Citations

Mechanical thrombectomy (MT) represents the mainstay of treatment for patients with acute ischemic stroke due to large-vessel occlusion (LVO). Intravenous thrombolysis has been associated with worse clinical outcome in patients presenting with high blood glucose levels at admission; to date the true effect of hyperglycemia in the setting of MT has not been fully elucidated. In this meta-analysis, we analyzed the influence of high blood glucose levels at admission on clinical outcome after MT. Ovid EMBASE, PubMed, Scopus, and Cochrane Library databases were searched from their dates of inception up to March 2021. An initial search identified 2118 articles representing 1235 unique studies. After applying selection criteria, three prospective and five retrospective studies were analyzed, yielding a pooled cohort of 5861 patients (2041 who presented with hyperglycemia, and 3820 who presented with normal blood glucose levels). Patients in the hyperglycemia group were less likely to have a modified Ranking Scale (mRS) score <3 (risk ratio (RR): 0.65; 95% CI 0.59 to 0.72; p<0.0001; I 2=13%), and had an increased risk of symptomatic intracranial hemorrhage (sICH) (RR: 2.07; 95% CI 1.65 to 2.60; p<0.0001; I 2=0%) and mortality (RR: 1.73; 95% CI 1.57 to 1.91; p<0.0001; I 2=0%). Patients who present with hyperglycemia and undergo MT for treatment of LVO have an increased risk of unfavorable clinical outcome, sICH, and mortality. Glucose levels at admission appear to be a prognostic factor in this subset of patients. Further studies should focus on evaluating control of the glucose level at admission as a modifiable risk factor in patients undergoing MT for LVO.

Objective Observational studies utilising diffusion tractography have suggested a common mechanism for tremor alleviation in deep brain stimulation for essential tremor: the decussating portion of the dentato-rubro-thalamic tract. We hypothesised that directional stimulation of the dentato-rubro-thalamic tract would result in greater tremor improvement compared to sham programming, as well as comparable improvement as more tedious standard-of-care programming. Methods A prospective, blinded crossover trial was performed to assess the feasibility, safety and outcomes of programming based solely on dentato-rubro-thalamic tract anatomy. Using magnetic resonance imaging diffusion-tractography, the dentato-rubro-thalamic tract was identified and a connectivity-based treatment setting was derived by modelling a volume of tissue activated using directional current steering oriented towards the dentato-rubro-thalamic tract centre. A sham setting was created at approximately 180° opposite the connectivity-based treatment. Standard-of-care programming at 3 months was compared to connectivity-based treatment and sham settings that were blinded to the programmer. The primary outcome measure was percentage improvement in the Fahn–Tolosa–Marín tremor rating score compared to the preoperative baseline. Results Among the six patients, tremor rating scores differed significantly among the three experimental conditions ( P=0.030). The mean tremor rating score improvement was greater with the connectivity-based treatment settings (64.6% ± 14.3%) than with sham (44.8% ± 18.6%; P=0.031) and standard-of-care programming (50.7% ± 19.2%; P=0.062). The distance between the centre of the dentato-rubro-thalamic tract and the volume of tissue activated inversely correlated with the percentage improvement in the tremor rating score (R 2 =0.24; P=0.04). No significant adverse events were encountered. Conclusions Using a blinded, crossover trial design, we have shown the technical feasibility, safety and potential efficacy of connectivity-based stimulation settings in deep brain stimulation for treatment of essential tremor.

Purpose Exploration of the effect of chronic recurrent seizures in focal epilepsy on brain volumes has produced many conflicting reports. To determine differences in brain structure in temporal lobe epilepsy (TLE) and extratemporal epilepsy (using frontal lobe epilepsy (FLE) a surrogate) further, we performed a retrospective analysis of a large cohort of patients with seizure-onset zone proven by intracranial monitoring. Methods A total of 120 TLE patients, 86 FLE patients, and 54 healthy controls were enrolled in this study. An analysis of variance of voxel-based morphometry (VBM) was used to seek morphometric brain differences among TLE patients, FLE patients, and healthy controls. Additionally, a vertex-based surface analysis was utilized to analyze the hippocampus and thalamus. Significant side-specific differences in hippocampal gray matter volume were present between the left TLE (LTLE), right TLE RTLE (RTLE), and control groups ( p<0.05, family-wise error (FWE) corrected). Results Vertex analyses revealed significant volume reduction in inferior parts of the left hippocampus in the LTLE group and lateral parts of the right hippocampus in the RTLE group compared to controls ( p<0.05, FWE corrected). Significant differences were also detected between the LTLE and control group in the bilateral medial and inferior thalamus ( p<0.05, FWE corrected). FLE patients did not exhibit focal atrophy of gray matter across the brain. Conclusion Our results highlight the variation in morphometric lateralized changes in the brain between different epilepsy onset zones, providing critical insight into the natural history of people with drug-resistant focal epilepsies.

