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Glioblastomas are known for their immunosuppressive tumor microenvironment, which may explain the failure of most clinical trials in the past decade. Recent studies have emphasized the significance of stratifying glioblastoma patients to predict better therapeutic responses and survival outcomes. This study aims to investigate the prognostic relevance of peripheral immune cell counts sampled prior to surgery, with a special focus on methylation‐based subclassification. Peripheral blood was sampled in patients with newly diagnosed (n = 176) and recurrent (n = 41) glioblastoma at the time of surgery and analyzed for neutrophils, monocytes, leukocytes, platelets, neutrophil–lymphocyte ratio, lymphocyte–monocyte ratio, and platelet–lymphocyte ratio. Peripheral immune cell counts were correlated with patients' survival after combined radiochemotherapy. In addition, 850 k genome‐wide DNA methylation was assessed on tissue for defining tumor subclasses and performing cell‐type deconvolution. In newly diagnosed glioblastoma, patients with higher peripheral neutrophil counts had an unfavorable overall survival (OS) (p = 0.01, median overall‐survival (mOS) 17.0 vs. 10.0 months). At the time of first recurrence, a significant decrease of peripheral immune cell counts was observed, and elevated monocyte (p = 0.03), neutrophil (p = 0.04), and platelet (p = 0.01) counts were associated with poorer survival outcomes. DNA methylation subclass‐stratified analysis revealed a significant survival influence of neutrophils (p = 0.007) and lymphocytes (p = 0.04) in the mesenchymal (MES) subclass. Integrating deconvolution of matched tumor tissue showed that platelets and monocytes were correlated with a more differentiated, tumor‐progressive cell state, and peripheral immune cell counts were most accurately reflected in tissue of the MES subclass. This study illustrates a restricted prognostic significance of peripheral immune cell counts in newly diagnosed glioblastoma and a constrained representation in matched tumor tissue, but it demonstrates a more pertinent situation at the time of recurrence and after DNA methylation‐based stratification. This study illustrates the prognostic relevance of epigenetic molecular profiling and the peripheral immune cell counts in newly diagnosed and matched recurrent glioblastoma patients.

Traumatic brain injury (TBI) causes the release of danger-associated molecular patterns (DAMP) from damaged or dead cells, which contribute to secondary brain damage after TBI. Cell-free DNA (cfDNA) is a DAMP known to cause disruption of the blood–brain barrier (BBB), promote procoagulant processes, brain edema, and neuroinflammation. This study tested the hypothesis that administration of deoxyribonuclease-I (DNase-I) has a beneficial effect after TBI. Mice (n = 84) were subjected to controlled cortical impact (CCI) and posttraumatic intraperitoneal injections of low dose (LD) or high dose (HD) of DNase-I or vehicle solution at 30 min and 12 h after CCI. LD was most effective to reduce lesion volume ( p  = 0.003), brain water content ( p  < 0.0001) and to stabilize BBB integrity ( p  = 0.019) 1 day post-injury (dpi). At 6 h post injury LD-treated animals showed less cleavage of fibrin ( p  = 0.0014), and enhanced perfusion as assessed by micro-computer-tomography ( p  = 0.027). At 5 dpi the number of Iba1-positive cells ( p  = 0.037) were reduced, but the number of CD45-positive cells, motoric function and brain lesion volume was not different. Posttraumatic-treatment with DNase-I therefore stabilizes the BBB, reduces the formation of brain edema, immune response, and delays secondary brain damage. DNase-I might be a new approach to extend the treatment window after TBI.

