Recurrent Glioblastoma-Molecular Underpinnings and Evolving Treatment Paradigms.

Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.

Global, Regional, and National Economic Consequences of Stroke.

BACKGROUND: An understanding of global, regional, and national macroeconomic losses caused by stroke is important for allocation of clinical and research resources. The authors investigated the macroeconomic consequences of stroke disease burden in the year 2019 in 173 countries. METHODS: Disability-adjusted life year data for overall stroke and its subtypes (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) were collected from the GBD study (Global Burden of Disease) 2019 database. Gross domestic product (GDP, adjusted for purchasing power parity [PPP]) data were collected from the World Bank; GDP and disability-adjusted life year data were combined to estimate macroeconomic losses using a value of lost welfare (VLW) approach. All results are presented in 2017 international US dollars adjusted for PPP. RESULTS: Globally, in 2019, VLW due to stroke was $2059.67 billion or 1.66% of the global GDP. Global VLW/GDP for stroke subtypes was 0.78% (VLW=$964.51 billion) for ischemic stroke, 0.71% (VLW=$882.81 billion) for intracerebral hemorrhage, and 0.17% (VLW=$212.36 billion) for subarachnoid hemorrhage. The Central European, Eastern European, and Central Asian GBD super-region reported the highest VLW/GDP for stroke overall (3.01%), ischemic stroke (1.86%), and for subarachnoid hemorrhage (0.26%). The Southeast Asian, East Asian, and Oceanian GBD super-region reported the highest VLW/GDP for intracerebral hemorrhage (1.48%). CONCLUSIONS: The global macroeconomic consequences related to stroke are vast even when considering stroke subtypes. The present quantification may be leveraged to help justify increased spending of finite resources on stroke in an effort to improve outcomes for patients with stroke globally.

Focused Ultrasound Thalamotomy for Tremor in Parkinson's Disease: Outcomes in a Large, Prospective Cohort.

BACKGROUND: Magnetic resonance guided focused ultrasound (MRgFUS) is United States Food and Drug Administration approved for the treatment of tremor-dominant Parkinson's disease (TdPD), but only limited studies have been described in practice. OBJECTIVES: To report the largest prospective experience of unilateral MRgFUS thalamotomy for the treatment of medically refractory TdPD. METHODS: Clinical outcomes of 48 patients with medically refractory TdPD who underwent MRgFUS thalamotomy were evaluated. Tremor outcomes were assessed using the Fahn-Tolosa-Marin scale and adverse effects were categorized using a structured questionnaire and clinical exam at 1 month (n = 44), 3 months (n = 34), 1 year (n = 22), 2 years (n = 5), and 3 years (n = 2). Patients underwent magnetic resonance imaging <24 hours post-procedure. RESULTS: Significant tremor control persisted at all follow-ups (P < 0.001). All side effects were mild. At 3 months, these included gait imbalance (38.24%), sensory deficits (26.47%), motor weakness (17.65%), dysgeusia (5.88%), and dysarthria (5.88%), with some persisting at 1 year. CONCLUSIONS: MRgFUS thalamotomy is an effective treatment for sustained tremor control in patients with TdPD. © 2023 International Parkinson and Movement Disorder Society.

Focused Ultrasound Thalamotomy: Correlation of Postoperative Imaging with Neuropathological Findings.

Magnetic resonance-guided high-intensity focused ultrasound (MRgFUS) is a rapidly developing technique used for tremor relief in tremor-predominant Parkinson's disease (PD) and essential tremor that has demonstrated successful results. Here, we describe the neuropathological findings in a woman who died from a fall 10 days after successful MRgFUS for tremor-predominant PD. Histological analysis demonstrates the characteristic early postoperative MRI findings including 3 distinct zones on T2-weighted imaging: (1) a hypointense core, (2) a hyperintense region with hypointense rim, and (3) a slightly hyperintense, poorly marginated surrounding area. Histopathological analyses also demonstrate the suspected cellular processes composing each of these regions including central hemorrhagic necrosis with surrounding cytotoxic edema and a rim of mostly unaffected vasogenic edema with some reactive and reparative processes. Overall, this case demonstrates the correlation of postoperative imaging findings with the subacute neuropathological findings after MRgFUS for PD.

