Magnetic Resonance Imaging-Guided Frameless Stereotactic Injections of the Bilateral Cerebellar Dentate Nuclei in Nonhuman Primates: Technical Note.

BACKGROUND AND OBJECTIVES: Nonhuman primates (NHPs) are important preclinical models for evaluating therapeutics because of their anatomophysiological similarities to humans, and can be especially useful for testing new delivery targets. With the growing promise of cell and gene therapies for the treatment of neurological diseases, it is important to ensure the accurate and safe delivery of these agents to target structures in the brain. However, a standard guideline or method has not been developed for stereotactic targeting in NHPs. In this article, we describe the safe use of a magnetic resonance imaging-guided frameless stereotactic system to target bilateral cerebellar dentate nuclei for accurate, real-time delivery of viral vector in NHPs. METHODS: Seventeen rhesus macaques (Macaca mulatta) underwent stereotactic surgery under real-time MRI guidance using the ClearPoint® system. Bilateral cerebellar dentate nuclei were targeted through a single parietal entry point with a transtentorial approach. Fifty microliters of contrast-impregnated infusate was delivered to each dentate nucleus, and adjustments were made as necessary according to real-time MRI monitoring of delivery. Perioperative clinical outcomes and postoperative volumes of distribution were recorded. RESULTS: All macaques underwent bilateral surgery successfully. Superficial pin site infection occurred in 4/17 (23.5%) subjects, which resolved with antibiotics. Two episodes of transient neurological deficit (anisocoria and unilateral weakness) were recorded, which did not require additional postoperative treatment and resolved over time. Volume of distribution of infusate achieved satisfactory coverage of target dentate nuclei, and only 1 incidence (2.9%) of cerebrospinal fluid penetration was recorded. Mean volume of distribution was 161.22 ± 39.61 mm3 (left, 173.65 ± 48.29; right, 148.80 ± 23.98). CONCLUSION: MRI-guided frameless stereotactic injection of bilateral cerebellar dentate nuclei in NHPs is safe and feasible. The use of this technique enables real-time modification of the surgical plan to achieve adequate target coverage and can be readily translated to clinical use.

Seizure onset patterns predict outcome after stereo-electroencephalography-guided laser amygdalohippocampotomy.

OBJECTIVE: Stereotactic laser amygdalohippocampotomy (SLAH) is an appealing option for patients with temporal lobe epilepsy, who often require intracranial monitoring to confirm mesial temporal seizure onset. However, given limited spatial sampling, it is possible that stereotactic electroencephalography (stereo-EEG) may miss seizure onset elsewhere. We hypothesized that stereo-EEG seizure onset patterns (SOPs) may differentiate between primary onset and secondary spread and predict postoperative seizure control. In this study, we characterized the 2-year outcomes of patients who underwent single-fiber SLAH after stereo-EEG and evaluated whether stereo-EEG SOPs predict postoperative seizure freedom. METHODS: This retrospective five-center study included patients with or without mesial temporal sclerosis (MTS) who underwent stereo-EEG followed by single-fiber SLAH between August 2014 and January 2022. Patients with causative hippocampal lesions apart from MTS or for whom the SLAH was considered palliative were excluded. An SOP catalogue was developed based on literature review. The dominant pattern for each patient was used for survival analysis. The primary outcome was 2-year Engel I classification or recurrent seizures before then, stratified by SOP category. RESULTS: Fifty-eight patients were included, with a mean follow-up duration of 39 ± 12 months after SLAH. Overall 1-, 2-, and 3-year Engel I seizure freedom probability was 54%, 36%, and 33%, respectively. Patients with SOPs, including low-voltage fast activity or low-frequency repetitive spiking, had a 46% 2-year seizure freedom probability, compared to 0% for patients with alpha or theta frequency repetitive spiking or theta or delta frequency rhythmic slowing (log-rank test, p = .00015). SIGNIFICANCE: Patients who underwent SLAH after stereo-EEG had a low probability of seizure freedom at 2 years, but SOPs successfully predicted seizure recurrence in a subset of patients. This study provides proof of concept that SOPs distinguish between hippocampal seizure onset and spread and supports using SOPs to improve selection of SLAH candidates.

Remote effects of temporal lobe epilepsy surgery: Long-term morphological changes after surgical resection.

