Study protocol for investigating the clinical performance of an automated blood test for glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 blood concentrations in elderly patients with mild traumatic BRAIN Injury and reference values (BRAINI-2 Elderly European study): a prospective multicentre observational study

Computed tomography; Neurosurgery; Trauma managementTomografia computaritzada; Neurocirurgia; Gestió del traumaTomografía computarizada; Neurocirugía; Gestión del traumaIntroduction Two blood brain-derived biomarkers, glial fibrillar acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), can rule out intracranial lesions in patients with mild traumatic brain injury (mTBI) when assessed within the first 12 hours. Most elderly patients were excluded from previous studies due to comorbidities. Biomarker use in elderly population could be affected by increased basal levels. This study will assess the performance of an automated test for measuring serum GFAP and UCH-L1 in elderly patients to predict the absence of intracranial lesions on head CT scans after mTBI, and determine both biomarkers reference values in a non-TBI elderly population. Methods and analysis This is a prospective multicentre observational study on elderly patients (≥65 years) that will be performed in Spain, France and Germany. Two patient groups will be included in two independent substudies. (1) A cohort of 2370 elderly patients (1185<80 years and 1185≥80 years; BRAINI2-ELDERLY DIAGNOSTIC AND PROGNOSTIC STUDY) with mTBI and a brain CT scan that will undergo blood sampling within 12 hours after mTBI. The primary outcome measure is the diagnostic performance of GFAP and UCH-L1 measured using an automated assay for discriminating between patients with positive and negative findings on brain CT scans. Secondary outcome measures include the performance of both biomarkers in predicting early (1 week) and midterm (3 months) neurological status and quality of life after trauma. (2) A cohort of 480 elderly reference participants (BRAINI2-ELDERLY REFERENCE STUDY) in whom reference values for GFAP and UCHL1 will be determined. Ethics and dissemination Ethical approval was obtained from the Institutional Review Boards of Hospital 12 de Octubre in Spain (Re#22/027) and Southeast VI (Clermont Ferrand Hospital) (Re# 22.01782.000095) in France. The study’s results will be presented at scientific meetings and published in peer-review publications.This study was supported by a grant from the European Institute of Innovation and Technology (EIT) Health (BP 2022–2024). EIT Health is supported by EIT, a body of the European Union. BioMérieux is responsible for the development and manufacturing of the VIDAS GFAP and VIDAS UCH-L1 assays. BioMérieux will provide in-kind support to this study by supplying the assays for measuring UCH–L1 and GFAP necessary for this study

Diagnosis and treatment of Chiari malformation type 1 in children: the International Consensus Document

Malformació de Chiari 1; Nens; SiringomieliaMalformación de Chiari 1; Niños; SiringomieliaChiari 1 malformation; Children; SyringomyeliaBackground Chiari malformation type 1 (CM1) is a rare condition where agreed classification and treatment are still missing. The goal of this study is to achieve a consensus on the diagnosis and treatment of CM1 in children. Methods A multidisciplinary panel formulated 57 provisional statements based on a review of the literature. Thirty-four international experts (IE) participated in a Delphi study by independently rating each statement on a 4-point Likert scale (“strongly disagree,” “disagree,” “agree,” “strongly agree”). Statements that were endorsed (“agree” or “strongly agree”) by < 75% of raters were re-formulated, or new statements were added, and another Delphi round followed (up to a maximum of three). Results Thirty-five IE were contacted and 34 agreed to participate. A consensus was reached on 30/57 statements (52.6%) after round 1. Three statements were added, and one removed. After round 2, agreement was reached on 56/59 statements (94.9%). Finally, after round 3, which took place during the 2019 Chiari Consensus Conference (Milan, Italy), agreement was reached on 58/59 statements (98.3%) about four main sections (Definition and Classification, Planning, Surgery, Isolated Syringomyelia). Only one statement did not gain a consensus, which is the “definition of radiological failure 24 month post-surgery.” Conclusions The consensus document consists of 58 statements (24 on diagnosis, 34 on treatment), serving clinicians and researchers following children with CM1. There is a clear need for establishing an international network and registry and to promote collaborative studies to increase the evidence base and optimize the long-term care of this patient population.Open access funding provided by Università Cattolica del Sacro Cuore within the CRUI-CARE Agreement

Effect of a Multistrain Probiotic on Cognitive Function and Risk of Falls in Patients With Cirrhosis: A Randomized Trial.