Tumor-Associated Macrophages/Microglia in Glioblastoma Oncolytic Virotherapy: A Double-Edged Sword.

Oncolytic virotherapy is a rapidly progressing field that uses oncolytic viruses (OVs) to selectively infect malignant cells and cause an antitumor response through direct oncolysis and stimulation of the immune system. Despite demonstrated pre-clinical efficacy of OVs in many cancer types and some favorable clinical results in glioblastoma (GBM) trials, durable increases in overall survival have remained elusive. Recent evidence has emerged that tumor-associated macrophage/microglia (TAM) involvement is likely an important factor contributing to OV treatment failure. It is prudent to note that the relationship between TAMs and OV therapy failures is complex. Canonically activated TAMs (i.e., M1) drive an antitumor response while also inhibiting OV replication and spread. Meanwhile, M2 activated TAMs facilitate an immunosuppressive microenvironment thereby indirectly promoting tumor growth. In this focused review, we discuss the complicated interplay between TAMs and OV therapies in GBM. We review past studies that aimed to maximize effectiveness through immune system modulation-both immunostimulatory and immunosuppressant-and suggest future directions to maximize OV efficacy.

Differential Time-To-Promotion Trajectories Among Female and Male Neurosurgeons Contribute to Gender Disparities in Academic Rank Achievement.

OBJECTIVE: Despite the increasing representation of females in neurosurgical training, the fraction of female to male neurosurgeons decreases dramatically as faculty rank (Assistant, Associate, or Full Professor) increases. To assess this discrepancy, we quantified self-reported time-to-promotion trajectories for female and male neurosurgeons holding academic appointments. METHODS: In this cross-sectional institutional review board (IRB)-approved study, 147 female and 84 male neurosurgeons currently holding faculty positions in the US were contacted via email and invited to complete an anonymous, standardized survey. Respondents provided the calendar year of postgraduate training completion, promotion to different faculty ranks, geographic region of current practice (Western, Midwest, Southern, Northeast), and practice subspecialty. RESULTS: The response rate was 44.2% for females and 59.5% for males, with 114 participants included (65 female, 49 male). On average, female neurosurgeons required 25% longer to become an Associate Professor (P = 0.017), 34% longer to become a Full Professor (P = 0.004), 37% longer for promotion from Assistant to Associate Professor (P < 0.001), and 32% longer from Assistant to Full Professor (P = 0.012). Promotion timelines did not vary by region or specialty among male and female cohorts. Linear regressions revealed that female neurosurgeons with more recent training completion experienced shorter time-to-promotion to Associate and Full Professor compared to females of earlier generations (P = 0.005 and 0.001, respectively), while male timelines remained stable. CONCLUSIONS: This study identifies a significant delay in time-to-promotion for female neurosurgeons compared to their male counterparts. Investigation and standardization of promotion timelines are necessary to ensure meaningful representation gains from the increased number of women entering neurosurgical training.

Benign Natural Progression of Small Cavernous Carotid Aneurysms Suggests Limited Clinical Utility of Serial Longitudinal Follow-up.

