bluuebunny/crossref_metadata_2025 huggingface dataset:
1245 Malignant Meningioma Survival, Recurrence and Functional Outcomes in an International Multicenter Cohort
Authors: Rebchuk Alexander , Tosefsky Kira , Wang Justin Z. , Ellenbogen Yosef , Drexler Richard , Ricklefs Franz Lennard , Sauvigny Thomas , Schüller Ulrich , Cutler Christopher , Lucke-Wold Brandon , Mehkri Yusuf , Lama Sanju , Sutherland Garnette R. , Karsy Michael , Hoh Brian Lim , Westphal Manfred , Zadeh Gelareh , Yip Stephen , Makarenko Serge
Published: March 2024

INTRODUCTION:

Meningiomas are the most common intracranial tumor. Grade 3 (malignant) meningiomas are the most aggressive subtype and represent 1-3% of all meningiomas cases.

METHODS:

Demographic, clinical and histopathological data from grade 3 intracranial meningioma cases were identified in the clinical databases from seven sites in North America and Europe from 1991-2022. Summary statistics and Kaplan-Meier OS and PFS curves were generated.

RESULTS:

We identified 108 patients, with a median age 65 years (IQR: 52, 72) and 53.7% were female. Median OS was 109 months (95% CIs: 88, 227) and 5-year OS rate was 65% (95% CIs: 56, 76). Median PFS was 38 months (95% CIs: 24, 56) and 5-year PFS rate was 37% (95% CIs: 28, 49). Older age (=65 years old) and male sex were independent predictors of worse OS and PFS in multivariate regression analysis. Postoperative radiotherapy was independently associated with improved OS in all patients and a sensitivity analysis including only patients =65 years old. Functional status, as measured by Karnofsky performance status, was stable between preoperative (median: 80 [IQR: 70, 90]), postoperative (median: 90 [IQR: 70, 98]) and 1-year postoperative (median: 70 [IQR: 50, 80]) timepoints.

CONCLUSIONS:

This study provides robust survival, recurrence, and functional outcome data for malignant meningiomas in North America and Europe over a 30-year period. We demonstrate that older age and male sex are associated with worse survival and recurrence outcomes. We further affirm that adjuvant radiotherapy confers a survival benefit in the treatment of malignant meningiomas, including in patients older than 65 years. Despite concerns around surgical and radiotherapy treatment complications, functional status remains stable in the first year following treatment of malignant meningiomas.
141 Motor and Somatosensory Applications for Nerve Cuff Electrodes in Clinical Neuroprosthesis and Neurorehabilitation
Authors: Abraham Mickey Ellis , Beyer Ryan , Brown Nolan James , Zomalan Brolyn , Lee Gold Justin , Sahyouni Ronald , Khalessi Alexander A. , Murthy Nikhil Krishna
Published: March 2024

INTRODUCTION:

Surgically implanted neuroprosthetics aim to restore motor and somatosensory function by delivering controlled electrical impulses to paralyzed nerves. Recently, nerve cuff electrodes (NCEs) have been increasingly studied and may eventually offer the potential to recover somatomotor function in patients with neurologic injury.

METHODS:

The PubMed, Google Scholar, and Web of Science databases were searched to identify relevant articles published between 2012 – 2022 describing use of neuroprosthetic NCEs for clinical somatomotor rehabilitation. Data from all relevant articles retrieved were collected and summarized.

RESULTS:

NCE-neural interfaces can restore both upper and lower extremity motor function in spinal cord injury patients and may provide a treatment modality superior to that of muscle-based electrodes. The search yielded 137 studies, and of those reviewed, 18 were original research articles that used peripheral nerve stimulation to elicit motor actions and/or somatosensory perceptions through NCEs. 10 studies looked at restoring motor function in patients with spinal cord injuries or stroke-related paralysis and 7 studies looked at somatosensory applications of NCEs in patients with amputations. Currently, sensory NCE interfacing can restore and improve multiple aspects of sensation in amputees. While there is room for further study in various applications, technological improvements and wider clinical adoption, NCEs have been demonstrated to provide a clinically acceptable option in reducing intraoperative duration and morbidity, while preserving long-term functional stability, threshold charge maintenance, and acceptable mechanical failure rates.

CONCLUSIONS:

NCEs appear to be a promising avenue for future research in the field of neuroprosthetics. As the translational avenue continues to mature and more clinical studies become avaiable, the utility of NCEs will be better understood.
145 Encoding Brain Dynamics: Neuropsychological Test Scores as Predictors of iEEG Spectral Features in Epilepsy
Authors: Hattab Tariq , Krieg Jordan , Kawtharani Sarah , Koenig Seth , Waldron Eric , Herman Alexander , Darrow David P.
Published: March 2024

INTRODUCTION:

Intracranial EEG is a valuable tool for investigating the neural mechanisms underlying medically refractory epilepsy (MRE). Despite the advances made in understanding the condition, there is a lack of research exploring the relationship between iEEG data and neuropsychological test performance in MRE patients.

METHODS:

We performed a retrospective analysis of resting-state iEEG data from 70 MRE patients, extracting spectral features from 4.4 million 10-second time windows across 5201 electrodes. Using MATLAB and FieldTrip toolbox, we processed the data and used two brain atlases for probabilistic electrode assignment. Neuropsychological test scores were corrected for demographic factors. Relationships between preoperative neuropsychological test scores and spectral features were explored using nested hierarchical generalized linear mixed effects (GLME) models, focusing on the hippocampus.