Cirrhosis; Probiotic; Cognitive functionCirrosis; Probiòtic; Funció cognitivaCirrosis; Probiótico; Función cognitivaProbiotics can modulate gut microbiota, intestinal permeability, and immune response and could therefore improve cognitive dysfunction and help avoid potential consequences, such as falls, in patients with cirrhosis. The aim of this study was to evaluate the effect of a multistrain probiotic on cognitive function, risk of falls, and inflammatory response in patients with cirrhosis. Consecutive outpatients with cirrhosis and cognitive dysfunction (defined by a Psychometric Hepatic Encephalopathy Score [PHES] < -4) and/or falls in the previous year were randomized to receive either a sachet of a high-concentration multistrain probiotic containing 450 billion bacteria twice daily for 12 weeks or placebo. We evaluated the changes in cognitive function (PHES); risk of falls (Timed Up and Go [TUG] test, gait speed, and incidence of falls); systemic inflammatory response; neutrophil oxidative burst; intestinal barrier integrity (serum fatty acid-binding protein 6 [FABP-6] and 2 [FABP-2] and zonulin and urinary claudin-3); bacterial translocation (lipopolysaccharide-binding protein [LBP]); and fecal microbiota. Thirty-six patients were included. Patients treated with the probiotic (n = 18) showed an improvement in the PHES (P = 0.006), TUG time (P = 0.015) and gait speed (P = 0.02), and a trend toward a lower incidence of falls during follow-up (0% compared with 22.2% in the placebo group [n = 18]; P = 0.10). In the probiotic group, we observed a decrease in C-reactive protein (P = 0.01), tumor necrosis factor alpha (P = 0.01), FABP-6 (P = 0.009), and claudin-3 (P = 0.002), and an increase in poststimulation neutrophil oxidative burst (P = 0.002). Conclusion: The multistrain probiotic improved cognitive function, risk of falls, and inflammatory response in patients with cirrhosis and cognitive dysfunction and/or previous falls

Rare functional genetic variants in COL7A1, COL6A5, COL1A2 and COL5A2 frequently occur in Chiari Malformation Type 1

Seqüenciació de gens; Genòmica; Imatges per ressonància magnèticaSecuenciación de genes; Genómica; Imágenes por resonancia magnéticaGene sequencing; Genomics; Magnetic resonance imagingChiari Malformation Type 1 (CM-1) is characterized by herniation of the cerebellar tonsils below the foramen magnum and the presence of headaches and other neurologic symptoms. Cranial bone constriction is suspected to be the most common biologic mechanism leading to CM-1. However, other mechanisms may also contribute, particularly in the presence of connective tissue disorders (CTDs), such as Ehlers Danlos Syndrome (EDS). Accumulating data suggest CM-1 with connective tissue disorders (CTD+) may have a different patho-mechanism and different genetic risk factors than CM-1 without CTDs (CTD-). To identify CM-1 genetic risk variants, we performed whole exome sequencing on a single large, multiplex family from Spain and targeted sequencing on a cohort of 186 unrelated adult, Caucasian females with CM-1. Targeted sequencing captured the coding regions of 21 CM-1 and EDS candidate genes, including two genes identified in the Spanish family. Using gene burden analysis, we compared the frequency of rare, functional variants detected in CM-1 cases versus publically available ethnically-matched controls from gnomAD. A secondary analysis compared the presence of rare variants in these genes between CTD+ and CTD- CM-1 cases. In the Spanish family, rare variants co-segregated with CM-1 in COL6A5, ADGRB3 and DST. A variant in COL7A1 was present in affected and unaffected family members. In the targeted sequencing analysis, rare variants in six genes (COL7A1, COL5A2, COL6A5, COL1A2, VEGFB, FLT1) were significantly more frequent in CM-1 cases compared to public controls. In total, 47% of CM-1 cases presented with rare variants in at least one of the four significant collagen genes and 10% of cases harbored variants in multiple significant collagen genes. Moreover, 26% of CM-1 cases presented with rare variants in the COL6A5 gene. We also identified two genes (COL7A1, COL3A1) for which the burden of rare variants differed significantly between CTD+ and CTD- CM-1 cases. A higher percentage of CTD+ patients had variants in COL7A1 compared to CTD+ patients, while CTD+ patients had fewer rare variants in COL3A1 than did CTD- patients. In summary, rare variants in several collagen genes are particularly frequent in CM-1 cases and those in COL6A5 co-segregated with CM-1 in a Spanish multiplex family. COL6A5 has been previously associated with musculoskeletal phenotypes, but this is the first association with CM-1. Our findings underscore the contribution of rare genetic variants in collagen genes to CM-1, and suggest that CM-1 in the presence and absence of CTD symptoms is driven by different genes.This work was supported by a grant from Conquer Chiari to AAK. Collection of the Chiari1000 study participants utilized in this study was supported by a grant from Conquer Chiari to FL at University of Akron. Collection of the Duke study participants utilized in this study was supported by a grant from the National Institutes of Health (NS063273). A.U. was the recipient of a Postdoctoral Fellowship from Fundación Ramón Areces (Spain). RL is the Executive Director of Conquer Chiari which provided some of the funding for this work. For the manuscript, he assisted with revising and editing the manuscript. The funders did have a role in study design, but had no role in data collection and analysis, decision to publish, or preparation of the manuscript

