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OBJECTIVE Hemispherectomy is a complex surgical intervention for medically refractory epilepsy, and its surgical sequelae continue to be defined. The incidence, timing, and predictors of postoperative hydrocephalus are not well understood. Correspondingly, the aim of this study was to define the natural history of the development of hydrocephalus after hemispherectomy based on the authors’ institutional experience. METHODS The authors performed a retrospective review of their departmental database for all relevant cases between 1988 and 2018. Demographic and clinical results were abstracted and analyzed using regression analyses to identify predictors of postoperative hydrocephalus. RESULTS Of the 114 patients who satisfied selection criteria, there were 53 females (46%) and 61 males (53%) with mean ages of 2.2 and 6.5 years at first seizure and at hemispherectomy, respectively. There were 16 patients (14%) with a history of previous seizure surgery. In terms of surgery, the mean estimated blood loss was 441 ml, with a mean operative time of 7 hours, and 81 patients (71%) required intraoperative transfusions. A planned postoperative external ventricular drain (EVD) was placed in 38 patients (33%). The most common procedural complications were infection and hematoma, occurring in 7 patients (6%) each. Overall, there were 13 patients (11%) with postoperative hydrocephalus requiring permanent CSF diversion, occurring at a median of 1 year (range 0.1–5 years) after surgery. On multivariable analysis, a postoperative EVD (OR 0.12, p < 0.01) was significantly associated with a decreased likelihood of postoperative hydrocephalus, whereas previous surgery history (OR 4.32, p = 0.03) and postoperative infection complication (OR 5.14, p = 0.04) were significantly associated with increased likelihood of postoperative hydrocephalus. CONCLUSIONS Postoperative hydrocephalus mandating permanent CSF diversion following hemispherectomy can be expected in approximately 1 in 10 cases, presenting months after surgery on average. A postoperative EVD appears to reduce this likelihood, whereas postoperative infection and previous history of seizure surgery were shown to statistically increase this likelihood. These parameters should be carefully considered in the management of pediatric hemispherectomy for medically refractory epilepsy.

OBJECTIVE The success rate of endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC) in the management of posthemorrhagic hydrocephalus (PHH) following intraventricular hemorrhage (IVH) in infants is not well defined. Furthermore, parameters of IVH at initial presentation have not been tested for predictive associations of ETV/CPC success in this setting. The authors sought to summarize their institutional outcomes to identify possible predictors of ETV/CPC success within this niche. METHODS A retrospective review was conducted of all ETV/CPC procedures performed at the authors’ institution for PHH between 2011 and 2021. Patients were screened against a set of selection criteria including follow-up time of at least 6 months. Associations with ETV/CPC failure were evaluated using regression and Kaplan-Meier analyses. RESULTS A total of 50 patients satisfied all criteria. There were 32 (64%) male and 18 (36%) female patients with a mean gestational birth age of 26 weeks. The presenting IVH was symmetric in 30 (60%) and asymmetric in 20 (40%) patients, and the maximum IVH grade was IV in 30 (60%) patients overall. Six months after the procedure, ETV/CPC success was seen in 18 (36%) patients and failure in 32 (64%) patients. The median overall follow-up was 42 months, at which point ETV/CPC success was observed in 11 (22%) patients and ETV/CPC failure in 39 (78%) patients. Regression analyses indicated that radiological IVH symmetry was a statistically significant predictor of ETV/CPC failure at 6 months (OR 3.46, p = 0.04) and overall (OR 5.33, p = 0.03). Overall rates of failure were 89% versus 62% (p = 0.02) when comparing symmetric versus asymmetric IVH patients, and time to failure occurred at median times of 1.4 versus 6.5 months (p = 0.03) after the initial procedure. Higher maximum IVH grade and younger age at initial ETV/CPC only trended toward increased failure rates. When the etiology component of the ETV Success Score was adjusted such that symmetric IVH was scored 0, the area under the curve for failure at 6 months increased from 0.58 to 0.69. CONCLUSIONS Overall, approximately 1 in 5 infants with PHH can expect to not require further intervention following ETV/CPC. The authors demonstrate that IVH symmetry is statistically predictive of ETV/CPC failure in this setting independent of all other parameters, where PHH infants with symmetric IVH are more likely to experience failure, and sooner, than PHH infants with asymmetric IVH. When discussing possible success rates of ETV/CPC for PHH, IVH symmetry should be considered.