OBJECTIVE: Epilepsy surgery is an effective treatment for drug-resistant patients. However, how different surgical approaches affect long-term brain structure remains poorly characterized. Here, we present a semiautomated method for quantifying structural changes after epilepsy surgery and compare the remote structural effects of two approaches, anterior temporal lobectomy (ATL), and selective amygdalohippocampectomy (SAH). METHODS: We studied 36 temporal lobe epilepsy patients who underwent resective surgery (ATL = 22, SAH = 14). All patients received same-scanner MR imaging preoperatively and postoperatively (mean 2 years). To analyze postoperative structural changes, we segmented the resection zone and modified the Advanced Normalization Tools (ANTs) longitudinal cortical pipeline to account for resections. We compared global and regional annualized cortical thinning between surgical treatments. RESULTS: Across procedures, there was significant cortical thinning in the ipsilateral insula, fusiform, pericalcarine, and several temporal lobe regions outside the resection zone as well as the contralateral hippocampus. Additionally, increased postoperative cortical thickness was seen in the supramarginal gyrus. Patients treated with ATL exhibited greater annualized cortical thinning compared with SAH cases (ATL: -0.08 ± 0.11 mm per year, SAH: -0.01 ± 0.02 mm per year, t = 2.99, P = 0.006). There were focal postoperative differences between the two treatment groups in the ipsilateral insula (P = 0.039, corrected). Annualized cortical thinning rates correlated with preoperative cortical thickness (r = 0.60, P < 0.001) and had weaker associations with age at surgery (r = -0.33, P = 0.051) and disease duration (r = -0.42, P = 0.058). SIGNIFICANCE: Our evidence suggests that selective procedures are associated with less cortical thinning and that earlier surgical intervention may reduce long-term impacts on brain structure.

Normative intracranial EEG maps epileptogenic tissues in focal epilepsy.

Planning surgery for patients with medically refractory epilepsy often requires recording seizures using intracranial EEG. Quantitative measures derived from interictal intracranial EEG yield potentially appealing biomarkers to guide these surgical procedures; however, their utility is limited by the sparsity of electrode implantation as well as the normal confounds of spatiotemporally varying neural activity and connectivity. We propose that comparing intracranial EEG recordings to a normative atlas of intracranial EEG activity and connectivity can reliably map abnormal regions, identify targets for invasive treatment and increase our understanding of human epilepsy. Merging data from the Penn Epilepsy Center and a public database from the Montreal Neurological Institute, we aggregated interictal intracranial EEG retrospectively across 166 subjects comprising >5000 channels. For each channel, we calculated the normalized spectral power and coherence in each canonical frequency band. We constructed an intracranial EEG atlas by mapping the distribution of each feature across the brain and tested the atlas against data from novel patients by generating a z-score for each channel. We demonstrate that for seizure onset zones within the mesial temporal lobe, measures of connectivity abnormality provide greater distinguishing value than univariate measures of abnormal neural activity. We also find that patients with a longer diagnosis of epilepsy have greater abnormalities in connectivity. By integrating measures of both single-channel activity and inter-regional functional connectivity, we find a better accuracy in predicting the seizure onset zones versus normal brain (area under the curve = 0.77) compared with either group of features alone. We propose that aggregating normative intracranial EEG data across epilepsy centres into a normative atlas provides a rigorous, quantitative method to map epileptic networks and guide invasive therapy. We publicly share our data, infrastructure and methods, and propose an international framework for leveraging big data in surgical planning for refractory epilepsy.

Policies Restricting Overlapping Surgeries Negatively Impact Access to Care, Clinical Efficiency, and Hospital Revenue: A Forecasting Model for Surgical Scheduling.

