Acute low-pressure hydrocephalus in aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Acute and chronic hydrocephalus are common pathologies after aneurysmal subarachnoid hemorrhage (SAH). Generally, the presence of acute hydrocephalus is associated with elevated intracranial pressure (ICP) treated with a ventricular drain. Subsequently, however, pronounced hydrocephalus without elevated ICP may develop in some patients with SAH in the postacute phase. This is described as acute low-pressure hydrocephalus (aLPH), and there are very limited data in the literature of this pathology. The aim of this study was to evaluate the rate of and factors associated with aLPH and describe its clinical course. METHODS: In this retrospective single-center cohort study, the frequency and clinical characteristics of SAH-associated aLPH were investigated. Acute LPH was defined as an increase in ventricular size as measured by the Evans index, ICP within the normal range (< 5 mm Hg) at the time of ventricular enlargement, and timely neurological improvement after indwelling ventricular CSF drainage with negative pressure up to 5 cm H2O below normal level. Demographic and SAH-specific factors in patients with SAH treated using an external ventricular drain were extracted from the electronic medical chart and further analyzed. RESULTS: From November 2010 to May 2020, 15 (3.7.%) of 406 patients with SAH fulfilled the criteria for aLPH. Acute LPH was diagnosed after an average of 13.1 ± 7.7 days. The presence of IVH and its extension were associated with the occurrence of aLPH. After undergoing the transient phase of aLPH, these patients subsequently developed a chronic, typical malresorptive hydrocephalus requiring a ventriculoperitoneal shunt more often (66.7% vs 17.4%, p < 0.001) and stayed longer in the intensive care unit (27 vs 20.5 days, p = 0.043) and in the hospital (36.4 vs 26.3 days, p = 0.004). CONCLUSIONS: Acute LPH is a rare pathology in patients with SAH and negatively impacts the clinical course. It should be especially considered in patients with a lack of neurological improvement, an increase in ventricular width, and normal ICP values, so that forced CSF drainage is implemented.

Real-life analysis of 280 patients with surgically treated acromegaly: a single-center experience from 2008 to 2015.

OBJECTIVE: The purpose of this study was to analyze the clinical and biochemical outcome of consecutive patients with acromegaly after microscopic transsphenoidal surgery (MTS) at a single center over an 8-year period. METHODS: A retrospective analysis of patients with acromegaly treated via MTS between 2008 and 2015 at the authors' center was performed. The mean follow-up was 29 months (range 1-120 months). Parameters investigated included tumor size, pre- and postoperative insulin-like growth factor-I, growth hormone levels, pretreatment, perioperative complications, and clinical outcome. RESULTS: A total of 280 patients with acromegaly were treated surgically at the authors' center over the abovementioned time frame and were included in analyses. For 231 of these patients, complete follow-up data were available for evaluation. One hundred eighty-eight patients (81%) showed remission initially according to current criteria. So far, 23 of these patients relapsed in the further course, so that on follow-up 165 patients (71%) demonstrated full remission by surgery alone. Most patients in whom remission after surgery failed were treated with somatostatin receptor ligands and/or dopamine agonists as second-line treatment. The main postoperative complications included transient hyponatremia and diabetes insipidus (13/280; 4.6%). CSF leakage only occurred in 2 cases (2/280; 0.7%). No surgery-related death occurred. CONCLUSIONS: The data underline the effectiveness of MTS in acromegaly. Many patients with recurrent disease or incomplete tumor resection can be successfully managed pharmacologically.

Evaluation of a New Multiparameter Brain Probe for Simultaneous Measurement of Brain Tissue Oxygenation, Cerebral Blood Flow, Intracranial Pressure, and Brain Temperature in a Porcine Model.

