogenous anti-oxidants and dysfunction of the blood brain barrier. An understanding of the natural history of oxidative stress and inflammatory changes in traumatic brain injury can help design appropriate management protocols to reduce mortality and morbidity in these patients. Aim of the study: The aim of this study was to identify potential biomarkers that are predictive of fatality in patients with moderate to severe traumatic brain injury. Methods: This was a prospective study of patients with moderate to severe traumatic brain injury managed at the Nelson Mandela Academic Hospital during the period March 2014 - March 2016. Following admission and management, the patient demographics (sex, age) and admission Glasgow Coma Score were recorded. Oxidative stress and inflammatory biomarkers in blood and cerebrospinal fluid where sampled on day 1 to 7. On day 14 only blood was sampled for the same biomarkers. The primary outcome was the Glasgow Outcome score assessed on day 90. Due to its simplicity the Glasgow Outcome scale was used to assess clinical outcomes at day 90. Because of difficulty in regular follow up due to the vastness of our region, difficult terrain and long travel distances a 3 month follow up period was used to avoid default. Results: Of the 64-patient’s, fatality was noted in 12.5% of them. There was a significant association between fatality and the; ages of the patients, anti-oxidant levels, proinflammatory biomarkers and admission Glasgow Coma Score. Conclusion: The admission Glasgow Coma Score, low anti-oxidant levels and elevated serum interleukin-1β levels were associated with fatal outcomes.

CGRP-dependent and independent mechanisms of acute and persistent post-traumatic headache following mild traumatic brain injury in mice.

Acute and persistent post-traumatic headache are often debilitating consequences of traumatic brain injury. Underlying physiological mechanisms of post-traumatic headache and its persistence remain unknown, and there are currently no approved therapies for these conditions. Post-traumatic headache often presents with a migraine-like phenotype. As calcitonin-gene related peptide promotes migraine headache, we explored the efficacy and timing of intervention with an anti- calcitonin-gene related peptide monoclonal antibody in novel preclinical models of acute post-traumatic headache and persistent post-traumatic headache following a mild traumatic brain injury event in mice. Male, C57Bl/6 J mice received a sham procedure or mild traumatic brain injury resulting from a weight drop that allowed free head rotation while under minimal anesthesia. Periorbital and hindpaw tactile stimulation were used to assess mild traumatic brain injury-induced cutaneous allodynia. Two weeks after the injury, mice were challenged with stress, a common aggravator of migraine and post-traumatic headache, by exposure to bright lights (i.e. bright light stress) and cutaneous allodynia was measured hourly for 5 hours. A murine anti- calcitonin-gene related peptide monoclonal antibody was administered after mild traumatic brain injury at different time points to allow evaluation of the consequences of either early and sustained calcitonin-gene related peptide sequestration or late administration only prior to bright light stress. Mice with mild traumatic brain injury, but not a sham procedure, exhibited both periorbital and hindpaw cutaneous allodynia that resolved by post-injury day 13. Following resolution of injury-induced cutaneous allodynia, exposure to bright light stress re-instated periorbital and hindpaw cutaneous allodynia in injured, but not sham mice. Repeated administration of anti-calcitonin-gene related peptide monoclonal antibody at 2 hours, 7 and 14 days post mild traumatic brain injury significantly attenuated the expression of cutaneous allodynia when evaluated over the 14-day post injury time course and also prevented bright light stress-induced cutaneous allodynia in injured mice. Administration of anti-calcitonin-gene related peptide monoclonal antibody only at 2 hours and 7 days after mild traumatic brain injury blocked injury-induced cutaneous allodynia and partially prevented bright light stress-induced cutaneous allodynia. A single administration of anti-calcitonin-gene related peptide monoclonal antibody after the resolution of the peak injury-induced cutaneous allodynia, but prior to bright light stress challenge, did not prevent bright light stress-induced cutaneous allodynia. We used a clinically relevant mild traumatic brain injury event in mice along with a provocative stimulus as novel models of acute post-traumatic headache and persistent post-traumatic headache. Following mild traumatic brain injury, mice demonstrated transient periorbital and hindpaw cutaneous allodynia suggestive of post-traumatic headache-related pain and establishment of central sensitization. Following resolution of injury-induced cutaneous allodynia, exposure to bright light stress re-established cutaneous allodynia, suggestive of persistent post-traumatic headache-related pain. Continuous early sequestration of calcitonin-gene related peptide prevented both acute post-traumatic headache and persistent post-traumatic headache. In contrast, delayed anti-calcitonin-gene related peptide monoclonal antibody treatment following establishment of central sensitization was ineffective in preventing persistent post-traumatic headache. These observations suggest that mechanisms involving calcitonin-gene related peptide underlie the expression of acute post-traumatic headache, and drive the development of central sensitization, increasing vulnerability to headache triggers and promoting persistent post-traumatic headache. Early and continuous calcitonin-gene related peptide blockade following mild traumatic brain injury may represent a viable treatment option for post-traumatic headache and for the prevention of post-traumatic headache persistence. CA Cutaneous allodynia CGRP Calcitonin gene-related peptide mTBI Mild traumatic brain injury PTH Post-traumatic headache APTH Acute post-traumatic headache PPTH Persistent post-traumatic headache.