Effects of Albumin on Survival after a Hepatic Encephalopathy Episode: Randomized Double-Blind Trial and Meta-Analysis

Albúmina; Assaig clínic; MetanàlisiAlbumin; Clinical trial; Meta-analysisAlbúmina; Ensayo clínico; MetaanálisisNo therapies have been proven to increase survival after a hepatic encephalopathy (HE) episode. We hypothesize that two doses of albumin could improve 90-day survival rates after a HE episode. Methods: (1) A randomized double-blind, placebo-controlled trial (BETA) was conducted in 12 hospitals. The effect of albumin (1.5 g/kg at baseline and 1 g/kg on day 3) on 90-day survival rates after a HE episode grade II or higher was evaluated. (2) A meta-analysis of individual patient’s data for survival including two clinical trials (BETA and ALFAE) was performed. Results: In total, 82 patients were included. Albumin failed to increase the 90-day transplant-free survival (91.9% vs. 80.5%, p = 0.3). A competing risk analysis was performed, observing a 90-day cumulative incidence of death of 9% in the albumin group vs. 20% in the placebo (p = 0.1). The meta-analysis showed a benefit in the albumin group, with a lower rate of clinical events (death or liver transplant) than patients in the placebo (HR, 0.44; 95% CI, 0.21–0.82), when analyzed by a competing risk analysis (90-days mortality rate of 11% in the albumin group vs. 30% in the placebo, p = 0.02). Conclusions: Repeated doses of albumin might be beneficial for patient’s survival as an add-on therapy after an HE episode, but an adequately powered trial is needed.This work was supported by grants ICI14/00352 and PI/18/00947 from Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (ERDF/ESF, “Investing in your future”—Una manera de hacer Europa). MVC and MST are both recipients of Juan Rodes grants from ISCIII. JG is a recipient of a research intensification grant from the ISCIII. CIBERehd is supported by ISCIII. ACS is a recipient of the Rio Hortega grant from ISCIII. The work was independent of all funding

The Sport Concussion Assessment Tool (SCAT2) for evaluating civilian mild traumatic brain injury

