Rachel P. Berger

Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making.

Purpose of reviewEmerging data suggest that biomarkers of brain injury have potential utility as diagnostic, prognostic, and therapeutic adjuncts in the setting of traumatic and ischemic brain injury. Two approaches are being used, namely, assessing markers of structural damage and quantifying mediators of the cellular, biochemical, or molecular cascades in secondary injury or repair. Novel proteomic, multiplex, and lipidomic methods are also being applied. Recent findingsBiochemical markers of neuronal, glial, and axonal damage such as neuron-specific enolase, S100B, and myelin basic protein, respectively, are readily detectable in biological samples such as serum or cerebrospinal fluid and are being studied in patients with ischemic and traumatic brain injury. In addition, a number of studies have demonstrated that novel tools to assess simultaneously multiple biomarkers can provide unique insight such as details on specific molecular participants in cell death cascades, inflammation, or oxidative stress. SummaryMultifaceted cellular, biochemical, and molecular monitoring of proteins and lipids is logical as an adjunct to guiding therapies and improving outcomes in traumatic and ischemic brain injury and we appear to be on the verge of a breakthrough with the use of these markers as diagnostic, prognostic, and monitoring adjuncts, in neurointensive care.

Identification of inflicted traumatic brain injury in well-appearing infants using serum and cerebrospinal markers: a possible screening tool

OBJECTIVE. Inflicted traumatic brain injury (iTBI) is the leading cause of death from TBI in infants. Misdiagnosis of iTBI is common and results in increased morbidity and mortality. Biomarkers may be able to assist in screening infants who are at high risk for iTBI and whose injury might otherwise be missed. We investigated whether serum and/or cerebrospinal fluid (CSF) concentrations of neuron-specific enolase (NSE), S100B, and myelin-basic protein (MBP) are sensitive and specific for iTBI in high-risk infants. METHODS. A prospective case-control study was conducted of 98 well-appearing infants who presented with nonspecific symptoms and no history of trauma. Serum or CSF was collected. NSE, S100B, and MBP concentrations were measured by enzyme-linked immunosorbent assay. Abnormal marker concentrations were defined a priori. Patients were followed for 12 months to assess for subsequent abuse. RESULTS. Fourteen patients received a clinical diagnosis of iTBI. Using preestablished cutoffs, NSE was 77% sensitive and 66% specific and MBP was 36% sensitive and 100% specific for iTBI. S100B was neither sensitive nor specific for iTBI. Five patients who were not identified with iTBI at enrollment were identified at follow-up as being possible victims of abuse; 4 had an increased NSE concentration at enrollment. CONCLUSIONS. Serum and/or CSF concentrations of NSE and MBP may be useful as a screening test to identify infants who are at increased risk for iTBI and may benefit from additional evaluation with a head computed tomography scan. S100B is neither sensitive nor specific for iTBI in this study population. The ability to identify iTBI that might otherwise be missed has important implications for decreasing the morbidity and the mortality from iTBI.

Serum Concentrations of Ubiquitin C-Terminal Hydrolase-L1 and αII-Spectrin Breakdown Product 145 kDa Correlate with Outcome after Pediatric TBI

Predicting outcome after pediatric traumatic brain injury (TBI) is important for providing information to families and prescribing rehabilitation services. Previously published studies evaluating the ability of serum biomarkers to predict outcome after pediatric TBI have focused on three markers: neuron-specific enolase (NSE), S100B, and myelin-basic protein (MBP), all of which have important limitations. The study objectives were to measure serum concentrations of two novel serum biomarkers, ubiquitin C-terminal hydrolase (UCH-L1) and αII-spectrin breakdown product 145 kDa (SBDP145), in children with TBI and healthy controls and to assess the ability of these markers to predict outcome as assessed by a dichotomous Glasgow Outcome Scale (GOS) score. We also sought to compare the predictive ability of UCH-L1 and SBDP145 to that of the clinical gold standard, the Glasgow Coma Scale (GCS) score, and to that of the well-accepted biomarkers NSE, S100B, and MBP. Serum UCH-L1 and SBDP145 concentrations were significantly greater in subjects than in controls. The increase in UCH-L1 and SBDP145 was exclusively seen in subjects with moderate and severe TBI; there was no increase after mild TBI. Both markers had a significant negative partial correlation with the GCS after controlling for age. Both UCH-L1 and SBDP145 were correlated with GOS, and this correlation was stronger than the correlations with NSE, S100B, or MBP. These results suggest that these two markers may be useful in assessing outcome after moderate and severe pediatric TBI.