Traumatic brain injury (TBI) involves primary mechanical damage and delayed secondary damage caused by vascular dysfunction and neuroinflammation. Intracellular components released into the parenchyma and systemic circulation, termed danger-associated molecular patterns (DAMPs), are major drivers of vascular dysfunction and neuroinflammation. These DAMPs include cell-free RNAs (cfRNAs), which damage the blood–brain barrier (BBB), thereby promoting edema, procoagulatory processes, and infiltration of inflammatory cells. We tested the hypothesis that intraperitoneal injection of Ribonuclease-1 (RNase1, two doses of 20, 60, or 180 µg/kg) at 30 min and 12 h after controlled-cortical-impact (CCI) can reduce secondary lesion expansion compared to vehicle treatment 24 h and 120 h post-CCI. The lowest total dose (40 µg/kg) was most effective at reducing lesion volume (− 31% RNase 40 µg/kg vs. vehicle), brain water accumulation (− 5.5%), and loss of BBB integrity (− 21.6%) at 24 h post-CCI. RNase1 also reduced perilesional leukocyte recruitment (− 53.3%) and microglial activation (− 18.3%) at 120 h post-CCI, but there was no difference in lesion volume at this time and no functional benefit. Treatment with RNase1 in the early phase following TBI stabilizes the BBB and impedes leukocyte immigration, thereby suppressing neuroinflammation. RNase1-treatment may be a novel approach to delay brain injury to extend the window for treatment opportunities after TBI.

Cerebral hypoperfusion is a key factor for determining the outcome after subarachnoid hemorrhage (SAH). A subset of SAH patients develop neurogenic stress cardiomyopathy (NSC), but it is unclear to what extent cerebral hypoperfusion is influenced by cardiac dysfunction after SAH. The aims of this study were to examine the association between cardiac function and cerebral perfusion in a murine model of SAH and to identify electrocardiographic and echocardiographic signs indicative of NSC. We quantified cortical perfusion by laser SPECKLE contrast imaging, and myocardial function by serial high-frequency ultrasound imaging, for up to 7 days after experimental SAH induction in mice by endovascular filament perforation. Cortical perfusion decreased significantly whereas cardiac output and left ventricular ejection fraction increased significantly shortly post-SAH. Transient pathological ECG and echocardiographic abnormalities, indicating NSC (right bundle branch block, reduced left ventricular contractility), were observed up to 3 h post-SAH in a subset of model animals. Cerebral perfusion improved over time after SAH and correlated significantly with left ventricular end-diastolic volume at 3, 24, and 72 h. The murine SAH model is appropriate to experimentally investigate NSC. We conclude that in addition to cerebrovascular dysfunction, cardiac dysfunction may significantly influence cerebral perfusion, with LVEDV presenting a potential parameter for risk stratification.

Quantification of cerebral vasospasm after subarachnoid hemorrhage (SAH) is crucial in animal studies as well as clinical routine. We have developed a method for computer-based volumetric assessment of intracranial blood vessels from cross-sectional imaging data. Here we demonstrate the quantification of vasospasm from micro computed tomography (micro-CT) data in a rodent SAH model and the transferability of the volumetric approach to clinical data. We obtained rodent data by performing an ex vivo micro-CT of murine brains after sham surgery or SAH by endovascular filament perforation on day 3 post hemorrhage. Clinical CT angiography (CTA) was performed for diagnostic reasons unrelated to this study. We digitally reconstructed and segmented intracranial vascular trees, followed by calculating volumes of defined vessel segments by standardized protocols using Amira® software. SAH animals demonstrated significantly smaller vessel diameters compared with sham (MCA: 134.4±26.9μm vs.165.0±18.7μm, p<0.05). We could highlight this difference by analyzing vessel volumes of a defined MCA-ICA segment (SAH: 0.044±0.017μl vs. sham: 0.07±0.006μl, p<0.001). Analysis of clinical CTA data allowed us to detect and volumetrically quantify vasospasm in a series of 5 SAH patients. Vessel diameters from digital reconstructions correlated well with those measured microscopically (rodent data, correlation coefficient 0.8, p<0.001), or angiographically (clinical data, 0.9, p<0.001). Our methodological approach provides accurate anatomical reconstructions of intracranial vessels from cross-sectional imaging data. It allows volumetric assessment of entire vessel segments, hereby highlighting vasospasm-induced changes objectively in a murine SAH model. This method could also be a helpful tool for analysis of clinical CTA.

