Jason A. Demery

Factors moderating neuropsychological outcomes following mild traumatic brain injury: A meta-analysis

There continues to be debate about the long-term neuropsychological impact of mild traumatic brain injury (MTBI). A meta-analysis of the relevant literature was conducted to determine the impact of MTBI across nine cognitive domains. The analysis was based on 39 studies involving 1463 cases of MTBI and 1191 control cases. The overall effect of MTBI on neuropsychological functioning was moderate (d = .54). However, findings were moderated by cognitive domain, time since injury, patient characteristics, and sampling methods. Acute effects (less than 3 months postinjury) of MTBI were greatest for delayed memory and fluency (d = 1.03 and .89, respectively). In unselected or prospective samples, the overall analysis revealed no residual neuropsychological impairment by 3 months postinjury (d = .04). In contrast, clinic-based samples and samples including participants in litigation were associated with greater cognitive sequelae of MTBI (d = .74 and .78, respectively at 3 months or greater). Indeed, litigation was associated with stable or worsening of cognitive functioning over time. The implications and limitations of these findings are discussed.

Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury

Objective:Ubiquitin C-terminal hydrolase (UCH-L1), also called neuronal-specific protein gene product (PGP 9.3), is highly abundant in neurons. To assess the reliability of UCH-L1 as a potential biomarker for traumatic brain injury (TBI) this study compared cerebrospinal fluid (CSF) levels of UCH-L1 from adult patients with severe TBI to uninjured controls; and examined the relationship between levels with severity of injury, complications and functional outcome. Design:This study was designed as prospective case control study. Patients:This study enrolled 66 patients, 41 with severe TBI, defined by a Glasgow coma scale (GCS) score of ≤8, who underwent intraventricular intracranial pressure monitoring and 25 controls without TBI requiring CSF drainage for other medical reasons. Setting:Two hospital system level I trauma centers. Measurements and Main Results:Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, 120, 144, and 168 hrs following TBI and analyzed for UCH-L1. Injury severity was assessed by the GCS score, Marshall Classification on computed tomography and a complicated postinjury course. Mortality was assessed at 6 wks and long-term outcome was assessed using the Glasgow outcome score 6 months after injury. TBI patients had significantly elevated CSF levels of UCH-L1 at each time point after injury compared to uninjured controls. Overall mean levels of UCH-L1 in TBI patients was 44.2 ng/mL (±7.9) compared with 2.7 ng/mL (±0.7) in controls (p <.001). There were significantly higher levels of UCH-L1 in patients with a lower GCS score at 24 hrs, in those with postinjury complications, in those with 6-wk mortality, and in those with a poor 6-month dichotomized Glasgow outcome score. Conclusions:These data suggest that this novel biomarker has the potential to determine injury severity in TBI patients. Further studies are needed to validate these findings in a larger sample.

Elevated Levels of Serum Glial Fibrillary Acidic Protein Breakdown Products in Mild and Moderate Traumatic Brain Injury Are Associated With Intracranial Lesions and Neurosurgical Intervention

STUDY OBJECTIVE This study examines whether serum levels of glial fibrillary acidic protein breakdown products (GFAP-BDP) are elevated in patients with mild and moderate traumatic brain injury compared with controls and whether they are associated with traumatic intracranial lesions on computed tomography (CT) scan (positive CT result) and with having a neurosurgical intervention. METHODS This prospective cohort study enrolled adult patients presenting to 3 Level I trauma centers after blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale (GCS) score of 9 to 15. Control groups included normal uninjured controls and trauma controls presenting to the emergency department with orthopedic injuries or a motor vehicle crash without traumatic brain injury. Blood samples were obtained in all patients within 4 hours of injury and measured by enzyme-linked immunosorbent assay for GFAP-BDP (nanograms/milliliter). RESULTS Of the 307 patients enrolled, 108 were patients with traumatic brain injury (97 with GCS score 13 to 15 and 11 with GCS score 9 to 12) and 199 were controls (176 normal controls and 16 motor vehicle crash controls and 7 orthopedic controls). Receiver operating characteristic curves demonstrated that early GFAP-BDP levels were able to distinguish patients with traumatic brain injury from uninjured controls with an area under the curve of 0.90 (95% confidence interval [CI] 0.86 to 0.94) and differentiated traumatic brain injury with a GCS score of 15 with an area under the curve of 0.88 (95% CI 0.82 to 0.93). Thirty-two patients with traumatic brain injury (30%) had lesions on CT. The area under these curves for discriminating patients with CT lesions versus those without CT lesions was 0.79 (95% CI 0.69 to 0.89). Moreover, the receiver operating characteristic curve for distinguishing neurosurgical intervention from no neurosurgical intervention yielded an area under the curve of 0.87 (95% CI 0.77 to 0.96). CONCLUSION GFAP-BDP is detectable in serum within an hour of injury and is associated with measures of injury severity, including the GCS score, CT lesions, and neurosurgical intervention. Further study is required to validate these findings before clinical application.

