The role of frailty in the clinical management of neurofibromatosis type 1: a mixed-effects modeling study using the Nationwide Readmissions Database.

OBJECTIVE: Frailty embodies a state of increased medical vulnerability that is most often secondary to age-associated decline. Recent literature has highlighted the role of frailty and its association with significantly higher rates of morbidity and mortality in patients with CNS neoplasms. There is a paucity of research regarding the effects of frailty as it relates to neurocutaneous disorders, namely, neurofibromatosis type 1 (NF1). In this study, the authors evaluated the role of frailty in patients with NF1 and compared its predictive usefulness against the Elixhauser Comorbidity Index (ECI). METHODS: Publicly available 2016-2017 data from the Nationwide Readmissions Database was used to identify patients with a diagnosis of NF1 who underwent neurosurgical resection of an intracranial tumor. Patient frailty was queried using the Johns Hopkins Adjusted Clinical Groups frailty-defining indicator. ECI scores were collected in patients for quantitative measurement of comorbidities. Propensity score matching was performed for age, sex, ECI, insurance type, and median income by zip code, which yielded 60 frail and 60 nonfrail patients. Receiver operating characteristic (ROC) curves were created for complications, including mortality, nonroutine discharge, financial costs, length of stay (LOS), and readmissions while using comorbidity indices as predictor values. The area under the curve (AUC) of each ROC served as a proxy for model performance. RESULTS: After propensity matching of the groups, frail patients had an increased mean ± SD hospital cost ($85,441.67 ± $59,201.09) compared with nonfrail patients ($49,321.77 ± $50,705.80) (p = 0.010). Similar trends were also found in LOS between frail (23.1 ± 14.2 days) and nonfrail (10.7 ± 10.5 days) patients (p = 0.0020). For each complication of interest, ROC curves revealed that frailty scores, ECI scores, and a combination of frailty+ECI were similarly accurate predictors of variables (p > 0.05). Frailty+ECI (AUC 0.929) outperformed using only ECI for the variable of increased LOS (AUC 0.833) (p = 0.013). When considering 1-year readmission, frailty (AUC 0.642) was outperformed by both models using ECI (AUC 0.725, p = 0.039) and frailty+ECI (AUC 0.734, p = 0.038). CONCLUSIONS: These findings suggest that frailty and ECI are useful in predicting key complications, including mortality, nonroutine discharge, readmission, LOS, and higher costs in NF1 patients undergoing intracranial tumor resection. Consideration of a patient's frailty status is pertinent to guide appropriate inpatient management as well as resource allocation and discharge planning.

Neural network modeling for prediction of recurrence, progression, and hormonal non-remission in patients following resection of functional pituitary adenomas.

PURPOSE: Functional pituitary adenomas (FPAs) cause severe neuro-endocrinopathies including Cushing's disease (CD) and acromegaly. While many are effectively cured following FPA resection, some encounter disease recurrence/progression or hormonal non-remission requiring adjuvant treatment. Identification of risk factors for suboptimal postoperative outcomes may guide initiation of adjuvant multimodal therapies. METHODS: Patients undergoing endonasal transsphenoidal resection for CD, acromegaly, and mammosomatotroph adenomas between 1992 and 2019 were identified. Good outcomes were defined as hormonal remission without imaging/biochemical evidence of disease recurrence/progression, while suboptimal outcomes were defined as hormonal non-remission or MRI evidence of recurrence/progression despite adjuvant treatment. Multivariate regression modeling and multilayered neural networks (NN) were implemented. The training sets randomly sampled 60% of all FPA patients, and validation/testing sets were 20% samples each. RESULTS: 348 patients with mean age of 41.7 years were identified. Eighty-one patients (23.3%) reported suboptimal outcomes. Variables predictive of suboptimal outcomes included: Requirement for additional surgery in patients who previously had surgery and continue to have functionally active tumor (p = 0.0069; OR = 1.51, 95%CI 1.12-2.04), Preoperative visual deficit not improved after surgery (p = 0.0033; OR = 1.12, 95%CI 1.04-1.20), Transient diabetes insipidus (p = 0.013; OR = 1.27, 95%CI 1.05-1.52), Higher MIB-1/Ki-67 labeling index (p = 0.038; OR = 1.08, 95%CI 1.01-1.15), and preoperative low cortisol axis (p = 0.040; OR = 2.72, 95%CI 1.06-7.01). The NN had overall accuracy of 87.1%, sensitivity of 89.5%, specificity of 76.9%, positive predictive value of 94.4%, and negative predictive value of 62.5%. NNs for all FPAs were more robust than for CD or acromegaly/mammosomatotroph alone. CONCLUSION: We demonstrate capability of predicting suboptimal postoperative outcomes with high accuracy. NNs may aid in stratifying patients for risk of suboptimal outcomes, thereby guiding implementation of adjuvant treatment in high-risk patients.

