The use of high frequency oscillations to guide neocortical resections in children with medically-intractable epilepsy: How do we ethically apply surgical innovations to patient care?

AbstractPurposeResective surgical strategies are increasingly applied to treat medically-intractable epilepsy in children as uncontrolled seizures are associated with poor cognitive, developmental and behavioral outcomes. Innovative surgical strategies are, however, needed to improve outcomes and minimize the morbidity of such procedures.MethodThe current article utilizes an axiological approach to explore and highlight ethical issues in the use of high frequency oscillations (HFOs) to guide surgical resections in children with medically-intractable epilepsy. We frame our discussion in the context of the broader challenges in the application of surgical innovation to patient care.ResultsDespite a paucity of knowledge regarding their pathogenesis, limited evidence suggests the use of HFOs as biomarkers of epileptogenicity in resective procedures can improve seizure outcome. Clinicians must therefore weigh deficiencies in knowledge against the limited evidence supporting the utility of HFOs and make ethical decisions for the treatment of individual patients. Important ethical considerations for clinicians include the extent of deviation from established practice, the extent of evidence required to establish clinical validity, and the impact of technique implementation on equitable distribution of healthcare.ConclusionThe use of HFO signatures to guide neocortical resections represents a novel approach for the treatment of epilepsy. It is hoped that the issues discussed herein will contribute to and advance meaningful dialog on the ethical application of this surgical innovation to the treatment of a very vulnerable patient population

Predictors of seizure outcomes in children with tuberous sclerosis complex and intractable epilepsy undergoing resective epilepsy surgery: an individual participant data meta-analysis.

ObjectiveTo perform a systematic review and individual participant data meta-analysis to identify preoperative factors associated with a good seizure outcome in children with Tuberous Sclerosis Complex undergoing resective epilepsy surgery.Data sourcesElectronic databases (MEDLINE, EMBASE, CINAHL and Web of Science), archives of major epilepsy and neurosurgery meetings, and bibliographies of relevant articles, with no language or date restrictions.Study selectionWe included case-control or cohort studies of consecutive participants undergoing resective epilepsy surgery that reported seizure outcomes. We performed title and abstract and full text screening independently and in duplicate. We resolved disagreements through discussion.Data extractionOne author performed data extraction which was verified by a second author using predefined data fields including study quality assessment using a risk of bias instrument we developed. We recorded all preoperative factors that may plausibly predict seizure outcomes.Data synthesisTo identify predictors of a good seizure outcome (i.e. Engel Class I or II) we used logistic regression adjusting for length of follow-up for each preoperative variable.ResultsOf 9863 citations, 20 articles reporting on 181 participants were eligible. Good seizure outcomes were observed in 126 (69%) participants (Engel Class I: 102(56%); Engel class II: 24(13%)). In univariable analyses, absence of generalized seizure semiology (OR = 3.1, 95%CI = 1.2-8.2, p = 0.022), no or mild developmental delay (OR = 7.3, 95%CI = 2.1-24.7, p = 0.001), unifocal ictal scalp electroencephalographic (EEG) abnormality (OR = 3.2, 95%CI = 1.4-7.6, p = 0.008) and EEG/Magnetic resonance imaging concordance (OR = 4.9, 95%CI = 1.8-13.5, p = 0.002) were associated with a good postoperative seizure outcome.ConclusionsSmall retrospective cohort studies are inherently prone to bias, some of which are overcome using individual participant data. The best available evidence suggests four preoperative factors predictive of good seizure outcomes following resective epilepsy surgery. Large long-term prospective multicenter observational studies are required to further evaluate the risk factors identified in this review

Glioblastoma—a moving target

The slow development of effective treatment of glioblastoma is contrasted by the rapidly advancing research on the molecular mechanisms underlying the disease. Amplification and overexpression of receptor tyrosine kinases, particularly EGFR and PDGFRA, are complemented by mutations in the PI3K, RB1, and p53 signaling pathways. In addition to finding effective means to target these pathways, we may take advantage of the recent understanding of the hierarchical structure of tumor cell populations, where the progressive expansion of the tumor relies on a minor subpopulation of glioma stem cells, or glioma-initiating cells. Finding ways to reprogram these cells and block their self-renewal is one of the most important topics for future research

Disruption of Rolandic Gamma-Band Functional Connectivity by Seizures is Associated with Motor Impairments in Children with Epilepsy

Although children with epilepsy exhibit numerous neurological and cognitive deficits, the mechanisms underlying these impairments remain unclear. Synchronization of oscillatory neural activity in the gamma frequency range (>30 Hz) is purported to be a mechanism mediating functional integration within neuronal networks supporting cognition, perception and action. Here, we tested the hypothesis that seizure-induced alterations in gamma synchronization are associated with functional deficits. By calculating synchrony among electrodes and performing graph theoretical analysis, we assessed functional connectivity and local network structure of the hand motor area of children with focal epilepsy from intracranial electroencephalographic recordings. A local decrease in inter-electrode phase synchrony in the gamma bands during ictal periods, relative to interictal periods, within the motor cortex was strongly associated with clinical motor weakness. Gamma-band ictal desychronization was a stronger predictor of deficits than the presence of the seizure-onset zone or lesion within the motor cortex. There was a positive correlation between the magnitude of ictal desychronization and impairment of motor dexterity in the contralateral, but not ipsilateral hand. There was no association between ictal desynchronization within the hand motor area and non-motor deficits. This study uniquely demonstrates that seizure-induced disturbances in cortical functional connectivity are associated with network-specific neurological deficits