Post-concussion symptoms; SCAT2; Head injurySíntomas posteriores a la conmoción cerebral; SCAT2; Lesión cranealSímptomes posteriors a la commoció cerebral; SCAT2; Lesió cranialSelf-report measures, particularly symptom inventories, are critical tools for identifying patients with persistent post-concussion symptoms and their follow-up. Unlike in military or sports-related assessment, in general civilian settings pre-injury levels of concussion-like symptoms are lacking. Normative data are available in adolescent and college populations, but no reference data exist to guide clinical adult explorations. The purpose of this study was to use the second edition of the Sport Concussion Assessment Tool (SCAT2) to profile a cohort of 60 healthy community volunteers who had not sustained a head injury. Participating volunteers underwent MRI scanning and were evaluated with the Hospital Anxiety and Depression Scale (HADS). Participants reported a median of 3 concussion-like symptoms and the 97.5 percentile score was found at 10.5 symptoms, out of a total of 22. The median severity score was 4.9 points, and 28.9 was the upper limit of the reference interval. Only 10 participants (16.7%) did not endorse any symptom. The most frequently endorsed symptom was feeling difficulty in concentrating, with 41.7% of the sample reporting it. Age, sex and general distress, anxiety and depressive symptoms were not associated with concussion-like symptoms. Our data yielded elevated cut-offs scores for both the number of symptoms and the symptom severity. In conclusion, postconcussive-like symptoms are frequent in the general non-concussed adult population and it should be taken into account in any future models developed for screening patients at risk of developing physical, cognitive, and psychological complaints following mild traumatic injury.UNINN is supported by a Grant from the Generalitat de Catalunya (SGR 2014-844, http://agaur.gencat.cat). This work has been supported in part by the Fondo de Investigacion Sanitaria (Instituto de Salud Carlos III, https://portalfis.isciii.es) with grants FIS PI11/00700 (J.S.) and grant FIS PI13/02397 (M.A.P.), which were co-financed by the European Regional Development Fund (ERDF). A.R. was a recipient of a pre-doctoral grant from the Fundacio Institut de Recerca VHIR (PRED-VHIR-2012-26, http://en.vhir.org)

Transcranial optical monitoring for detecting intracranial pressure alterations in children with benign external hydrocephalus: a proof-of-concept study

Hydrocephalus; Optical techniques; PathophysiologyHidrocefalia; Técnicas ópticas; FisiopatologíaHidrocefàlia; Tècniques òptiques; FisiopatologiaSignificance Benign external hydrocephalus (BEH) is considered a self-limiting pathology with a good prognosis. However, some children present a pathological intracranial pressure (ICP) characterized by quantitative and qualitative alterations (the so-called B-waves) that can lead to neurological sequelae. Aim Our purpose was to evaluate whether there were cerebral hemodynamic changes associated with ICP B-waves that could be evaluated with noninvasive neuromonitoring. Approach We recruited eleven patients (median age 16 months, range 7 to 55 months) with BEH and an unfavorable evolution requiring ICP monitoring. Bedside, nocturnal monitoring using near-infrared time-resolved and diffuse correlation spectroscopies synchronized to the clinical monitoring was performed. Results By focusing on the timing of different ICP patterns that were identified manually by clinicians, we detected significant tissue oxygen saturation (StO2) changes (p = 0.002) and blood flow index (BFI) variability (p = 0.005) between regular and high-amplitude B-wave patterns. A blinded analysis looking for analogs of ICP patterns in BFI time traces achieved 90% sensitivity in identifying B-waves and 76% specificity in detecting the regular patterns. Conclusions We revealed the presence of StO2 and BFI variations—detectable with optical techniques—during ICP B-waves in BEH children. Finally, the feasibility of detecting ICP B-waves in hemodynamic time traces obtained noninvasively was shown.This work was realized with the support of the Department of Cirugía and Ciencias Morfológicas of the Universitat Autònoma de Barcelona. The work was supported by the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie (Grant No. 675332) (BitMap: brain injury and trauma monitoring using advanced photonics) and the European Union’s Horizon 2020 Research and Innovation Program [Grant No. 101017113 (TinyBrains) and Grant No. 101016087 (VASCOVID)]; Fondo de Investigación Sanitaria (Instituto de Salud Carlos III) (Grant No. PI18/00468); Fundació CELLEX Barcelona, Fundació Mir Puig, Agencia Estatal de Investigación (PHOTOMETABO, Grant No. PID2019106481RBC31); the “Severo Ochoa” Program for Centers of Excelence in R&D (Grant No. CEX2019-000910-S); the Obra social “La Caixa” Foundation (LlumMedBcn), Generalitat de Catalunya (CERCA, AGAUR-2017-SGR-1380, RIS3CAT-001-P-001682 CECH), FEDER EC and LASERLAB EUROPE V (EC H2020 No. 871124); KidsBrainIT (ERANET NEURON); Fundació La Marató de TV3 (Grant Nos. 201724.31 and 201709.31)

