Common data elements for pediatric traumatic brain injury: Recommendations from the working group on demographics and clinical assessment

The Common Data Elements (CDEs) initiative is a National Institutes of Health (NIH) interagency effort to standardize naming, definitions, and data structure for clinical research variables. Comparisons of the results of clinical studies of neurological disorders have been hampered by variability in data coding, definitions, and procedures for sample collection. The CDE project objective is to enable comparison of future clinical trials results in major neurological disorders, including traumatic brain injury (TBI), stroke, multiple sclerosis, and epilepsy. As part of this effort, recommendations for CDEs for research on TBI were developed through a 2009 multi-agency initiative. Following the initial recommendations of the Working Group on Demographics and Clinical Assessment, a separate workgroup developed recommendations on the coding of clinical and demographic variables specific to pediatric TBI studies for subjects younger than 18 years. This article summarizes the selection of measures by the Pediatric TBI Demographics and Clinical Assessment Working Group. The variables are grouped into modules which are grouped into categories. For consistency with other CDE working groups, each variable was classified by priority (core, supplemental, and emerging). Templates were produced to summarize coding formats, guide selection of data points, and provide procedural recommendations. This proposed standardization, together with the products of the other pediatric TBI working groups in imaging, biomarkers, and outcome assessment, will facilitate multi-center studies, comparison of results across studies, and high-quality meta-analyses of individual patient data

Epidemiology of Pediatric Traumatic Brain Injury and Hypothalamic-Pituitary Disorders in Arizona

Traumatic brain injury (TBI) in children can result in long-lasting social, cognitive, and neurological impairments. In adults, TBI can lead to endocrinopathies (endocrine system disorders), but this is infrequently reported in children. Untreated endocrinopathies can elevate risks of subsequent health issues, such that early detection in pediatric TBI survivors can initiate clinical interventions. To understand the risk of endocrinopathies following pediatric TBI, we identified patients who had experienced a TBI and subsequently developed a new-onset hypothalamic regulated endocrinopathy (n = 498). We hypothesized that pediatric patients who were diagnosed with a TBI were at higher risk of being diagnosed with a central endocrinopathy than those without a prior diagnosis of TBI. In our epidemiological assessment, we identified pediatric patients enrolled in the Arizona Health Care Cost Containment System (AHCCCS) from 2008 to 2014 who were diagnosed with one of 330 TBI International Classification of Diseases (ICD)-9 codes and subsequently diagnosed with one of 14 central endocrinopathy ICD-9 codes. Additionally, the ICD-9 code data from over 600,000 Arizona pediatric patients afforded an estimate of the incidence, prevalence, relative risk, odds ratio, and number needed to harm, regarding the development of a central endocrinopathy after sustaining a TBI in Arizona Medicaid pediatric patients. Children with a TBI diagnosis had 3.22 times the risk of a subsequent central endocrine diagnosis compared with the general population (±0.28). Pediatric AHCCCS patients with a central endocrine diagnosis had 3.2-fold higher odds of a history of a TBI diagnosis than those without an endocrine diagnosis (±0.29). Furthermore, the number of patients with a TBI diagnosis for one patient to receive a diagnosis of a central endocrine diagnosis was 151.2 (±6.12). Female subjects were more likely to present with a central endocrine diagnosis after a TBI diagnosis compared to male subjects (64.1 vs. 35.9%). These results are the first state-wide epidemiological study conducted to determine the risk of developing a hypothalamic-pituitary disorder after a TBI in the pediatric population. Our results contribute to a body of knowledge demonstrating a TBI etiology for idiopathic endocrine disorders, and thus advise physicians with regard to TBI follow-up care that includes preventive screening for endocrine disorders.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats

