Pharmacological targeting of secondary brain damage following ischemic or hemorrhagic stroke, traumatic brain injury, and bacterial meningitis - a systematic review and meta-analysis

Background: The effectiveness of pharmacological strategies exclusively targeting secondary brain damage (SBD) following ischemic stroke, aneurysmal subarachnoid hemorrhage, aSAH, intracerebral hemorrhage (ICH), traumatic brain injury (TBI) and bacterial meningitis is unclear. This meta-analysis studied the effect of SBD targeted treatment on clinical outcome across the pathological entities. Methods: Randomized, controlled, double-blinded trials on aforementioned entities with ‘death’ as endpoint were identified. Effect sizes were analyzed and expressed as pooled risk ratio (RR) estimates with 95% confidence intervals (CI). 123 studies fulfilled the criteria, with data on 66,561 patients. Results: In the pooled analysis, there was a minor reduction of mortality for aSAH [RR 0.93 (95% CI:0.85–1.02)], ICH [RR 0.92 (95% CI:0.82–1.03)] and bacterial meningitis [RR 0.86 (95% CI:0.68–1.09)]. No reduction of mortality was found for ischemic stroke [RR 1.05 (95% CI:1.00–1.11)] and TBI [RR 1.03 (95% CI:0.93–1.15)]. Additional analysis of “poor outcome” as endpoint gave similar results. Subgroup analysis with respect to effector mechanisms showed a tendency towards a reduced mortality for the effector mechanism category “oxidative metabolism/stress” for aSAH with a risk ratio of 0.86 [95% CI: 0.73–1.00]. Regarding specific medications, a statistically significant reduction of mortality and poor outcome was confirmed only for nimodipine for aSAH and dexamethasone for bacterial meningitis. Conclusions: Our results show that only a few selected SBD directed medications are likely to reduce the rate of death and poor outcome following aSAH, and bacterial meningitis, while no convincing evidence could be found for the usefulness of SBD directed medications in ischemic stroke, ICH and TBI. However, a subtle effect on good or excellent outcome might remain undetected. These results should lead to a new perspective of secondary reactions following cerebral injury. These processes should not be seen as suicide mechanisms that need to be fought. They should be rather seen as well orchestrated clean-up mechanisms, which may today be somewhat too active in a few very specific constellations, such as meningitis under antibiotic treatment and aSAH after surgical or endovascular exclusion of the aneurysm

Spontaneous regression of multiple flow-related aneurysms following treatment of an associated brain arteriovenous malformation: A case report.

INTRODUCTION There is no consensus in the treatment strategy of intracranial aneurysms (IAs) associated with brain arteriovenous malformation (BAVM). In particular, it is unknown if a more aggressive approach should be considered in patients harboring a BAVM, in whom multiple aneurysms or a history of aneurysmal subarachnoid hemorrhage (aSAH) is present. CASE PRESENTATION We report on an elderly woman harboring multiple aneurysms with a history of SAH due to rupture of an unrelated IA. On evaluation, she was also found to harbor a contralateral, left parietal convexity BAVM. Following resection of the latter, spontaneous regression of two large flow-related aneurysms was encountered. DISCUSSION We discuss the therapeutic decision-making, risk stratification, and functional outcome in this patient with regard to the pertinent literature on the risk of hemorrhage in IAs associated with BAVM

Randomized, open-label, phase 1/2a study to determine the maximum tolerated dose of intraventricular sustained release nimodipine for subarachnoid hemorrhage (NEWTON [Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage])

BACKGROUND AND PURPOSE—: We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. METHODS—: Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. RESULTS—: Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P=0.027) enteral nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). CONCLUSIONS—: EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. CLINICAL TRIAL REGISTRATION—: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01893190

Proposed Definition of Experimental Secondary Ischemia for Mouse Subarachnoid Hemorrhage.

Inconsistency in outcome parameters for delayed cerebral ischemia (DCI) makes it difficult to compare results between mouse studies, in the same way inconsistency in outcome parameters in human studies has for long obstructed adequate comparison. The absence of an established definition may in part be responsible for the failed translational results. The present article proposes a standardized definition for DCI in experimental mouse models, which can be used as outcome measure in future animal studies. We used a consensus-building approach to propose a definition for "experimental secondary ischemia" (ESI) in experimental mouse subarachnoid hemorrhage that can be used as an outcome measure in preclinical studies. We propose that the outcome measure should be as follows: occurrence of focal neurological impairment or a general neurological impairment compared with a control group and that neurological impairment should occur secondarily following subarachnoid hemorrhage (SAH) induction compared with an initial assessment following SAH induction. ESI should not be used if the condition can be explained by general anesthesia or if other means of assessments sufficiently explain function impairment. If neurological impairment cannot reliably be evaluated, due to scientific setup. Verification of a significant secondary impairment of the cerebral perfusion compared with a control group is mandatory. This requires longitudinal examination in the same animal. The primary aim is that ESI should be distinguished from intervention-related ischemia or neurological deficits, in order establish a uniform definition for experimental SAH in mice that is in alignment with outcome measures in human studies