BACKGROUND: A novel multiparameter brain sensor (MPBS) allows the simultaneous measurement of brain tissue oxygenation (ptiO2), cerebral blood flow (CBF), intracranial pressure (ICP), and brain temperature with a single catheter. This laboratory investigation evaluates the MPBS in an animal model in relation to established reference probes. METHODS: The study group consisted of 17 juvenile male pigs. Four MPBS and four reference probes were implanted per pig and compared simultaneously. The measured parameters were challenged by standardized provocations such as hyperoxia, dobutamine, and norepinephrine application, hypercapnia and hypoxia in combination with and without a controlled cortical impact (CCI) injury. Mean values over 2 min were collected for predefined time points and were analyzed using Bland-Altman plots. RESULTS: The protocol was successfully conducted in 15 pigs of which seven received CCI. ICP and ptiO2 were significantly influenced by the provocations. Subtraction of MPBS from reference values revealed a mean difference (limits of agreement) of 3.7 (- 20.5 to 27.9) mm Hg, - 2.9 (- 7.9 to 2.1) mm Hg, and 5.1 (- 134.7 to 145.0) % for ptiO2, ICP, and relative CBF, respectively. CONCLUSIONS: The MPBS is a promising measurement tool for multiparameter neuromonitoring. The conducted study demonstrates the in vivo functionality of the probe. Comparison with standard probes revealed a deviation which is mostly analogous to other multiparameter devices. However, further evaluation of the device is necessary before it can reliably be used for clinical decision making.

Prior malignancies in patients harboring glioblastoma: an institutional case-study of 2164 patients.

More patients are surviving long-term following a cancer diagnosis and as such are at risk for second malignancies. As the most common primary brain tumor, glioblastoma (GBM) will not infrequently occur in this population. No study has examined the incidence of prior cancer (PC) in patients harboring GBM. Here we evaluate the epidemiological features, as well as the molecular and clinical characteristics of GBM as a second cancer. Utilizing a web-based cancer data management system at our institution, we identified 2164 patients harboring GBM from 2007 to 2014. We collected baseline demographic, molecular, and clinical data. Univariate analysis was performed to compare the cohort of GBM patients with and without PC diagnosis. Survival differences were analyzed with Kaplan-Meier and log-rank testing. A Cox-proportional hazards model was fit for multivariable analysis. 170 patients (7.9%) harboring GBM had a PC diagnosis. The median interval between diagnoses was 79 months. The most common pathologies were breast (18.8%) and prostate (18.8%) cancer. Patients with a PC were older at the time of GBM diagnosis than those without PC (66 vs. 59 years, p < 0.001) and were more likely to be white (88.2 vs. 72.8%, p < 0.001). Patients with PC were more likely to harbor an EGFR (20 vs. 12.3%, p < 0.001) or MGMT mutation (17.6 vs. 11.6%, p < 0.001). Median survival was 13 months in the PC cohort and 15 months in the cohort without PC (p = NS). Age, KPS, and diagnosis year were the only factors which influenced outcome in multivariable analysis. Patients who develop GBM following a prior malignancy constitute ~8% of patients with GBM. Despite significant molecular differences these two cohorts appear to have a similar overall prognosis and clinical course. Thus, whether or not a patient harbors a malignancy prior to diagnosis of GBM should not exclude him or her from aggressive treatment or for consideration of novel investigational therapies.

The Cerebral Collateral Cascade: Comprehensive Blood Flow in Ischemic Stroke.

BACKGROUND AND PURPOSE: Robust cerebral collaterals are associated with favorable outcomes in patients with acute ischemic stroke due to large vessel occlusion treated by thrombectomy. However, collateral status assessment mostly relies on single imaging biomarkers and a more comprehensive holistic approach may provide deeper insights into the biology of collateral perfusion on medical imaging. Comprehensive collateralization is defined as blood flow of cerebral arteries through the brain tissue and into draining veins. We hypothesized that a comprehensive analysis of the cerebral collateral cascade (CCC) on an arterial, tissue and venous level would predict clinical and radiological outcomes. MATERIALS AND METHODS: Multicenter retrospective cohort study of acute stroke patients undergoing thrombectomy triage. CCC was determined by quantifying pial arterial collaterals, tissue-level collaterals, and venous outflow. Pial arterial collaterals were determined by CT angiography, tissue-level collaterals were assessed on CT perfusion. Venous outflow was assessed on CT angiography using the cortical vein opacification score. 3 groups were defined: CCC+ (good pial collaterals, tissue-level collaterals, and venous outflow), CCC- (poor pial collaterals, tissue-level collaterals, and venous outflow) and CCCmixed (remainder of patients). Primary outcome was functional independence (modified Rankin Scale: 0-2) at 90-days. Secondary outcome was final infarct volume. RESULTS: 647 patients met inclusion criteria: 176 CCC+, 345 CCC mixed and 126 CCC-. Multivariable ordinal logistic regression showed that CCC+ predicted good functional outcomes (OR=18.9 [95% CI 8-44.5]; p<0.001) compared to CCC- and CCCmixed patients. CCCmixed patients likely had better functional outcomes compared to CCC- patients (OR=2.5 [95% CI 1.2-5.4]; p=0.014). Quantile regression analysis (50th percentile) showed that CCC+ (ß: -78.5, 95% CI -96.0- -61.1; p<0.001) and CCCmixed (ß: -64.0, 95% CI -82.4- -45.6; p<0.001) profiles were associated with considerably lower final infarct volumes compared to CCC- profiles. CONCLUSION: Comprehensive assessment of the collateral blood flow cascade in acute stroke patients is a strong predictor of clinical and radiological outcomes in patients treated by thrombectomy.