OBJECTIVE: To model the financial impact of policies governing the scheduling of overlapping surgeries, and to identify optimal solutions that maximize operating efficiency that satisfy the fiduciary duty to patients. BACKGROUND: Hospitals depend on procedural revenue to maintain financial health as the recent pandemic has revealed. Proposed policies governing the scheduling of overlapping surgeries may dramatically impact hospital revenue. To date, the potential financial impact has not been modeled. METHODS: A linear forecasting model based on a logic matrix decision tree enabled an analysis of surgeon productivity annualized over a fiscal year. The model applies procedural and operational variables to policy constraints limiting surgical scheduling. Model outputs included case and financial metrics modeled over 1000-surgeon-year simulations. case metrics included annual case volume, case mix, operating room (OR) utilization, surgeon utilization, idle time, and staff overtime hours. Financial outputs included annual revenue, expenses, and contribution margin. RESULTS: The model was validated against surgical data. case and financial metrics decreased as a function of increasingly restrictive scheduling scenarios, with the greatest contribution margin loses ($1,650,000 per surgeon-year) realized with the introduction of policies mandating that a second patient could not enter the OR until the critical portion of the first surgery was completed. We identify an optimal scheduling scenario that maximizes surgeon efficiency, minimizes OR idle time and revenue loses, and satisfies ethical obligations to patients. CONCLUSIONS: Hospitals may expect significant financial loses with the introduction of policies restricting OR scheduling. We identify an optimal solution that maximizes efficiency while satisfying ethical duty to patients. This forecast is immediately relevant to any hospital system that depends upon procedural revenue.

Toxicity after AAV delivery of RNAi expression constructs into nonhuman primate brain.

RNA interference (RNAi) for spinocerebellar ataxia type 1 can prevent and reverse behavioral deficits and neuropathological readouts in mouse models, with safety and benefit lasting over many months. The RNAi trigger, expressed from adeno-associated virus vectors (AAV.miS1), also corrected misregulated microRNAs (miRNA) such as miR150. Subsequently, we showed that the delivery method was scalable, and that AAV.miS1 was safe in short-term pilot nonhuman primate (NHP) studies. To advance the technology to patients, investigational new drug (IND)-enabling studies in NHPs were initiated. After AAV.miS1 delivery to deep cerebellar nuclei, we unexpectedly observed cerebellar toxicity. Both small-RNA-seq and studies using AAVs devoid of miRNAs showed that this was not a result of saturation of the endogenous miRNA processing machinery. RNA-seq together with sequencing of the AAV product showed that, despite limited amounts of cross-packaged material, there was substantial inverted terminal repeat (ITR) promoter activity that correlated with neuropathologies. ITR promoter activity was reduced by altering the miS1 expression context. The surprising contrast between our rodent and NHP findings highlight the need for extended safety studies in multiple species when assessing new therapeutics for human application.

Electrocorticography and stereo EEG provide distinct measures of brain connectivity: implications for network models.

Brain network models derived from graph theory have the potential to guide functional neurosurgery, and to improve rates of post-operative seizure freedom for patients with epilepsy. A barrier to applying these models clinically is that intracranial EEG electrode implantation strategies vary by centre, region and country, from cortical grid & strip electrodes (Electrocorticography), to purely stereotactic depth electrodes (Stereo EEG), to a mixture of both. To determine whether models derived from one type of study are broadly applicable to others, we investigate the differences in brain networks mapped by electrocorticography and stereo EEG in a cohort of patients who underwent surgery for temporal lobe epilepsy and achieved a favourable outcome. We show that networks derived from electrocorticography and stereo EEG define distinct relationships between resected and spared tissue, which may be driven by sampling bias of temporal depth electrodes in patients with predominantly cortical grids. We propose a method of correcting for the effect of internodal distance that is specific to electrode type and explore how additional methods for spatially correcting for sampling bias affect network models. Ultimately, we find that smaller surgical targets tend to have lower connectivity with respect to the surrounding network, challenging notions that abnormal connectivity in the epileptogenic zone is typically high. Our findings suggest that effectively applying computational models to localize epileptic networks requires accounting for the effects of spatial sampling, particularly when analysing both electrocorticography and stereo EEG recordings in the same cohort, and that future network studies of epilepsy surgery should also account for differences in focality between resection and ablation. We propose that these findings are broadly relevant to intracranial EEG network modelling in epilepsy and an important step in translating them clinically into patient care.

Enhanced Fiber Tractography Using Edema Correction: Application and Evaluation in High-Grade Gliomas.

