The heme-hemopexin scavenging system is active in the brain, and associates with outcome after subarachnoid hemorrhage

Background and Purpose – Long-term outcome after subarachnoid hemorrhage (SAH) is potentially linked to cytotoxic heme. Free heme is bound by hemopexin (Hpx) and rapidly scavenged by CD91. We hypothesized that heme scavenging in the brain would be associated with outcome after haemorrhage. Methods - Using cerebrospinal fluid (CSF) and tissue from SAH patients and control individuals, the activity of the intracranial CD91-Hpx system was examined using enzyme-linked immunoassays, ultra-high performance liquid chromatography and immunohistochemistry. Results - In control individuals, CSF Hpx was mainly synthesized intrathecally. After SAH, CSF Hpx was high in one-third of cases, and these patients had a higher probability of delayed cerebral ischaemia and poorer neurological outcome. The intracranial CD91-Hpx system was active after SAH since CD91 positively correlated with iron deposition in brain tissue. Heme-Hpx uptake saturated rapidly after SAH, since bound heme accumulated early in the CSF. When the blood-brain barrier was compromised following SAH, serum Hpx level was lower, suggesting heme transfer to the circulation for peripheral CD91 scavenging. Conclusions - The CD91-heme-Hpx scavenging system is important after SAH and merits further study as a potential prognostic marker and therapeutic target

Haptoglobin Treatment for Aneurysmal Subarachnoid Hemorrhage: Review and Expert Consensus on Clinical Translation

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body’s first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin’s anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation

Prospective, multicentre study of external ventricular drainage-related infections in the UK and Ireland.

OBJECTIVES: External ventricular drain (EVD) insertion is a common neurosurgical procedure. EVD-related infection (ERI) is a major complication that can lead to morbidity and mortality. In this study, we aimed to establish a national ERI rate in the UK and Ireland and determine key factors influencing the infection risk. METHODS: A prospective multicentre cohort study of EVD insertions in 21 neurosurgical units was performed over 6 months. The primary outcome measure was 30-day ERI. A Cox regression model was used for multivariate analysis to calculate HR. RESULTS: A total of 495 EVD catheters were inserted into 452 patients with EVDs remaining in situ for 4700 days (median 8 days; IQR 4-13). Of the catheters inserted, 188 (38%) were antibiotic-impregnated, 161 (32.5%) were plain and 146 (29.5%) were silver-bearing. A total of 46 ERIs occurred giving an infection risk of 9.3%. Cox regression analysis demonstrated that factors independently associated with increased infection risk included duration of EVD placement for ≥8 days (HR=2.47 (1.12-5.45); p=0.03), regular sampling (daily sampling (HR=4.73 (1.28-17.42), p=0.02) and alternate day sampling (HR=5.28 (2.25-12.38); p<0.01). There was no association between catheter type or tunnelling distance and ERI. CONCLUSIONS: In the UK and Ireland, the ERI rate was 9.3% during the study period. The study demonstrated that EVDs left in situ for ≥8 days and those sampled more frequently were associated with a higher risk of infection. Importantly, the study showed no significant difference in ERI risk between different catheter types

Red Blood Cells in the Cerebrospinal Fluid Compartment After Subarachnoid Haemorrhage: Significance and Emerging Therapeutic Strategies

Subarachnoid haemorrhage (SAH) is a subtype of stroke that predominantly impacts younger individuals. It is associated with high mortality rates and can cause long-term disabilities. This review examines the contribution of the initial blood load and the dynamics of clot clearance to the pathophysiology of SAH and the risk of adverse outcomes. These outcomes include hydrocephalus and delayed cerebral ischaemia (DCI), with a particular focus on the impact of blood located in the cisternal spaces, as opposed to ventricular blood, in the development of DCI. The literature described underscores the prognostic value of haematoma characteristics, such as volume, density, and anatomical location. The limitations of traditional radiographic grading systems are discussed, compared with the more accurate volumetric quantification techniques for predicting patient prognosis. Further, the significance of red blood cells (RBCs) and their breakdown products in secondary brain injury after SAH is explored. The review presents novel interventions designed to accelerate clot clearance or mitigate the effects of toxic byproducts released from erythrolysis in the cerebrospinal fluid following SAH. In conclusion, this review offers deeper insights into the complex dynamics of SAH and discusses the potential pathways available for advancing its management

SVM Optimization for Brain Tumor Identification Using Infrared Spectroscopic Samples.

The work presented in this paper is focused on the use of spectroscopy to identify the type of tissue of human brain samples employing support vector machine classifiers. Two different spectrometers were used to acquire infrared spectroscopic signatures in the wavenumber range between 1200⁻3500 cm-1. An extensive analysis was performed to find the optimal configuration for a support vector machine classifier and determine the most relevant regions of the spectra for this particular application. The results demonstrate that the developed algorithm is robust enough to classify the infrared spectroscopic data of human brain tissue at three different discrimination levels.This work has been supported in part by the European Commission through the FP7 FET Open Programme ICT-2011.9.2, European Project HELICoiD “HypErspectral Imaging Cancer Detection” under Grant Agreement 618080. This work has been also supported in part by the Canary Islands Government through the ACIISI (Canarian Agency for Research, Innovation and the Information Society), ITHACA project “Hyperespectral identification of Brain tumors” under Grant Agreement ProID2017010164. Additionally, this work has been supported in part by the 2016 PhD Training Program for Research Staff of the University of Las Palmas de Gran Canaria. Finally, this work was completed while Samuel Ortega was beneficiary of a pre-doctoral grant given by the “Agencia Canaria de Investigacion, Innovacion y Sociedad de la Información (ACIISI)” of the “Conserjería de Economía, Industria, Comercio y Conocimiento” of the “Gobierno de Canarias”, which is part-financed by the European Social Fund (FSE) (POC 2014-2020, Eje 3 Tema Prioritario 74 (85%))