Parametric manipulation of working memory load in traumatic brain injury: behavioral and neural correlates.

Traumatic brain injury (TBI) is often associated with enduring impairments in high-level cognitive functioning, including working memory (WM). We examined WM function in predominantly chronic patients with mild, moderate and severe TBI and healthy comparison subjects behaviorally and, in a small subset of moderate-to-severe TBI patients, with event-related functional magnetic resonance imaging (fMRI), using a visual n-back task that parametrically varied WM load. TBI patients showed severity-dependent and load-related WM deficits in performance accuracy, but not reaction time. Performance of mild TBI patients did not differ from controls; patients with moderate and severe TBI were impaired, relative to controls and mild TBI patients, but only at higher WM-load levels. fMRI results show that TBI patients exhibit altered patterns of activation in a number of WM-related brain regions, including the dorsolateral prefrontal cortex and Brocas area. Examination of the pattern of behavioral responding and the temporal course of activations suggests that WM deficits in moderate-to-severe TBI are due to associative or strategic aspects of WM, and not impairments in active maintenance of stimulus representations. Overall, results demonstrate that individuals with moderate-to-severe TBI exhibit WM deficits that are associated with dysfunction within a distributed network of brain regions that support verbally mediated WM.

Serum levels of ubiquitin C-terminal hydrolase distinguish mild traumatic brain injury from trauma controls and are elevated in mild and moderate traumatic brain injury patients with intracranial lesions and neurosurgical intervention.

BACKGROUND: This study compared early serum levels of ubiquitin C-terminal hydrolase (UCH-L1) from patients with mild and moderate traumatic brain injury (TBI) with uninjured and injured controls and examined their association with traumatic intracranial lesions on computed tomography (CT) scan (CT positive) and the need for neurosurgical intervention (NSI). METHODS: This prospective cohort study enrolled adult patients presenting to three tertiary care Level I trauma centers after blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale (GCS) score 9 to 15. Control groups included normal uninjured controls and nonhead injured trauma controls presenting to the emergency department with orthopedic injuries or motor vehicle crash without TBI. Blood samples were obtained in all trauma patients within 4 hours of injury and measured by enzyme-linked immunosorbent assay for UCH-L1 (ng/mL ± standard error of the mean). RESULTS: There were 295 patients enrolled, 96 TBI patients (86 with GCS score 13–15 and 10 with GCS score 9–12), and 199 controls (176 uninjured, 16 motor vehicle crash controls, and 7 orthopedic controls). The AUC for distinguishing TBI from uninjured controls was 0.87 (95% confidence interval [CI], 0.82–0.92) and for distinguishing those TBIs with GCS score 15 from controls was AUC 0.87 (95% CI, 0.81–0.93). Mean UCH-L1 levels in patients with CT negative versus CT positive were 0.620 (±0.254) and 1.618 (±0.474), respectively (p < 0.001), and the AUC was 0.73 (95% CI, 0.62–0.84). For patients without and with NSI, levels were 0.627 (0.218) versus 2.568 (0.854; p < 0.001), and the AUC was 0.85 (95% CI, 0.76–0.94). CONCLUSION: UCH-L1 is detectable in serum within an hour of injury and is associated with measures of injury severity including the GCS score, CT lesions, and NSI. Further study is required to validate these findings before clinical application. LEVEL OF EVIDENCE: II, prognostic study.

αII-Spectrin Breakdown Product Cerebrospinal Fluid Exposure Metrics Suggest Differences in Cellular Injury Mechanisms after Severe Traumatic Brain Injury

Traumatic brain injury (TBI) produces alphaII-spectrin breakdown products (SBDPs) that are potential biomarkers for TBI. To further understand these biomarkers, the present study examined (1) the exposure and kinetic characteristics of SBDPs in cerebrospinal fluid (CSF) of adults with severe TBI, and (2) the relationship between these exposure and kinetic metrics and severity of injury. This clinical database study analyzed CSF concentrations of 150-, 145-, and 120-kDa SBDPs in 38 severe TBI patients. Area under the curve (AUC), mean residence time (MRT), maximum concentration (C(max)), time to maximum concentration (T(max)), and half-life (t(1/2)) were determined for each SBDP. Markers of calpain proteolysis (SBDP150 and SBDP145) had a greater median AUC and C(max) and a shorter MRT than SBDP120, produced by caspase-3 proteolysis in the CSF in TBI patients ( p < 0.001). AUC and MRT for SBDP150 and SBDP15 were significantly greater in patients with worse Glasgow Coma Scale (GCS) scores at 24 h after injury compared to those whose GCS scores improved (AUC p=0.013, MRT p=0.001; AUC p=0.009, MRT p=0.021, respectively). A positive correlation was found between patients with longer elevations in intracranial pressure (ICP) measurements of 25mmHg or higher and those with a greater AUC and MRT for all three biomarkers. This is the first study to show that the biomarkers of proteolysis differentially associated with calpain and caspase-3 activity have distinct CSF exposure profiles following TBI that suggest a prominent role for calpain activity. Further studies are being conducted to determine if exposure and kinetic metrics for biofluid-based biomarkers can predict clinical outcome.