BACKGROUND AND OBJECTIVES: Aneurysms in the cavernous segment of the internal carotid artery (ICA) often present in an indolent fashion with limited morbidity. However, their growth progression and possible rupture over time remains poorly defined, thereby limiting optimization of serial follow-up. Thus, we aim to describe the progression of cavernous ICA aneurysms over time, as well as the patient and aneurysm characteristics associated with possible growth and rupture status. METHODS: We identified a consecutive cohort of 157 patients from 2007 to 2021 with cavernous ICA aneurysms. Patient demographic data, possible risk factors, presenting symptoms, radiographic features of aneurysms, size progression, rupture status, and concomitant noncavernous aneurysm rupture data were manually extracted. RESULTS: One hundred and fifty-seven patients (mean age at diagnosis 57.2 ± 15.6 years; 85.4% females) with 174 cavernous carotid aneurysms (CCAs) were followed for an average of 7.1 ± 4.8 years. 76.4% of aneurysms were identified incidentally, with predominantly ocular palsies as the presenting symptoms in remaining primary cases. Most aneurysms were small, and of the 168 aneurysms that were followed, 98.2% did not demonstrate appreciable growth. Of the aneurysms that grew, it took an average of 6.0 years to grow 1.6 ± 0.2 mm. Demographic data, hypertension, and smoking status were not associated with aneurysm growth. Most radiographic features also were not associated with growth, except long-axis diameter, which had an odds ratio of 1.4 (CI: 1.2, 1.8) on multivariable analysis. Presenting clinical symptoms were not associated with growth. No CCAs ruptured during follow-up. CONCLUSION: Cavernous ICA aneurysms in our series demonstrate no rupture and limited growth over years of clinical follow-up. No radiographic or patient risk factors were associated with growth except initial aneurysm size. Hence, small CCAs may not require close follow-up over time.

Magnetic resonance-guided focused ultrasound thalamotomy for essential tremor patients with low skull density ratio: a case-matched analysis.

Introduction: Skull density ratio (SDR) is the ratio between the mean Hounsfield units of marrow and cortical bone, impacting energy transmission through the skull. Low SDR has been used as an exclusion criterion in major trials of magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor (ET). However, some studies have suggested that patients with low SDR can safely undergo MRgFUS with favorable outcomes. In this case-matched study, we aim to compare the characteristics, sonication parameters, lesion sizes, and clinical outcomes of patients with low SDR vs. patients with high SDR who underwent unilateral MRgFUS thalamotomy for medication-refractory ET. Methods: Between March 2016 and April 2023, all patients (n = 270) who underwent unilateral MRgFUS thalamotomy for medication-refractory ET at a single institution were classified as low SDR (<0.40) and high SDR (≥0.40). All clinical and radiological data was prospectively collected and retrospectively analyzed using non-case-matched and 1:1 case-matched methodology. Results: Thirty-one patients had low SDR, and 239 patients had high SDR. Fifty-six patients (28 in each cohort) were included in 1:1 case-matched analysis. There were no significant differences in baseline characteristics between the two groups in both non-case-matched and 1:1 case-matched analyses. In both analyses, compared to patients with high SDR, patients with low SDR required a significantly higher maximum sonication power, energy, and duration, and reached a lower maximum temperature with smaller lesion volumes. In the non-case-matched and case-matched analyses, low SDR patients did not have significantly less tremor control at any postoperative timepoints. However, there was a higher chance of procedure failure in the low SDR group with three patients not obtaining an appropriately sized lesion. In both analyses, imbalance was observed more often in high SDR patients on postoperative day 1 and month 3. Discussion: ET patients with SDR <0.40 can be safely and effectively treated with MRgFUS, though there may be higher rates of treatment failure and intraoperative discomfort.

Active Teaching Techniques Using Virtual Didactics: Novel Experience From a National Neurosurgery Resident Course.