RESULTS:

We found significant associations between neuropsychological tests and hippocampal power spectral densities (PSDs). Rey Auditory verbal learning test (RAVLT) recognition correct and short-term retention percentages were significantly associated with relative power (RP) in the beta-range (p < 0.05, FDR-corrected). The Boston naming test and Trail Making Test (TMT)-A finishing time showed significant associations with high-beta/low-gamma PSD (p < 0.05, FDR-corrected). TMT-B errors are positively correlated with delta/theta RP (p < 0.05, FDR-corrected).

CONCLUSIONS:

Our study provides novel insights into the relationship between iEEG spectral features and neuropsychological test performance in MRE patients. The findings suggest that the heterogeneity in spectral features may explain relevant cognitive performance, highlighting the biological basis and circuits of neuropsychological testing.
146 Intracranial Correlates of Fear Memory in Freely Moving Humans During Virtual Reality
Authors: Gill Jay , Langevi Jean-Philippe , Suthana Nanthia
Published: March 2024

INTRODUCTION:

Distressing reactions to perceived threats in safe environments is a hallmark feature of anxiety-related disorders such as post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). The development of targeted neural circuit therapies requires an understanding of how neurophysiological activity relates to behavior and subjective emotional experience.

METHODS:

The task induced memories fear memories, a critical component of anxiety-related disorders etiology, using a novel virtual reality platform. Here, participants freely explored a virtual reality environment via walking or joystick. Participants were instructed to stop movement following color change of the room. When the room turned green (CS+), a noxious virtual reality stimulus (insect) attacked the participant (US) 6 seconds following color change onset. When the room turned blue (CS-), no noxious VR stimulus occurred. In addition to intracranial electroencephalography (iEEG) activity, we recorded physiological and behavioral metrics of fear.

RESULTS:

We found that the same neural signature indicative of fear memory retrieval in rodents (increased amygdala theta oscillations) was significantly elevated for the fear compared to the neutral cue in freely behaving humans.

CONCLUSIONS:

These findings represent an important step in translating decades of research in rodents to humans and provide putative electrophysiological signatures of fear behavior that can be used as putative targets for treatment with closed loop brain stimulation therapies. We believe that this combined collection of simultaneous autonomic responses to subjective emotional (fear ratings and physiology), clinical symptoms (anxiety scales) and neural activity has immense transdiagnostic clinical potential for anxiety-related disorders and can inform neurosurgical approaches to treating severe psychopathology.
152 Integrated Clinical Genomic Analysis Reveals Xenobiotic Metabolic Genes are Downregulated in Meningiomas of Current Smokers
Authors: Basit Khan A. Basit , Patel Rajan , McDonald Malcolm F. , Goethe Eric , English Collin , Gadot Ron , Shetty Arya , Harmanci Arif , Harmanci Akdes , Klisch Tiemo , Patel Akash J.
Published: March 2024

INTRODUCTION:

Meningiomas are the most common primary intracranial tumor. We sought to identify clinical drivers of different molecular changes in meningioma. As such, clinical and genomic consequences of smoking in patients with meningiomas remain unexplored.

METHODS:

88 tumor samples were analyzed. Whole exome sequencing (WES) was used to assess somatic mutation burden. RNA sequencing data was used to identify differentially expressed genes (DEG) and genes sets (GSEA).

RESULTS:

Fifty-seven patients had no history of smoking, thirty-one patients had history of ever smoking. Smokers were less likely to present with headache (p = 0.045) or have incidentally discovered meningiomas (p = 0.049). WES revealed no difference in canonical mutation burden. Smokers had increased mutation rate in KRTAP1-3, RECQL4, PTPRT, and PLB1 compared to never smokers (p < 0.05). Mutational signature from smokers showed disrupted DNA mismatch repair (cosine-similarity = .784). DEG analysis of current smokers as compared to past or never smokers revealed the xenobiotic metabolic genes UGT2A1 and UGT2A2 were both significantly downregulated in current smokers compared to past (Log2FC = -3.97, padj = 0.0347 and Log2FC = -4.18, padj = 0.0304) and never smokers (Log2FC = -3.86, padj = 0.0235 and Log2FC = -4.20, padj = 0.0149). GSEA analysis of current smokers showed downregulation of xenobiotic metabolism and enrichment for G2M checkpoint, E2F targets, and mitotic spindle compared to past and never smokers (FDR <25% each).

CONCLUSIONS:

There are limited differences in the clinical course of meningioma patients who smoke. There is no difference in burden of canonical mutations in meningiomas from patients who smoke, but differential mutation in several novel meningioma genes is identified. Mutational signatures in meningiomas from smokers show disrupted DNA mismatch repair. Meningiomas from current smokers demonstrate downregulation of xenobiotic metabolic enzymes UGT2A1 and UGT2A2, which are downregulated in other smoking related cancers. Taken together, our demonstrate novel alterations in meningioma molecular biology in response to systemic carcinogens.
179 Stem Progenitor Cell Proliferation in the Brainstem After Spinal Cord Injury: A Potential Target for Therapeutic Intervention Distant From the Site of Injury
Authors: Carmichael Marc , Hayes Nancy , Nowakowski Richard
Published: March 2024

INTRODUCTION:

Though there has been an increasing number of clinical trials focused on modulating stem/progenitor cell proliferation in the spinal cord after spinal cord injury (SCI), little is known about the acute response of stem/progenitor cells in supraspinal structures. We hypothesized that the signals stimulating stem/progenitor cell proliferation in the spinal cord after SCI activate similar responses in supraspinal regions because pathways injured in the spinal cord have their targets or sources in the brain.

METHODS:

We employed a mouse model of SCI, bromodeoxyuridine (BrdU) labeling of cells in S-phase, and co-labeling of markers of astrocytes, microglia, glial/oligodendrocyte precursor cells, and neuronal lineages to characterize the proliferative response within the brainstem of C57BL/6J mice 96 hours after a thoracic SCI. The extent of SCI and white matter (WM) spared was quantified by labeling of beta amyloid precursor protein and eriochrome cyanine R staining, respectively.