Use of Skeletal Surveys to Evaluate for Physical Abuse: Analysis of 703 Consecutive Skeletal Surveys

OBJECTIVES: The goals were to assess the use of the skeletal survey (SS) to evaluate for physical abuse in a large consecutive sample, to identify characteristics of children most likely to have unsuspected fractures, and to determine how often SS results influenced directly the decision to make a diagnosis of abuse. METHODS: A retrospective, descriptive study of a consecutive sample of children who underwent an SS at a single childrens hospital over 4 years was performed. Data on demographic characteristics, clinical presentation, SS results, and effects of SS results on clinical diagnoses were collected. A positive SS result was defined as a SS which identified a previously unsuspected fracture(s). RESULTS: Of the 703 SSs, 10.8% yielded positive results. Children <6 months of age, children with an apparent life-threatening event or seizure, and children with suspected abusive head trauma had the highest rates of positive SS results. Of children with positive SS results, 79% had ≥1 healing fracture. CONCLUSIONS: This is the largest study to date to describe the use of the SS. Almost 11% of SS results were positive. The SS results influenced directly the decision to make a diagnosis of abuse for 50% of children with positive SS results. These data, combined with the high morbidity rates for missed abuse and the large proportion of children with healing fractures detected through SS, suggest that broader use of SS, particularly for high-risk populations, may be warranted.

Systematic Review of Clinical Research on Biomarkers for Pediatric Traumatic Brain Injury

Abstract The objective was to systematically review the medical literature and comprehensively summarize clinical research performed on biomarkers for pediatric traumatic brain injury (TBI) and to summarize the studies that have assessed serum biomarkers acutely in determining intracranial lesions on CT in children with TBI. The search strategy included a literature search of PubMed,(®) MEDLINE,(®) and the Cochrane Database from 1966 to August 2011, as well as a review of reference lists of identified studies. Search terms used included pediatrics, children, traumatic brain injury, and biomarkers. Any article with biomarkers of traumatic brain injury as a primary focus and containing a pediatric population was included. The search initially identified 167 articles. Of these, 49 met inclusion and exclusion criteria and were critically reviewed. The median sample size was 58 (interquartile range 31-101). The majority of the articles exclusively studied children (36, 74%), and 13 (26%) were studies that included both children and adults in different proportions. There were 99 different biomarkers measured in these 49 studies, and the five most frequently examined biomarkers were S100B (27 studies), neuron-specific enolase (NSE) (15 studies), interleukin (IL)-6 (7 studies), myelin basic protein (MBP) (6 studies), and IL-8 (6 studies). There were six studies that assessed the relationship between serum markers and CT lesions. Two studies found that NSE levels ≥15 ng/mL within 24 h of TBI was associated with intracranial lesions. Four studies using serum S100B were conflicting: two studies found no association with intracranial lesions and two studies found a weak association. The flurry of research in the area over the last decade is encouraging but is limited by small sample sizes, variable practices in sample collection, inconsistent biomarker-related data elements, and disparate outcome measures. Future studies of biomarkers for pediatric TBI will require rigorous and more uniform research methodology, common data elements, and consistent performance measures.

Multiplex assessment of serum biomarker concentrations in well-appearing children with inflicted traumatic brain injury.

Proper diagnosis of mild inflicted traumatic brain injury (ITBI) is difficult; children often present without a history of trauma and with nonspecific symptoms, such as vomiting. Previous studies suggest that biomarkers may be able to screen for brain injury in this population, but these studies focused on only a few biomarkers. We hypothesized that using multiplex bead technology we would be able to identify multiple differences in the serum biomarker profile between in children with ITBI and those without brain injury. We compared the concentrations of 44 serum biomarkers in 16 infants with mild ITBI and 20 infants without brain injury. There were significant group differences in the concentrations of nine of the 44 markers. Vascular cellular adhesion molecule (VCAM) (p < 0.00) and IL-6 (IL-6) (p < 0.00) had the most significant group differences; IL-6 was higher after ITBI, whereas VCAM was lower. Using VCAM and IL-6 in classification algorithms, we could discriminate the groups with a sensitivity and specificity of 87% and 90%, respectively. The results suggest significant changes in the serum biomarker profile after mild ITBI. Future research is needed to determine whether these biomarkers can screen for brain injury in infants with nonspecific symptoms.

S100b as a Prognostic Biomarker in Outcome Prediction for Patients with Severe Traumatic Brain Injury

As an astrocytic protein specific to the central nervous system, S100b is a potentially useful marker in outcome prediction after traumatic brain injury (TBI). Some studies have questioned the validity of S100b, citing the extracerebral origins of the protein as reducing the specificity of the marker. This study evaluated S100b as a prognostic biomarker in adult subjects with severe TBI (sTBI) by comparing outcomes with S100b temporal profiles generated from both cerebrospinal fluid (CSF) (n = 138 subjects) and serum (n = 80 subjects) samples across a 6-day time course. Long-bone fracture, Injury Severity Score (ISS), and isolated head injury status were variables used to assess extracerebral sources of S100b in serum. After TBI, CSF and serum S100b levels were increased over healthy controls across the first 6 days post-TBI (p ≤ 0.005 and p ≤ 0.031). Though CSF and serum levels were highly correlated during early time points post-TBI, this association diminished over time. Bivariate analysis showed that subjects who had temporal CSF profiles with higher S100b concentrations had higher acute mortality (p < 0.001) and worse Glasgow Outcome Scale (GOS; p = 0.002) and Disability Rating Scale (DRS) scores (p = 0.039) 6 months post-injury. Possibly as a result of extracerebral sources of S100b in serum, as represented by high ISS scores (p = 0.032), temporal serum profiles were associated with acute mortality (p = 0.015). High CSF S100b levels were observed in women (p = 0.022) and older subjects (p = 0.004). Multivariate logistic regression confirmed CSF S100b profiles in predicting GOS and DRS and showed mean and peak serum S100b as acute mortality predictors after sTBI.