PurposeTo analyze the reliability of the classification of intraoperative adverse events (ClassIntra) to reflect intraoperative complications of neurosurgical procedures and the potential to predict the postoperative outcome including the neurological performance. The ClassIntra classification was recently introduced and found to be reliable for assessing intraoperative adverse events and predicting postoperative complications across different surgical disciplines. Nevertheless, its potential role for neurosurgical procedures remains elusive.MethodsThis is a prospective, monocentric cohort study assessing the ClassIntra in 422 adult patients who underwent a neurosurgical procedure and were hospitalized between July 1, 2021, to December 31, 2021. The primary outcome was the occurrence of intraoperative complications graded according to ClassIntra and the association with postoperative outcome reflected by the Clavien-Dindo classification and comprehensive complication index (CCI). The ClassIntra is defined as intraoperative adverse events as any deviation from the ideal course on a grading scale from grade 0 (no deviation) to grade V (intraoperative death) and was set at sign-out in agreement between neurosurgeon and anesthesiologist. Secondary outcomes were the neurological outcome after surgery as defined by Glasgow Coma Scale (GCS), modified Rankin scale (mRS), Neurologic Assessment in Neuro-Oncology (NANO) scale, National Institute Health of Strokes Scale (NIHSS), and Karnofsky Performance Score (KPS), and need for unscheduled brain scan.ResultsOf 442 patients (mean [SD] age, 56.1 [16.2]; 235 [55.7%] women and 187 [44.3%] men) who underwent a neurosurgical procedure, 169 (40.0%) patients had an intraoperative adverse event (iAE) classified as ClassIntra I or higher. The NIHSS score at admission (OR, 1.29; 95% CI, 1.03–1.63, female gender (OR, 0.44; 95% CI, 0.23–0.84), extracranial procedures (OR, 0.17; 95% CI, 0.08–0.61), and emergency cases (OR, 2.84; 95% CI, 1.53–3.78) were independent risk factors for a more severe iAE. A ClassIntra ≥ II was associated with increased odds of postoperative complications classified as Clavien-Dindo (p < 0.01), neurological deterioration at discharge (p < 0.01), prolonged hospital (p < 0.01), and ICU stay (p < 0.01). For elective craniotomies, severity of ClassIntra was associated with the CCI (p < 0.01) and need for unscheduled CT or MRI scan (p < 0.01). The proportion of a ClassIntra ≥ II was significantly higher for emergent craniotomies (56.2%) and associated with in-hospital mortality, and an unfavorable neurological outcome (p < 0.01).ConclusionFindings of this study suggest that the ClassIntra is sensitive for assessing intraoperative adverse events and sufficient to identify patients with a higher risk for developing postoperative complications after a neurosurgical procedure.

Cerebral hypoperfusion in the first hours after subarachnoid haemorrhage (SAH) is a major determinant of poor neurological outcome. However, the underlying pathophysiology is only partly understood. Here we induced neutropenia in C57BL/6N mice by anti-Ly6G antibody injection, induced SAH by endovascular filament perforation, and analysed cerebral cortical perfusion with laser SPECKLE contrast imaging to investigate the role of neutrophils in mediating cerebral hypoperfusion during the first 24 h post-SAH. SAH induction significantly increased the intracranial pressure (ICP), and significantly reduced the cerebral perfusion pressure (CPP). At 3 h after SAH, ICP had returned to baseline and CPP was similar between SAH and sham mice. However, in SAH mice with normal neutrophil counts cortical hypoperfusion persisted. Conversely, despite similar CPP, cortical perfusion was significantly higher at 3 h after SAH in mice with neutropenia. The levels of 8-iso-prostaglandin-F2α in the subarachnoid haematoma increased significantly at 3 h after SAH in animals with normal neutrophil counts indicating oxidative stress, which was not the case in neutropenic SAH animals. These results suggest that neutrophils are important mediators of cortical hypoperfusion and oxidative stress early after SAH. Targeting neutrophil function and neutrophil-induced oxidative stress could be a promising new approach to mitigate cerebral hypoperfusion early after SAH.