Cerebral venous outflow profiles are associated with the first pass effect in endovascular thrombectomy.

BACKGROUND: Recent studies found that favorable venous outflow (VO) profiles are associated with higher reperfusion rates after mechanical thrombectomy (MT) in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). Fewer retrieval attempts and first-pass revascularization during MT lead to better functional outcomes. OBJECTIVE: To examine the hypothesis that favorable VO profiles assessed on baseline CT angiography (CTA) images correlate with successful vessel reperfusion after the first retrieval attempt and fewer retrieval attempts. METHODS: A multicenter retrospective cohort study of patients with AIS-LVO treated by MT. Baseline CTA was used to determine the cortical vein opacification score (COVES). Favorable VO was defined as COVES ≥3. Primary outcomes were successful with excellent vessel reperfusion status, defined as Thrombolysis in Cerebral Infarction (TICI) 2b/3 and 2c/3 after first retrieval attempt. RESULTS: 617 patients were included in this study, of whom 205 (33.2%) had first pass reperfusion. In univariate analysis, ordinal COVES (p=0.011) values were significantly higher in patients with first pass than in those with non-first pass reperfusion, while the number of patients exhibiting favorable pial arterial collaterals using the Maas scale on CTA did not differ (p=0.243). In multivariable logistic regression analysis, higher COVES were independently associated with TICI 2b/3 (OR=1.25, 95% CI 1.1 to 1.42; p=0.001) and TICI 2c/3 (OR=1.2, 95% CI 1.04 to 1.36; p=0.011) reperfusion after one retrieval attempt, controlling for penumbra volume and time from symptom onset to vessel reperfusion. CONCLUSIONS: Favorable VO, classified as higher COVES, is independently associated with successful and excellent first pass reperfusion in patients with AIS-LVO treated by endovascular thrombectomy.

Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1.

Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.

Intrathecal and systemic alterations of L-arginine metabolism in patients after intracerebral hemorrhage.

Alterations in the concentration of nitric oxide (NO) and L-arginine metabolites have been associated with the pathophysiology of different vascular diseases. Here, we describe striking changes in L-arginine metabolism after hemorrhagic stroke. Blood and cerebrospinal fluid (CSF) samples of patients with intracerebral hemorrhage (ICH) and/or intraventricular hemorrhage were collected over a ten-day period. Liquid chromatography-tandem mass spectrometry was used to quantify key substrates and products of L-arginine metabolizing enzymes as well as asymmetric (ADMA) and symmetric dimethylarginine (SDMA). Changes in the plasma were limited to early reductions in L-ornithine, L-lysine, and L-citrulline concentrations. Intrathecally, we observed signs of early NO synthase (NOS) upregulation followed by a decrease back to baseline accompanied by a rise in the level of its endogenous NOS-inhibitor ADMA. SDMA demonstrated increased levels throughout the observation period. For arginase, a pattern of persistently elevated activity was measured and arginine:glycine amidinotransferase (AGAT) appeared to be reduced in its activity at later time points. An early reduction in CSF L-arginine concentration was an independent risk factor for poor outcome. Together, these findings further elucidate pathophysiological mechanisms after ICH potentially involved in secondary brain injury and may reveal novel therapeutic targets.

Early Prediction of Malignant Cerebellar Edema in Posterior Circulation Stroke Using Quantitative Lesion Water Uptake.