Trajectory Analysis of Serum Biomarker Concentrations Facilitates Outcome Prediction after Pediatric Traumatic and Hypoxemic Brain Injury

Traumatic brain injury (TBI) and hypoxic ischemic encephalopathy (HIE) are leading causes of morbidity and mortality in children. Several studies over the past several years have evaluated the use of serum biomarkers to predict outcome after pediatric brain injury. These studies have all used simple point estimates such as initial and peak biomarker concentrations to predict outcome. However, this approach does not recognize patterns of change over time. Trajectory analysis is a type of analysis which can capture variance in biomarker concentrations over time and has been used with success in the social sciences. We used trajectory analysis to evaluate the ability of the serum concentrations of 3 brain-specific biomarkers – S100B, neuron-specific enolase (NSE) and myelin basic protein (MBP) – to predict poor outcome (Glasgow Outcome Scale scores 3–5) after pediatric TBI and HIE. Clinical and biomarker data from 100 children with TBI or HIE were evaluated. For each biomarker, we validated 2-, 3- and 4-group models for outcome prediction, using sensitivity and specificity. For S100B, the 3-group model predicted poor outcome with a sensitivity of 59% and specificity of 100%. For NSE, the 3-group model predicted poor outcome with a sensitivity of 48% and specificity of 98%. For MBP, the 3-group model predicted poor outcome with a sensitivity of 73% and specificity of 61%. Thus, when the models predicted a poor outcome, there was a very high probability of a poor outcome. In contrast, 17% of subjects with a poor outcome were predicted to have a good outcome by all 3 biomarker trajectories. These data suggest that trajectory analysis of biomarker data may provide a useful approach for predicting outcome after pediatric brain injury.

Urinary S100B concentrations are increased after brain injury in children: A preliminary study.

Objective: S100B is a renally excreted protein concentrated in glial cells of the nervous system. Increases in serum S100B concentrations reflect brain injury. However, increases in serum are rapid and transient and therefore may be of limited use in certain patients. Urinary S100B concentrations may be able to provide information about brain injury in this subgroup of patients. Design: Prospective, descriptive study. Setting: Level I trauma center. Patients: Fifteen children with acute traumatic or hypoxemic brain injury (subjects) and 14 healthy controls. Interventions: Urine and serum samples were collected from subjects and controls. Serial samples were collected in brain injury subjects up to every 12 hrs for 3 days. S100B concentrations were measured by enzyme-linked immunosorbent assay (Nanogen, San Diego CA). Outcome was assessed by Glasgow Outcome Scale score. Measurements and Main Results: Urinary S100B concentrations were detectable in 80% of subjects with increased serum S100B concentrations and 0% of controls. Peak urinary S100B concentrations occurred significantly later than peak serum S100B concentrations: 55.3 (29.8) (mean [sd]) vs. 14.6 (11.8) hrs after injury (p = .002). All subjects with an undetectable urinary S100B had a good outcome vs. only 20% of subjects with a detectable urinary S100B. Subjects with increased serum S100B were more likely to have a poor outcome than those with normal S100B (p = .01). Conclusions: Increases in urinary S100B are found in the majority of children with acute brain injury and an increased serum S100B. Urinary S100B concentrations peak later than serum concentrations, suggesting that measurement of urinary S100B may be helpful in subjects in whom early serum S100B is unavailable. Urinary and/or serum S100B concentrations may be useful to assist in the prediction of outcome after pediatric brain injury.

Prevalence of abusive injuries in siblings and household contacts of physically abused children.

OBJECTIVE: Siblings and other children who share a home with a physically abused child are thought to be at high risk for abuse, but rates of injury in these contact children are unknown and screening of contacts is highly variable. Our objective was to determine the prevalence of abusive injuries identified by a common screening protocol among contacts of physically abused children. METHODS: This is an observational, multicenter cross-sectional study of children evaluated for physical abuse, and their contacts, by 20 US child abuse teams who used a common screening protocol for the contacts of physically abused children with serious injuries. Contacts underwent physical examination if they were <5 years old, physical examination and skeletal survey (SS) if they were <24 months old, and physical examination, SS, and neuroimaging if they were <6 months old. RESULTS: Protocol-indicated SS identified at least 1 abusive fracture in 16 of 134 contacts (11.9%, 95% confidence interval [CI] 7.5–18.5) <24 months of age. None of these fractures had associated findings on physical examination. No injuries were identified by neuroimaging in 19 of 25 eligible contacts (0.0%, 95% CI 0.0–13.7). Twins were at substantially increased risk of fracture relative to nontwin contacts (odds ratio 20.1, 95% CI 5.8–69.9). CONCLUSIONS: SS should be obtained in the contacts of injured, abused children for contacts who are <24 months old, regardless of physical examination findings. Twins are at higher risk of abusive fractures relative to nontwin contacts.