Mortality in polytrauma patients with moderate to severe TBI on par with isolated TBI patients: TBI as last frontier in polytrauma patients.

BACKGROUND: Mortality caused by Traumatic Brain Injury (TBI) remains high, despite improvements in trauma and critical care. Polytrauma is naturally associated with high mortality. This study compared mortality rates between isolated TBI (ITBI) patients and polytrauma patients with TBI (PTBI) admitted to ICU to investigate if concomitant injuries lead to higher mortality amongst TBI patients. METHODS: A 3-year cohort study compared polytrauma patients with TBI (PTBI) with AIS head ≥3 (and AIS of other body regions ≥3) from a prospective collected database to isolated TBI (ITBI) patients from a retrospective collected database with AIS head ≥3 (AIS of other body regions ≤2), both admitted to a single level-I trauma center ICU. Patients <16 years of age, injury caused by asphyxiation, drowning, burns and ICU transfers from and to other hospitals were excluded. Patient demographics, shock and resuscitation parameters, multiple organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), and mortality data were collected and analyzed for group differences. RESULTS: 259 patients were included; 111 PTBI and 148 ITBI patients. The median age was 54 [33-67] years, 177 (68%) patients were male, median ISS was 26 [20-33]. Seventy-nine (31%) patients died. Patients with PTBI developed more ARDS (7% vs. 1%, p = 0.041) but had similar MODS rates (18% vs. 10%, p = 0.066). They also stayed longer on the ventilator (7 vs. 3 days, p=<0.001), longer in ICU (9 vs. 4 days, p=<0.001) and longer in hospital (24 vs. 11 days, p=<0.001). TBI was the most prevalent cause of death in polytrauma patients. Patients with PTBI showed no higher in-hospital mortality rate. Moreover, mortality rates were skewed towards ITBI patients (24% vs. 35%, p = 0.06). DISCUSSION: There was no difference in mortality rates between PTBI and ITBI patients, suggesting TBI-severity as the predominant factor for ICU mortality in an era of ever improving acute trauma care.

Diagnostic value of emergency medical services provider judgement in the identification of head injuries among trauma patients.

BACKGROUND AND PURPOSE: Previous studies have reported that many patients with a severe head injury are not transported to a higher-level trauma centre where the necessary round-the-clock neurosurgical care is available. The aim of this study was to analyse the diagnostic value of emergency medical services (EMS) provider judgement in the identification of a head injury. METHODS: In this multicentre cohort study, all trauma patients aged 16 years and over who were transported with highest priority to a trauma centre were evaluated. The diagnostic value of EMS provider judgement was determined using an Abbreviated Injury Scale score of ≥1 in the head region as reference standard. RESULTS: A total of 980 (35.4%) of the 2766 patients who were included had a head injury. EMS provider judgement (Abbreviated Injury Scale score ≥1) had a sensitivity of 67.9% and a specificity of 87.7%. In the cohort, 208 (7.5%) patients had a severe head injury. Of these, 68% were transported to a level I trauma centre. CONCLUSIONS: Identification of a head injury on-scene is challenging. EMS providers could not identify 32% of the patients with a head injury and 21% of the patients with a severe head injury. Additional education, training and a supplementary protocol with predictors of a severe head injury could help EMS providers in the identification of these patients.

Outcome in Patients with Isolated Moderate to Severe Traumatic Brain Injury.

INTRODUCTION: Traumatic brain injury (TBI) remains a major cause of death. Withdrawal of life-sustaining treatment (WLST) can be initiated if there is little anticipated chance of recovery to an acceptable quality of life. The aim of this study was firstly to investigate WLST rates in patients with moderate to severe isolated TBI and secondly to assess outcome data in the survivor group. MATERIAL AND METHODS: A retrospective cohort study was performed. Patients aged ≥ 18 years with moderate or severe isolated TBI admitted to the ICU of a single academic hospital between 2011 and 2015 were included. Exclusion criteria were isolated spinal cord injury and referrals to and from other hospitals. Gathered data included demographics, mortality, cause of death, WLST, and Glasgow Outcome Scale (GOS) score after three months. Good functional outcome was defined as GOS > 3. RESULTS: Of 367 patients, 179 patients were included after applying inclusion and exclusion criteria. 55 died during admission (33%), of whom 45 (82%) after WLST. Patients undergoing WLST were older, had worse neurological performance at presentation, and had more radiological abnormalities than patients without WLST. The decision to withdraw life-sustaining treatment was made on the day of admission in 40% of patients. In 33% of these patients, this decision was made while the patient was in the Emergency Department. 71% of survivors had a good functional outcome after three months. No patient left hospital with an unresponsive wakefulness syndrome (UWS) or suffered from UWS after three months. One patient died within three months of discharge. CONCLUSION: In-hospital mortality in isolated brain injured patients was 33%. The vast majority died after a decision to withdraw life-sustaining treatment. None of the patients were discharged with an unresponsive wakefulness syndrome.