BACKGROUND: Malignant cerebellar edema (MCE) is a life-threatening complication of ischemic posterior circulation stroke that requires timely diagnosis and management. Yet, there is no established imaging biomarker that may serve as predictor of MCE. Early edematous water uptake can be determined using quantitative lesion water uptake, but this biomarker has only been applied in anterior circulation strokes. OBJECTIVE: To test the hypothesis that lesion water uptake in early posterior circulation stroke predicts MCE. METHODS: A total 179 patients with posterior circulation stroke and multimodal admission CT were included. A total of 35 (19.5%) patients developed MCE defined by using an established 10-point scale in follow-up CT, of which ≥4 points are considered malignant. Posterior circulation net water uptake (pcNWU) was quantified in admission CT based on CT densitometry and compared with posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) as predictor of MCE using receiver operating curve (ROC) analysis and logistic regression analysis. RESULTS: Acute pcNWU within the early ischemic lesion was 24.6% (±8.4) for malignant and 7.2% (±7.4) for nonmalignant infarctions, respectively (P < .0001). Based on ROC analysis, pcNWU above 14.9% identified MCE with high discriminative power (area under the curve: 0.94; 95% CI: 0.89-0.97). Early pcNWU (odds ratio [OR]: 1.28; 95% CI: 1.15-1.42, P < .0001) and pc-ASPECTS (OR: 0.71, 95% CI: 0.53-0.95, P = .02) were associated with MCE, adjusted for age and recanalization status. CONCLUSION: Quantitative pcNWU in early posterior circulation stroke is an important marker for MCE. Besides pc-ASPECTS, lesion water uptake measurements may further support identifying patients at risk for MCE at an early stage indicating stricter monitoring and consideration for further therapeutic measures.

Initial pupil status is a strong predictor for in-hospital mortality after aneurysmal subarachnoid hemorrhage.

Prognosis of patients with high-grade aneurysmal subarachnoid hemorrhage (aSAH) is only insufficiently displayed by current standard prognostic scores. This study aims to evaluate the role of pupil status for mortality prediction and provide improved prognostic models. Anonymized data of 477 aSAH patients admitted to our medical center from November 2010 to August 2018 were retrospectively analyzed. Identification of variables independently predicting in-hospital mortality was performed by multivariable logistic regression analysis. Final regression models included Hunt & Hess scale (H&H), pupil status and age or in a simplified variation only H&H and pupil status, leading to the design of novel H&H-Pupil-Age score (HHPA) and simplified H&H-Pupil score (sHHP), respectively. In an external validation cohort of 402 patients, areas under the receiver operating characteristic curves (AUROC) of HHPA (0.841) and sHHP (0.821) were significantly higher than areas of H&H (0.794; p < 0.001) or World Federation of Neurosurgical Societies (WFNS) scale (0.775; p < 0.01). Accordingly, including information about pupil status improves the predictive performance of prognostic scores for in-hospital mortality in patients with aSAH. HHPA and sHHP allow simple, early and detailed prognosis assessment while predictive performance remained strong in an external validation cohort suggesting adequate generalizability and low interrater variability.

Description of the response of a new multi-parametric brain sensor to physiological and pathophysiological challenges in the cortex of juvenile pigs.

AIM: Monitoring of intracranial pressure (ICP), local cerebral blood flow (CBF) and oxygen is part of modern intensive critical care medicine. Preclinical evaluation of newly developed catheters that should monitor several parameters simultaneously is reported poorly in the literature. The goal of our study was (1) to evaluate a new multi-parametric sensor in brain tissue and (2) to establish a testing protocol using pathophysiological challenges that target measured parameters of the sensor and autoregulatory boundaries and could be used as preclinical standard protocol in future studies. MATERIAL AND METHODS: We describe data from 12 new multi-parametric brain sensors (MPBS) that were implanted into 3 porcine brains and combined measurement of brain tissue oxygenation (ptiO2), ICP, CBF and brain temperature for the first time. Pigs were treated with a period of hyperoxygenation, hypercapnia, hypoxia, dobutamine, and norepinephrine. RESULTS: None of the 12 MPBS failed. Our testing protocol induced standardized pathophysiological changes that were picked up by the new MPBS as significant alterations in brain ptiO2, ICP and CBF. The magnitude of changes was >20% in most tested MPBS. CONCLUSION: An experimental protocol with pre-defined end-points for O2, CO2, blood pressure and cardiac output should be standardized and reported if new sensors for multi-parametric brain monitoring are evaluated. The use of several sensors per brain of only a few animals is sufficient to determine functionality of new sensors in vivo as basis for a larger study with reference sensors and brain injury.