OBJECTIVE: To investigate the attitudes of neurosurgery residents regarding active teaching techniques and virtual didactics based on a national neurosurgery resident sample. We also evaluated the relative cost and time commitment required for faculty participation in virtual versus in-person resident courses. DESIGN: The Society of Neurological Surgeons (SNS) national junior resident courses (JRCs) were reformatted for active teaching in a virtual setting in 2020 due to the COVID-19 pandemic. We analyzed course evaluations from the virtual 2020 courses in comparison to the 2019 in-person SNS JRCs. We also compared course budgets and agendas from these courses to identify comparative costs and the time commitment for faculty participation using these 2 course models. SETTING: Survey of nationwide participants in virtual junior resident courses. PARTICIPANTS: A total of 122 residents from 80 ACGME neurosurgery residency training programs attended the 2020 virtual JRC. RESULTS: The survey response rate of attendees was 36%. In-class engagement was thought to be good to great by 73% to 80% of the virtual learners. In-class activities and active learning techniques also were evaluated positively by 61% to 82% of respondents. Expenses were significantly lower for the virtual course, at $118 per course participant, than for the in-person course ($2722 per participant). There also was a 97.3% reduction of faculty hours and a 97.6% reduction of faculty cost for the virtual JRC compared to the in-person course. CONCLUSIONS: Neurosurgeon residents embraced the active teaching techniques used to teach portions of the prepandemic JRCs in a virtual format. Other aspects of the course curriculum could not be replicated virtually. Virtual courses were dramatically less expensive to produce, used fewer faculty teachers and required less time per faculty member. The data from this study may inform the choice of active teaching techniques for other neurosurgery residency and continuing medical education courses to optimize learner engagement and participant satisfaction in the virtual setting. We recommend that the curriculum of in-person courses emphasize hands-on, experiential learning and professional enculturation that cannot be recreated in the virtual space. Curricular elements suitable to virtual learning should take advantage of lower costs, reduced faculty time requirements, and scalability. They should also utilize active teaching techniques to improve learner engagement.

Surgical management of status epilepticus: A systematic review.

Status Epilepticus (SE), unresponsive to medical management, is associated with high morbidity and mortality. Surgical management is typically considered in these refractory cases. The best surgical approach for affected patients remains unclear; however, given the lack of controlled trials exploring the role of surgery. We performed a systematic review according to PRIMSA guidelines, including case reports and series describing surgical interventions for patients in SE. Cases (157 patients, median age 12.9 years) were followed for a median of 12 months. Patients were in SE for a median of 21 days before undergoing procedures including: focal resection (36.9%), functional hemispherectomy (21%), lobar resection (12.7%), vagus nerve stimulation (VNS) (12.7%), deep brain stimulation (DBS) (6.4%), multiple subpial transection (MST) (3.8%), responsive neurostimulation (RNS) (1.9%), and cortical stimulator placement (1.27%), with 24 patients undergoing multiple procedures. Multiple SE semiologies were identified. 47.8% of patients had focal seizures, and 65% of patients had focal structural abnormalities on MRI. SE persisted for 36.8 ± 47.7 days prior to surgical intervention. SE terminated following surgery in 81.5%, terminated with additional adjuncts in 10.2%, continued in 1.9%, and was not specified in 6.4% of patients. Long-term seizure outcomes were favorable, with the majority improved and 51% seizure-free. Eight patients passed away in follow-up, of which three were in SE. Seizures emerging from one hemisphere were both more likely to immediately terminate (OR 4.7) and lead to long-term seizure-free status (OR 3.9) compared to nonunilateral seizures. No other predictors, including seizure focality, SE duration, or choice of surgical procedure, were predictors of SE termination. Surgical treatment of SE can be effective in terminating SE and leading to sustained seizure freedom, with many different procedures showing efficacy if matched appropriately with SE semiology and etiology. PLAIN LANGUAGE SUMMARY: Patients with persistent seizures (Status Epilepticus) that do not stop following medications can be treated effectively with surgery. Here, we systematically review the entirety of existing literature on surgery for treating status epilepticus to better identify how and when surgery is used and what patients do after surgery.

Erector spinae plane blocks for opioid-sparing multimodal pain management after pediatric cardiac surgery.