BACKGROUND: A limitation of diffusion tensor imaging (DTI)-based tractography is peritumoral edema that confounds traditional diffusion-based magnetic resonance metrics. OBJECTIVE: To augment fiber-tracking through peritumoral regions by performing novel edema correction on clinically feasible DTI acquisitions and assess the accuracy of the fiber-tracks using intraoperative stimulation mapping (ISM), task-based functional magnetic resonance imaging (fMRI) activation maps, and postoperative follow-up as reference standards. METHODS: Edema correction, using our bi-compartment free water modeling algorithm (FERNET), was performed on clinically acquired DTI data from a cohort of 10 patients presenting with suspected high-grade glioma and peritumoral edema in proximity to and/or infiltrating language or motor pathways. Deterministic fiber-tracking was then performed on the corrected and uncorrected DTI to identify tracts pertaining to the eloquent region involved (language or motor). Tracking results were compared visually and quantitatively using mean fiber count, voxel count, and mean fiber length. The tracts through the edematous region were verified based on overlay with the corresponding motor or language task-based fMRI activation maps and intraoperative ISM points, as well as at time points after surgery when peritumoral edema had subsided. RESULTS: Volume and number of fibers increased with application of edema correction; concordantly, mean fractional anisotropy decreased. Overlay with functional activation maps and ISM-verified eloquence of the increased fibers. Comparison with postsurgical follow-up scans with lower edema further confirmed the accuracy of the tracts. CONCLUSION: This method of edema correction can be applied to standard clinical DTI to improve visualization of motor and language tracts in patients with glioma-associated peritumoral edema.

Design and Validation of a Multi-Point Injection Technology for MR-Guided Convection Enhanced Delivery in the Brain.

Convection enhanced delivery (CED) allows direct intracranial administration of neuro-therapeutics. Success of CED relies on specific targeting and broad volume distributions (VD). However, to prevent off-target delivery and tissue damage, CED is typically conducted with small cannulas and at low flow rates, which critically limit the maximum achievable VD. Furthermore, in applications such as gene therapy requiring injections of large fluid volumes into broad subcortical regions, low flow rates translate into long infusion times and multiple surgical trajectories. The cannula design is a major limiting factor in achieving broad VD, while minimizing infusion time and backflow. Here we present and validate a novel multi-point cannula specifically designed to optimize distribution and delivery time in MR-guided intracranial CED of gene-based therapeutics. First, we evaluated the compatibility of our cannula with MRI and common viral vectors for gene therapy. Then, we conducted CED tests in agarose brain phantoms and benchmarked the results against single-needle delivery. 3T MRI in brain phantoms revealed minimal susceptibility-induced artifacts, comparable to the device dimensions. Benchtop CED of adeno-associated virus demonstrated no viral loss or inactivation. CED in agarose brain phantoms at 3, 6, and 9 µL/min showed >3x increase in volume distribution and 60% time reduction compared to single-needle delivery. This study confirms the validity of a multi-point delivery approach for improving infusate distribution at clinically-compatible timescales and supports the feasibility of our novel cannula design for advancing safety and efficacy of MR-guided CED to the central nervous system.

Gels, jets, mosquitoes, and magnets: a review of implantation strategies for soft neural probes.

Implantable neuroelectronic interfaces have enabled breakthrough advances in the clinical diagnosis and treatment of neurological disorders, as well as in fundamental studies of brain function, behavior, and disease. Intracranial electroencephalography (EEG) mapping with stereo-EEG (sEEG) depth electrodes is routinely adopted for precise epilepsy diagnostics and surgical treatment, while deep brain stimulation has become the standard of care for managing movement disorders. Intracortical microelectrode arrays for high-fidelity recordings of neural spiking activity have led to impressive demonstrations of the power of brain-machine interfaces for motor and sensory functional recovery. Yet, despite the rapid pace of technology development, the issue of establishing a safe, long-term, stable, and functional interface between neuroelectronic devices and the host brain tissue still remains largely unresolved. A body of work spanning at least the last 15 years suggests that safe, chronic integration between invasive electrodes and the brain requires a close match between the mechanical properties of man-made components and the neural tissue. In other words, the next generation of invasive electrodes should be soft and compliant, without sacrificing biological and chemical stability. Soft neuroelectronic interfaces, however, pose a new and significant surgical challenge: bending and buckling during implantation that can preclude accurate and safe device placement. In this topical review, we describe the next generation of soft electrodes and the surgical implantation methods for safe and precise insertion into brain structures. We provide an overview of the most recent innovations in the field of insertion strategies for flexible neural electrodes such as dissolvable or biodegradable carriers, microactuators, biologically-inspired support structures, and electromagnetic drives. In our analysis, we also highlight approaches developed in different fields, such as robotic surgery, which could be potentially adapted and translated to the insertion of flexible neural probes.