Investigating the blood-spinal cord barrier in preclinical models: a systematic review of in vivo imaging techniques.

STUDY DESIGN: This study is a systematic review. OBJECTIVES: To evaluate current in vivo techniques used in the investigation of the blood-spinal cord barrier (BSCB). METHODS: Search of English language literature for animal studies that investigated the BSCB in vivo. Data extraction included animal model/type, protocol for BSCB evaluation, and study outcomes. Descriptive syntheses are provided. RESULTS: A total of 40 studies were included, which mainly investigated rodent models of experimental autoimmune encephalomyelitis (EAE) or spinal cord injury (SCI). The main techniques used were magnetic resonance imaging (MRI) and intravital microscopy (IVM). MRI served as a reliable tool to longitudinally track BSCB permeability changes with dynamic contrast enhancement (DCE) using gadolinium, or assess inflammatory infiltrations with targeted alternative contrast agents. IVM provided high-resolution visualization of cellular and molecular interactions across the microvasculature, commonly with either epi-fluorescence or two-photon microscopy. MRI and IVM techniques enabled the evaluation of therapeutic interventions and mechanisms that drive spinal cord dysfunction in EAE and SCI. A small number of studies demonstrated the feasibility of DCE-computed tomography, ultrasound, bioluminescent, and fluorescent optical imaging methods to evaluate the BSCB. Technique-specific limitations and multiple protocols for image acquisition and data analyses are described for all techniques. CONCLUSION: There are few in vivo investigations of the BSCB. Additional studies are needed in less commonly studied spinal cord disorders, and to establish standardized protocols for data acquisition and analysis. Further development of techniques and multimodal approaches could overcome current imaging limitations to the spinal cord. These advancements might promote wider adoption of techniques, and can provide greater potential for clinical translation.

Transcranial eddy current damping sensors for detection and imaging of hemorrhagic stroke: feasibility in benchtop experimentation.

OBJECTIVE: Spontaneous intracerebral hemorrhage occurs in an estimated 10% of stroke patients, with high rates of associated mortality. Portable diagnostic technologies that can quickly and noninvasively detect hemorrhagic stroke may prevent unnecessary delay in patient care and help rapidly triage patients with ischemic versus hemorrhagic stroke. As such, the authors aimed to develop a rapid and portable eddy current damping (ECD) hemorrhagic stroke sensor for proposed in-field diagnosis of hemorrhagic stroke. METHODS: A tricoil ECD sensor with microtesla-level magnetic field strengths was constructed. Sixteen gelatin brain models with identical electrical properties to live brain tissue were developed and placed within phantom skull replicas, and saline was diluted to the conductivity of blood and placed within the brain to simulate a hemorrhage. The ECD sensor was used to detect modeled hemorrhages on benchtop models. Data were saved and plotted as a filtered heatmap to represent the lesion location. The individuals performing the scanning were blinded to the bleed location, and sensors were tangentially rotated around the skull models to localize blood. Data were also used to create heatmap images using MATLAB software. RESULTS: The sensor was portable (11.4-cm maximum diameter), compact, and cost roughly $100 to manufacture. Scanning time was 2.43 minutes, and heatmap images of the lesion were produced in near real time. The ECD sensor accurately predicted the location of a modeled hemorrhage in all (n = 16) benchtop experiments with excellent spatial resolution. CONCLUSIONS: Benchtop experiments demonstrated the proof of concept of the ECD sensor for rapid transcranial hemorrhagic stroke diagnosis. Future studies with live human participants are warranted to fully establish the feasibility findings derived from this study.

A systematic review of next-generation point-of-care stroke diagnostic technologies.

OBJECTIVE: Stroke is a leading cause of morbidity and mortality. Current diagnostic modalities include CT and MRI. Over the last decade, novel technologies to facilitate stroke diagnosis, with the hope of shortening time to treatment and reducing rates of morbidity and mortality, have been developed. The authors conducted a systematic review to identify studies reporting on next-generation point-of-care stroke diagnostic technologies described within the last decade. METHODS: A systematic review was performed according to PRISMA guidelines to identify studies reporting noninvasive stroke diagnostics. The QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool was utilized to assess risk of bias. PubMed, Web of Science, and Scopus databases were utilized. Primary outcomes assessed included accuracy and timing compared with standard imaging, potential risks or complications, potential limitations, cost of the technology, size/portability, and range/size of detection. RESULTS: Of the 2646 reviewed articles, 19 studies met the inclusion criteria and included the following modalities of noninvasive stoke detection: microwave technology (6 studies, 31.6%), electroencephalography (EEG; 4 studies, 21.1%), ultrasonography (3 studies, 15.8%), near-infrared spectroscopy (NIRS; 2 studies, 10.5%), portable MRI devices (2 studies, 10.5%), volumetric impedance phase-shift spectroscopy (VIPS; 1 study, 5.3%), and eddy current damping (1 study, 5.3%). Notable medical devices that accurately predicted stroke in this review were EEG-based diagnosis, with a maximum sensitivity of 91.7% for predicting a stroke, microwave-based diagnosis, with an area under the receiver operating characteristic curve (AUC) of 0.88 for differentiating ischemic stroke and intracerebral hemorrhage (ICH), ultrasound with an AUC of 0.92, VIPS with an AUC of 0.93, and portable MRI with a diagnostic accuracy similar to that of traditional MRI. NIRS offers significant potential for more superficially located hemorrhage but is limited in detecting deep-seated ICH (2.5-cm scanning depth). CONCLUSIONS: As technology and computational resources have advanced, several novel point-of-care medical devices show promise in facilitating rapid stroke diagnosis, with the potential for improving time to treatment and informing prehospital stroke triage.

