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Joshua W. Gatson, Cari Stebbins, Dana Mathews, Thomas S. Harris, Christopher Madden, Hunt Batjer, Ramon Diaz-Arrastia and Joseph P. Minei

Traumatic brain injury (TBI) is a major risk factor for Alzheimer’s disease. With respect to amyloid deposition, there are no published serial data regarding the deposition rate of amyloid throughout the brain after TBI. The authors conducted serial 18F-AV-45 (florbetapir F18) positron emission tomography (PET) imaging in 2 patients with severe TBI at 1, 12, and 24 months after injury. A total of 12 brain regions were surveyed for changes in amyloid levels.

Case 1 involved a 50-year-old man who experienced a severe TBI. Compared with the 1-month time point, of the 12 brain regions that were surveyed, a decrease in amyloid (as indicated by standard uptake value ratios) was only observed in the hippocampus (−16%, left; −12%, right) and caudate nucleus (−18%, left; −18%, right), suggesting that initial amyloid accumulation in the brain was cleared between time points 1 and 12 months after injury. Compared to the scan at 1 year, a greater increase in amyloid (+15%) was observed in the right hippocampus at the 24-month time point. The patient in Case 2 was a 37-year-old man who suffered severe trauma to the head and a subsequent stroke; he had poor cognitive/functional outcomes and underwent 1.5 years of rehabilitation. Due to a large infarct area on the injured side of the brain (right side), the authors focused primarily on brain regions affected within the left hemisphere. Compared with the 1-month scan, they only found an increase in brain amyloid within the left anterior putamen (+11%) at 12 months after injury. In contrast, decreased amyloid burden was detected in the left caudate nucleus (−48%), occipital cortex (−21%), and precuneus (−19%) brain regions at the 12-month time point, which is indicative of early accumulation and subsequent clearance. In comparison with 12-month values, more clearance was observed, since a reduction in amyloid was found at 24 months after trauma within the left anterior putamen (−12%) and occipital cortex (−15%). Also, by 24 months, most of the amyloid had been cleared and the patient demonstrated improved results on the Rivermead symptom questionnaire, Glasgow Outcome Scale-Extended, and Disability Rating Scale. With respect to APOE status, the patient in Case 1 had two ε3 alleles and the patient in Case 2 had one ε2 and one ε3 allele.

In comparison to the findings of the initial scan at 1 month after TBI, by 12 and 24 months after injury amyloid was cleared in some brain regions and increased in others. Serial imaging conducted here suggests that florbetapir F18 PET imaging may be useful in monitoring amyloid dynamics within specific brain regions following severe TBI and may be predictive of cognitive deficits.

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Joshua W. Gatson, Jennifer Barillas, Linda S. Hynan, Ramon Diaz-Arrastia, Steven E. Wolf and Joseph P. Minei

Object

In previous studies of traumatic brain injury (TBI), neural biomarkers of injury correlate with injury severity and predict neurological outcome. The object of this paper was to characterize neurofilament-H (NFL-H) as a predictor of injury severity in patients who have suffered mild TBI (mTBI). Thus, the authors hypothesized that phosphorylated NFL-H (pNFL-H) levels are higher in mTBI patients than in healthy controls and identify which subjects experienced a more severe injury such as skull fractures, intracranial hemorrhaging, and/or contusions as detected by CT scans.

Methods

In this prospective clinical study, blood (8 ml) was collected from subjects (n = 34) suffering from mTBI (as defined by the American Congress of Rehabilitation and Glasgow Coma Scale scores between 13 and 15) at Parkland Hospital, Dallas, Texas, on Days 1 and 3 after injury). Additional clinical findings from the CT scans were also used to categorize the TBI patients into those with and those without clinical findings on the scans (CT+ and CTgroups, respectively). The serum levels of pNFL-H were measured using the enzyme-linked immunosorbent assay.

Results

Compared with healthy controls, the mTBI patients exhibited a significant increase in the serum levels of pNFL-H on Days 1 (p = 0.00001) and 3 (p = 0.0001) after TBI. An inverse correlation was observed between pNFL-H serum levels and Glasgow Coma Scale scores, which was significant. Additionally, using receiver operating characteristic curve analysis to compare the mTBI cases with controls to determine sensitivity and specificity, an area under the curve of 100% was achieved for both (p = 0.0001 for both). pNFL-H serum levels were only significantly higher on Day 1 in mTBI patients in the CT+ group (p < 0.008) compared with the CT− group. The area under the curve (82.5%) for the CT+ group versus the CT− group was significant (p = 0.021) with a sensitivity of 87.5% and a specificity of 70%, using a cutoff of 1071 pg/ml of pNFL-H in serum.