Abstract BACKGROUND Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an increasingly utilized treatment of drug-resistant epilepsy. To date, the effect of high-frequency stimulation (HFS) vs low-frequency stimulation (LFS) in ANT DBS is poorly understood. OBJECTIVE To assess differences in the acute effect of LFS vs HFS in ANT DBS utilizing blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI). METHODS In this prospective study of 5 patients with ANT DBS for epilepsy, BOLD activation and deactivation were modeled for 145-Hz and 30-Hz ANT stimulation using an fMRI block design. Data were analyzed with a general linear model and combined via 2-stage mixed-effects analysis. Z-score difference maps were nonparametrically thresholded using cluster threshold of z > 3.1 and a (corrected) cluster significance threshold of P = .05. RESULTS HFS produced significantly greater activation within multiple regions, in particular the limbic and default mode network (DMN). LFS produced minimal activation and failed to produce significant activation within these same networks. HFS produced widespread cortical and subcortical deactivation sparing most of the limbic and DMN regions. Meanwhile, LFS produced deactivation in most DMN and limbic structures. CONCLUSION Our results show that HFS and LFS produce substantial variability in both local and downstream network effects. In particular, largely opposing effects were identified within the limbic network and DMN. These findings may serve as a mechanistic basis for understanding the potential of HFS vs LFS in various epilepsy syndromes.

Abstract Neurosurgical training is being challenged by rigorous work-hour restrictions and the COVID-19 pandemic. 1 Now, more than ever, surgical simulation plays a pivotal role in resident education and psychomotor skill development. Three-dimensional (3D) printing technologies enable the construction of inexpensive, patient-specific, anatomically accurate physical models for a more convenient and realistic simulation of complex skull base approaches in a safe environment. 2 All stages of the surgical procedure can be simulated, from positioning and exposure to deep microdissection, which has an unparalleled educational value. The complex approach-specific anatomy, narrow working angles, and pathoanatomic relationships can be readily explored from the surgeon's perspective or point of view. 2,3 Furthermore, different thermoplastic polymers can be utilized to replicate the visual and tactile feedback of bone (cortical/cancellous), neurological, and vascular tissues. 4 Retrosigmoid craniectomies are widely used in neurosurgery with various applications, including microvascular decompressions in patients with trigeminal neuralgia. 5-7 Removal of the suprameatal tubercle (SMT) extends the retrosigmoid approach superiorly to the middle fossa and Meckel's cave, and anteriorly to the clivus. 8,9 This maneuver may be necessary in patients with prominent SMTs obstructing the view of the trigeminal nerve and in patients with a more anterosuperior neurovascular conflict. This video illustrates a microsurgical training tool for learning and honing the technique of retrosigmoid craniectomy and suprameatal drilling using an affordable (29.00 USD) biomimetic 3D-printed simulator that closely recapitulates not only the anatomy but also the tactile feedback of drilling and manipulating neurological tissues (see Table and Graph 1; minute 07:11) as it happens at the time of surgery.

Abstract Introduction: Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. The interaction of GBM with the lateral ventricles (LVs) has a significant effect on patient outcome, where LV-proximal GBM results in increased distal recurrence, increased stem cell marker expression, and decreased overall survival compared to LV-distal counterparts. Though the reason for this is unknown, it may be due in part to interaction of GBM with the subventricular zone (SVZ), the largest neurogenic niche. The SVZ contains populations of neural stem cells (NSCs) throughout life that produce many proteins supporting stem cell growth and maintenance. The goal of this project is to identify a bidirectional signaling axis between GBM cells and NSCs and determine its contribution to GBM malignancy. Methods: In vitro, patient-derived GBM brain tumor initiating cells (BTICs) were co-cultured with human fetal NSCs for 48 hours. Both BTICs and NSCs were analyzed for levels of viability, proliferation, migration, and the expression of malignancy-associated factors at a gene and protein level. A method for unbiased cell-specific proteomic labeling was established in vitro by cloning L274G-mutated methionyl tRNA synthetase (MetRS*) into a lentivirus with puromycin resistance. In vivo, Nestin-Cre-ERT2 mice were crossed with the STOPflox R26-MetRS line to establish a tamoxifen-inducible model to label NSC proteins. Results: BTICs co-cultured with NSCs showed increased viability, proliferation, and migration compared to controls. NSCs showed decreased proliferation and increased migration when co-cultured with BTICs. Both show increased levels of malignancy-associated genes and proteins including osteopontin, vimentin, tenascin C, and PDGFA upon co-culture. MetRS*-labeled cells successfully incorporate azide-labeled methionine analog in a cell-specific manner, and labeled proteins are able to be isolated for future proteomic analysis. In vivo, tamoxifen successfully induces the expression of MetRS* and GFP. Conclusion: We have determined that there is a bidirectional signaling axis between NSCs and BTICs that contributes to proliferation, migration, and malignancy-associated factors in GBM. Future studies looking at proteomic changes in both GBM and NSCs using the MetRS* labeling are needed to fully characterize the interaction between these cells in vitro and in vivo to identify new therapeutic targets for LV-associated GBM. Citation Format: Emily S. Norton, Lauren A. Whaley, Anna Carrano, Natanael Zarco, Montserrat A. Lara-Velazquez, Alfredo Quinones-Hinojosa, Hugo Guerrero-Cazares. Exploring the malignancy-promoting interaction between neural stem cells and lateral ventricle-associated glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3073.