RESULTS:

Compared to sham-operated mice, there was a significant increase (3-fold; p < 0.01) in BrdU-labeled cells in the ventral-caudal medulla of injured mice. This response was consistent with the extent of SCI and primarily in WM tracts (57%) and the inferior olive (41%; IO). Co-labeling with cell-specific markers indicated that this response is glial (i.e., NG-2+ glial/oligodendrocyte precursor cells and GFAP+ astrocytes) with the largest increase in the number of BrdU-labeled cells occurring in the IO (6-fold increase; p < 0.01). Notably, there were no BrdU-labeled cells that co-labeled with markers of microglia or neuronal lineages.

CONCLUSIONS:

Our results demonstrate a stem/progenitor cell response within days of SCI that occurs distant from the injury site, notably in brainstem structures involved in motor learning and coordination. These findings highlight an acute response of glial/oligodendrocyte precursor cells in the brainstem as a potential target for future studies and therapeutic intervention after SCI.
180 The Impact of Brain Tissue Oxygen Monitoring With Intracranial Pressure Monitoring on Patients With Severe TBI: A National Trauma Bank Data Analysis
Authors: Nosova Kristin , Jukic Alma , Bauer Isabel L. , Deaver Courtney , Pico Annemarie Campbell , Bates Bryan , He Jack , Keric Natasha , Nakaji Peter , Bina Robert Wagner
Published: March 2024

INTRODUCTION:

While numerous studies have demonstrated the importance of ICP monitoring in improving the mortality rate for severe traumatic brain injuries (TBI), the benefits of brain oxygenation monitoring (PbO2) in combination with ICP monitoring are still currently under investigation as part of the BOOST III trial.

METHODS:

Patients with severe TBI based on the Glascow Coma Scale were identified using National Trauma Bank data from 2019-2021. Patients who died in the ED, had ED disposition inconsistent with severe TBI, or were transferred to another hospital were excluded. Summary statistics, t-tests, chi-square tests, non-parametric tests, multivariate logistic models, and log-log regression models were used to evaluate and model the data.

RESULTS:

13,139 patients with severe TBI who underwent ICP monitoring were identified, with 709 (5%) undergoing PbO2 monitoring. Patients with PbO2 monitors had longer ICU length of stay (17.3 days vs. 14.3 days p < .05) and a longer duration of ventilation (14.5 days vs. 12 days p < .05). Additionally, patients with PbO2 monitors experienced increased rates of deep vein thrombosis and pulmonary embolism (OR 1.57 95% CI; 1.22-2.01). There was no significant difference in mortality rate with PbO2 monitoring after controlling for severity (4.5% vs. 4%, p = 0.07).

CONCLUSIONS:

PbO2 monitoring was associated with longer ICU length of stay and days ventilated, consistent with prior studies. Patients with PbO2 monitoring experienced higher rates of deep vein thrombosis and pulmonary embolism. Different from previous studies, our results indicate PbO2 monitoring does not impact mortality outcomes. Data about functional outcomes are not yet available. Further studies are needed to address this discrepancy; the ongoing BOOST III trial may provide a better understanding on the proper use of PbO2 monitoring.
182 Purification and Characterization of Human Neural Stem and Progenitor Cells
Authors: He Joy , Liu Daniel , Sinha Rahul , Eastman Anna , Toland Angus , Morri Maurizio , Neff Norma , Vogel Hannes , Uchida Nobuko , Weissman Irving
Published: March 2024

INTRODUCTION:

The human brain undergoes rapid development at mid-gestation from a pool of neural stem and progenitor cells (NSPCs) that give rise to the neurons, oligodendrocytes, and astrocytes of the mature brain. Functional study of these cell types has been hampered by a lack of precise purification methods.

METHODS:

We combine high-dimensional flow cytometry with single cell transcriptomics to comprehensively purify and functionally characterize NSPCs from the developing human brain during mid-gestation. We utilize index sorting based on the combinatorial expression of cell-surface markers (immunophenotype) to directly link surface-marker expression to the expressed transcriptomes of single cells, allowing for rigorous validation of sort purity. We further demonstrate the functional properties of each identified cell type in vitro and in vivo.

RESULTS:

CD24-THY1-/lo cells were enriched for radial glia, which robustly engrafted and differentiated into all three neural lineages in the mouse brain.THY1hi cells marked unipotent oligodendrocyte precursors committed to an oligodendroglial fate, and CD24+ THY1-/lo cells marked committed excitatory and inhibitory neuronal lineages. Notably, we identify and functionally characterize a novel transcriptomically distinct THY1hiEGFRhiPDGFRA- bipotent glial progenitor cell, which is lineage-restricted to astrocytes and oligodendrocytes, but not to neurons.

CONCLUSIONS:

The results presented here are strong proof-of-concept that distinct cell types from the developing brain can be prospectively isolated based on the expression of multiple surface markers. The combined results from scRNA-seq, in vitro differentiation, and in vivo transplantation offers the most rigorous interrogation of NSPCs’ transcriptomic identities and functional behavior. The modular nature of our antibody panel allows for the easy expansion or simplification of the panel, based on the cell-type of interest, thus providing a valuable tool for future investigation of both molecular and functional NSPC heterogeneity.
187 Achondroplasia Natural History Study (CLARITY): 60-Year Experience With Hydrocephalus in Achondroplasia From Four Skeletal Dysplasia Centers
Authors: Campbell Jeffrey , Piatt Joseph , Hoover-Fong Julie Elizabeth , Bober Michael , Lagare Janet M.
Published: March 2024

INTRODUCTION:

This study is the largest to date to look at the treatment of hydrocephalus in achondroplasia.