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

Changing Global Trends in Seizure Outcomes Following Resective Surgery for Tuberous Sclerosis in Children with Medically Intractable Epilepsy

Introduction. Tuberous sclerosis (TS) is the leading cause of genetic epilepsy worldwide. Here, we evaluate changes in seizure outcomes following resective epilepsy surgery in children with TS over time. Methods. A systematic review of the literature was performed to identify studies reporting seizure outcomes following resective epilepsy surgery in children with TS. Using an individual participant meta-analysis approach, seizure outcomes and associated covariates were combined. Multivariate logistic regression was used to determine significant associations between seizure outcomes and time of surgery. Results. Twenty studies from 1966 to present, yielding 186 participants, met the inclusion criteria for the study. On univariate analysis, there was a significant improvement in seizure outcomes in children who underwent resective epilepsy surgery within the last 15 years compared to older cohorts (chi-square 4.1; P=0.043). On multivariate analysis, adjusting for length of followup, this trend was not significant (OR 0.52; 95% CI 0.23–1.17; P=0.11). In the last 15 years, a greater proportion of younger children also underwent resective surgery compared to older cohorts (OR 0.93; 95% CI 0.89–0.97; P<0.01). Conclusions. A trend towards improved seizure outcomes following resective surgery for TS was observed from 1966 to present on multivariate analysis

Changing global trends in seizure outcomes following resective surgery for tuberous sclerosis in children with medically intractable epilepsy.

Introduction. Tuberous sclerosis (TS) is the leading cause of genetic epilepsy worldwide. Here, we evaluate changes in seizure outcomes following resective epilepsy surgery in children with TS over time. Methods. A systematic review of the literature was performed to identify studies reporting seizure outcomes following resective epilepsy surgery in children with TS. Using an individual participant meta-analysis approach, seizure outcomes and associated covariates were combined. Multivariate logistic regression was used to determine significant associations between seizure outcomes and time of surgery. Results. Twenty studies from 1966 to present, yielding 186 participants, met the inclusion criteria for the study. On univariate analysis, there was a significant improvement in seizure outcomes in children who underwent resective epilepsy surgery within the last 15 years compared to older cohorts (chi-square 4.1; P = 0.043). On multivariate analysis, adjusting for length of followup, this trend was not significant (OR 0.52; 95% CI 0.23-1.17; P = 0.11). In the last 15 years, a greater proportion of younger children also underwent resective surgery compared to older cohorts (OR 0.93; 95% CI 0.89-0.97; P &lt; 0.01). Conclusions. A trend towards improved seizure outcomes following resective surgery for TS was observed from 1966 to present on multivariate analysis

Toward an understanding of sexual harassment in neurosurgery

OBJECTIVE: The goal of this study was the creation and administration of a survey to assess the depth and breadth of sexual harassment across neurosurgery. METHODS: A survey was created to 1) assess perceived attitudes toward systemic issues that might be permissive of sexual harassment; 2) measure the reported prevalence and severity of sexual harassment; and 3) determine the populations at highest risk and those most likely to perpetrate sexual harassment. Demographic information was also included to facilitate further analysis. The SurveyMonkey platform was used, and a request to complete the survey was sent to all Society of Neurological Surgeons and Congress of Neurological Surgeons (CNS) active and resident members as well as CNS transitional, emeritus, and inactive members. Data were analyzed using RStudio version 1.2.5019. RESULTS: Nearly two-thirds of responders indicated having witnessed sexual harassment in some form (62%, n = 382). Males were overwhelmingly identified as the offenders in allegations of sexual harassment (72%), with individuals in a superior position identified as offenders in 86%. Less than one-third of responders addressed the incidents of sexual harassment when they happened (yes 31%, no 62%, unsure 7%). Of those who did report, most felt there was either no impact or a negative one (negative: 34%, no impact: 38%). Almost all (85%) cited barriers to taking action about sexual harassment, including retaliation/retribution (87%), impact on future career (85%), reputation concerns (72%), and associated stress (50%). Female neurosurgeons were statistically more likely than male neurosurgeons to report witnessing or experiencing sexual harassment, as well as assessing it as a problem. CONCLUSIONS: This study demonstrates that neurosurgeons report significant sexual harassment across all ages and practice settings. Sexual harassment impacts both men and women, with more than half personally subjected to this behavior and two-thirds having witnessed it. Male dominance, a hierarchical environment, and a permissive environment remain prevalent within the neurosurgical community. This is not just a historical problem, but it continues today. A change of culture will be required for neurosurgery to shed this mantle, which must include zero tolerance of this behavior, new policies, awareness of unconscious bias, and commitment to best practices to enhance diversity. Above all, it will require that all neurosurgeons and neurosurgical leaders develop an awareness of sexual harassment in the workplace and establish consistent mechanisms to mitigate against its highly deleterious effects in the specialty