Conclusions

This study describes the serum profile of pNFL-H in patients suffering from mTBI with and without CT findings on Days 1 and 3 after injury. These results suggest that detection of pNFL-H may be useful in determining which individuals require CT imaging to assess the severity of their injury.

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Catherine O. Anglin, Jeffrey S. Spence, Matthew A. Warner, Christopher Paliotta, Caryn Harper, Carol Moore, Ravi Sarode, Christopher Madden and Ramon Diaz-Arrastia

Object

Coagulopathy and thrombocytopenia are common after traumatic brain injury (TBI), yet transfusion thresholds for mildly to moderately abnormal ranges of international normalized ratio and platelet count remain controversial. This study evaluates associations between fresh frozen plasma (FFP) and platelet transfusions with long-term functional outcome and survival in TBI patients with moderate hemostatic laboratory abnormalities.

Methods

This study is a retrospective review of prospectively collected data of patients with mild to severe TBI. Data include patient demographics, several initial injury severity metrics, daily laboratory values, Glasgow Outcome Score- Extended (GOSE) scores, Functional Status Examination (FSE) scores, and survival to 6 months. Correlations were evaluated between these variables and transfusion of FFP, platelets, packed red blood cells (RBCs), cryoprecipitate, recombinant factor VIIa, and albumin. Ordinal regression was performed to account for potential confounding variables to further define relationships between transfusion status and long-term outcome. By analyzing collected data, mild to moderate coagulopathy was defined as an international normalized ratio 1.4–2.0, moderate thrombocytopenia as platelet count 50 × 109/L to 107 × 109/L, and moderate anemia as 21%–30% hematocrit.

Results

In patients with mild to moderate laboratory hematological abnormalities, univariate analysis shows significant correlations between poor outcome scores and FFP, platelet, or packed RBC transfusion; the volume of FFP or packed RBCs transfused also correlated with poor outcome. Several measures of initial injury and laboratory abnormalities also correlated with poor outcome. Patient age, initial Glasgow Coma Scale score, and highest recorded serum sodium were included in the ordinal regression model using backward variable selection. In the moderate coagulopathy subgroup, patients transfused with FFP were more likely to have a lower GOSE score relative to those who did not receive a transfusion (OR 5.20 [95% CI 1.72–15.73]). Patients with moderate coagulopathy who received FFP and packed RBCs were even more likely to be have a lower GOSE score (OR 7.17 [95% CI 2.12–24.12]). Moderately anemic patients who received packed RBCs alone were more likely to have a worse long-term functional outcome as determined by GOSE and FSE scores (GOSE: OR 2.41 [95% CI 1.51–3.85]; and FSE: OR 3.27 [95% CI 2.00–5.35]). No transfusion types or combinations were noted to significantly correlate with the 6-month mortality in ordinal regression.

Conclusions

In TBI patients with moderate coagulopathy, FFP transfusions alone or a combination of FFP and packed RBCs were associated with poorer long-term functional outcomes as measured by the GOSE. Red blood cell transfusions were associated with poor long-term functional outcome in TBI patients with moderate anemia. Platelet transfusion in patients with moderate thrombocytopenia was not significantly associated with outcome. Although transfusion is beneficial to many patients with severe hematological abnormalities, it is not without risk, and the indications for transfusion should be carefully considered in patients with moderate hematological abnormalities.

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Matthew A. Warner, Terence O'Keeffe, Premal Bhavsar, Rashmi Shringer, Carol Moore, Caryn Harper, Christopher J. Madden, Ravi Sarode, Larry M. Gentilello and Ramon Diaz-Arrastia

Object

In this paper, the authors' goal was to examine the relationship between transfusion and long-term functional outcomes in moderately anemic patients (lowest hematocrit [HCT] level 21–30%) with traumatic brain injury (TBI). While evidence suggests that transfusions are associated with poor hospital outcomes, no study has examined transfusions and long-term functional outcomes in this population. The preferred transfusion threshold remains controversial.

Methods

The authors performed a retrospective review of patients who were admitted with TBI between September 2005 and November 2007, extracting data such as HCT level, status of red blood cell transfusion, admission Glasgow Coma Scale (GCS) score, serum glucose, and length of hospital stay. Outcome measures assessed at 6 months were Glasgow Outcome Scale-Extended score, Functional Status Examination score, and patient death. A multivariate generalized linear model controlling for confounding variables was used to assess the association between transfusion and outcome.

Results

During the study period, 292 patients were identified, and 139 (47.6%) met the criteria for moderate anemia. Roughly half (54.7%) underwent transfusions. Univariate analyses showed significant correlations between outcome score and patient age, admission GCS score, head Abbreviated Injury Scale score, number of days with an HCT level < 30%, highest glucose level, number of days with a glucose level > 200 mg/dl, length of hospital stay, number of patients receiving a transfusion, and transfusion volume. In multivariate analysis, admission GCS score, receiving a transfusion, and transfusion volume were the only variables associated with outcome (F = 2.458, p = 0.007; F = 11.694, p = 0.001; and F = 1.991, p = 0.020, respectively). There was no association between transfusion and death.