Expansion of a fly TBI model to four levels of injury severity reveals synergistic effects of repetitive injury for moderate injury conditions

ABSTRACTSeveral million traumatic brain injury (TBI) events are reported in the United States annually. However, mild TBI events often go unreported, and mild and repetitive mild TBI conditions are challenging to model. Fruit flies (Drosophila melanogaster) have gained traction for the study of TBI. The best-characterized fly TBI model is the high-impact trauma (HIT) method. We replicated the HIT method and confirmed several previous findings at the standard level of injury severity. We then expanded upon the HIT model by characterizing mortality across three reduced levels of injury severity. Importantly, we found reduced mortality with reduced injury severity and synergistic effects on mortality in response to repetitive TBI by our moderate injury conditions. Last, we compared moderate, repetitive TBI to a single severe TBI via assessment of the pattern of mortality and geotaxis performance in the 24 h following TBI. We found the number and severity of injuries could result in different patterns of death, while all TBI conditions led to impaired geotaxis compared to uninjured flies at 0.5 h and 6 h post-TBI. Thus, we have extended a well-characterized model of TBI in flies, and shown the utility of this model for making unique insights into TBI across various severities, injury numbers, and time-points post-injury.

Mammalian Models of Traumatic Brain Injury and a Place for Drosophila in TBI Research.

Traumatic brain injury (TBI), caused by a sudden blow or jolt to the brain that disrupts normal function, is an emerging health epidemic with ∼2.5 million cases occurring annually in the United States that are severe enough to cause hospitalization or death. Most common causes of TBI include contact sports, vehicle crashes and domestic violence or war injuries. Injury to the central nervous system is one of the most consistent candidates for initiating the molecular and cellular cascades that result in Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Not every TBI event is alike with effects varying from person to person. The majority of people recover from mild TBI within a short period of time, but repeated incidents can have deleterious long-lasting effects which depend on factors such as the number of TBIs sustained, time till medical attention, age, gender and genetics of the individual. Despite extensive research, many questions still remain regarding diagnosis, treatment, and prevention of long-term effects from TBI as well as recovery of brain function. In this review, we present an overview of TBI pathology, discuss mammalian models for TBI and focus on current methods using Drosophila melanogaster as a model for TBI study. The relatively small brain size (∼100,000 neurons and glia), conserved neurotransmitter signaling mechanisms and sophisticated genetics of Drosophila allows for cell biological, molecular and genetic analyses that are impractical in mammalian models of TBI.

