Link between both infratentorial and supratentorial intracranial pressure burdens and final outcome in patients with infratentorial brain injury.

OBJECTIVE: Increased intracranial pressure (ICP) is most likely not being transmitted uniformly within the cranium. The ICP profiles in the supra- and infratentorial compartments remain largely unclear. Increased ICP in the cerebellum, however, is insufficiently captured by supratentorial ICP (ICPsup) monitoring due to compartmentalization through the tentorium. The authors hypothesized that additional infratentorial ICP (ICPinf) monitoring can be clinically valuable in selected patients. The aims of this study were to demonstrate the safety and feasibility of ICPinf monitoring and to investigate the influence of the ICPinf on clinical outcome in a real-world setting. METHODS: Fifteen consecutive patients with posterior fossa (PF) lesions requiring surgery and anticipated prolonged neurointensive care between June 2019 and December 2021 were included. Simultaneous ICPsup and ICPinf were recorded. ICP burden was defined as a 15-minute interval with a mean ICP > 22 mm Hg. The Glasgow Outcome Scale score was assessed after 3 months. RESULTS: The mean ICPinf was substantially higher compared with ICPsup throughout the entire period of ICP recording (16.08 ± 4.44 vs 10.74 ± 3.6 mm Hg, p < 0.01). ICPinf was significantly higher in patients with unfavorable outcome when compared with those with favorable outcome (mean 17.2 ± 4.1 vs 11.4 ± 3.5 mm Hg, p < 0.05). Patients with unfavorable outcome showed significantly higher ICPinf burden compared with those with favorable outcome (mean 40.6 ± 43.8 vs 0.3 ± 0.4 hours, p < 0.05). Neither absolute ICPsup nor ICPsup burden was significantly associated with unfavorable outcome (p = 0.13). No monitoring-associated complications occurred. CONCLUSIONS: Supplementary ICPinf monitoring is safe and reliable. There is a significant transtentorial pressure gradient within the cranium showing elevated ICPs in the PF. Elevated ICP levels in the PF were strongly associated with unfavorable neurological outcome irrespective of ICPsup values.

CSF metabolomics alterations after aneurysmal subarachnoid hemorrhage: what do we know?

PURPOSE: The purpose of this mini review is to describe metabolomics in cerebrospinal fluid (CSF) and its potential in aneurysmal subarachnoid hemorrhage (aSAH). In brain injury, patients' micro dialysis enables detecting biochemical change in brain tissue. Indicators for ischemia were detected such as lactate, pyruvate, glucose, and glutamate. In aSAH patients, the pathophysiology and the factor for poor outcome are not completely understood yet. Routine use of biomarkers in CSF, particularly in aSAH patients, is still lacking. METHODS: This mini review was performed on the role of metabolomics alterations after aneurysmal subarachnoid hemorrhage. RESULTS: We identified five clinical studies that addressed metabolomics in patients with aneurysmal subarachnoid hemorrhage. CONCLUSION: There is increasing evidence suggesting that biomarkers can give insight in the pathogenesis and can serve as an outcome predictor. In this mini review, we present a brief overview of metabolomics profiling in neuroscience and wish to discuss the predictive and therapeutic value in aSAH patients.

Ultrasound-guided versus computed tomography-controlled periradicular injections of the first sacral nerve: a prospective randomized clinical trial.

AIM: To compare ultrasound (US)-guided versus computed tomography (CT)-controlled periradicular injections of the first sacral spinal (S1) nerve in a prospective randomized clinical trial. MATERIALS AND METHODS: Thirty-nine patients with S1-radiculopathy were consecutively enrolled for 40 periradicular injections and assigned to an US or CT guided group. Needle position after US-assisted placement was controlled by a low-dose CT-scan. Accessibility, accuracy, and intervention time were compared. The overall effect on pain was matched evaluating the visual analog scale (VAS) decrease before and one month after the intervention. RESULTS: The mean intervention time was lower in the US-group compared to the CT-group: 4.4±3.46 min (1.3-13.2) vs. 6.5±3.03 min (2.4-12.5). Using CT-controlled infiltration the mean number of needle passes was with 1.15 higher than utilizing US-guidance. The therapeutic effect (mean difference between pre- and post-intervention, VAS scores) for the CT-group was 4.85±2.52 and for the US-group 4.55±2.74 with no significant difference between the two groups (p=0.7). CONCLUSION: US-controlled infiltrations of the first sacral nerve show a similar therapeutic effect to the time consuming, and ionizing CT-controlled injections and result in a significant reduction of procedure expenditure and avoidance of radiation.