Background and purpose Deep brain stimulation of the thalamus is an effective treatment for multiple neurological disorders. The centromedian and parafascicular nuclei are recently emerging targets for multiple conditions, such as epilepsy and Tourette syndrome; however, their limited visibility on conventional magnetic resonance imaging sequences has been a major obstacle. The goal of this study was to demonstrate the feasibility of a high-resolution and high-contrast targeting sequence for centromedian-parafascicular deep brain stimulation using a recently described magnetic resonance imaging sequence, three-dimensional edge-enhancing gradient echo. Methods The three-dimensional edge-enhancing gradient echo sequence was performed on a normal volunteer for a total of six acquisitions. Multi-image co-registration and averaging was performed by first co-registering each of the six scans and then averaging to produce an edge-enhancing gradient echo-multi-image co-registration and averaging scan. The averaging was also performed for two, three, four and five scans to assess the change in the signal-to-noise ratio and identify the ideal balance of image quality and scan time. Results The edge-enhancing gradient echo-multi-image co-registration and averaging scan allowed clear boundary delineation of the centromedian and parafascicular nuclei. The signal-to-noise ratio increased as a function of increasing scan number, but the added gain was small beyond four scans for the imaging parameters used in this study. Conclusions The recently described three-dimensional edge-enhancing gradient echo sequence provides an easily implementable approach, using widely available magnetic resonance imaging technology without complex post-processing techniques, to delineate centromedian and parafascicular nuclei for deep brain stimulation targeting.

OBJECTIVE The authors’ goal was to use a multicenter, observational cohort study to determine whether supramarginal resection (SMR) of FLAIR-hyperintense tumor beyond the contrast-enhanced (CE) area influences the overall survival (OS) of patients with isocitrate dehydrogenase–wild-type (IDH-wt) glioblastoma after gross-total resection (GTR). METHODS The medical records of 888 patients aged ≥ 18 years who underwent resection of GBM between January 2011 and December 2017 were reviewed. Volumetric measurements of the CE tumor and surrounding FLAIR-hyperintense tumor were performed, clinical variables were obtained, and associations with OS were analyzed. RESULTS In total, 101 patients with newly diagnosed IDH-wt GBM who underwent GTR of the CE tumor met the inclusion criteria. In multivariate analysis, age ≥ 65 years (HR 1.97; 95% CI 1.01–2.56; p < 0.001) and contact with the lateral ventricles (HR 1.59; 95% CI 1.13–1.78; p = 0.025) were associated with shorter OS, but preoperative Karnofsky Performance Status ≥ 70 (HR 0.47; 95% CI 0.27–0.89; p = 0.006), MGMT promotor methylation (HR 0.63; 95% CI 0.52–0.99; p = 0.044), and increased percentage of SMR (HR 0.99; 95% CI 0.98–0.99; p = 0.02) were associated with longer OS. Finally, 20% SMR was the minimum percentage associated with beneficial OS (HR 0.56; 95% CI 0.35–0.89; p = 0.01), but > 60% SMR had no significant influence (HR 0.74; 95% CI 0.45–1.21; p = 0.234). CONCLUSIONS SMR is associated with improved OS in patients with IDH-wt GBM who undergo GTR of CE tumor. At least 20% SMR of the CE tumor was associated with beneficial OS, but greater than 60% SMR had no significant influence on OS.

Abstract Microglia have fundamental roles in health and disease, however effects of age, sex and genetic factors on human microglia have not been fully explored. We applied bulk and single cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex and APOE . We identified a novel microglial signature, characterized its expression in bulk data from 1,306 brain samples across 6 regions and in single cell microglia transcriptome. We discovered microglial co-expression network modules associated with age, sex and APOE -ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single cell transcriptomes revealed significant overlap between age-associated module genes and both pro-inflammatory and disease-associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2 and BIN1 . These data represent a well-characterized human microglial transcriptome resource; and highlight age, sex and APOE -related microglial immunometabolism perturbations with potential relevance in neurodegeneration.