Proinflammatory and amyloidogenic S100A9 induced by traumatic brain injury in mouse model

Traumatic brain injury (TBI) represents a significant risk factor for development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. The S100A9-driven amyloid-neuroinflammatory cascade occurring during primary and secondary TBI events can serve as a mechanistic link between TBI and Alzheimer’s as demonstrated recently in the human brain tissues. Here by using immunohistochemistry in the controlled cortical impact TBI mouse model we have found pro-inflammatory S100A9 in the brain tissues of all mice on the first and third post-TBI days, while 70% of mice did not show any S100A9 presence on seventh post-TBI day similar to controls. This indicates that defensive mechanisms effectively cleared S100A9 in these mouse brain tissues during post-TBI recovery. By using sequential immunohistochemistry we have shown that S100A9 was produced by both neuronal and microglial cells. However, Aβ peptide deposits characteristic for Alzheimer’s disease were not detected in any post-TBI animals. On the first and third post-TBI days S100A9 was found to aggregate intracellularly into amyloid oligomers, similar to what was previously observed in human TBI tissues. Complementary, by using Rayleigh scatting, intrinsic fluorescence and atomic force microscopy we demonstrated that in vitro S100A9 self-assembles into amyloid oligomers within minutes. Its amyloid aggregation is highly dependent on changes of environmental conditions such as variation of calcium levels, pH, temperature and reduction/oxidation, which might be relevant to perturbation of cellular and tissues homeostasis under TBI. Present results demonstrate that S100A9 induction mechanisms in TBI are similar in mice and humans, emphasizing that S100A9 is an important marker of brain injury and therefore can be a potential therapeutic target.

The overlooked aspect of excitotoxicity: Glutamate-independent excitotoxicity in traumatic brain injuries.

Traumatic brain injury (TBI) is a leading major cause of morbidity and mortality in youth and individuals under 45year age. A wide variety of cellular and molecular mechanisms have been identified contributing to the pathogenesis of TBI. A better understanding of the pathophysiology behind TBI is essential for providing more effective treatment. Excitotoxicity as one of the secondary molecular events is a major contributing factor in apoptosis and neuronal death following the initial injury in TBI. Excitotoxicity is the rapid overload and influx of calcium into the cell cytoplasm, activating a series of deleterious signaling cascades causing the cell to undergo apoptosis. Conventional understanding is that the rapid influx of calcium is initiated through glutamate release. However, there are overlooked glutamate-independent mechanisms that cause the rapid calcium influx into the neuronal cytoplasm, evoking or contributing to excitotoxicity. Therefore, the focus of this review will be on the role of the glutamate-independent excitotoxic mechanisms of the mechanosensitive response of NMDA receptors, mechanoporation of the cell membrane, ischemia, and the release of calcium from intracellular stores. In conclusion, the shear and stretch forces during a TBI event may result in the mechanosensitive activation of NMDA receptors which contribute to glutamate-independent excitotoxicity.

Epidemiology of Traumatic Brain Injury in Europe: A Living Systematic Review.

This systematic review provides a comprehensive, up-to-date summary of traumatic brain injury (TBI) epidemiology in Europe, describing incidence, mortality, age, and sex distribution, plus severity, mechanism of injury, and time trends. PubMed, CINAHL, EMBASE, and Web of Science were searched in January 2015 for observational, descriptive, English language studies reporting incidence, mortality, or case fatality of TBI in Europe. There were no limitations according to date, age, or TBI severity. Methodological quality was assessed using the Methodological Evaluation of Observational Research checklist. Data were presented narratively. Sixty-six studies were included in the review. Country-level data were provided in 22 studies, regional population or treatment center catchment area data were reported by 44 studies. Crude incidence rates varied widely. For all ages and TBI severities, crude incidence rates ranged from 47.3 per 100,000, to 694 per 100,000 population per year (country-level studies) and 83.3 per 100,000, to 849 per 100,000 population per year (regional-level studies). Crude mortality rates ranged from 9 to 28.10 per 100,000 population per year (country-level studies), and 3.3 to 24.4 per 100,000 population per year (regional-level studies.) The most common mechanisms of injury were traffic accidents and falls. Over time, the contribution of traffic accidents to total TBI events may be reducing. Case ascertainment and definitions of TBI are variable. Improved standardization would enable more accurate comparisons.