Stereotactic radiosurgery for clinoid meningiomas: a multi-institutional study.

PURPOSE: Resection of clinoid meningiomas can be associated with significant morbidity. Experience with stereotactic radiosurgery (SRS) for clinoid meningiomas remains limited. We studied the safety and effectiveness of SRS for clinoid meningiomas. METHODS: From twelve institutions participating in the International Radiosurgery Research Foundation, we pooled patients treated with SRS for radiologically suspected or histologically confirmed WHO grade I clinoid meningiomas. RESULTS: Two hundred seven patients (median age: 56 years) underwent SRS for clinoid meningiomas. Median treatment volume was 8.02 cm3, and 87% of tumors were immediately adjacent to the optic apparatus. The median tumor prescription dose was 12 Gy, and the median maximal dose to the anterior optic apparatus was 8.5 Gy. During a median post-SRS imaging follow-up of 51.1 months, 7% of patients experienced tumor progression. Greater margin SRS dose (HR = 0.700, p = 0.007) and pre-SRS radiotherapy (HR = 0.004, p < 0.001) were independent predictors of better tumor control. During median visual follow-up of 48 months, visual function declined in 8% of patients. Pre-SRS visual deficit (HR = 2.938, p = 0.048) and maximal radiation dose to the optic apparatus of ≥ 10 Gy (HR = 11.297, p = 0.02) independently predicted greater risk of post-SRS visual decline. Four patients experienced new post-SRS cranial nerve V neuropathy. CONCLUSIONS: SRS allows durable control of clinoid meningiomas and visual preservation in the majority of patients. Greater radiosurgical prescription dose is associated with better tumor control. Radiation dose to the optic apparatus of ≥ 10 Gy and visual impairment before the SRS increase risk of visual deterioration.

Role of botulinum neurotoxin-A in cerebral revascularization graft vasospasm prevention: current state of knowledge.

Graft stenosis and occlusion remain formidable complications in cerebral revascularization procedures, which can lead to significant morbidity and mortality. Graft vasospasm can result in early postoperative graft stenosis and occlusion and is believed to be at least partially mediated through adrenergic pathways. Despite various published treatment protocols, there is no single effective spasmolytic agent. Multiple factors, including anatomical and physiological variability in revascularization conduits, patient age, and comorbidities, have been associated with graft vasospasm pathogenesis and response to spasmolytics. The ideal spasmolytic agent thus likely needs to target multiple pathways to exert a generalizable therapeutic effect. Botulinum toxin (BTX)-A is a powerful neurotoxin widely used in clinical practice for the treatment of a variety of spastic conditions. Although its commonly described paradigm of cholinergic neural transmission blockade has been widely accepted, evidence for other mechanisms of action including inhibition of adrenergic transmission have been described in animal studies. Recently, the first pilot study demonstrating clinical use of BTX-A for cerebral revascularization graft spasm prevention has been reported. In this review, the mechanistic basis and potential future clinical role of BTX-A in graft vasospasm prevention is discussed.

Risk factors associated with the surgical management of craniopharyngiomas in pediatric patients: analysis of 1961 patients from a national registry database.