Effects of acute injury characteristics on neuropsychological status and vocational outcome following mild traumatic brain injury

Despite recent attempts to define acute injury characteristics of mild traumatic brain injury (MTBI), neuropsychological outcome is often unpredictable. One hundred MTBI cases were prospectively collected, which were consecutive referrals to a concussion clinic, and the roles of various acute neurologic variables were examined in relation to neuropsychological status and vocational outcome. Significant differences were found between subgroups of patients classified by (1) mechanism of injury (i.e. acceleration/deceleration trauma in which the head strikes an object (HSO) versus acceleration/deceleration trauma in which the head does not strike an object (HNSO) versus trauma in which an object strikes the head (OSH), and (2) type of injury (i.e. motor vehicle collision, fall, assault, motor vehicle-pedestrian collision, falling object, sports/recreation). There was no difference, with respect to neuropsychological status or vocational outcome, between patients who had positive findings on computerized tomography (CT) versus those who were CT negative. Additionally, there was no difference between patients who had suffered brief loss of consciousness (LOC) and those without LOC. These findings suggest that selective acute injury characteristics may be used to classify subtypes of MTBI patients.

GFAP out-performs S100β in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions.

Both glial fibrillary acidic protein (GFAP) and S100β are found in glial cells and are released into serum following a traumatic brain injury (TBI), however, the clinical utility of S100β as a biomarker has been questioned because of its release from bone. This study examined the ability of GFAP and S100β to detect intracranial lesions on computed tomography (CT) in trauma patients and also assessed biomarker performance in patients with fractures and extracranial injuries on head CT. This prospective cohort study enrolled a convenience sample of adult trauma patients at a Level I trauma center with and without mild or moderate traumatic brain injury (MMTBI). Serum samples were obtained within 4 h of injury. The primary outcome was the presence of traumatic intracranial lesions on CT scan. There were 397 general trauma patients enrolled: 209 (53%) had a MMTBI and 188 (47%) had trauma without MMTBI. Of the 262 patients with a head CT, 20 (8%) had intracranial lesions. There were 137 (35%) trauma patients who sustained extracranial fractures below the head to the torso and extremities. Levels of S100β were significantly higher in patients with fractures, compared with those without fractures (p<0.001) whether MMTBI was present or not. However, GFAP levels were not significantly affected by the presence of fractures (p>0.05). The area under the receiver operating characteristics curve (AUC) for predicting intracranial lesions on CT for GFAP was 0.84 (0.73-0.95) and for S100β was 0.78 (0.67-0.89). However, in the presence of extracranial fractures, the AUC for GFAP increased to 0.93 (0.86-1.00) and for S100β decreased to 0.75 (0.61-0.88). In a general trauma population, GFAP out-performed S100β in detecting intracranial CT lesions, particularly in the setting of extracranial fractures.

Cognitive control in closed head injury: context maintenance dysfunction or prepotent response inhibition deficit?

The authors contrasted 2 potential explanations for the cognitive control deficits observed in closed head injury (CHI): a prepotent response inhibition deficit or a deficit in context maintenance, defined as the guidance of appropriate responding by task-relevant information. Healthy and CHI participants performed the traditional card Stroop task and a single-trial Stroop task sensitive to context maintenance deficits. As predicted by a context maintenance deficit, moderate to severe CHI participants showed higher error rates in the single-trial Stroop task only, and only when task instructions had to be maintained over a long delay. Moreover, context maintenance impairment and generalized slowing were both related to reports of daily functioning in CHI participants. Thus, context maintenance could be a useful framework for characterizing cognitive control deficits in CHI.

Profound Amnesia and Confabulation Following Traumatic Brain Injury

Amnesia and confabulation may persist following acute aneurysmal hemorrhage of the anterior communicating artery, chronic alcoholic Korsakoff’s syndrome, and late-stage dementia of the Alzheimer type. However, there is a paucity of information regarding the persistence of these symptoms following traumatic brain injury. We present the case of JL, a 43-year-old male with persistent and severe anterograde amnesia for verbal and visual information with co-occurring provoked confabulation which persists well into the chronic phase of recovery after a severe traumatic brain injury. Neuropsychological testing at 7 weeks post-injury demonstrated severe anterograde amnesia with co-occurring confabulation. Follow-up testing at 9.5 months post-injury showed persistent and severe anterograde amnesia and provoked confabulation despite superior non-verbal intelligence and above average attentional and perceptual abilities. Late computed tomography showed chronic hypodense regions in the temporal lobes, bilaterally (L > R), and in the region of the left ventrolateral frontal lobe. This case demonstrates that anterograde amnesia and provoked confabulation may persist long after the acute phase of recovery after traumatic brain injury, and also supports previous research which asserts that medial temporal lobe damage must be accompanied by ventral frontal lobe pathology to produce the amnestic-confabulatory syndrome.