Bleeding and Thromboembolism After Traumatic Brain Injury in the Elderly: A Real Conundrum

BackgroundElderly patients presenting with a traumatic brain injury (TBI) often have comorbidities that increase risk of thromboembolic (TE) disease and recurrent TBI. A significant number are on anticoagulant therapy at the time of injury and studies suggest that continuing anticoagulation can prevent TE events. Understanding bleeding, recurrent TBI, and TE risk after TBI can help to guide therapy. Our objectives were to 1) evaluate the incidence of bleeding, recurrent TBI, and TE events after an initial TBI in older adults and 2) identify which factors contribute to this risk. MethodsRetrospective analysis of Medicare claims between May 30, 2006 and December 31, 2009 for patients hospitalized with TBI was performed. We defined TBI for the index admission, and hemorrhage (gastrointestinal bleeding or hemorrhagic stroke), recurrent TBI, and TE events (stroke, myocardial infarction, deep venous thrombosis, or pulmonary embolism) over the following year using ICD-9 codes. Unadjusted incidence rates and 95% confidence intervals (CIs) were calculated. Risk factors of these events were identified using logistic regression. ResultsAmong beneficiaries hospitalized with TBI, incidence of TE events (58.6 events/1000 person-years; 95% CI 56.2, 60.8) was significantly higher than bleeding (23.6 events/1000 person-years; 95% CI 22.2, 25.1) and recurrent TBI events (26.0 events/1000 person-years; 95% CI 24.5, 27.6). Several common factors predisposed to bleeding, recurrent TBI, and TE outcomes. ConclusionsAmong Medicare patients hospitalized with TBI, the incidence of TE was significantly higher than that of bleeding or recurrent TBI. Specific risk factors of bleeding and TE events were identified which may guide care of older adults after TBI.

Traumatic Brain Injury in Early Childhood and Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder

Early childhood (< 3 years of age) is a critical period for neurodevelopment. This study investigated the correlation between early childhood traumatic brain injury (TBI) and subsequent risk of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental delay (DD) by analyzing a national-scale cohort. Data from the National Health Insurance Research Database, which comprises health care information from > 99% of the Taiwanese population, were analyzed. Children with TBI in their early childhood were enrolled from 1998-2008, and the incidence of subsequent ADHD, ASD, or DD (according to ICD-9 criteria) was assessed and compared with controls without TBI. Patients' age, number of TBI events, and TBI severity were investigated for the risk of ADHD, ASD, or DD. A total of 7,801 and 31,204 children were enrolled in the TBI and control cohorts, respectively. The TBI cohort exhibited a higher incidence of subsequent ADHD, ASD, or DD than the controls (all P < .001). Diagnoses of ADHD, ASD, or DD in the TBI cohort were made at a younger age compared with the controls. Cox regression demonstrated the highest hazard ratios (HRs) of ADHD, ASD, or DD with repeated TBI events, severe TBI, and TBI events before 1 year of age, with the exception that the HR of ASD did not significantly increase after repeated TBI (P = .335). In addition, cumulative HRs (> 10 years) of ADHD, ASD, or DD were increased after TBI (all P < .001). Data from this study suggest that the incidence of ADHD, ASD, and DD significantly increased after TBI events in early childhood (< 3 years of age). The risk factors include severe TBI, repeated TBI events, and TBI at a younger age. The long-term follow-up demonstrated an increased cumulative risk of ADHD, ASD, and DD after TBI.

The clinical characteristics of posttraumatic epilepsy following moderate-to-severe traumatic brain injury in children

PurposeChildren with traumatic brain injury (TBI) are at increased risk of posttraumatic epilepsy (PTE); the risk increases according to TBI severity. We examined the long-term incidence and risk factors for developing PTE in a cohort of children hospitalised at one medical centre with moderate or severe TBI. MethodsModerate brain injury was classified as Glasgow Coma Score on Arrival (GCSOA) of 9–13, and severe brain injury as GCSOA ≤8. We collected demographics and clinical data from medical records and interviewed patients and parents at 5–11 years following the TBI event. ResultsDuring a median follow-up period of 7.3 years, 9 (9%) of 95 children with moderate-to-severe TBI developed PTE; 4 developed intractable epilepsy. The odds for developing PTE was 2.9 in patients with severe compared to moderate TBI. CT findings showed fractures in 7/9 (78%) of patients with PTE, compared to 40/86 (47%) of those without PTE (p = 0.09). Of the patients with fractures, all those with PTE had additional features on CT (such as haemorrhage, contusion and mass effect), compared to 29/40 (73%) of those without PTE. One of nine (11%) PTE patients and 10 of 86 (12%) patients without PTE had immediate seizures. Two (22%) children with PTE had their first seizure more than 2 years after the TBI. ConclusionAmong children with moderate or severe TBI, the presence of additional CT findings, other than skull fractures, seem to increase the risk of PTE. In our cohort, the occurrence of an early seizure did not confer an increased risk of PTE.