OBJECTIVE Patient demographic characteristics, hospital volume, and admission status have been shown to impact surgical outcomes of sellar region tumors in adults; however, the data available following the resection of craniopharyngiomas in the pediatric population remain limited. The authors sought to identify potential risk factors associated with outcomes following surgical management of pediatric craniopharyngiomas. METHODS The Nationwide Inpatient Sample database and Kids' Inpatient Database were analyzed to include admissions for pediatric patients (≤ 18 years) who underwent a transcranial or transsphenoidal craniotomy for resection of a craniopharyngioma. Patient-level factors, including age, race, comorbidities, and insurance type, as well as hospital factors were collected. Outcomes analyzed included mortality rate, endocrine and nonendocrine complications, hospital charges, and length of stay. A multivariate model controlling for variables analyzed was constructed to examine significant independent risk factors. RESULTS Between 2000 and 2011, 1961 pediatric patients were identified who underwent a transcranial (71.2%) or a transsphenoidal (28.8%) craniotomy for resection of a craniopharyngioma. A major predilection for age was observed with the selection of a transcranial (23.4% in < 7-year-olds, 28.1% in 7- to 12-year-olds, and 19.7% in 13- to 18-year-olds) versus transphenoidal (2.9% in < 7-year-olds, 7.4% in 7- to 12-year-olds, and 18.4% in 13- to 18-year-olds) approach. No significant outcomes were associated with a particular surgical approach, except that 7- to 12-year-old patients had a higher risk of nonendocrine complications (relative risk [RR] 2.42, 95% CI 1.04-5.65, p = 0.04) with the transsphenoidal approach when compared with 13- to 18-year-old patients. The overall inpatient mortality rate was 0.5% and the most common postoperative complication was diabetes insipidus (64.2%). There were no independent factors associated with inpatient mortality rates and no significant differences in outcomes among groups based on sex and race. The average length of stay was 11.8 days, and the mean hospital charge was $116,5 22. Hospitals with medium and large bed capacity were protective against nonendocrine complications (RR 0.53, 95% CI 0.3-0.93, p = 0.03 [medium]; RR 0.45, 95% CI 0.25-0.8, p < 0.01 [large]) and total complications (RR 0.73, 95% CI 0.55-0.97, p = 0.03 [medium]; RR 0.68, 95% CI 0.51-0.9, p < 0.01 [large]) when compared with hospitals with small bed capacity (< 200 beds). Patients admitted to rural hospitals had an increased risk for nonendocrine complications (RR 2.56, 95% CI 1.11-5.9, p = 0.03). The presence of one or more medical comorbidities increased the risk of higher total complications (RR 1.38, 95% CI 1.14-1.68), p < 0.01 [1 comorbidity]; RR 2.37, 95% CI 1.98-2.84, p < 0.01 [≥ 2 comorbidities]) and higher total hospital charges (RR 2.9, 95% CI 1.08-7.81, p = 0.04 [1 comorbidity]; RR 9.1, 95% CI 3.74-22.12, p < 0.01 [≥ 2 comorbidities]). CONCLUSIONS This analysis identified patient age, comorbidities, insurance type, hospital bed capacity, and rural or nonteaching hospital status as independent risk factors for postoperative complications and/or increased hospital charges in pediatric patients with craniopharyngioma. Transsphenoidal surgery in younger patients with craniopharyngioma was a risk factor for nonendocrine complications.

Surgical Outcomes Following Vestibular Schwannoma Resection in Patients over the Age of Sixty-five.

Objective Vestibular schwannoma (VS) are benign, often slow growing neoplasms. Some institutions opt for radiosurgery in symptomatic patients of advanced age versus surgical resection. The aim of the study is to analyze surgical outcomes of VS in patients over the age of 65 who were either not candidates for or refused radiosurgery. Methods This includes retrospective analysis of VS patients between 1988 and 2020. Demographics, tumor characteristics, surgical records, and clinical outcomes were recorded. Patient preference for surgery over radiosurgery was recorded in the event that patients were offered both. Facial nerve outcomes were quantified using House-Brackmann (HB) scores. Tumor growth was defined by increase in size of >2 mm. Results In total, 64 patients were included of average age 72.4 years (65-84 years). Average maximum tumor diameter was 29 mm (13-55 mm). Forty-five patients were offered surgery or GKRS, and chose surgery commonly due to radiation aversion (48.4%). Gross total resection was achieved in 39.1% ( n = 25), near total 32.8% ( n = 21), and subtotal 28.1% ( n = 18). Average hospitalization was 5 days [2-17] with 75% ( n = 48) discharged home. Postoperative HB scores were good (HB1-2) in 43.8%, moderate (HB3-4) in 32.8%, and poor (HB5-6) in 23.4%. HB scores improved to good in 51.6%, moderate in 31.3%, and remained poor in 17.1%, marking a rate of facial nerve improvement of 10.9%. Tumor control was achieved in 95.3% of cases at an average follow-up time of 37.8 months. Conclusion VS resection can be safely performed in patients over the age of 65. Advanced age should not preclude a symptomatic VS patient from being considered for surgical resection.

Silent Corticotroph Staining Pituitary Neuroendocrine Tumors: Prognostic Significance in Radiosurgery.