OBJECTIVE: Peripheral regional anesthesia is proposed to enhance recovery. We sought to evaluate the efficacy of bilateral continuous erector spinae plane blocks (B-ESpB) for postoperative analgesia and the impact on recovery in children undergoing cardiac surgery. METHODS: Patients aged 2 through 17 years undergoing cardiac surgery in the enhanced recovery after cardiac surgery program were prospectively enrolled to receive B-ESpB at the end of the procedure, with continuous infusions via catheters postoperatively. Participants wore an activity monitor until discharge. B-ESpB patients were retrospectively matched with control patients in the enhanced recovery after cardiac surgery program. Outcomes of the matched clusters were compared using exact conditional logistic regression and generalized linear modeling. RESULTS: Forty patients receiving B-ESpB were matched to 78 controls. There were no major complications from the B-ESpB or infusions, and operating room time was longer by a median of 31 minutes. While blocks were infusing, patients with B-ESpB received fewer opioids in oral morphine equivalents than controls at 24 hours (0.60 ± 0.06 vs 0.78 ± 0.04 mg/kg; P = .02) and 48 hours (1.13 ± 0.08 vs 1.35 ± 0.06 mg/kg; P = .04), respectively. Both groups had low median pain scores per 12-hour period. There was no difference in early mobilization, length of stay, or complications. CONCLUSIONS: B-ESpBs are safe in children undergoing cardiac surgery. When performed as part of a multimodal pain strategy in an enhanced recovery after cardiac surgery program, pediatric patients with B-ESpB experience good pain control and require fewer opioids in the first 48 hours.

The Neurovascular Disease Management Course: A Medical Student Opportunity for Early Exposure and Technical Development in Vascular Neurosurgery.

BACKGROUND: As endovascular neurosurgery techniques continue to evolve, medical students in the United States have widely varying exposures to the field, particularly with respect to opportunities for hands-on experiences. Current medical school curricula could benefit from a novel and adaptive course on vascular neurosurgery to increase student exposure earlier in their training. METHODS: We launched a yearly hands-on vascular neurosurgery course for medical students and residents. The day-long course is a combination of lectures focused on neurovascular disease and management accompanied by hands-on sessions where students practiced fundamental microsurgery and angiography techniques using real microscopes and angiography simulators. We surveyed the students before and after each of the 2 courses. The survey following the second annual course included quiz questions the students had not previously seen. RESULTS: Over 2 courses, we had 149 attendees, 71.8% of which were first and second-year medical students representing fifteen institutions. The average survey completion rate was 41.4% for the 4 surveys across the 2 courses. Attendees' interest in pursuing a surgical specialty (t = 1.815, P = 0.039) along with their comfort with neuroanatomy (t = 8.780, P ≤ 0.001) and neurosurgical disease (t = 6.133, P ≤ 0.001) was significantly elevated after the completion of the second course. Responses to the post-survey showed a good grasp of the fundamentals with 68% of attendees answering 70% of the quiz questions correctly. CONCLUSIONS: An interactive course on vascular neurosurgery may be an effective vehicle to provide medical students with exposure to the field and the opportunity to learn the fundamentals.

Comparative effectiveness of stereotactic, subdural, or hybrid intracranial EEG monitoring in epilepsy surgery.

OBJECTIVE: Surgical intervention can be curative or palliative for drug-resistant focal epilepsy. However, if the seizure onset zone (SOZ) cannot be adequately localized via noninvasive tests, intracranial EEG (iEEG) recordings are often carried out to develop surgical plans in appropriate candidates. Stereotactic EEG (SEEG), subdural EEG (SDE), and SDE with depth electrodes (hybrid) are major tools used for investigation, but there is no class 1 or 2 evidence comparing the effectiveness of these modalities. METHODS: The authors identified an institutional cohort of patients who underwent iEEG monitoring between 2001 and 2022. Demographic data, preoperative clinical features, iEEG intervention, and follow-up data were identified. Primary study endpoints included the following: 1) likelihood of SOZ localization; 2) likelihood of surgical treatment after iEEG; 3) seizure outcomes; and 4) complications. RESULTS: A total of 329 patients were identified (176 in the SEEG, 60 in the SDE, and 93 in the hybrid cohort) who were followed for a median of 5.4 (IQR 6.8) years. Baseline characteristics, including demographics, mean age at epilepsy diagnosis, mean age at iEEG investigation, number of preoperative antiseizure medications, and preoperative seizure frequency, were not statistically different across the 3 cohorts. Patients in the SEEG cohort were more likely to have their SOZ localized than were the patients in the SDE group (OR 2.3) and were less likely to undergo subsequent resection (OR 0.3) or to have complications (OR 0.4), although there was no statistical difference with respect to likelihood of undergoing any subsequent neurosurgical treatment, or with respect to favorable seizure outcomes. Patients in the hybrid cohort were more likely to have SOZ localized than were patients in the SDE group (OR 3.1), but were more likely to undergo resection (OR 4.9) or any neurosurgical treatment (OR 2.5) compared to patients in the SEEG group. Patients in the hybrid cohort had better seizure outcomes compared to the SDE (OR 2.3) but not to the SEEG group. CONCLUSIONS: Patients in the SEEG group were more likely to have their SOZ localized and patients in the SDE group were more likely to undergo resection, but they did not differ with respect to seizure outcomes.

