Multiplex Assessment of Serum Biomarker Concentrations in Well-Appearing Children With Inflicted Traumatic Brain Injury

Abstract

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 Ͻ 0.00) and IL-6 (IL-6) (p Ͻ 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. Proper diagnosis of ITBI is often difficult even for experienced, astute physicians because caretakers rarely provide a history of trauma (4,5), children present with nonspecific symptoms, such as vomiting or fussiness (6) and physical examination can be normal (7,8). As a result, misdiagnosis is common and can have catastrophic medical consequences (9,10). The importance of timely diagnosis of ITBI cannot be overemphasized: if not recognized, child abuse is an escalating form of trauma that often ends in death or disability (11).The frequency with which ITBI is misdiagnosed and the resulting morbidity and mortality are compounded by the lack of a well-established screening test to help physicians identify children who might benefit from evaluation with cranial computed tomography (CT). We previously reported on the possible use of serum biomarkers as screening tools for infants at increased risk of missed ITBI-infants without a history of trauma and with nonspecific symptoms (12-15). We focused on three well-established and relatively brain-specific markers: neuron-specific enolase, S100B, and myelin-basic protein.Our study evaluating these markers as screening tools for ITBI in high-risk infants showed that a combination of neuronspecific enolase and myelin-basic protein was 79% sensitive and 70% specific for brain injury (14). Contrary to previous literature in adults and older children, S100B was not specific for brain injury in infants.Biomarker concentrations in our previous studies have been measured using ELISA. ELISA allows for measurement of only one biomarker at a time and requires up to 100 L of serum for each biomarker. In young children, it is difficult to collect large sample volumes and 100 L may be the entire sample.Multiplex bead...

Activation of Alpha 7 Cholinergic Nicotinic Receptors Reduce Blood–Brain Barrier Permeability following Experimental Traumatic Brain Injury

“…For example, we observed that CCI resulted in a mean plasma concentration of IL-6 of 90 pg/ml when assessed 6 h after injury. Previous studies of moderate-to-severe TBI in humans have reported that IL-6 levels increase dramatically within hours of injury, ranging from 80 to 100 pg/ml (Csuka et al, 1999;Berger et al, 2009). Although arterial/venous cytokine measurements have indicated that IL-6 and IL-10, at least in part, may be released from the injured brain into the circulation, serum IL-1␤ and TNF-␣ likely have a peripheral origin after TBI (McKeating et al, 1997;Csuka et al, 1999).…”

“…Although arterial/venous cytokine measurements have indicated that IL-6 and IL-10, at least in part, may be released from the injured brain into the circulation, serum IL-1␤ and TNF-␣ likely have a peripheral origin after TBI (McKeating et al, 1997;Csuka et al, 1999). As systemic inflammation has been implicated in a variety of neurodegenerative diseases, and is thought to exacerbate damage following CNS insults, strategies to reduce systemic inflammation may have clinical relevance (Perry, 2010;Anthony and Couch, 2014;Amor et al, 2014).…”

“…Each year in the United States, ϳ1.7 million people sustain a TBI. TBI predominately affects young men and women, the consequences of which can impair day-to-day activities and reduce quality of life (Bennett et al, 1989;Bazarian et al, 2005;Nolan, 2005;Heegaard and Biros, 2007). Unfortunately, effective treatments to reduce TBI pathology and improve outcome are currently unavailable.…”

The current state of biomarkers of mild traumatic brain injury

“…Regardless, there appears to be an association between proinflammatory proteins and poor clinical outcome in mTBI (90,94,95). A pilot study of 16 pediatric mTBI patients showed that increased concentrations of both IL-6 and MMP9 had a sensitivity of 81% and specificity of 94% for mTBI diagnosis (96). Further studies of inflammatory response molecules might yield other potential biomarkers.…”

Pediatric Neurocritical Care

“…These may have potential to act as markers of injury severity or predict outcome in patients with TBI [28][29][30]. In addition, biomarkers have been studied as a means to differentiate inflicted trauma from accidental trauma, to elucidate differences in the pathophsyiology of these injury types, and to serve as a screening tool for the diagnosis of iTBI [30][31][32][33][34][35]. These studies provide further evidence that the biochemical response to inflicted TBI may be different from noninflicted injury.…”