BACKGROUND AND OBJECTIVES: There is conflicting evidence on the significance of adrenocorticotrophic hormone (ACTH) staining in the prognosis of nonfunctioning pituitary neuroendocrine tumors (NFpitNETs). The objective of this study was to define the effect of ACTH immunostaining on clinical and radiographic outcomes of stereotactic radiosurgery (SRS) for NFpitNETs. METHODS: This retrospective, multicenter study included patients managed with SRS for NFpitNET residuals. The patients were divided into 2 cohorts: (1) silent corticotroph (SC) for NFpitNETs with positive ACTH immunostaining and (2) non-SC NFpitNETs. Rates of local tumor control and the incidence of post-treatment pituitary and neurological dysfunction were documented. Factors associated with radiological and clinical outcomes were also analyzed. RESULTS: The cohort included 535 patients from 14 centers with 84 (15.7%) patients harboring silent corticotroph NFpitNETs (SCs). At last follow-up, local tumor progression occurred in 11.9% of patients in the SC compared with 8.1% of patients in the non-SC cohort (P = .27). No statistically significant difference was noted in new-onset hypopituitarism rates (10.7% vs 15.4%, P = .25) or visual deficits (3.6% vs 1.1%, P = .088) between the 2 cohorts at last follow-up. When controlling for residual tumor volume, maximum dose, and patient age and sex, positive ACTH immunostaining did not have a significant correlation with local tumor progression (hazard ratio = 1.69, 95% CI = 0.8-3.61, P = .17). CONCLUSION: In contemporary radiosurgical practice with a single fraction dose of 8-25 Gy (median 15 Gy), ACTH immunostaining in NFpitNETs did not appear to confer a significantly reduced rate of local tumor control after SRS.

Endoscopic endonasal approaches for reconstruction of traumatic anterior skull base fractures and associated cerebrospinal fistulas: patient series.

BACKGROUND: Post-traumatic cerebrospinal fluid (CSF) leaks of the anterior skull base may arise after traumatic brain injury (TBI). Onset of CSF rhinorrhea may be delayed after TBI and without prompt treatment may result in debilitating consequences. Operative repair of CSF leaks caused by anterior skull base fractures may be performed via open craniotomy or endoscopic endonasal approaches (EEAs). The authors' objective was to review their institutional experience after EEA for repair of TBI-related anterior skull base defects and CSF leaks. OBSERVATIONS: A retrospective review of prospectively collected data from a major level 1 trauma center was performed to identify patients with TBI who developed CSF rhinorrhea. Persistent or refractory post-traumatic CSF leaks and anterior skull base defects were repaired via EEA in four patients. Intrathecal fluorescein was administered before EEA in three patients (75%) to help aid identification of the fistula site(s). CSF leaks were eventually repaired in all patients, though one reoperation was required. During a mean follow-up of 8.75 months, there were no instances of recurrent CSF leakage. LESSONS: Refractory, traumatic CSF leaks may be effectively repaired via EEA using a multilayer approach and nasoseptal flap reconstruction, thereby potentially obviating the need for additional craniotomy in the post-TBI setting.

Disparities in the Surgical Treatment of Cerebrovascular Pathologies: A Contemporary Systematic Review.

INTRODUCTION: This systematic review analyzes contemporary literature on racial/ethnic, insurance, and socioeconomic disparities within cerebrovascular surgery in the United States to determine areas for improvement. METHODS: We conducted an electronic database search of literature published between January 1990 and July 2020 using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for studies analyzing a racial/ethnic, insurance, or socioeconomic disparity within adult cerebrovascular surgery. RESULTS: Of 2873 articles screened for eligibility by title and abstract, 970 underwent full-text independent review by 3 authors. Twenty-seven additional articles were identified through references to generate a final list of 47 included studies for analysis. Forty-six were retrospective reviews and 1 was a prospective observational cohort study, thereby comprising Levels III and IV of evidence. Studies investigated carotid artery stenting (11/47, 23%), carotid endarterectomy (22/47, 46.8%), mechanical thrombectomy (8/47, 17%), and endovascular aneurysm coiling or surgical aneurysm clipping (20/47, 42.6%). Minority and underinsured patients were less likely to receive surgical treatment. Non-White patients were more likely to experience a postoperative complication, although this significance was lost in some studies using multivariate analyses to account for complication risk factors. White and privately insured patients generally experienced shorter length of hospital stay, had lower rates of in-hospital mortality, and underwent routine discharge. Twenty-five papers (53%) reported no disparities within at least one examined metric. CONCLUSIONS: This comprehensive contemporary systematic review demonstrates the existence of disparity gaps within the field of adult cerebrovascular surgery. It highlights the importance of continued investigation into sources of disparity and efforts to promote equity within the field.

Systematic Review of Racial, Socioeconomic, and Insurance Status Disparities in Neurosurgical Care for Intracranial Tumors.