A primate-specific short GluN2A-NMDA receptor isoform is expressed in the human brain

Glutamate receptors of the N-methyl-D-aspartate (NMDA) family are coincident detectors of pre- and postsynaptic activity, allowing Ca2+ influx into neurons. These properties are central to neurological disease mechanisms and are proposed to be the basis of associative learning and memory. In addition to the well-characterised canonical GluN2A NMDAR isoform, large-scale open reading frames in human tissues had suggested the expression of a primate-specific short GluN2A isoform referred to as GluN2A-S. Here, we confirm the expression of both GluN2A transcripts in human and primate but not rodent brain tissue, and show that they are translated to two corresponding GluN2A proteins present in human brain. Furthermore, we demonstrate that recombinant GluN2A-S co-assembles with the obligatory NMDAR subunit GluN1 to form functional NMDA receptors. These findings suggest a more complex NMDAR repertoire in human brain than previously thought

Quantifying the contribution of intracranial pressure and arterial blood pressure to spontaneous tympanic membrane displacement

Objective: Although previous studies have shown associations between patient symptoms/outcomes and the spontaneous tympanic membrane displacement (spTMD) pulse amplitude, the contribution of the underlying intracranial pressure (ICP) signal to the spTMD pulse remains largely unknown. We have assessed the relative contributions of ICP and arterial blood pressure (ABP) on spTMD at different frequencies in order to determine whether spTMD contains information about the ICP above and beyond that contained in the ABP. Approach: Eleven patients, who all had invasive ICP and ABP measurements in situ, were recruited from our intensive care unit. Their spTMD was recorded and the power spectral densities of the three signals, as well as coherences between the signals, were calculated in the range 0.1–5 Hz. Simple and multiple coherences, coupled with statistical tests using surrogate data, were carried out to quantify the relative contributions of ABP and ICP to spTMD. Main results: Most power of the signals was found to predominate at respiration rate, heart rate, and their harmonics, with little outside of these frequencies. Analysis of the simple coherences found a slight preference for ICP transmission, beyond that from ABP, to the spTMD at lower frequencies (7/11 patients at respiration, 7/10 patients at respiration 1st harmonic) which is reversed at the higher frequencies (2/11 patients at heart rate and its 1st harmonic). Both ICP and ABP were found to independently contribute to the spTMD. The multiple coherence reinforced that ICP is preferentially being transmitted at respiration and respiration 1st harmonic. Significance: Both ABP and ICP contribute independently to the spTMD signal, with most power occurring at clear physiological frequencies—respiration and harmonics and heart rate and harmonics. There is information shared between the ICP and spTMD that is not present in ABP. This analysis has indicated that lower frequencies appear to favour ICP as the driver for spTMD

Pulsatile tympanic membrane displacement is associated with cognitive score in healthy subjects

To test the hypothesis that pulsing of intracranial pressure has an association with cognition, we measured cognitive score and pulsing of the tympanic membrane in 290 healthy subjects. This hypothesis was formed on the assumptions that large intracranial pressure pulses impair cognitive performance and tympanic membrane pulses reflect intracranial pressure pulses. 290 healthy subjects, aged 20–80 years, completed the Montreal Cognitive Assessment Test. Spontaneous tympanic membrane displacement during a heart cycle was measured from both ears in the sitting and supine position. We applied multiple linear regression, correcting for age, heart rate, and height, to test for an association between cognitive score and spontaneous tympanic membrane displacement. Significance was set at P < 0.0125 (Bonferroni correction.) A significant association was seen in the left supine position (p = 0.0076.) The association was not significant in the right ear supine (p = 0.28) or in either ear while sitting. Sub-domains of the cognitive assessment revealed that executive function, language and memory have been primarily responsible for this association. In conclusion, we have found that spontaneous pulses of the tympanic membrane are associated with cognitive performance and believe this reflects an association between cognitive performance and intracranial pressure pulses

Outcome Following Hemorrhage From Cranial Dural Arteriovenous Fistulae Analysis of the Multicenter International CONDOR Registry:Analysis of the Multicenter International CONDOR Registry

BACKGROUND AND PURPOSE: Dural arteriovenous fistulae can present with hemorrhage, but there remains a paucity of data regarding subsequent outcomes. We sought to use the CONDOR (Consortium for Dural Arteriovenous Fistula Outcomes Research), a multi-institutional registry, to characterize the morbidity and mortality of dural arteriovenous fistula-related hemorrhage.METHODS: A retrospective review of patients in CONDOR who presented with dural arteriovenous fistula-related hemorrhage was performed. Patient characteristics, clinical follow-up, and radiographic details were analyzed for associations with poor outcome (defined as modified Rankin Scale score ≥3).RESULTS: The CONDOR dataset yielded 262 patients with incident hemorrhage, with median follow-up of 1.4 years. Poor outcome was observed in 17.0% (95% CI, 12.3%-21.7%) at follow-up, including a 3.6% (95% CI, 1.3%-6.0%) mortality. Age and anticoagulant use were associated with poor outcome on multivariable analysis (odds ratio, 1.04, odds ratio, 5.1 respectively). Subtype of hemorrhage and venous shunting pattern of the lesion did not affect outcome significantly.CONCLUSIONS: Within the CONDOR registry, dural arteriovenous fistula-related hemorrhage was associated with a relatively lower morbidity and mortality than published outcomes from other arterialized cerebrovascular lesions but still at clinically consequential rates.</p