METHODS:

CLARITY (The Achondroplasia Natural History Study) is a registry for clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2017. Data included surgeries with indications and complications, medical diagnoses, and radiographic information.

RESULTS:

1374 patients with achondroplasia were included in this study. 124 (9%) of these patients underwent treatment of hydrocephalus at a median age of 14.6 months. There was wide variation by center and decade of birth, with treatment ranging from 0% to 28% of patients, although in the most recent decade, it fell to 3.4% of patients. Requiring cervicomedullary decompression (CMD) predicted treatment of hydrocephalus with an odds ratio of 5.8 (95% CI 3.9-8.4), although that association has disappeared in those born since 2010 with an odd’s ratio of 1.1 (95% CI 0.2-5.7). In patients born since 1990, treatment of hydrocephalus with an ETV has become more common. Kaplan Meier analysis suggests a single ETV will treat hydrocephalus in roughly half of these patients.

CONCLUSIONS:

While children with achondroplasia have enlarged intracranial CSF spaces and macrocephaly, treatment of hydrocephalus has become relatively unusual in the last twenty years. Historically there was a significant association between symptomatic foramen magnum (FM) stenosis and treatment of hydrocephalus, although concurrent treatment of both has fallen out of favor since CMD alone will treat hydrocephalus in some patients. While understood as communicating hydrocephalus, endoscopic third ventriculostomy (ETV) appears to be reasonably successful in certain patients and should be considered an option in selected patients.
194 Responsive Neurostimulation Targeting the Centromedian Nucleus of the Thalamus Improves Seizure Control in Idiopathic Generalized Epilepsy and Select Multifocal Disease
Authors: Nanda Pranav , Walton Ashley , Sisterson Nathaniel , Richardson Robert Mark
Published: March 2024

INTRODUCTION:

Although more than 30% of epilepsy patients are drug resistant, many have not traditionally been considered surgical candidates due to generalized or multifocal disease. However, responsive neurostimulation (RNS) of the centromedian nucleus (CM) of the thalamus appears promising for this patient population. We present outcomes following CM RNS for patients with idiopathic generalized epilepsy (IGE) or multifocal disease, with subgroup analyses of patients’ seizure types and targeting methodology.

METHODS:

21 patients with drug resistant epilepsy underwent bilateral CM RNS implantation. Electrodes were localized and volumes of tissue activation (VTAs) were modeled in Lead-DBS. Outcome measures were extracted from electronic medical records. Clinical outcomes over time were compared between patients’ seizure types and RNS recorded long-episodes, and VTA overlap with thalamic nuclei was compared between patients with direct and indirect targeting methodologies.

RESULTS:

For patients with at least 1-year of follow up, average seizure reduction from pre-operative baseline was 81.3%, with 3 Engel class 1 patients, 5 Engel class 2, 8 Engel class 3, and 0 Engel class 4. Average seizure reduction was greatest for non-lesional multifocal patients. Average time to worthwhile seizure reduction was 217 days, and was shortest for myoclonic IGE patients. Long-episodes were associated with seizure reduction in IGE patients only. Direct targeting led to more anterior and medial electrodes with greater VTA overlap with CM.

CONCLUSIONS:

CM RNS may provide significant relief for IGE and multifocal epilepsy patients. Subsets of these patient populations may particularly benefit from CM RNS. Direct targeting may facilitate more selective stimulation of the CM. The refinement of stimulation targeting, tuning of RNS system parameters, and deliberate patient selection are ongoing areas of investigation.
200 DWI and ADC Changes in Patients With Glioblastoma IDH-Wild Type Following Surgical Tumor Resection
Authors: Rojas Pavel Pichardo , Bandopadhay Josh , Nunez Luis C. , Esquenazi Yoshua , Dono Ostorga Antonio Gabriel , Rodriguez Andres , Tandon Nitin , Riascos Roy
Published: March 2024

INTRODUCTION:

Current standard of care for glioblastoma (GBM) entails maximal tumor resection to achieve better outcomes while preserving neurological function. Early postoperative DWI has elucidated that peritumoral ischemia is common following glioma resection, but radiographic characteristics, risk factors, and outcomes have not been well described.

METHODS:

This retrospective cohort included 324 patients (18-86 years) who underwent surgical resection for glioblastoma IDH-wildtype between 2005 and 2022. All patients had structural MRI and DWI acquired preoperatively and within 72 hrs after resection. Areas of restricted diffusion on postoperative DWI were classified as rim, sector, mixed, or remote.

RESULTS:

Areas of restricted diffusion on postoperative DWI were found in 173 (53%) patients. 55 (32%) were rim-shaped, 103 (59%) sector-shaped, 10 (6%) mixed, and 5 (3%) remote. Preoperative tumor volume was positively correlated with areas of ischemia (p = 0.048), but peritumoral DWI was not correlated with decreased overall survival (OS) or Karnofsky Performance Score (KPS). In the full cohort analysis, gross total resection (GTR) correlated with improved OS compared to subtotal total resection (STR) (p = 0.016); however, subgroup analysis revealed that this survival benefit was exclusively found in patients without peritumoral infarction on DWI (21 months vs. 13 months, p = 0.043).