Combination Immunotherapy with Vaccine and Oncolytic HSV Virotherapy Is Time Dependent.

Oncolytic virotherapy or immunovirotherapy is a strategy that utilizes viruses to selectively infect and kill tumor cells while also stimulating an immune response against the tumor. Early clinical trials in both pediatric and adult patients using oncolytic herpes simplex viruses (oHSV) have demonstrated safety and promising efficacy; however, combinatorial strategies designed to enhance oncolysis while also promoting durable T-cell responses for sustaining disease remission are likely required. We hypothesized that combining the direct tumor cell killing and innate immune stimulation by oHSV with a vaccine that promotes T cell-mediated immunity may lead to more durable tumor regression. To this end, we investigated the preclinical efficacy and potential synergy of combining oHSV with a self-assembling nanoparticle vaccine codelivering peptide antigens and Toll-like receptor 7 and 8 agonists (referred to as SNAPvax),which induces robust tumor-specific T-cell immunity. We then assessed how timing of the treatments (i.e., vaccine before or after oHSV) impacts T-cell responses, viral replication, and preclinical efficacy. The sequence of treatments was critical, as survival was significantly enhanced when the SNAPvax vaccine was given prior to oHSV. Increased clinical efficacy was associated with reduced tumor volume and increases in virus replication and tumor antigen-specific CD8+ T cells. These findings substantiate the criticality of combination immunotherapy timing and provide preclinical support for combining SNAPvax with oHSV as a promising treatment approach for both pediatric and adult tumors.

Intraventricular immunovirotherapy; a translational step forward.

Oncolytic virotherapy with intratumoral engineered type-1 herpes simplex virus (HSV) has been proven safe with promising efficacy in recent clinical trials for treatment of both pediatric and adult high-grade glioma. However, this approach excludes patients with tumors in surgically inaccessible and/or eloquent brain regions. Current delivery methods are also unable to access/treat those patients with metastatic disease in the spinal cord and/or leptomeningeal disease. A recent preclinical study has paved the way for clinical translation of intraventricular administration of oHSV by identifying and mitigating the toxicity associated with this route for therapeutic benefit in murine models of disseminated medulloblastoma. This work may ultimately allow for targeting of intractable disease and provides a feasible option for the repetitive dosing of clinically relevant immunovirotherapy, G207.

Recent oncolytic virotherapy clinical trials outline a roadmap for the treatment of high-grade glioma.

Adult and pediatric high-grade gliomas (HGGs) are aggressive cancers of the central nervous system that confer dismal clinical prognoses. Standard radiation and chemotherapy have demonstrated only limited efficacy in HGGs, motivating the accelerated investigation of novel modalities such as oncolytic virus (OV) therapies. OV centered therapies work through a mixed mechanism centered on oncolysis and the stimulation of an antitumor immune response. Three recent clinical trials utilizing herpes simplex virus-1 and adenovirus-based oncolytic virotherapy demonstrated not only the safety and efficacy of OVs but also novel dosing strategies that augment OV response potential. Considering these recent trials, herein we present a roadmap for future clinical trials of oncolytic immunovirotherapy in both adult and pediatric HGG, as well as persistent roadblocks related to the assessment of OV efficacy within and between trials.