A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity.

Glioblastomas exhibit vast inter- and intra-tumoral heterogeneity, complicating the development of effective therapeutic strategies. Current in vitro models are limited in preserving the cellular and mutational diversity of parental tumors and require a prolonged generation time. Here, we report methods for generating and biobanking patient-derived glioblastoma organoids (GBOs) that recapitulate the histological features, cellular diversity, gene expression, and mutational profiles of their corresponding parental tumors. GBOs can be generated quickly with high reliability and exhibit rapid, aggressive infiltration when transplanted into adult rodent brains. We further demonstrate the utility of GBOs to test personalized therapies by correlating GBO mutational profiles with responses to specific drugs and by modeling chimeric antigen receptor T cell immunotherapy. Our studies show that GBOs maintain many key features of glioblastomas and can be rapidly deployed to investigate patient-specific treatment strategies. Additionally, our live biobank establishes a rich resource for basic and translational glioblastoma research.

Undiagnosed Obstructive Sleep Apnea as Predictor of 90-Day Readmission for Brain Tumor Patients.

BACKGROUND: Previously undiagnosed obstructive sleep apnea (OSA) is a known contributor to negative postoperative outcomes. The STOP-Bang questionnaire is a screening tool for OSA that has been validated in both medical and surgical populations. The authors have previously studied this screening tool in a brain tumor population at 30 days. The present study seeks to investigate the effectiveness of this questionnaire, for predicting 90-day readmissions in a population of brain tumor patients with previously undiagnosed OSA. METHODS: Included for analysis were all patients undergoing craniotomy for supratentorial neoplasm at a multihospital, single academic medical center. Data were collected from supratentorial craniotomy cases for which the patient was alive at 90 days after surgery (n = 238). Simple logistic regression analyses were used to assess the ability of the STOP-Bang questionnaire and subsequent single variables to accurately predict patient outcomes at 90 days. RESULTS: The sample included 238 brain tumor admissions, of which 50% were female (n = 119). The average STOP-Bang score was 1.95 ± 1.24 (range 0-7). A 1-unit higher increase in STOP-Bang score accurately predicted 90-day readmissions (odds ratio [OR] = 1.65, P = 0.001), 30- to 90-day emergency department visits (OR = 1.85, P < 0.001), and 30- to 90-day reoperation (OR = 2.32, P < 0.001) with fair accuracy as confirmed by the receiver operating characteristic (C-statistic = 0.65-0.76). However, the STOP-Bang questionnaire did not correlate with home discharge (P = 0.315). CONCLUSIONS: The results of this study suggest that undiagnosed OSA, as evaluated by the STOP-Bang questionnaire, is an effective predictor of readmission risk and health system utilization in a brain tumor craniotomy population with previously undiagnosed OSA.

Virtual resection predicts surgical outcome for drug-resistant epilepsy.

Patients with drug-resistant epilepsy often require surgery to become seizure-free. While laser ablation and implantable stimulation devices have lowered the morbidity of these procedures, seizure-free rates have not dramatically improved, particularly for patients without focal lesions. This is in part because it is often unclear where to intervene in these cases. To address this clinical need, several research groups have published methods to map epileptic networks but applying them to improve patient care remains a challenge. In this study we advance clinical translation of these methods by: (i) presenting and sharing a robust pipeline to rigorously quantify the boundaries of the resection zone and determining which intracranial EEG electrodes lie within it; (ii) validating a brain network model on a retrospective cohort of 28 patients with drug-resistant epilepsy implanted with intracranial electrodes prior to surgical resection; and (iii) sharing all neuroimaging, annotated electrophysiology, and clinical metadata to facilitate future collaboration. Our network methods accurately forecast whether patients are likely to benefit from surgical intervention based on synchronizability of intracranial EEG (area under the receiver operating characteristic curve of 0.89) and provide novel information that traditional electrographic features do not. We further report that removing synchronizing brain regions is associated with improved clinical outcome, and postulate that sparing desynchronizing regions may further be beneficial. Our findings suggest that data-driven network-based methods can identify patients likely to benefit from resective or ablative therapy, and perhaps prevent invasive interventions in those unlikely to do so.