CONCLUSIONS:

Larger tumor volume was a risk factor for larger peritumoral infarction. The survival benefit of GTR was only seen in patients who did not experience postoperative peritumoral infarction, underscoring the importance of maximal safe tumor resection. Future study on specific causes of postoperative peritumoral infarctions may improve surgical management and outcomes in glioblastoma patients.
207 Intraoperative Functional Re-mapping Unveils Evolving Patterns of Cortical Plasticity
Authors: Ng Sam , Valdes Pablo Andres , Moritz-Gasser Sylvie , Lemaitre Anne-Laure , Duffau Hugues , Herbet Guillaume
Published: March 2024

INTRODUCTION:

Diffuse low-grade gliomas (DLGG) induce a compensatory modulation of the anatomo-functional architecture, making this kind of brain tumours an ideal lesion model to study the dynamics of neuroplasticity. Direct electrostimulation (DES) mapping is a well-tried procedure used during awake resection surgeries to spare cortical epicenters which are critical for a range of functions. Because DLGG is a chronic disease, it inevitably relapses years after the initial surgery, and thus requires a second surgery to reduce tumour volume again.

METHODS:

We capitalized on a series of 101 DLGG patients who benefited from two DES-guided neurosurgeries usually spaced several years apart, resulting in a DES dataset of 2082 cortical sites. We used a multi-step approach to generate probabilistic neuroplasticity maps that reflected the dynamic rearrangements of cortical mappings from one surgery to another, both at the population and individual-level.

RESULTS:

Voxel-wise neuroplasticity maps revealed regions with a high potential of evolving reorganizations, including the supplementary motor area (SMA), the dorsolateral prefrontal cortex (dlPFC), the anterior ventral premotor cortex (vPMC) and the middle superior temporal gyrus (STG). Parcel-wise neuroplasticity maps confirmed this potential for the dlPFC, the anterior and the ventral precentral gyrus. A series of clustering analyses revealed a topological migration of clusters, especially within the left dlPFC and STG (language sites); the left vPMC (speech arrest/dysarthria sites) and the right SMA (negative motor response sites). At the individual level, these dynamic changes were confirmed for the dlPFC (bilateral), the left vPMC and the anterior left STG (threshold free cluster enhancement, 5000 permutations, family-wise-error-corrected).

CONCLUSIONS:

Our results provide a critical insight into the dynamic potential of DLGG-induced continuing rearrangements of the cerebral cortex, with considerable implications for re-operations.
215 Reexamining Nimodipine's Effect on Neurological Outcomes After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis
Authors: Derrico Nicholas , Lucas Kathryn , Washington Chad W.
Published: March 2024

INTRODUCTION:

Nimodipine therapy is a guideline-directed treatment to improve neurological outcomes after ruptured aneurysmal subarachnoid hemorrhage (aSAH).

METHODS:

We performed a systematic review and meta-analysis of ruptured aSAH trials reporting ‘good’ neurological outcomes, defined as Modified Rankin Scale 0-2 or the study’s own criteria. ‘Pre-nimodipine’ studies included those prior to the use of nimodipine. ‘Nimodipine’ studies gave nimodipine as an investigational drug, leading to its widespread acceptance. ‘Post-nimodipine’ studies gave nimodipine as standard-of-care to controls. 172 studies were screened, 122 were evaluated in full for eligibility, and 52 were included. Rates of ‘good’ outcomes were aggregated and compared with respect to era and nimodipine status.

RESULTS:

‘Nimodipine’ era nimodipine recipients had exceptionally high rates of ‘good’ neurological outcome at 81% (95% CI 68-92%). ‘Post-nimodipine’ era nimodipine recipients had a 67% (95% CI 64-70%) rate of ‘good’ neurological outcome. When subcategorized by decade, this was stable at 68% (95% CI 62-73%), 64% (95% CI 58-69%), and 70% (95% CI 64-73%). Those not receiving nimodipine in the ‘pre-nimodipine’ and ‘nimodipine’ eras also had a similar chance of ‘good’ neurological outcome at 60% (95% CI 49-71%) and 69% (95% CI 55-82%) respectively. ‘Nimodipine’ era studies were too heterogeneous to be statistically different, however 5 of the 7 are outside 95% confidence intervals when compared to any other group.

CONCLUSIONS:

Approximately 60-70% of patients in randomized studies of ruptured aSAH have ‘good’ neurologic outcomes regardless of nimodipine status or era of treatment. The studies that examined nimodipine as an intervention, leading to its acceptance as the standard of care, are historical outliers. This raises concerns about nimodipine’s overall efficacy in treating aSAH, and the validity of its recommendation in the ruptured aSAH management guidelines.
230 Machine Learning for Automated and Real-time 2D-3D Registration of the Spine Using Only a Single Radiograph
Authors: Abumoussa Andrew , Gopalakrishnan Vivek , Succop Benjamin Sterling , Galgano Michael Anthony , Jaikumar Sivakumar , Lee Yueh , Bhowmick Deb A.
Published: March 2024

INTRODUCTION:

Authors present a 2-dimensional to 3-dimensional (2D-3D) registration algorithm that identifies the position of a C-arm relative to a 3D volume.

METHODS:

This work utilizes digitally reconstructed radiographs (DRR) which are synthetic radiographic images generated by simulating the x-ray projections as they would pass through a CT volume. To evaluate our algorithm, we used cone-beam CT data from 127 patients obtained from a de-identified registry of cervical, thoracic, and lumbar scans. We systematically evaluated and tuned a self-supervised algorithm, quantified the limitations and convergence rate of our model by simulating C-arm registrations with 80 randomly simulated DRRs for each CT volume. The endpoints for this study were the time to convergence, accuracy of convergence for each of the C-arm's degrees of freedom (DoF), and overall registration accuracy based on a voxel-by-voxel measurement.