Traumatic brain injury (TBI) can occur at any age, from youth to the elderly, and its contribution to age-related neuropathology remains unknown. Few studies have investigated the relationship between age-at-injury and pathophysiology at a discrete biological age. In this study, we report the immunohistochemical analysis of na&iuml;ve rat brains compared to those subjected to diffuse TBI by midline fluid percussion injury (mFPI) at post-natal day (PND) 17, PND35, 2-, 4-, or 6-months of age. All brains were collected when rats were 10-months of age (n = 6&ndash;7/group). Generalized linear mixed models were fitted to analyze binomial proportion and count data with R Studio. Amyloid precursor protein (APP) and neurofilament (SMI34, SMI32) neuronal pathology were counted in the corpus callosum (CC) and primary sensory barrel field (S1BF). Phosphorylated TAR DNA-binding protein 43 (pTDP-43) neuropathology was counted in the S1BF and hippocampus. There was a significantly greater extent of APP and SMI34 axonal pathology and pTDP-43 neuropathology following a TBI compared with na&iuml;ves regardless of brain region or age-at-injury. However, age-at-injury did determine the extent of dendritic neurofilament (SMI32) pathology in the CC and S1BF where all brain-injured rats exhibited a greater extent of pathology compared with na&iuml;ve. No significant differences were detected in the extent of astrocyte activation between brain-injured and na&iuml;ve rats. Microglia counts were conducted in the S1BF, hippocampus, ventral posteromedial (VPM) nucleus, zona incerta, and posterior hypothalamic nucleus. There was a significantly greater proportion of deramified microglia, regardless of whether the TBI was recent or remote, but this only occurred in the S1BF and hippocampus. The proportion of microglia with colocalized CD68 and TREM2 in the S1BF was greater in all brain-injured rats compared with na&iuml;ve, regardless of whether the TBI was recent or remote. Only rats with recent TBI exhibited a greater proportion of CD68-positive microglia compared with naive in the hippocampus and posterior hypothalamic nucleus. Whilst, only rats with a remote brain-injury displayed a greater proportion of microglia colocalized with TREM2 in the hippocampus. Thus, chronic alterations in neuronal and microglial characteristics are evident in the injured brain despite the recency of a diffuse brain injury.</p

Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

Up to 50% of traumatic brain injury (TBI) survivors demonstrate persisting and late-onset anxiety disorders indicative of limbic system dysregulation, yet the pathophysiology underlying the symptoms is unclear. We hypothesize that the development of TBI-induced anxiety-like behavior in an experimental model of TBI is mediated by changes in glutamate neurotransmission within the amygdala. Adult, male Sprague-Dawley rats underwent midline fluid percussion injury or sham surgery. Anxiety-like behavior was assessed at 7 and 28 days post-injury (DPI) followed by assessment of real-time glutamate neurotransmission in the basolateral amygdala (BLA) and central nucleus of the amygdala (CeA) using glutamate-selective microelectrode arrays. The expression of anxiety-like behavior at 28 DPI coincided with decreased evoked glutamate release and slower glutamate clearance in the CeA, not BLA. Numerous factors contribute to the changes in glutamate neurotransmission over time. In two additional animal cohorts, protein levels of glutamatergic transporters (Glt-1 and GLAST) and presynaptic modulators of glutamate release (mGluR2, TrkB, BDNF, and glucocorticoid receptors) were quantified using automated capillary western techniques at 28 DPI. Astrocytosis and microglial activation have been shown to drive maladaptive glutamate signaling and were histologically assessed over 28 DPI. Alterations in glutamate neurotransmission could not be explained by changes in protein levels for glutamate transporters, mGluR2 receptors, astrocytosis, and microglial activation. Presynaptic modulators, BDNF and TrkB, were significantly decreased at 28 DPI in the amygdala. Dysfunction in presynaptic regulation of glutamate neurotransmission may contribute to anxiety-related behavior and serve as a therapeutic target to improve circuit function.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Network-Targeted Approach and Postoperative Resting-State Functional Magnetic Resonance Imaging Are Associated with Seizure Outcome

Objective Postoperative resting‐state functional magnetic resonance imaging (MRI) in children with intractable epilepsy has not been quantified in relation to seizure outcome. Therefore, its value as a biomarker for epileptogenic pathology is not well understood. Methods In a sample of children with intractable epilepsy who underwent prospective resting‐state seizure onset zone (SOZ)‐targeted epilepsy surgery, postoperative resting‐state functional MRI (rs‐fMRI) was performed 6 to 12 months later. Graded normalization of the postoperative resting‐state SOZ was compared to seizure outcomes, patient, surgery, and anatomical MRI characteristics. Results A total of 64 cases were evaluated. Network‐targeted surgery, followed by postoperative rs‐fMRI normalization was significantly (p < 0.001) correlated with seizure reduction, with a Spearman rank correlation coefficient of 0.83. Of 39 cases with postoperative rs‐fMRI SOZ normalization, 38 (97%) became completely seizure free. In contrast, of the 25 cases without complete rs‐fMRI SOZ normalization, only 3 (5%) became seizure free. The accuracy of rs‐fMRI as a biomarker predicting seizure freedom is 94%, with 96% sensitivity and 93% specificity. Interpretation Among seizure localization techniques in pediatric epilepsy, network‐targeted surgery, followed by postoperative rs‐fMRI normalization, has high correlation with seizure freedom. This study shows that rs‐fMRI SOZ can be used as a biomarker of the epileptogenic zone, and postoperative rs‐fMRI normalization is a biomarker for SOZ quiescence

A Gel-Based Proteomic Comparison of Human Cerebrospinal Fluid between Inflicted and Non-Inflicted Pediatric Traumatic Brain Injury

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63392/1/neu.2006.0061.lowlink.pdf_v03.pd

International Neurotrauma Training Based on North-South Collaborations: Results of an Inter-institutional Program in the Era of Global Neurosurgery.