High interictal connectivity within the resection zone is associated with favorable post-surgical outcomes in focal epilepsy patients.

Patients with drug-resistant focal epilepsy are often candidates for invasive surgical therapies. In these patients, it is necessary to accurately localize seizure generators to ensure seizure freedom following intervention. While intracranial electroencephalography (iEEG) is the gold standard for mapping networks for surgery, this approach requires inducing and recording seizures, which may cause patient morbidity. The goal of this study is to evaluate the utility of mapping interictal (non-seizure) iEEG networks to identify targets for surgical treatment. We analyze interictal iEEG recordings and neuroimaging from 27 focal epilepsy patients treated via surgical resection. We generate interictal functional networks by calculating pairwise correlation of iEEG signals across different frequency bands. Using image coregistration and segmentation, we identify electrodes falling within surgically resected tissue (i.e. the resection zone), and compute node-level and edge-level synchrony in relation to the resection zone. We further associate these metrics with post-surgical outcomes. Greater overlap between resected electrodes and highly synchronous electrodes is associated with favorable post-surgical outcomes. Additionally, good-outcome patients have significantly higher connectivity localized within the resection zone compared to those with poorer postoperative seizure control. This finding persists following normalization by a spatially-constrained null model. This study suggests that spatially-informed interictal network synchrony measures can distinguish between good and poor post-surgical outcomes. By capturing clinically-relevant information during interictal periods, our method may ultimately reduce the need for prolonged invasive implants and provide insights into the pathophysiology of an epileptic brain. We discuss next steps for translating these findings into a prospectively useful clinical tool.

Undiagnosed obstructive sleep apnea as a predictor of 30-day readmission for brain tumor patients.

OBJECTIVE: Obstructive sleep apnea (OSA) is known to be associated with negative outcomes and is underdiagnosed. The STOP-Bang questionnaire is a screening tool for OSA that has been validated in both medical and surgical populations. Given that readmission after surgical intervention is an undesirable event, the authors sought to investigate, among patients not previously diagnosed with OSA, the capacity of the STOP-Bang questionnaire to predict 30-day readmissions following craniotomy for a supratentorial neoplasm. METHODS: For patients undergoing craniotomy for treatment of a supratentorial neoplasm within a multiple-hospital academic medical center, data were captured in a prospective manner via the Neurosurgery Quality Improvement Initiative (NQII) EpiLog tool. Data were collected over a 1-year period for all supratentorial craniotomy cases. An additional criterion for study inclusion was that the patient was alive at 30 postoperative days. Statistical analysis consisted of simple logistic regression, which assessed the ability of the STOP-Bang questionnaire and additional variables to effectively predict outcomes such as 30-day readmission, 30-day emergency department (ED) visit, and 30-day reoperation. The C-statistic was used to represent the receiver operating characteristic (ROC) curve, which analyzes the discrimination of a variable or model. RESULTS: Included in the sample were all admissions for supratentorial neoplasms treated with craniotomy (352 patients), 49.72% (n = 175) of which were female. The average STOP-Bang score was 1.91 ± 1.22 (range 0-7). A 1-unit higher STOP-Bang score accurately predicted 30-day readmissions (OR 1.31, p = 0.017) and 30-day ED visits (OR 1.36, p = 0.016) with fair accuracy as confirmed by the ROC curve (C-statistic 0.60-0.61). The STOP-Bang questionnaire did not correlate with 30-day reoperation (p = 0.805) or home discharge (p = 0.315). CONCLUSIONS: The results of this study suggest that undiagnosed OSA, as assessed via the STOP-Bang questionnaire, is a significant predictor of patient health status and readmission risk in the brain tumor craniotomy population. Further investigations should be undertaken to apply this prediction tool in order to enhance postoperative patient care to reduce the need for unplanned readmissions.

Addressing barriers to surgical evaluation for patients with epilepsy.