Cerebrospinal fluid markers before and after shunting in patients with secondary and idiopathic normal pressure hydrocephalus

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to explore biochemical changes in the cerebrospinal fluid (CSF) induced by shunt surgery and the relationship between these changes and clinical improvement.</p> <p>Methods</p> <p>We measured clinical symptoms and analysed lumbar CSF for protein content, neurodegeneration and neurotransmission markers in patients with secondary (SNPH, n = 17) and idiopathic NPH (INPH, n = 18) before and 3 months after shunt surgery. Patients were divided into groups according to whether or not there was improvement in clinical symptoms after surgery.</p> <p>Results</p> <p>Preoperatively, the only pathological findings were elevated neurofilament protein (NFL), significantly more so in the SNPH patients than in the INPH patients, and elevated albumin content. Higher levels of NFL correlated with worse gait, balance, wakefulness and neuropsychological performance. Preoperatively, no differences were seen in any of the CSF biomarkers between patients that improved after surgery and those that did not improve. Postoperatively, a greater improvement in gait and balance performance correlated with a more pronounced reduction in NFL. Levels of albumin, albumin ratio, neuropeptide Y, vasoactive intestinal peptide and ganglioside GD3 increased significantly after shunting in both groups. In addition, Gamma amino butyric acid increased significantly in SNPH and tau in INPH.</p> <p>Conclusion</p> <p>We conclude that a number of biochemical changes occur after shunt surgery, but there are no marked differences between the SNPH and INPH patients. The results indicate that NFL may be a marker that can predict a surgically reversible state in NPH.</p

In vivo monitoring of neuronal loss in traumatic brain injury: a microdialysis study

Traumatic brain injury causes diffuse axonal injury and loss of cortical neurons. These features are well recognized histologically, but their in vivo monitoring remains challenging. In vivo cortical microdialysis samples the extracellular fluid adjacent to neurons and axons. Here, we describe a novel neuronal proteolytic pathway and demonstrate the exclusive neuro-axonal expression of Pavlov’s enterokinase. Enterokinase is membrane bound and cleaves the neurofilament heavy chain at positions 476 and 986. Using a 100 kDa microdialysis cut-off membrane the two proteolytic breakdown products, extracellular fluid neurofilament heavy chains NfH476−986 and NfH476−1026, can be quantified with a relative recovery of 20%. In a prospective clinical in vivo study, we included 10 patients with traumatic brain injury with a median Glasgow Coma Score of 9, providing 640 cortical extracellular fluid samples for longitudinal data analysis. Following high-velocity impact traumatic brain injury, microdialysate extracellular fluid neurofilament heavy chain levels were significantly higher (6.18 ± 2.94 ng/ml) and detectable for longer (>4 days) compared with traumatic brain injury secondary to falls (0.84 ± 1.77 ng/ml, <2 days). During the initial 16 h following traumatic brain injury, strong correlations were found between extracellular fluid neurofilament heavy chain levels and physiological parameters (systemic blood pressure, anaerobic cerebral metabolism, excessive brain tissue oxygenation, elevated brain temperature). Finally, extracellular fluid neurofilament heavy chain levels were of prognostic value, predicting mortality with an odds ratio of 7.68 (confidence interval 2.15–27.46, P = 0.001). In conclusion, this study describes the discovery of Pavlov’s enterokinase in the human brain, a novel neuronal proteolytic pathway that gives rise to specific protein biomarkers (NfH476−986 and NfH476−1026) applicable to in vivo monitoring of diffuse axonal injury and neuronal loss in traumatic brain injury