Objective: Shortage of general neurosurgery and specialized neurotrauma care in low resource settings is a critical setback in the national surgical plans of low and middle-income countries (LMIC). Neurotrauma fellowship programs typically exist in high-income countries (HIC), where surgeons who fulfill the requirements for positions regularly stay to practice. Due to this issue, neurosurgery residents and medical students from LMICs do not have regular access to this kind of specialized training and knowledge-hubs. The objective of this paper is to present the results of a recently established neurotrauma fellowship program for neurosurgeons of LMICs in the framework of global neurosurgery collaborations, including the involvement of specialized parallel education for neurosurgery residents and medical students. Methods: The Global Neurotrauma Fellowship (GNTF) program was inaugurated in 2015 by a multi-institutional collaboration between a HIC and an LMIC. The course organizers designed it to be a 12-month program based on adapted neurotrauma international competencies with the academic support of the Barrow Neurological Institute at Phoenix Children's Hospital and Meditech Foundation in Colombia. Since 2018, additional support from the UK, National Institute of Health Research (NIHR) Global Health Research in Neurotrauma Project from the University of Cambridge enhanced the infrastructure of the program, adding a research component in global neurosurgery and system science. Results: Eight fellows from Brazil, Venezuela, Cuba, Pakistan, and Colombia have been trained and certified via the fellowship program. The integration of international competencies and exposure to different systems of care in high-income and low-income environments creates a unique environment for training within a global neurosurgery framework. Additionally, 18 residents (Venezuela, Colombia, Ecuador, Peru, Cuba, Germany, Spain, and the USA), and ten medical students (the United Kingdom, USA, Australia, and Colombia) have also participated in elective rotations of neurotrauma and critical care during the time of the fellowship program, as well as in research projects as part of an established global surgery initiative. Conclusion: We have shown that it is possible to establish a neurotrauma fellowship program in an LMIC based on the structure of HIC formal training programs. Adaptation of the international competencies focusing on neurotrauma care in low resource settings and maintaining international mentoring and academic support will allow the participants to return to practice in their home-based countries

Traumatic Brain Injury Characteristics Predictive of Subsequent Sleep-Wake Disturbances in Pediatric Patients

Simple Summary Traumatic brain injury is a leading cause of death and disabilities in children and adolescents. Poor sleep after brain injury can slow recovery and worsen outcomes. We investigated clinical sleep problems following pediatric brain injury. We examined characteristics of the injury and details about the patients that may be risk factors for developing sleep problems. The number of patients that developed problems with their sleep after a brain injury was similar between genders. The probability of insomnia increased with increasing patient age. The probability of &lsquo;difficulty sleeping&rsquo; was highest in 7&ndash;9 year-old brain-injured patients. Older patients had a shorter time between brain injury and sleep problems compared to younger patients. Patients with severe brain injury had the shortest time between brain injury and development of sleep problems, whereas patients with mild or moderate brain injury had comparable times between brain injury and the onset of poor sleep. Multiple characteristics of brain injury and patient details were identified as risk factors for developing sleep problems following a brain injury in children. Untreated sleep problems after a brain injury can worsen symptoms, lengthen hospital stays, and delay return to school. Identifying risk factors could improve the diagnosis, management, and treatment of sleep problems in survivors of pediatric brain injury. Abstract The objective of this study was to determine the prevalence of sleep-wake disturbances (SWD) following pediatric traumatic brain injury (TBI), and to examine characteristics of TBI and patient demographics that might be predictive of subsequent SWD development. This single-institution retrospective study included patients diagnosed with a TBI during 2008&ndash;2019 who also had a subsequent diagnosis of an SWD. Data were collected using ICD-9/10 codes for 207 patients and included the following: age at initial TBI, gender, TBI severity, number of TBIs diagnosed prior to SWD diagnosis, type of SWD, and time from initial TBI to SWD diagnosis. Multinomial logit and negative-binomial models were fit to investigate whether the multiple types of SWD and the time to onset of SWD following TBI could be predicted by patient variables. Distributions of SWD diagnosed after TBI were similar between genders. The probability of insomnia increased with increasing patient age. The probability of &lsquo;difficulty sleeping&rsquo; was highest in 7&ndash;9 year-old TBI patients. Older TBI patients had shorter time to SWD onset than younger patients. Patients with severe TBI had the shortest time to SWD onset, whereas patients with mild or moderate TBI had comparable times to SWD onset. Multiple TBI characteristics and patient demographics were predictive of a subsequent SWD diagnosis in the pediatric population. This is an important step toward increasing education among providers, parents, and patients about the risk of developing SWD following TBI. &nbsp;</p