OBJECTIVE: Patients with poorly controlled seizures are at elevated risk of epilepsy-related morbidity and mortality. For patients with drug-resistant epilepsy that is focal at onset, epilepsy surgery is the most effective treatment available and offers a 50-80% cure rate. Yet, it is estimated that only 1% of patients with drug-resistant epilepsy undergo surgery in a timely fashion, and delays to surgery completion are considerable. The aim of this study was to increase availability and decrease delay of surgical evaluation at our epilepsy center for patients with drug-resistant epilepsy by removing process barriers. METHODS: For this quality improvement (QI) initiative, we convened a multidisciplinary team to construct a presurgical pathway process map and complete root cause analysis. This inquiry revealed that the current condition allowed patients to proceed through the pathway without centralized oversight. Therefore, we appointed an epilepsy surgery nurse manager, and under her direction, multiple additional process improvement interventions were applied. We then retrospectively compared preintervention (2014-2015) and postintervention (2016-2017) cohorts of patient undergoing the presurgical pathway. The improvement measures were patient throughput and pathway sojourn times. As a balancing measure, we considered the proportion of potentially eligible patients (epilepsy monitoring unit (EMU) admissions) who ultimately completed epilepsy surgery. RESULTS: Following our intervention, patient throughput was substantially increased for each stage of the presurgical pathway (32%-96% growth). However, patient sojourn times were not improved overall. No difference was observed in the proportion of possible candidates who ultimately completed epilepsy surgery. SIGNIFICANCE: Although process improvement expanded the number of patients who underwent epilepsy surgical evaluation, we experienced concurrent prolongation of the time from pathway initiation to completion. Ongoing improvement cycles will focus on newly identified residual sources of bottleneck and delay.

Complications Predicting Perioperative Mortality in Patients Undergoing Elective Craniotomy: A Population-Based Study.

OBJECTIVE: The objective of this study was to assess the independent effect of complications on 30-day mortality in 32,695 patients undergoing elective craniotomy. METHODS: The American College of Surgeons National Surgical Quality Improvement Program was queried for patients undergoing elective craniotomy from 2006 to 2015. Multivariate logistic regression was used to examine the effect of complications on mortality independent of preoperative risk and other postoperative complications. This effect was further assessed in risk-stratified patient subgroups using the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator. RESULTS: Of 13 complications analyzed, the 5 most strongly associated with mortality independent of preoperative risk factors were unplanned intubation (odds ratio [OR], 12.1; 95% confidence interval [CI], 9.5-15.4; P < 0.001), stroke (OR, 11.1; 95% CI, 8.3-14.9; P < 0.001), ventilator requirement >48 hours after surgery (OR, 9.9; 95% CI, 7.9-12.6; P < 0.001), and renal failure (OR, 8.5; 95% CI, 4.4-16.2; P < 0.001). These same complications were also the 5 most associated with mortality independent of other postoperative complications. They were also associated with mortality across all risk-stratified patient subgroups. On the contrary, venous thromboembolism (OR, 1.3; 95% CI, 0.98-1.7; P = 0.06), urinary tract infection (OR, 1.1; 95% CI, 0.76-1.6; P = 0.61), unplanned reoperation (OR, 1.1; 95% CI, 0.83-1.4; P = 0.55), and surgical site infection (OR, 0.35; 95% CI, 0.18-0.71; P = 0.004) showed no significant link with increased mortality independent of other complications. CONCLUSIONS: Of 13 complications analyzed, myocardial infarction, unplanned intubation, prolonged ventilator requirement, stroke, and renal failure showed the strongest association with mortality independent of preoperative risk, independent of other complications, and across all risk-stratified subgroups. These findings help identify causes of perioperative mortality after elective craniotomy. Dedicating additional resources toward preventing and treating these complications postoperatively may help reduce rates of failure-to-rescue in the neurosurgical population.

The Effect of Underlying Liver Disease on Perioperative Outcomes Following Craniotomy for Tumor: An American College of Surgeons National Quality Improvement Program Analysis.