Defining activities in neurovascular microsurgery training : entrustable professional activities for vascular neurosurgery

Background Entrustable professional activities (EPAs) represent an assessment framework with an increased focus on competency-based assessment. Originally developed and adopted for undergraduate medical education, concerns over resident ability to practice effectively after graduation have led to its implementation in residency training but yet not in vascular neurosurgery. Subjective assessment of resident or fellow performance can be problematic, and thus, we aim to define core EPAs for neurosurgical vascular training. Methods We used a nominal group technique in a multistep interaction between a team of experienced neurovascular specialists and a medical educator to identify relevant EPAs. Panel members provided feedback on the EPAs until they reached consent. Results The process produced seven core procedural EPAs for vascular residency and fellowship training, non-complex aneurysm surgery, complex aneurysm surgery, bypass surgery, arteriovenous malformation resection, spinal dural fistula surgery, perioperative management, and clinical decision-making. Conclusion These seven EPAs for vascular neurosurgical training may support and guide the neurosurgical society in the development and implementation of EPAs as an evaluation tool and incorporate entrustment decisions in their training programs.Peer reviewe

Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide.

Glioblastoma (GBM) is a lethal disease with limited clinical treatment options available. Recently, a new inhibitor targeting the prominent cancer signaling pathway mTOR was discovered (Rapalink-1), but its therapeutic potential on stem cell populations of GBM is unknown. We applied a collection of physiological relevant organoid-like stem cell models of GBM and studied the effect of RL1 exposure on various cellular features as well as on the expression of mTOR signaling targets and stem cell molecules. We also undertook combination treatments with this agent and clinical GBM treatments tumor treating fields (TTFields) and the standard-of-care drug temozolomide, TMZ. Low nanomolar (nM) RL1 treatment significantly reduced cell growth, proliferation, migration, and clonogenic potential of our stem cell models. It acted synergistically to reduce cell growth when applied in combination with TMZ and TTFields. We performed an in silico analysis from the molecular data of diverse patient samples to probe for a relationship between the expression of mTOR genes, and mesenchymal markers in different GBM cohorts. We supported the in silico results with correlative protein data retrieved from tumor specimens. Our study further validates mTOR signaling as a druggable target in GBM and supports RL1, representing a promising therapeutic target in brain oncology

Spontaneous regression of multiple flow-related aneurysms following treatment of an associated brain arteriovenous malformation: A case report

IntroductionThere is no consensus in the treatment strategy of intracranial aneurysms (IAs) associated with brain arteriovenous malformation (BAVM). In particular, it is unknown if a more aggressive approach should be considered in patients harboring a BAVM, in whom multiple aneurysms or a history of aneurysmal subarachnoid hemorrhage (aSAH) is present.Case presentationWe report on an elderly woman harboring multiple aneurysms with a history of SAH due to rupture of an unrelated IA. On evaluation, she was also found to harbor a contralateral, left parietal convexity BAVM. Following resection of the latter, spontaneous regression of two large flow-related aneurysms was encountered.DiscussionWe discuss the therapeutic decision-making, risk stratification, and functional outcome in this patient with regard to the pertinent literature on the risk of hemorrhage in IAs associated with BAVM

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

Abstract: Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply of macromolecular precursors by targeting enzymes involved in biosynthesis is a promising strategy in cancer therapy. Several tumors excessively metabolize glutamine to generate precursors for nonessential amino acids, nucleotides, and lipids, in a process called glutaminolysis. Here we show that pharmacological inhibition of glutaminase (GLS) eradicates glioblastoma stem-like cells (GSCs), a small cell subpopulation in glioblastoma (GBM) responsible for therapy resistance and tumor recurrence. Treatment with small molecule inhibitors compound 968 and CB839 effectively diminished cell growth and in vitro clonogenicity of GSC neurosphere cultures. However, our pharmaco-metabolic studies revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivates into the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivity markedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models as compared with neural stem cells (NSC). Moreover, our study demonstrates the usefulness of in vitro pharmaco-metabolomics to score target specificity of compounds thereby refining drug development and risk assessment