BACKGROUND: The impact of race, socioeconomic status (SES), insurance status, and other social metrics on the outcomes of patients with intracranial tumors has been reported in several studies. However, these findings have not been comprehensively summarized. METHODS: We conducted a PRISMA systematic review of all published articles between 1990 and 2020 that analyzed intracranial tumor disparities, including race, SES, insurance status, and safety-net hospital status. Outcomes measured include access, standards of care, receipt of surgery, extent of resection, mortality, complications, length of stay (LOS), discharge disposition, readmission rate, and hospital charges. RESULTS: Fifty-five studies were included. Disparities in mortality were reported in 27 studies (47%), showing minority status and lower SES associated with poorer survival outcomes in 14 studies (52%). Twenty-seven studies showed that African American patients had worse outcomes across all included metrics including mortality, rates of surgical intervention, extent of resection, LOS, discharge disposition, and complication rates. Thirty studies showed that privately insured patients and patients with higher SES had better outcomes, including lower mortality, complication, and readmission rates. Six studies showed that worse outcomes were associated with treatment at safety-net and/or low-volume hospitals. The influence of Medicare or Medicaid status, or inequities affecting other minorities, was less clearly delineated. Ten studies (18%) were negative for evidence of disparities. CONCLUSIONS: Significant disparities exist among patients with intracranial tumors, particularly affecting patients of African American race and lower SES. Efforts at the hospital, state, and national level must be undertaken to identify root causes of these issues.

Systematic Review of Racial, Socioeconomic, and Insurance Status Disparities in the Treatment of Pediatric Neurosurgical Diseases in the United States.

BACKGROUND: Increasing light is being shed on how race, insurance, and socioeconomic status (SES) may be related to outcomes from disease in the United States. To better understand the impact of these health care disparities in pediatric neurosurgery, we performed a systematic review of the literature. METHODS: We conducted a systematic review using PRISMA guidelines and MeSH terms involving neurosurgical conditions and racial, ethnic, and SES disparities. Three independent reviewers screened articles and analyzed texts selected for full analysis. RESULTS: Thirty-eight studies were included in the final analysis, of which all but 2 were retrospective database reviews. Thirty-four studies analyzed race, 22 analyzed insurance status, and 13 analyzed SES/income. Overall, nonwhite patients, patients with public insurance, and patients from lower SES were shown to have reduced access to treatment and greater rates of adverse outcomes. Nonwhite patients were more likely to present at an older age with more severe disease, less likely to undergo surgery at a high-volume surgical center, and more likely to experience postoperative morbidity and mortality. Underinsured and publicly insured patients were more likely to experience delay in surgical referral, less likely to undergo surgical treatment, and more likely to experience inpatient mortality. CONCLUSIONS: Health care disparities are present within multiple populations of patients receiving pediatric neurosurgical care. This review highlights the need for continued investigation into identifying and addressing health care disparities in pediatric neurosurgery patients.

Cerebral Bypass Using the Descending Branch of the Lateral Circumflex Femoral Artery: A Case Series.

BACKGROUND: When performing extracranial to intracranial (EC-IC) and intracranial to intracranial (IC-IC) bypass, the choice of donor vessel and interposition graft depends on several factors: vessel size and accessibility, desired blood flow augmentation, revascularization site anatomy, and pathology. The descending branch of the lateral circumflex femoral artery (DLCFA) is an attractive conduit for cerebrovascular bypass. OBJECTIVE: To present our institutional experience using DLCFA grafts for cerebral revascularization. METHODS: Retrospective review of perioperative data and outcomes for patients undergoing cerebrovascular bypass surgery using a DLCFA graft from 2016 to 2019. RESULTS: Twenty consecutive patients underwent EC-IC bypass using a DLCFA interposition graft. Bypass indications included 13 (65%) intracranial aneurysms, 4 (20%) medically refractory atherosclerotic large artery occlusions (internal carotid artery or middle cerebral artery), 2 (10%) internal carotid artery dissections, and 1 (5%) patient with moyamoya disease. Most commonly, a donor superior temporal artery was bypassed to a recipient middle cerebral artery (14 of 20; 70%). Two cases demonstrated graft spasm. Graft occlusion occurred in one patient and was asymptomatic. Perioperative bypass surgery-related ischemia occurred in 3 patients: 1 patient with insufficient bypass flow, 1 patient with graft stenosis because of an adventitial band, and 1 patient with focal status epilepticus in the bypassed territory resulting in cortical ischemia. One donor site hematoma occurred. The median (range) modified Rankin scale (mRS) score on follow-up was 1.5 (1-4) at 7.8 (1-27) months, with most patients achieving good functional outcomes (mRS ≤2). CONCLUSION: The DLCFA is a versatile graft for cerebral revascularization surgery, demonstrating good outcomes with minimal graft harvest site morbidity and an acceptable graft patency rate.

Epigenetic dysregulation in meningiomas.