BACKGROUND: The association between underlying liver disease and poor surgical outcomes has been well documented across a wide variety of surgical disciplines. However, little is known about the importance of liver disease in neurosurgery. In this report, we assess the independent effect of liver disease on perioperative outcomes in patients undergoing craniotomy for tumor. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for patients undergoing craniotomy for tumor from 2006 to 2015. Presence and severity of underlying liver disease was assessed with the aspartate aminotransferase-to-platelet ratio index and the Model for End-Stage Liver Disease-Sodium scores, computed from preoperative laboratory values. RESULTS: Among 11,897 patients, mild and advanced disease was identified in 2.4% and 1.9% of patients, respectively. Rates of 30-day mortality were 4.5% and 15.8% in these patients, compared with 3.1% in patients with healthy livers. The 30-day complication rate was 40.3%, 28.0%, and 19.8% in patients with advanced, mild, and no liver disease, respectively. In multivariate analysis, the presence of any liver disease (mild or advanced) was independently associated with mortality (OR = 2.46; 95% confidence interval [CI], 1.68-3.59; P < 0.001), morbidity (OR, 1.49; 95% CI, 1.18-1.87; P = 0.001), and length of hospital stay over 10 days (OR, 1.35; 95% CI, 1.07-1.70; P = 0.012), when compared with 13 covariates. Liver disease showed the strongest independent association with mortality of all risk factors analyzed. CONCLUSIONS: Liver disease is an independent predictor of poor 30-day outcomes following craniotomy for tumor. Consideration of underlying liver function can have a role in surgical decision making and postoperative care for these patients.

Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is a chronic epilepsy syndrome defined by seizures and progressive neurological disabilities, including cognitive impairments, anxiety, and depression. Here, human TLE specimens were investigated focusing on the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and complex 2 (mTORC2) activities in the brain, given that both pathways may represent unique targets for treatment. METHODS: Surgically resected hippocampal and temporal lobe samples from therapy-resistant TLE patients were analyzed by western blotting to quantify the expression of established mTORC1 and mTORC2 activity markers and upstream or downstream signaling pathways involving the two complexes. Histological and immunohistochemical techniques were used to assess hippocampal and neocortical structural abnormalities and cell-specific expression of individual biomarkers. Samples from patients with focal cortical dysplasia (FCD) type II served as positive controls. RESULTS: We found significantly increased expression of phospho-mTOR (Ser2448), phospho-S6 (Ser235/236), phospho-S6 (Ser240/244), and phospho-Akt (Ser473) in TLE samples compared to controls, consistent with activation of both mTORC1 and mTORC2. Our work identified the phosphoinositide 3-kinase and Ras/extracellular signal-regulated kinase signaling pathways as potential mTORC1 and mTORC2 upstream activators. In addition, we found that overactive mTORC2 signaling was accompanied by induction of two protein kinase B-dependent prosurvival pathways, as evidenced by increased inhibitory phosphorylation of forkhead box class O3a (Ser253) and glycogen synthase kinase 3 beta (Ser9). INTERPRETATION: Our data demonstrate that mTOR signaling is significantly dysregulated in human TLE, offering new targets for pharmacological interventions. Specifically, clinically available drugs that suppress mTORC1 without compromising mTOR2 signaling, such as rapamycin and its analogs, may represent a new group of antiepileptogenic agents in TLE patients. Ann Neurol 2018;83:311-327.

Topical Vancomycin Reduces Surgical-Site Infections After Craniotomy: A Prospective, Controlled Study.

BACKGROUND: Surgical-site infections (SSIs) are an important cause of morbidity and mortality in neurosurgical patients. Topical antibiotics are one potential method to reduce the incidence of these infections. OBJECTIVE: To examine the efficacy of topical vancomycin applied within the wound during craniotomy in a large prospective cohort study at a major academic center. METHODS: Three hundred fifty-five patients were studied prospectively in this cohort study; 205 patients received 1 g of topical vancomycin powder in the subgaleal space while 150 matched control patients did not. Patients otherwise received identical care. The primary outcome variable was SSI rate factored by cohort. Secondary analysis examined cost savings from vancomycin usage estimated from hospital costs associated with SSI in craniotomy patients. RESULTS: The addition of topical vancomycin was associated with a significantly lower rate of SSI than standard of care alone (0.49% [1/205] vs 6% [9/150], P = .002). Based on the costs of revision surgery for infections, topical vancomycin usage was estimated to save $1367 446 per 1000 craniotomy patients. No adverse reactions occurred. CONCLUSION: Topical vancomycin is a safe, effective, and cost-saving measure to prevent SSIs following craniotomy. These results have broad implications for standard of care in craniotomy.