Cerebral Energy Status and Altered Metabolism in Early Brain Injury After Aneurysmal Subarachnoid Hemorrhage: A Prospective 31P-MRS Pilot Study.

Background: Acute changes of cerebral energy metabolism in early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) may play a crucial role for overall neurological outcome. However, direct detection of these alterations is limited. Phosphorous magnetic resonance spectroscopy (31P-MRS) is a molecular-based advanced neuroimaging technique allowing measurements of pathophysiological processes and tissue metabolism based on various phosphorous compound metabolites. This method may provide objective assessment of both primary and secondary changes. Objective: The aim of this pilot study was to evaluate the feasibility and the diagnostic potential of early 31P-MRS in aSAH. Methods: Patients with aSAH treated for ruptured aneurysms between July 2016 and October 2017 were prospectively included in the study. 3-Tesla-MRI including 31P-MRS was performed within the first 72 h after hemorrhage. Data of the vascular territories of the anterior, middle, and posterior cerebral arteries (ACA, MCA, PCA) and the basal ganglia were separately analyzed and compared with data of a healthy age- and sex-matched control group. Phosphorous compound metabolites were quantified, and ratios of these metabolites were further evaluated. Influence of treatment modality, clinical conditions, and analgosedation were analyzed. Results: Data of 13 patients were analyzed. 31P-MRS showed significant changes in cerebral energy metabolism after aSAH in all cerebrovascular territories. Both PCr/ATP and PCr/Pi ratio were notably increased (P < 0.001). Also, Pi/ATP was significantly decreased in all cerebrovascular territories (P = 0.014). PME/PDE ratio was overall significant decreased (P < 0.001). Conclusion: 31P-MRS is a promising non-invasive imaging tool for the assessment of changes in energy metabolism after aSAH. It allows a detailed insight into EBI and seems to harbor a high potential for clinical practice.

Time Course of Metabolomic Alterations in Cerebrospinal Fluid After Aneurysmal Subarachnoid Hemorrhage.

Object: The aim of this study was to investigate metabolite levels in cerebrospinal fluid (CSF) in their time-dependent course after aneurysmal subarachnoid hemorrhage (aSAH) comparing them to patients harboring unruptured intracranial aneurysms. Methods: Eighty CSF samples of 16 patients were analyzed. The study population included patients undergoing endovascular/microsurgical treatment of ruptured intracranial aneurysms (n = 8), which were assessed for 9 days after aSAH. Control samples were collected from the basal cisterns in elective aneurysm surgery (n = 8). The CSF samples were consecutively collected with extraventricular drain (EVD) placement/intraoperatively, 6 h later, and daily thereafter (day 1-9). The endogenous metabolites were analyzed with a targeted quantitative and quality controlled metabolomics approach using the AbsoluteIDQ®p180Kit. Differences inbetween timepoints and compared to the control group were evaluated. Results: Numerous alterations of amino acid (AA) levels were detected within the first hours after bleeding. The highest mean concentrations occurred 1 week after aSAH. AA levels were continuously increasing over time starting 6 h after aSAH. Taurine concentration was highest briefly after aSAH starting to decrease already after 6 h (vs. day 1-9, p = 0.02). The levels of sphingomyelins/ phosphatidylcholines/ lysophosphatidylcholines/mono-unsaturated fatty acid chain were highly elevated on day 0 (compared to other timepoints or controls, p < 0.01) and decreased over the next several days to concentrations comparable to the control group. Carnitine concentrations were decreased after SAH (vs. day 7, p < 0.01), while they recovered within the next day. The Fischer ratio of branched-chain AA to aromatic AA was lowest immediately after SAH and increased in 7 days (p < 0.001). Conclusion: AA levels in CSF increased overtime and often differ from patients without SAH. There was a peak concentration of structural AA within the first 6 h after aneurysm treatment. Time-dependent alterations of CSF metabolites and compounds may elucidate pathophysiological processes after aSAH, providing potential predictors assessed non-invasively by routine lab testing.