Background: Meningiomas are the most common primary brain tumor. Though typically benign with a low mutational burden, tumors with benign histology may behave aggressively and there are no proven chemotherapies. Although DNA methylation patterns distinguish subgroups of meningiomas and have higher predictive value for tumor behavior than histologic classification, little is known about differences in DNA methylation between meningiomas and surrounding normal dura tissue. Methods: Whole-exome sequencing and methylation array profiling were performed on 12 dura/meningioma pairs (11 WHO grade I and 1 WHO grade II). Single-nucleotide polymorphism (SNP) genotyping and methylation array profiling were performed on an additional 19 meningiomas (9 WHO grade I, 5 WHO grade II, 4 WHO grade III). Results: Using multimodal studies of meningioma/dura pairs, we identified 4 distinct DNA methylation patterns. Diffuse DNA hypomethylation of malignant meningiomas readily facilitated their identification from lower-grade tumors by unsupervised clustering. All clusters and 12/12 meningioma-dura pairs exhibited hypomethylation of the gene promoters of a module associated with the craniofacial patterning transcription factor FOXC1 and its upstream lncRNA FOXCUT. Furthermore, we identified an epigenetic continuum of increasing hypermethylation of polycomb repressive complex target promoters with increasing histopathologic grade. Conclusion: These findings support future investigations of the role of epigenetic dysregulation of FOXC1 and cranial patterning genes in meningioma formation as well as studies of the utility of polycomb inhibitors for the treatment of malignant meningiomas.

Use of predictive spatial modeling to reveal that primary cancers have distinct central nervous system topography patterns of brain metastasis.

OBJECTIVE: Brain metastasis is the most common intracranial neoplasm. Although anatomical spatial distributions of brain metastasis may vary according to primary cancer subtype, these patterns are not understood and may have major implications for treatment. METHODS: To test the hypothesis that the spatial distribution of brain metastasis varies according to cancer origin in nonrandom patterns, the authors leveraged spatial 3D coordinate data derived from stereotactic Gamma Knife radiosurgery procedures performed to treat 2106 brain metastases arising from 5 common cancer types (melanoma, lung, breast, renal, and colorectal). Two predictive topographic models (regional brain metastasis echelon model [RBMEM] and brain region susceptibility model [BRSM]) were developed and independently validated. RESULTS: RBMEM assessed the hierarchical distribution of brain metastasis to specific brain regions relative to other primary cancers and showed that distinct regions were relatively susceptible to metastasis, as follows: bilateral temporal/parietal and left frontal lobes were susceptible to lung cancer; right frontal and occipital lobes to melanoma; cerebellum to breast cancer; and brainstem to renal cell carcinoma. BRSM provided probability estimates for each cancer subtype, independent of other subtypes, to metastasize to brain regions, as follows: lung cancer had a propensity to metastasize to bilateral temporal lobes; breast cancer to right cerebellar hemisphere; melanoma to left temporal lobe; renal cell carcinoma to brainstem; and colon cancer to right cerebellar hemisphere. Patient topographic data further revealed that brain metastasis demonstrated distinct spatial patterns when stratified by patient age and tumor volume. CONCLUSIONS: These data support the hypothesis that there is a nonuniform spatial distribution of brain metastasis to preferential brain regions that varies according to cancer subtype in patients treated with Gamma Knife radiosurgery. These topographic patterns may be indicative of the abilities of various cancers to adapt to regional neural microenvironments, facilitate colonization, and establish metastasis. Although the brain microenvironment likely modulates selective seeding of metastasis, it remains unknown how the anatomical spatial distribution of brain metastasis varies according to primary cancer subtype and contributes to diagnosis. For the first time, the authors have presented two predictive models to show that brain metastasis, depending on its origin, in fact demonstrates distinct geographic spread within the central nervous system. These findings could be used as a predictive diagnostic tool and could also potentially result in future translational and therapeutic work to disrupt growth of brain metastasis on the basis of anatomical region.

Demographic-Dependent Risk of Developing Severe Novel Psychiatric Disorders after Concussion.

Current guidelines for patients experiencing a concussion or mild traumatic brain injury (mTBI) often focus on conservative care and observation. However, mTBI may increase the risk of severe novel psychiatric disorders (NPDs) within 180 days, and long-term management of mTBI should include psychiatric evaluation in patient populations. Retrospective cohort analysis was conducted using 8 years of the Nationwide Readmission Database. All individuals who were admitted for concussion and were readmitted within 180 days were queried. This cohort was then subdivided based on age, sex, and whether they experienced loss of consciousness (LOC) to control for demographic-dependent confounding. A binary decision tree provided recommendations for patients who may be at risk of developing severe NPDs. Analysis included 12,080 patients who experienced concussion. Males and females with LOC had higher rates of depression in all age quartiles within 180 days (p < 0.05). Young females with LOC had increased rates of suicidal ideation (p < 0.01), and those >25 years of age had increased rates of anxiety (p < 0.005). Adult males with LOC had increased rates of suicidal ideation (p < 0.002) and males >75 years of age had increased rates of anxiety at readmission (p < 0.05). Males without LOC had increased rates of depression (p < 0.005), with men in the second quartile also at higher risk of developing anxiety (p < 0.05). Females without LOC showed the fewest number of NPDs at readmission. Concussion may be associated with increased rates of NPDs in the first 6 months following discharge. We use these data to develop recommendations for psychiatric screening of patients with mTBI.