An objective score to identify psychogenic seizures based on age of onset and history

ObjectivePsychogenic nonepileptic seizure (PNES) is a common diagnosis after evaluation of medication resistant or atypical seizures with video-electroencephalographic monitoring (VEM), but usually follows a long delay after the development of seizures, during which patients are treated for epilepsy. Therefore, more readily available diagnostic tools are needed for earlier identification of patients at risk for PNES. A tool based on patient-reported psychosocial history would be especially beneficial because it could be implemented in the outpatient clinic. MethodsBased on the data from 1375 patients with VEM-confirmed diagnoses, we used logistic regression to compare the frequency of specific patient-reported historical events, demographic information, age of onset, and delay from first seizure until VEM in five mutually exclusive groups of patients: epileptic seizures (ES), PNES, physiologic nonepileptic seizure-like events (PSLE), mixed PNES plus ES, and inconclusive monitoring. To determine the diagnostic utility of this information to differentiate PNES only from ES only, we used multivariate piecewise-linear logistic regression trained using retrospective data from chart review and validated based on data from 246 prospective standardized interviews. ResultsThe prospective area under the curve of our weighted multivariate piecewise-linear by-sex score was 73%, with the threshold that maximized overall retrospective accuracy resulting in a prospective sensitivity of 74% (95% CI: 70–79%) and prospective specificity of 71% (95% CI: 64–82%). The linear model and piecewise linear without an interaction term for sex had very similar performance statistics. In the multivariate piecewise-linear sex-split predictive model, the significant factors positively associated with ES were history of febrile seizures, current employment or active student status, history of traumatic brain injury (TBI), and longer delay from first seizure until VEM. The significant factors associated with PNES were female sex, older age of onset, mild TBI, and significant stressful events with sexual abuse, in particular, increasing the likelihood of PNES. Delays longer than 20years, age of onset after 31years for men, and age of onset after 40years for women had no additional effect on the likelihood of PNES. DiscussionOur promising results suggest that an objective score has the potential to serve as an early outpatient screening tool to identify patients with greater likelihood of PNES when considered in combination with other factors. In addition, our analysis suggests that sexual abuse, more than other psychological stressors including physical abuse, is more associated with PNES. There was a trend of increasing frequency of PNES for women during childbearing years and plateauing outside those years that was not observed in men.

Repetitive Transcranial Magnetic Stimulation for Treatment of Depression in a Patient With Severe Traumatic Brain Injury

Traumatic brain injury (TBI) commonly presents with a constellation of findings, including physical, cognitive, and psychological disturbances. Traditionally, few options have been available for long-term management of mood symptoms for post-TBI patients who are refractory to medications. Repetitive transcranial magnetic stimulation (rTMS) is a promising alternative treatment. A 37-year-old male with history of anxiety and bipolar depression incurred a TBI after a 60-foot fall. After his physical recovery, the patient had refractory depression. Eight months after the TBI event, he underwent a 6-week course of rTMS treatment and had a 70.8% improvement in mood symptoms by the end of the therapy as indicated by the Patient Health Questionnaire-9, transitioning from severe to mild depression according to the scoring system. Clinical correlation during the months following conclusion of rTMS therapy showed no signs of remission or adverse side effects. The patient remains stable and lives independently 1 year after treatment with mood-stabilizing medications. This case provides evidence for successful treatment of refractory depressive symptoms after severe TBI with the addition of rTMS to psychotherapy and mood-stabilizing medications, supporting the safety and tolerability of this novel therapeutic approach. Further studies are needed to validate the contribution of rTMS for management of mood symptoms in patients with TBI.