Transcallosal, transchoroidal clipping of a hypothalamic collateral vessel aneurysm in Moyamoya disease.

Peripheral collateral vessel aneurysms in Moyamoya disease (MMD) remain difficult to treat due to their deep location, small size, and vascular fragility. We report the case of an aneurysm localized in the hypothalamus, which was rapidly increasing in size with repeated hemorrhage despite revascularization surgery. Aneurysm clipping was performed to prevent further progress and rerupture with favorable outcome. To our best knowledge, this is the first description of a hypothalamic aneurysm in MMD being clipped via a transcallosal, transchoroidal approach through the third ventricle.

Autophagy after Subarachnoid Hemorrhage: Can Cell Death be Good?

BACKGROUND: Autophagy is a prosurvival, reparative process that maintainsww cellular homeostasis through lysosomal degradation of selected cytoplasmic components and programmed death of old, dysfunctional, or unnecessary cytoplasmic entities. According to growing evidence, autophagy shows beneficial effects following subarachnoid hemorrhage (SAH). SAH is considered one of the most devastating forms of stroke. METHODS: In this review lies in revealing the pathophysiological pathways and the effects of autophagy. Current results from animal studies will be discussed focusing on the effects of inhibitors and inducers of autophagy. In addition, this review discusses the clinical translation of potential neuropharmacological targets that can help prevent early brain injury (EBI) following SAH by incorporating programmed cell death into clinical management. RESULTS: Published data showed that autophagy mechanisms have a prosurvival effect to reduce apoptotic cell death after SAH. However, if SAH exceeds a certain stress threshold, autophagy mechanisms lead to increased apoptotic cell death, more brain injury, and worse outcome. CONCLUSION: Future investigation on the differences and molecular switches between protective mechanisms of autophagy and excessive "self-eating" autophagy leading to cell death is needed to achieve more insight into the complex pathophysiology of brain injury after SAH. If autophagy after SAH can be controlled to lead to beneficial effects only, as the physiological self-control mechanism, this could be an important target for treatment.

IVIG activates FcγRIIB-SHIP1-PIP3 Pathway to stabilize mast cells and suppress inflammation after ICH in mice.

Following intracerebral hemorrhage (ICH), the activation of mast cell contributes to brain inflammation and brain injury. The mast cell activation is negatively regulated by an inhibitory IgG-receptor. It's signals are mediated by SHIP (Src homology 2-containing inositol 5' phosphatase), in particular SHIP1, which activation leads to hydrolyzation of PIP3 (Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3, leading to the inhibition of calcium mobilization and to the attenuation of mast cell activation. Intravenous immunoglobulin (IVIG) is a FDA-approved drug containing IgG. We hypothesized that IVIG will attenuate the ICH-induced mast cell activation via FcγRIIB/SHIP1 pathway, resulting in a decrease of brain inflammation, protection of the blood-brain-barrier, and improvement of neurological functions after ICH. To prove this hypothesis we employed the ICH collagenase mouse model. We demonstrated that while ICH induced mast cell activation/degranulation, IVIG attenuated post-ICH mast cell activation. Mast cell deactivation resulted in reduced inflammation, consequently attenuating brain edema and improving of neurological functions after ICH. Furthermore using siRNA-induced in vivo knockdown approach we demonstrated that beneficial effects of IVIG were mediated, at least partly, via SHIP1/PIP3 pathway. We conclude that IVIG treatment represents a promising therapeutic approach potentially able to decrease mortality and morbidity after ICH in experimental models.

"I am not afraid of death"-a survey on preferences concerning neurosurgical interventions among patients over 75 years.