Minocycline decreases blood-brain barrier permeability following aneurysmal subarachnoid hemorrhage: a randomized, double-blind, controlled trial.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH)-induced vasospasm is linked to increased inflammatory cell trafficking across a permeable blood-brain barrier (BBB). Elevations in serum levels of matrix metalloprotease 9 (MMP9), a BBB structural protein, have been implicated in the pathogenesis of vasospasm onset. Minocycline is a potent inhibitor of MMP9. The authors sought to detect an effect of minocycline on BBB permeability following aSAH. METHODS: Patients presenting within 24 hours of symptom onset with imaging confirmed aSAH (Fisher grade 3 or 4) were randomized to high-dose (10 mg/kg) minocycline or placebo. The primary outcome of interest was BBB permeability as quantitated by contrast signal intensity ratios in vascular regions of interest on postbleed day (PBD) 5 magnetic resonance permeability imaging. Secondary outcomes included serum MMP9 levels and radiographic and clinical evidence of vasospasm. RESULTS: A total of 11 patients were randomized to minocycline (n = 6) or control (n = 5) groups. No adverse events or complications attributable to minocycline were reported. High-dose minocycline administration was associated with significantly lower permeability indices on imaging analysis (p < 0.01). There was no significant difference with respect to serum MMP9 levels between groups, although concentrations trended upward in both cohorts. Radiographic vasospasm was noted in 6 patients (minocycline = 3, control = 3), with only 1 patient developing symptoms of clinical vasospasm in the minocycline cohort. There was no difference between cohorts with respect to Lindegaard ratios, transcranial Doppler values, or onset of vasospasm. CONCLUSIONS: Minocycline at high doses is well tolerated in the ruptured cerebral aneurysm population. Minocycline curtails breakdown of the BBB following aSAH as evidenced by lower permeability indices, though minocycline did not significantly alter serum MMP9 levels. Larger randomized clinical trials are needed to assess minocycline as a neuroprotectant against aSAH-induced vasospasm. Clinical trial registration no.: NCT04876638 (clinicaltrials.gov).

Evaluating the predictive value of comorbidity indices in pituitary surgery: a mixed-effects modeling study using the Nationwide Readmissions Database.

OBJECTIVE: Although pituitary adenomas (PAs) are common intracranial tumors, literature evaluating the utility of comorbidity indices for predicting postoperative complications in patients undergoing pituitary surgery remains limited, thereby hindering the development of complex models that aim to identify high-risk patient populations. We utilized comparative modeling strategies to evaluate the predictive validity of various comorbidity indices and combinations thereof in predicting key pituitary surgery outcomes. METHODS: The Nationwide Readmissions Database was used to identify patients who underwent pituitary tumor operations (n = 19,653) in 2016-2017. Patient frailty was assessed using the Johns Hopkins Adjusted Clinical Groups (ACG) System. The Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI) were calculated for each patient. Five sets of generalized linear mixed-effects models were developed, using as the primary predictors 1) frailty, 2) CCI, 3) ECI, 4) frailty + CCI, or 5) frailty + ECI. Complications of interest investigated included inpatient mortality, nonroutine discharge (e.g., to locations other than home), length of stay (LOS) within the top quartile (Q1), cost within Q1, and 1-year readmission rates. RESULTS: Postoperative mortality occurred in 73 patients (0.4%), 1-year readmission was reported in 2994 patients (15.2%), and nonroutine discharge occurred in 2176 patients (11.1%). The mean adjusted all-payer cost for the procedure was USD $25,553.85 ± $26,518.91 (Q1 $28,261.20), and the mean LOS was 4.8 ± 7.4 days (Q1 5.0 days). The model using frailty + ECI as the primary predictor consistently outperformed other models, with statistically significant p values as determined by comparing areas under the curve (AUCs) for most complications. For prediction of mortality, however, the frailty + ECI model (AUC 0.831) was not better than the ECI model alone (AUC 0.831; p = 0.95). For prediction of readmission, the frailty + ECI model (AUC 0.617) was not better than the frailty model alone (AUC 0.606; p = 0.10) or the frailty + CCI model (AUC 0.610; p = 0.29). CONCLUSIONS: This investigation is to the authors' knowledge the first to implement mixed-effects modeling to study the utility of common comorbidity indices in a large, nationwide cohort of patients undergoing pituitary surgery. Knowledge gained from these models may help neurosurgeons identify high-risk patients who require additional clinical attention or resource utilization prior to surgical planning.