RESULTS:

10,160 unique fluoroscopic images were simulated from 127 CT scans. Our algorithm successfully converged to the correct solution 81% of the time with an average of 1.97 seconds of computation. The fluoroscopic images for which the algorithm converged to the solution achieved 99.9% registration accuracy despite only utilizing single-precision computation for speed. Our algorithm was found to be optimized for convergence when the search space was limited to a ± 45° offset in the RAO/LAO, cranial/caudal and receiver rotation angles with the radiographic isocenter contained within 8000cm3 of the volumetric center of the CT volume.

CONCLUSIONS:

The machine learning algorithm we present has the potential to aid surgeons with many aspects of spine surgery through an automated 2D-3D registration process. Future work will focus on algorithmic optimizations adn deep-learning to improve the convergence rate and speed profile.
235 IL-4/13 Blocking Peptide (KROS-401) Inhibits M2 Macrophage Polarization in vitro and Demonstrates Anti-tumor Activity in a Murine Model of Glioblastoma
Authors: Michel Michelot , Israel Liron , Tusa Lavieri Miguel Eduardo , Wang Hongqiang , Miyaguchi Ken , Mohyeddinipour Sarah , Watanabe Junji , Black Keith L. , Murali Ramachandran , Yu John
Published: March 2024

INTRODUCTION:

Glioblastoma (GBM) is the most aggressive primary brain malignancy with a median survival of 14 months. Tumor-associated macrophages (TAMs) comprise up to 40% of the GBM tumor mass and are significant enablers of an immunosuppressive tumor microenvironment (TME), limiting immunotherapeutic efficacy. TAMs are generally classified as M2 macrophages that demonstrate a pro-tumor phenotype and increased CD206 surface marker expression. Reducing the M2 macrophage population in tumors has shown benefit in preclinical studies across various cancers. Interleukins (IL)-4 and -13 both play a role in polarizing macrophages to an M2 state. We developed a peptide inhibitor (KROS-401) that targets the shared IL-4Ra subunit of the IL-4 and -13 receptor complex to inhibit macrophage polarization to an M2 phenotype and reprogram the immunosuppressive TME.

METHODS:

Human peripheral blood mononuclear cell (PBMC)-derived macrophages were isolated and treated with KROS-401 in the presence of IL-4 and IL-13 cytokines. M2 (CD206) surface markers were assessed by flow cytometry. The efficacy of KROS-401 peptide was examined using an intracranially implanted syngeneic murine model with luciferase-expressing GL261, a glioma cell line. Mice were inspected daily for survival and tumor growth was tracked by non-invasive in vivo bioluminescent imaging (BLI).

RESULTS:

Human PBMC-derived macrophages treated with KROS-401 displayed a dose-dependent decrease in M2 (CD206) cell surface markers. KROS-401 peptide inhibitor demonstrated anti-tumor activity in GL261 glioma-bearing mice with a significantly increased probability of survival compared to control (p = 0.0046) with a median survival of >40 days versus 27 days, respectively.

CONCLUSIONS:

KROS-401 inhibits M2 polarization of human macrophages in vitro and tumor growth in vivo. These findings highlight this IL-4/IL-13 peptide inhibitor as a potential immunomodulator of the TME for the treatment of GBM.
238 Quality of Life After Chronic Subdural Hematoma Surgery—GET-UP Randomized Clinical Trial's 1 Year Results
Authors: Sousa Sérgio , Pinto Vasco Sá , Grande Ana , Fernandes Armindo Picão , Batata Rodrigo , Costa Tiago , Silva João Fernandes , Rangel Rui , Calheiros Alfredo
Published: March 2024

INTRODUCTION:

Timing for mobilization after chronic subdural hematoma (cSDH) surgery is highly heterogeneous among neurosurgical centers around the world. Nonetheless, there is a scarcity of high-quality evidence addressing this question.

METHODS:

A total of 208 patients were randomized to either an early mobilization group (EMG), where mobilization is required within the first 12 hours post-op; or to a bed rest group (BRG) where they remain recumbent for 48 hours after surgery. All 208 patients were interviewed by telephone one year after surgery. A score of 16 or more in the Mini Mental State Examination was mandatory for study inclusion. Quality of life was assessed by applying the 36-Item Short Form Health Survey (SF-36).

RESULTS:

A total of 134 patients (73 in the EMG and 61 in the BRG) were included. EMG patients performed significantly better in six of the eight domains of SF-36 questionnaire. The mean scores obtained were, in the EMG and in the BRG, respectively, 73.4 and 61.7 in the Physical Functioning (p = 0.017); 88.6 and 75.8 in the Social Functioning (p = 0.004); 67.6 and 61.4 in Mental Health (p = 0.029); 87.4 and 78.6 in Emotional Performance (p = 0.036); 61.2 and 50.4 in Vitality (p = 0.011); and 58.5 and 47.1 in General Health (p = 0.007). In the two remaining dimensions, Physical Performance and Body Pain, results were also superior in the EMG but without statistical significance. Quality of life was negatively impacted by the occurrence of medical complications, with the Physical Performance domain reaching statistical significance (p = 0.016).

CONCLUSIONS:

GET-UP trial’s results argue strongly towards an early mobilization protocol, as this strategy leads to a significant improvement in the quality of life of patients after cSDH surgery.
246 Algorithmic CT Scan Analysis for Prognosticating Brain Injury: A Preliminary Effort
Authors: Broadbent Charles , Sridhar Sharada Kadaba , Gupta Rishabh , Sterk Brett , Koller Michael , Kuang Rui , Samadani Uzma
Published: March 2024

INTRODUCTION:

Predicting which trauma patients will progress to brain death is currently based on history, physical examination and radiographic findings.