INTRODUCTION: Treatment decisions in elderly patients with traumatic brain injury (TBI) are mainly determined by trauma severity and patient age. The aim of this study was to explore personal preferences of potential patients regarding life-prolonging neurosurgical interventions by interviewing ambulatory, autonomous elderly people. METHODS: One hundred consecutive patients older than 75 years frequenting the outpatient clinic of the Department of Neurosurgery were interviewed about their attitudes regarding the hypothetical case of an 81-year-old patient with TBI and a space-occupying acute subdural hematoma (aSDH) using a 21-point questionnaire. RESULTS: Fifty-one percent of the consulted persons declined life-prolonging surgical measures. If surgery was associated with physical disability, 68% of the people wished no surgery. In case of cognitive impairment after surgery, 91% were against any surgical intervention. The majority feared being a burden to relatives (76%) and becoming unable to master an independent life (75%). Four-fifths of the interviewed patients (82%) were not afraid of death. CONCLUSIONS: The majority of elderly patients only consent to surgical measures if no relevant disabilities are involved and if they can return to their previous life. These findings need consideration in case of life-threatening neurosurgical emergencies as well as in the surgical treatment of elderly patients in general.

Phase I and Phase II Therapies for Acute Ischemic Stroke: An Update on Currently Studied Drugs in Clinical Research.

Acute ischemic stroke is a devastating cause of death and disability, consequences of which depend on the time from ischemia onset to treatment, the affected brain region, and its size. The main targets of ischemic stroke therapy aim to restore tissue perfusion in the ischemic penumbra in order to decrease the total infarct area by maintaining blood flow. Advances in research of pathological process and pathways during acute ischemia have resulted in improvement of new treatment strategies apart from restoring perfusion. Additionally, limiting the injury severity by manipulating the molecular mechanisms during ischemia has become a promising approach, especially in animal research. The purpose of this article is to review completed and ongoing phases I and II trials for the treatment of acute ischemic stroke, reviewing studies on antithrombotic, thrombolytic, neuroprotective, and antineuroinflammatory drugs that may translate into more effective treatments.

Pharmacological Management Options to Prevent and Reduce Ischemic Hemorrhagic Transformation.

BACKGROUND: Hemorrhagic transformation (HT) is a common and natural complication after acute ischemic stroke. The only FDA-approved treatment so far for acute ischemic stroke is rapid reperfusion with recombinant tissue plasminogen activator (rtPA). Although it has been shown to exaggerate the risk and severity of HT and to be associated with increased morbidity and mortality. OBJECTIVE: The aim of this review is to discuss the multifactorial pathophysiology of hemorrhagic transformation, promising interventional targets, and pharmacological treatment options. RESULTS AND CONCLUSION: Understanding HT is essential to restore cerebral blood flow to ischemic brain by reperfusion therapy without causing this complication and additional brain injury. Therefore methods for the prevention and treatment of HT are needed. Although experimental studies showed promising results, clinical translation remains unsatisfactory to date.

Neuroprotective Strategies after Neonatal Hypoxic Ischemic Encephalopathy.

Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating disease that primarily causes neuronal and white matter injury and is among the leading cause of death among infants. Currently there are no well-established treatments; thus, it is important to understand the pathophysiology of the disease and elucidate complications that are creating a gap between basic science and clinical translation. In the development of neuroprotective strategies and translation of experimental results in HIE, there are many limitations and challenges to master based on an appropriate study design, drug delivery properties, dosage, and use in neonates. We will identify understudied targets after HIE, as well as neuroprotective molecules that bring hope to future treatments such as melatonin, topiramate, xenon, interferon-beta, stem cell transplantation. This review will also discuss some of the most recent trials being conducted in the clinical setting and evaluate what directions are needed in the future.

What's New in Traumatic Brain Injury: Update on Tracking, Monitoring and Treatment.

Traumatic brain injury (TBI), defined as an alteration in brain functions caused by an external force, is responsible for high morbidity and mortality around the world. It is important to identify and treat TBI victims as early as possible. Tracking and monitoring TBI with neuroimaging technologies, including functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET), and high definition fiber tracking (HDFT) show increasing sensitivity and specificity. Classical electrophysiological monitoring, together with newly established brain-on-chip, cerebral microdialysis techniques, both benefit TBI. First generation molecular biomarkers, based on genomic and proteomic changes following TBI, have proven effective and economical. It is conceivable that TBI-specific biomarkers will be developed with the combination of systems biology and bioinformation strategies. Advances in treatment of TBI include stem cell-based and nanotechnology-based therapy, physical and pharmaceutical interventions and also new use in TBI for approved drugs which all present favorable promise in preventing and reversing TBI.