Author Correction: Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS.

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS; n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene (ELP2). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35, and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.

Tau levels do not influence human ALS or motor neuron degeneration in the SOD1G93A mouse.

BACKGROUND: The microtubule-associated protein tau is thought to play a pivotal role in neurodegeneration. Mutations in the tau coding gene MAPT are a cause of frontotemporal dementia, and the H1/H1 genotype of MAPT, giving rise to higher tau expression levels, is associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson disease (PD). Furthermore, tau hyperphosphorylation and aggregation is a hallmark of Alzheimer disease (AD), and reducing endogenous tau has been reported to ameliorate cognitive impairment in a mouse model for AD. Tau hyperphosphorylation and aggregation have also been described in amyotrophic lateral sclerosis (ALS), both in human patients and in the mutant SOD1 mouse model for this disease. However, the precise role of tau in motor neuron degeneration remains uncertain. METHODS: The possible association between ALS and the MAPT H1/H2 polymorphism was studied in 3,540 patients with ALS and 8,753 controls. Furthermore, the role of tau in the SOD1(G93A) mouse model for ALS was studied by deleting Mapt in this model. RESULTS: The MAPT genotype of the H1/H2 polymorphism did not influence ALS susceptibility (odds ratio = 1.08 [95% confidence interval 0.99-1.18], p = 0.08) and did not affect the clinical phenotype. Lowering tau levels in the SOD1(G93A) mouse failed to delay disease onset (p = 0.302) or to increase survival (p = 0.557). CONCLUSION: These findings suggest that the H1/H2 polymorphism in MAPT is not associated with human amyotrophic lateral sclerosis, and that lowering tau levels in the mutant SOD1 mouse does not affect the motor neuron degeneration in these animals.

A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS.

BACKGROUND: Six candidate gene studies report a genetic association of DNA variants within the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). However, several other large studies, including five genome-wide association studies, have not duplicated this finding. METHODS: We conducted a meta-analysis of 10 published studies and one unpublished study of the paraoxonase locus, encompassing 4,037 ALS cases and 4,609 controls, including genome-wide association data from 2,018 ALS cases and 2,425 controls. RESULTS: The combined fixed effects odds ratio (OR) for rs662 (PON1 Q192R) was 1.09 (95% confidence interval [CI], 1.02-1.16, p = 0.01); the genotypic OR for RR homozygotes at Q192R was 1.25 (95% CI, 1.07-1.45, p = 0.0004); the combined OR for rs854560 (PON1 L55M) was 0.97 (95% CI, 0.86-1.10, p = 0.62); the OR for rs10487132 (PON2) was 1.08 (95% CI, 0.92-1.27, p = 0.35). Although the rs662 polymorphism reached a nominal level of significance, no polymorphism was significant after multiple testing correction. In the subanalysis of samples with genome-wide data from which population outliers were removed, rs662 had an OR of 1.06 (95% CI, 0.97-1.16, p = 0.22). CONCLUSIONS: In contrast to previous positive smaller studies, our genetic meta-analysis showed no significant association of amyotrophic lateral sclerosis (ALS) with the PON locus. This is the largest meta-analysis of a candidate gene in ALS to date and the first ALS meta-analysis to include data from whole genome association studies. The findings reinforce the need for much larger and more collaborative investigations of the genetic determinants of ALS.

Progranulin genetic variability contributes to amyotrophic lateral sclerosis.

OBJECTIVES: Null mutations in progranulin (PGRN) cause ubiquitin-positive frontotemporal dementia (FTD) linked to chromosome 17q21 (FTDU-17). Here we examined PGRN genetic variability in amyotrophic lateral sclerosis (ALS), a neurodegenerative motor neuron disease that overlaps with FTD at a clinical, pathologic, and epidemiologic level. METHODS: We sequenced all exons, exon-intron boundaries, and 5' and 3' regulatory regions of PGRN in a Belgian sample of 230 patients with ALS. The frequency of observed genetic variants was determined in 436 healthy control individuals. The contribution of eight frequent polymorphisms to ALS risk, onset age, and survival was assessed in an association study in the Belgian sample and a replication series of 308 Dutch patients with ALS and 345 Dutch controls. RESULTS: In patients with ALS we identified 11 mutations, 5 of which were predicted to affect PGRN protein sequence or levels (four missense mutations and one 5' regulatory variant). Moreover, common variants (rs9897526, rs34424835, and rs850713) and haplotypes were significantly associated with a reduction in age at onset and a shorter survival after onset of ALS in both the Belgian and the Dutch studies. CONCLUSION: PGRN acts as a modifier of the course of disease in patients with amyotrophic lateral sclerosis, through earlier onset and shorter survival.