METHODS:

38 trauma subjects, 18 which progressed to brain death (BD), who suffered from high-velocity trauma with presumed diffuse axonal injury, cardiopulmonary/respiratory arrest, and/or found down were included. BLAST-CT was used to identify four lesion types: intraparenchymal hemorrhage, extra-axial hemorrhage, perilesional oedema, and intraventricular hemorrhage. Cerebrospinal fluid volumes were extracted using SimpleITK. These two sets of features were obtained from whole head CT scans and within 117 standardized brain atlas regions. Five ROC curves for classifying BD versus non-BD were generated using a support vector machine trained on (1) BLAST-CT (4 features), (2) Regional BLAST-CT (468 features), (3) Regional CSF volumes (117), (4) BLAST-CT + Regional CSF volumes (121 features), and (5) Regional BLAST-CT + Regional CSF volumes (585 features).

RESULTS:

For BLAST-CT alone, area under the curve (AUC), sensitivity, specificity, and accuracy in classifying BD were 0.7806, 61.11%, 95.00%, and 78.95% respectively. For regional BLAST CT, they were 0.7611, 55.56%, 100%, and 78.95% respectively. For regional CSF volume, they were 0.7056, 94.44%, 50.00%, and 71.05%. For BLAST-CT + regional CSF volumes, they were 0.8389, 94.44%, 65.00%, and 79.85%. For regional BLAST-CT + regional CSF volumes, they were 0.9083, 83.33%, 100%, 92.11%.

CONCLUSIONS:

Results indicate that the present model using regional BLAST-CT + regional CSF volumes is able to classify brain death with a large specificity, sensitivity, and accuracy above 90%. Given the clinical value of a tool to assist physicians in predicting progression to BD, additional prospective trials with larger samples and testing cohorts should be conducted.
255 Frailty Is Associated With Decreased 365-day Survival in Adult Patients With Operative and Nonoperative Traumatic Subdural Hemorrhage
Authors: Courville Evan , Owodunni Oluwafemi , Courville Jordyn , Kassicieh Alex James , Hynes Allison , Schmidt Meic H. , Bowers Christian Andrew
Published: March 2024

INTRODUCTION:

Traumatic subdural hematoma (tSDH) is observed frequently in traumatic brain injury (TBI) patients and is one of the commonest neurosurgical emergencies. tSDH patients require rapid evaluation and treatment in order to achieve the best possible results. There is a paucity of literature on frailty’s impact in TBI patients.

METHODS:

We performed a retrospective review of tSDH patients in the ACS-TQIP® database between 2007-2020. We employed multivariable regression models to examine the independent relationship of frailty, identified by the modified frailty index-5 (mFI-5) with the endpoints of major complications, length of stay (LOS), mortality, and discharge to a higher level of care. Additionally, we employ Kaplan-Meier (K-M) plots to examine the probability of survival following tSDH across the various mFI-5 frailty risk strata.

RESULTS:

340,096 patients were managed nonoperatively and 41,658 operatively. The median age of the patients was 70.0 (IQR: 54.0, 81.0) nonoperative, and 71.0 (57.0, 80.0) operative cohorts. Multivariate analysis demonstrates a stepwise dose response relationship with outcomes p < 0.001. In both cohorts, there was an 18-86% in mortality i.e. nonoperative: frail (OR: 1.18 [95% CI 1.13, 1.23]), very frail (OR: 1.75 [95% CI 1.65, 1.86]); and operative: frail (OR: 1.21 [95% CI 1.12, 1.32]), very frail (OR: 1.86 [95% CI 1.66, 2.09]). Survival probability markedly decreased across frailty strata within the first 100 days.

CONCLUSIONS:

Frailty was associated with major complications, LOS, mortality, and discharge to a higher-level care facility in patients with tSDH. Rapid deployment of point of care frailty risk-assessment allows clinicians to improve prognostication for patients and their families and allocate resources more precisely in order to try to achieve better outcomes.
262 The BRAF V600E Mutation and Tumor Cells Are Frequently Seen in Seemingly Normal Brain Parenchyma Beyond Ganglioglioma Tumor Borders: Implications for Seizure and Tumor Control
Authors: Bokhari Rakan Farouk Y. , Karamchandani Jason , Jabado Nada , Guiot Marie-Christine , Dudley Roy W. R.
Published: March 2024

INTRODUCTION:

Gangliogliomas are WHO grade I glioneural tumors that are frequently encountered in the work up of medically refractory focal epilepsy. Their management typically involves gross total resection of the MRI-visible tumor. However, seizures may continue to be experienced by the patient post-operatively with no clear explanation.

Recent evidence suggested both the unexpected invasive nature of these tumors, as well as an inherent epileptogenic nature of the BRAF-V600 mutation independent of tumor presence.

METHODS:

We analyzed the peri-lesional tissue resected in epilepsy surgical cases secondary to gangliogliomas in seven patients.

RESULTS:

Unexpectedly, we identified either satellite tumors within the tissue, or evidence of extension of the BRAF mutation into morphologically normal tissue in four of the five patients with BRAF-V600 positive tumors. No such findings were encountered in the two BRAF-V600 negative cases.