Prevalence and Predictors of Inappropriate Antithrombotic Prescription in Patients Presenting With Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: A growing proportion of the US population is on antithrombotic therapy (AT), most significantly within the older subpopulation. Decision to use AT is a balance between the intended benefits and known bleeding risk, especially after traumatic brain injury (TBI). Preinjury inappropriate AT offers no benefit for the patient and also increases the risk of intracranial hemorrhage and worse outcome in the setting of TBI. Our objective was to examine the prevalence and predictors of inappropriate AT among patients presenting with TBI to a Level-1 Trauma Center. METHODS: A retrospective chart review was performed on all patients with TBI and preinjury AT who presented to our institution between January 2016 and September 2020. Demographic and clinical data were collected. Appropriateness of AT was determined through established clinical guidelines. Clinical predictors were determined by logistic regression. RESULTS: Of 141 included patients, 41.8% were female (n = 59) and the average age (mean ± SD) was 80.6 ± 9.9. The prescribed antithrombotic agents included aspirin (25.5%, n = 36), clopidogrel (22.7%, n = 32), warfarin (46.8%, n = 66), dabigatran (2.1%, n = 3), rivaroxaban (Janssen) (10.6%, n = 15), and apixaban (Bristol-Myers Squibb Co.) (18.4%, n = 26). The indications for AT were atrial fibrillation (66.7%, n = 94), venous thromboembolism (13.4%, n = 19), cardiac stent (8.5%, n = 12), and myocardial infarction/residual coronary disease (11.3%, n = 16). Inappropriate antithrombotic therapy use varied significantly by antithrombotic indication ( P < .001) with the highest rates seen with venous thromboembolism. Predictive factors also include age ( P = .005) with higher rates younger than 65 years and older than 85 years and female sex ( P = .049). Race and antithrombotic agent were not significant predictors. CONCLUSION: Overall, 1 in 10 patients presenting with TBI were found to be on inappropriate AT. Our study is the first to describe this problem and warrants investigation into possible workflow interventions to prevent post-TBI continuation of inappropriate AT.

Longitudinal MR imaging after unilateral MR-guided focused ultrasound thalamotomy: clinical and radiological correlation.

Introduction: Magnetic-resonance-guided focused ultrasound (MRgFUS) thalamotomy uses multiple converging high-energy ultrasonic beams to produce thermal lesions in the thalamus. Early postoperative MR imaging demonstrates the location and extent of the lesion, but there is no consensus on the utility or frequency of postoperative imaging. We aimed to evaluate the evolution of MRgFUS lesions and describe the incidence, predictors, and clinical effects of lesion persistence in a large patient cohort. Methods: A total of 215 unilateral MRgFUS thalamotomy procedures for essential tremor (ET) by a single surgeon were retrospectively analyzed. All patients had MR imaging 1 day postoperatively; 106 had imaging at 3 months and 32 had imaging at 1 year. Thin cut (2 mm) axial and coronal T2-weighted MRIs at these timepoints were analyzed visually on a binary scale for lesion presence and when visible, lesion volumes were measured. SWI and DWI sequences were also analyzed when available. Clinical outcomes including tremor scores and side effects were recorded at these same time points. We analyzed if patient characteristics (age, skull density ratio), preoperative tremor score, and sonication parameters influenced lesion evolution and if imaging characteristics correlated with clinical outcomes. Results: Visible lesions were present in all patients 1 day post- MRgFUS and measured 307.4 ± 128.7 mm3. At 3 months, residual lesions (excluding patients where lesions were not visible) were 83.6% smaller and detectable in only 54.7% of patients (n = 58). At 1 year, residual lesions were detected in 50.0% of patients (n = 16) and were 90.7% smaller than 24 h and 46.5% smaller than 3 months. Lesions were more frequently visible on SWI (100%, n = 17), DWI (n = 38, 97.4%) and ADC (n = 36, 92.3%). At 3 months, fewer treatment sonications, higher maximum power, and greater distance between individual sonications led to larger lesion volumes. Volume at 24 h did not predict if a lesion was visible later. Lesion visibility at 3 months predicted sensory side effects but was not correlated with tremor outcomes. Discussion: Overall, lesions are visible on T2-weighted MRI in about half of patients at both 3 months and 1 year post-MRgFUS thalamotomy. Certain sonication parameters significantly predicted persistent volume, but residual lesions did not correlate with tremor outcomes.