PurposeSpinal abnormalities frequently occur in patients with mucopolysaccharidosis (MPS) types I, II, IV, and VI. The symptoms are manifold, which sometimes prolongs the diagnostic process and delays therapy. Spinal stenosis (SS) with spinal cord compression due to bone malformations and an accumulation of storage material in soft tissue are serious complications of MPS disease. Data on optimal perioperative therapeutic care of SS is limited.MethodsA retrospective chart analysis of patients with MPS and SS for the time period 01/1998 to 03/2021 was performed. Demographics, clinical data, neurological status, diagnostic evaluations (radiography, MRI, electrophysiology), and treatment modalities were documented. The extent of the SS and spinal canal diameter were analyzed. A Cox regression analysis was performed to identify prognostic factors for neurological outcomes.ResultsOut of 209 MPS patients, 15 were included in this study. The most dominant type of MPS was I (–H) (n = 7; 46.7%). Preoperative neurological deterioration was the most frequent indication for further diagnostics (n = 12; 80%). The surgical procedure of choice was dorsal instrumentation with microsurgical decompression (n = 14; 93.3%). A univariate Cox regression analysis showed MPS type I (–H) to be associated with favorable neurological outcomes.ConclusionEarly detection of spinal stenosis is highly relevant in patients with MPS. Detailed neurological assessment during follow-up is crucial for timeous detection of patients at risk. The surgical intervention of choice is dorsal instrumentation with microsurgical decompression and resection of thickened intraspinal tissue. Patients with MPS type I (–H) demonstrated the best neurological course.

Clinical studies on subarachnoid hemorrhage (SAH) have shown discrepancies between large vessel vasospasm, cerebral perfusion, and clinical outcome. We set out to analyze the contribution of large vessel vasospasm to impaired cerebral perfusion and neurological impairment in a murine model of SAH. SAH was induced in C57BL/6 mice by endovascular filament perforation. Vasospasm was analyzed with microcomputed tomography, cortical perfusion by laser SPECKLE contrast imaging, and functional impairment with a quantitative neuroscore. SAH animals developed large vessel vasospasm, as shown by significantly lower vessel volumes of a 2.5-mm segment of the left middle cerebral artery (MCA) (SAH 5.6 ± 0.6 nL, sham 8.3 ± 0.5 nL, p  < 0.01). Induction of SAH significantly reduced cerebral perfusion of the corresponding left MCA territory compared to values before SAH, which only recovered partly (SAH vs. sham, 15 min 35.7 ± 3.1 vs. 101.4 ± 10.2%, p  < 0.01; 3 h, 85.0 ± 8.6 vs. 121.9 ± 13.4, p  < 0.05; 24 h, 75.3 ± 4.6 vs. 110.6 ± 11.4%, p  < 0.01; 72 h, 81.8 ± 4.8 vs. 108.5 ± 14.5%, n.s.). MCA vessel volume did not correlate significantly with MCA perfusion after 72 h ( r  = 0.34, p  = 0.25). Perfusion correlated moderately with neuroscore (24 h: r  = − 0.58, p  < 0.05; 72 h: r  = − 0.44, p  = 0.14). There was no significant correlation between vessel volume and neuroscore after 72 h ( r  = − 0.21, p  = 0.50). In the murine SAH model, cerebral hypoperfusion occurs independently of large vessel vasospasm. Neurological outcome is associated with cortical hypoperfusion rather than large vessel vasospasm.

Study Design Retrospective cohort study. Objective Cavernous malformations (CMs) and hemangioblastomas (HBs) of the spinal cord exhibit distinct differences in histopathology but similarities in the neurological course. The aim of our study was to analyze the clinical differences between the vascular pathologies and a benign tumor of the spinal cord in a perioperative situation. Methods We performed a retrospective analysis of patients who had undergone surgery for lesions in the spinal cord between 1984 and 2015. Patients were screened for CMs and HBs as the primary inclusion criteria. General patient information, surgical data, and disease-specific data were collected from the records. Cooper–Epstein scores for clinical symptoms were evaluated preoperatively, at discharge, and at the 6-month follow-up. Results A total of 112 patients were included, of which 46 had been diagnosed with CMs and 66 with HBs. Patients with CMs often demonstrated more preoperative neurological deterioration compared to those with HBs (P < .05); accordingly, in took longer to diagnose HBs. Complete resection was possible for 96.8% of all patients with CMs and 90% of those with HBs. At the 6-month follow-up, patients with HBs more often presented with persisting neurologic impairment of the upper extremities compared to the CM patients (P < .001). Conclusion CMs and HBs of the spinal cord have similarities but also exhibit significant differences in neurological presentation and perioperative course. Surgical therapy is the treatment of choice for symptomatic lesions, and complete surgical resection is possible in the majority of cases for both entities. Neurologic outcomes are usually favorable, although patients with HBs retain neurologic deficits more often.