CONCLUSIONS:

This work highlights the need of extending research efforts into the parenchyma beyond structural lesions in these cases, as our preliminary results suggest a role for field cancerization in these tumors. In addition, these findings have significant implications on the understanding and management of these tumors, which appear to have a poorly described invasive nature. It also provides a potential explanation and treatment target for seizures persisting in patients despite a gross total resection of MRI-visible tumor.
266 Combination Drug Therapy in H3 K27-Altered Diffuse Midline Glioma Enhances Tumor Retention and Treatment Efficacy
Authors: Rechberger Julian , Anderson Jacob , Ge Jizhi , Zhang Liang , Daniels David J.
Published: March 2024

INTRODUCTION:

Diffuse midline gliomas (DMG) with H3 K27 alterations are uniformly lethal tumors for which no therapy has been found to be effective. One reason for our therapy failure is the blood-brain barrier (BBB), which severely restricts uptake and accumulation of systemically administered drugs in the brain. Convection-enhanced delivery (CED) has emerged as a technique that circumvents the BBB by directly infusing therapeutics into the tumor parenchyma through generation of a mechanical pressure gradient, allowing for homogenous drug distribution at high local concentrations with minimal systemic toxicity. However, efflux transport proteins expressed by the BBB and the tumor, including P-gp and BCRP, rapidly clear the majority of drugs given by CED, severely limiting its therapeutic potential.

METHODS:

A panel of FDA-approved drugs (ponatinib, topotecan, tretinoin) were evaluated alone and in combination with the known efflux transporter inhibitor everolimus.

RESULTS:

A high degree of formal synergy was observed in multiple DMG cell lines in vitro, which was attributed to everolimus’ ability to inhibit mTOR signaling and P-gp/BCRP. In vivo, drugs that were expected to penetrate the BBB and be less likely to undergo active efflux persisted at the site of infusion the longest following CED. Concurrent dosing with everolimus further enhanced this effect, which was particularly apparent with the dual P-gp/BCRP substrate ponatinib.

CONCLUSIONS:

The proclivity of many drugs to be rapidly cleared from the brain by efflux transporters generates a vulnerability that can be exploited for the development of novel therapeutic regimens in DMG, such as with concomitant dosing of P-gp/BCRP-inhibiting drugs when using CED.
268 Integrative Genomics Identifies Evolutionary, Temporal, and Cell-lineage Origin of Hydrocephalus Risk Gene
Authors: Hale Andrew T. , Song Yuwei , Chong Zechen
Published: March 2024

INTRODUCTION:

Our previous work identified MAEL, a gene involved in regulation of DNA transposon activity and histone methylation, as a transcriptome-wide predictor of pediatric hydrocephalus (Hale et al., Cell Reports, 2021). Here we aim to characterize the function of MAEL across timescales and cell-lineages in the developing human brain to understand the pathophysiological basis of hydrocephalus.

METHODS:

We performed taxonomic analysis of MAEL across species using Ensemble. Analysis of single-cell RNA sequencing (scRNA-seq) of 49 brain regions across the prenatal period from the Developing Human Brain Atlas (Allen Institute) and an atlas of late-prenatal cortical tissue identified temporospatial MAEL expression patterns. Finally, to estimate the degree to which in vitro models recapitulate expression patterns of MAEL in the developing brain, we analyzed scRNA-seq from human neural and choroid-plexus organoids.

RESULTS:

We performed taxonomic evolutionary gene-mapping to define the evolutionary origin of MAEL to assess suitability for mechanistic characterization in model systems. MAEL is among the top 0.01% human-specific genes and shares < 50% sequence homology with mammalian model organisms. scRNA-seq identified MAEL first detected in the telencephalon at 9 weeks post-conception, highest expressed in the sub-ventricular zone at 16 weeks, and lowest expressed in the hippocampus at 21 weeks post conception. Temporospatial expression of MAEL in the late-prenatal cortex identifies MAEL expression largely restricted to the neural progenitor cells before reaching steady-state expression throughout the cortical layers at 39 weeks gestation. Finally, spatial MAEL expression is largely preserved in brain organoids and robustly expressed in choroid plexus organoids highlighting the utility of these models in future mechanistic studies.

CONCLUSIONS:

We delineate the evolutionary origin and temporospatial patterns of MAEL expression in the developing human brain and organoid models. These data provide the premise for understanding the detailed molecular-genetic underpinnings of hydrocephalus.
274 Predicting Reoperation in Surgically Managed Pediatric Chiari I Malformation
Authors: Johnstone Thomas , Barros Guinle Maria Isabel , Grant Gerald
Published: March 2024

INTRODUCTION:

Chiari I malformation (CMI) involves the herniation of cerebellar tonsils into the spinal canal, without brainstem involvement. When patients are symptomatic, surgical decompression is recommended, but reoperation rates can be as high as 30%.

METHODS:

Patients were queried from the 2007-2016 MarketScan Databases with the CPT code (61343) for CM decompression. To be included, a patient had to have been diagnosed with CMI, received decompressive surgery, and be eighteen or younger at the time of first operation. Patients were excluded if they had a diagnosis of any other class of Chiari malformation at any point. Next, the Elixhauser Comorbidity Index was constructed for each patient. These variables were then used as covariates in a multivariate regression model to predict reoperation following surgical decompression. Odds ratios, their corresponding confidence intervals, and metrics of significance were determined.

RESULTS:

2,823 patients were included, with an average age of 10.4 (SD = 5.4). 169 (6.0%) patients underwent reoperations. As patient age at first operation increased, their reoperation rate decreased steadily (OR = 0.95, 95% CI = 0.93-0.98, p = 0.002). This association was primarily driven by a sharp decline in reoperation rate after the first three years of life. Patients in their first year had a mean reoperation rate of 17.6%; by age three, the reoperation rate declined to 5.2%, remaining fairly stable from age four (5.1%) to eighteen (4.9%). Use of duraplasty (OR = 0.75, 95% CI = 0.52-1.06, p = 0.112) did not alter the likelihood of reoperation.

CONCLUSIONS:

In a national pediatric cohort of patients with surgically managed Chiari I malformations, there was a significantly increased likelihood of reoperation in younger children. Our findings suggest that, when medically feasible, initial CMI surgery should be delayed until the age of three to minimize the chance of reoperation.