Conclusions

Transfusions may contribute to poor long-term functional outcomes in anemic patients with TBI. Transfusion strategies should be aimed at patients with symptomatic anemia or physiological compromise, and transfusion volume should be minimized.

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Joshua Wayne Gatson, Victoria Warren, Kareem Abdelfattah, Steven Wolf, Linda S. Hynan, Carol Moore, Ramon Diaz-Arrastia, Joseph P. Minei, Christopher Madden and Jane G. Wigginton

Object

Traumatic brain injury (TBI) is known to be a risk factor for Alzheimer-like dementia. In previous studies, an increase in β-amyloid (Aβ) monomers, such as β-amyloid 42 (Aβ42), in the CSF of patients with TBI has been shown to correlate with a decrease in amyloid plaques in the brain and improved neurological outcomes. In this study, the authors hypothesized that the levels of toxic high-molecular-weight β-amyloid oligomers are increased in the brain and are detectable within the CSF of TBI patients with poor neurological outcomes.

Methods

Samples of CSF were collected from 18 patients with severe TBI (Glasgow Coma Scale Scores 3–8) and a ventriculostomy. In all cases the CSF was collected within 72 hours of injury. The CSF levels of neuron-specific enolase (NSE) and Aβ42 were measured using enzyme-linked immunosorbent assay. The levels of high-molecular-weight β-amyloid oligomers were measured using Western blot analysis.

Results

Patients with good outcomes showed an increase in the levels of CSF Aβ42 (p = 0.003). Those with bad outcomes exhibited an increase in CSF levels of β-amyloid oligomers (p = 0.009) and NSE (p = 0.001). In addition, the CSF oligomer levels correlated with the scores on the extended Glasgow Outcome Scale (r = −0.89, p = 0.0001), disability rating scale scores (r = 0.77, p = 0.005), CSF Aβ42 levels (r = −0.42, p = 0.12), and CSF NSE levels (r = 0.70, p = 0.004). Additionally, the receiver operating characteristic curve yielded an area under the curve for β-amyloid oligomers of 0.8750 ± 0.09.

Conclusions

Detection of β-amyloid oligomers may someday become a useful clinical tool for determining injury severity and neurological outcomes in patients with TBI.

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Ross C. Puffer, John K. Yue, Matthew Mesley, Julia B. Billigen, Jane Sharpless, Anita L. Fetzick, Ava Puccio, Ramon Diaz-Arrastia and David O. Okonkwo

OBJECTIVE

Following traumatic brain injury (TBI), midline shift of the brain at the level of the septum pellucidum is often caused by unilateral space-occupying lesions and is associated with increased intracranial pressure and worsened morbidity and mortality. While outcome has been studied in this population, the recovery trajectory has not been reported in a large cohort of patients with TBI. The authors sought to utilize the Citicoline Brain Injury Treatment (COBRIT) trial to analyze patient recovery over time depending on degree of midline shift at presentation.

METHODS

Patient data from the COBRIT trial were stratified into 4 groups of midline shift, and outcome measures were analyzed at 30, 90, and 180 days postinjury. A recovery trajectory analysis was performed identifying patients with outcome measures at all 3 time points to analyze the degree of recovery based on midline shift at presentation.

RESULTS

There were 892, 1169, and 895 patients with adequate outcome data at 30, 90, and 180 days, respectively. Rates of favorable outcome (Glasgow Outcome Scale–Extended [GOS-E] scores 4–8) at 6 months postinjury were 87% for patients with no midline shift, 79% for patients with 1–5 mm of shift, 64% for patients with 6–10 mm of shift, and 47% for patients with > 10 mm of shift. The mean improvement from unfavorable outcome (GOS-E scores 2 and 3) to favorable outcome (GOS-E scores 4–8) from 1 month to 6 months in all groups was 20% (range 4%–29%). The mean GOS-E score for patients in the 6- to 10-mm group crossed from unfavorable outcome (GOS-E scores 2 and 3) into favorable outcome (GOS-E scores 4–8) at 90 days, and the mean GOS-E of patients in the > 10-mm group nearly reached the threshold of favorable outcome by 180 days postinjury.

CONCLUSIONS

In this secondary analysis of the Phase 3 COBRIT trial, TBI patients with less than 10 mm of midline shift on admission head CT had significantly improved functional outcomes through 180 days after injury compared with those with greater than 10 mm of midline shift. Of note, nearly 50% of patients with > 10 mm of midline shift achieved a favorable outcome (GOS-E score 4–8) by 6 months postinjury.