Positioning SUMO as an immunological facilitator of oncolytic viruses for high-grade glioma.

Oncolytic viral (OV) therapies are promising novel treatment modalities for cancers refractory to conventional treatment, such as glioblastoma, within the central nervous system (CNS). Although OVs have received regulatory approval for use in the CNS, efficacy is hampered by obstacles related to delivery, under-/over-active immune responses, and the "immune-cold" nature of most CNS malignancies. SUMO, the Small Ubiquitin-like Modifier, is a family of proteins that serve as a high-level regulator of a large variety of key physiologic processes including the host immune response. The SUMO pathway has also been implicated in the pathogenesis of both wild-type viruses and CNS malignancies. As such, the intersection of OV biology with the SUMO pathway makes SUMOtherapeutics particularly interesting as adjuvant therapies for the enhancement of OV efficacy alone and in concert with other immunotherapeutic agents. Accordingly, the authors herein provide: 1) an overview of the SUMO pathway and its role in CNS malignancies; 2) describe the current state of CNS-targeted OVs; and 3) describe the interplay between the SUMO pathway and the viral lifecycle and host immune response.

Applying objective metrics to neurosurgical skill development with simulation and spaced repetition learning.

OBJECTIVE: Surgical skills laboratories augment educational training by deepening one's understanding of anatomy and allowing the safe practice of technical skills. Novel, high-fidelity, cadaver-free simulators provide an opportunity to increase access to skills laboratory training. The neurosurgical field has historically evaluated skill by subjective assessment or outcome measures, as opposed to process measures with objective, quantitative indicators of technical skill and progression. The authors conducted a pilot training module with spaced repetition learning concepts to evaluate its feasibility and impact on proficiency. METHODS: The 6-week module used a simulator of a pterional approach representing skull, dura mater, cranial nerves, and arteries (UpSurgeOn S.r.l.). Neurosurgery residents at an academic tertiary hospital completed a video-recorded baseline examination, performing supraorbital and pterional craniotomies, dural opening, suturing, and anatomical identification under a microscope. Participation in the full 6-week module was voluntary, which precluded randomizing by class year. The intervention group participated in four additional faculty-guided trainings. In the 6th week, all residents (intervention and control) repeated the initial examination with video recording. Videos were evaluated by three neurosurgical attendings who were not affiliated with the institution and who were blinded to participant grouping and year. Scores were assigned via Global Rating Scales (GRSs) and Task-based Specific Checklists (TSCs) previously built for craniotomy (cGRS, cTSC) and microsurgical exploration (mGRS, mTSC). RESULTS: Fifteen residents participated (8 intervention, 7 control). The intervention group included a greater number of junior residents (postgraduate years 1-3; 7/8) compared to the control group (1/7). External evaluators had internal consistency within 0.5% (kappa probability > Z of 0.00001). The total average time improved by 5:42 minutes (p < 0.003; intervention, 6:05, p = 0.07; control, 5:15, p = 0.001). The intervention group began with lower scores in all categories and surpassed the comparison group in cGRS (10.93 to 13.6/16) and cTSC (4.0 to 7.4/10). Percent improvements for the intervention group were cGRS 25% (p = 0.02), cTSC 84% (p = 0.002), mGRS 18% (p = 0.003), and mTSC 52% (p = 0.037). For controls, improvements were cGRS 4% (p = 0.19), cTSC 0.0% (p > 0.99), mGRS 6% (p = 0.07), and mTSC 31% (p = 0.029). CONCLUSIONS: Participants who underwent a 6-week simulation course showed significant objective improvement in technical indicators, particularly individuals who were early in their training. Small, nonrandomized grouping limits generalizability regarding degree of impact; however, introducing objective performance metrics during spaced repetition simulation would undoubtedly improve training. A larger multiinstitutional randomized controlled study will help elucidate the value of this educational method.