OBJECTIVE Resection and disconnection surgeries for epilepsy in the pediatric demographic (patients ≤ 18 years of age) are two separate, definitive intervention options in medically refractory cases. Questions remain regarding the role of surgery when seizures persist after an initial incomplete surgery. The aim of this study was to review the contemporary literature and summarize the metadata on the outcomes of repeat surgery in this specific demographic. METHODS Searches of seven electronic databases from inception to July 2022 were conducted using PRISMA guidelines. Articles were screened using prespecified criteria. Metadata from the articles were abstracted and pooled by random-effects meta-analysis of proportions. RESULTS Eleven studies describing 12 cohorts satisfied all criteria, reporting outcomes of 170 pediatric patients with epilepsy who underwent repeat resection or disconnection surgery. Of these patients, 55% were male, and across all studies, median ages at initial and repeat surgeries were 7.2 and 9.4 years, respectively. The median follow-up duration after repeat surgery was 47.7 months. The most commonly reported etiology for epilepsy was cortical dysplasia. Overall, the estimated incidence of complete seizure freedom (Engel class I) following repeat surgery was 48% (95% CI 40%–56%, p value for heterogeneity = 0.93), and the estimated incidence of postoperative complications following repeat surgery was 25% (95% CI 12%–39%, p = 0.04). There were six cohorts each that described outcomes for repeat resection and repeat disconnection surgeries. There was no statistical difference between these two subgroups with respect to estimated incidence of complete seizure freedom (p value for interaction = 0.92), but postoperative complications were statistically more common following repeat resection (p ≤ 0.01). CONCLUSIONS For both resection and disconnection surgeries, repeat epilepsy surgery in children is likely to confer complete seizure freedom in approximately half of the patients who experience unsuccessful initial incomplete epilepsy surgery. More data are needed to elucidate the impact on efficacy based on surgical approach selection. Judicious discussion and planning between the patient, family, and a multidisciplinary team of epilepsy specialists is recommended to optimize expectations and outcomes in this setting.

OBJECTIVE Magnetic resonance–guided focused ultrasound (MRgFUS) is an incisionless procedure capable of thermoablation through the focus of multiple acoustic beams. Although MRgFUS is currently approved for the treatment of tremor in adults, its safety and feasibility profile for intracranial lesions in the pediatric and young adult population remains unknown. METHODS The long-term outcomes of a prospective single-center, single-arm trial of MRgFUS at Nicklaus Children’s Hospital in Miami, Florida, are presented. Patients 15–22 years of age with centrally located lesions were recruited, clinically consistent with WHO grade I tumors that require surgical intervention. This cohort consisted of 4 patients with hypothalamic hamartoma (HH), and 1 patient with tuberous sclerosis complex harboring a subependymal giant cell astrocytoma (SEGA). RESULTS In each case, high-intensity FUS was used to target the intracranial lesion. Real-time MRI was used to monitor the thermoablations. Primary outcomes of interest were tolerability, feasibility, and safety of FUS. The radiographic ablation volume on intra- and postoperative MRI was also assessed. All 5 patients tolerated the procedure without any complications. Successful thermoablation was achieved in 4 of the 5 cases; the calcified SEGA was undertreated due to intratumor calcification, which prevented attainment of the target ablation temperature. The HHs underwent target tissue thermoablations that led to MR signal changes at the treatment site. For the patients harboring HHs, FUS thermoablations occurred without procedure-related complications and led to improvement in seizure control or hypothalamic hyperphagia. All 5 patients were discharged home on postoperative day 1 or 2, without any readmissions. There were no cases of hemorrhage, electrolyte derangement, endocrinopathy, or new neurological deficit in this cohort. CONCLUSIONS This experience demonstrates that FUS thermoablation of centrally located brain lesions in adolescents and young adults can be performed safely and that it provides therapeutic benefit for associated symptoms.

There is substantial variability in reported seizure outcome following pediatric epilepsy surgery, and lack of individualized predictive tools that could evaluate the probability of seizure freedom postsurgery. The aim of this study was to develop and validate a supervised machine learning (ML) model for predicting seizure freedom after pediatric epilepsy surgery.This is a multicenter retrospective study of children who underwent epilepsy surgery at five pediatric epilepsy centers in North America. Clinical information, diagnostic investigations, and surgical characteristics were collected, and used as features to predict seizure-free outcome 1 year after surgery. The dataset was split randomly into 80% training and 20% testing data. Thirty-five combinations of five feature sets with seven ML classifiers were assessed on the training cohort using 10-fold cross-validation for model development. The performance of the optimal combination of ML classifier and feature set was evaluated in the testing cohort, and compared with logistic regression, a classical statistical approach.Of the 801 patients included, 61.3% were seizure-free 1 year postsurgery. During model development, the best combination was XGBoost ML algorithm with five features from the univariate feature set, including number of antiseizure medications, magnetic resonance imaging lesion, age at seizure onset, video-electroencephalography concordance, and surgery type, with a mean area under the curve (AUC) of .73 (95% confidence interval [CI] = .69-.77). The combination of XGBoost and univariate feature set was then evaluated on the testing cohort and achieved an AUC of .74 (95% CI = .66-.82; sensitivity = .87, 95% CI = .81-.94; specificity = .58, 95% CI = .47-.71). The XGBoost model outperformed the logistic regression model (AUC = .72, 95% CI = .63-.80; sensitivity = .72, 95% CI = .63-.82; specificity = .66, 95% CI = .53-.77) in the testing cohort (p = .005).This study identified important features and validated an ML algorithm, XGBoost, for predicting the probability of seizure freedom after pediatric epilepsy surgery. Improved prognostication of epilepsy surgery is critical for presurgical counseling and will inform treatment decisions.

Traumatic brain injury (TBI) in pediatric patients is a major burden to public health. Understanding clinical associations with severity and short hospitalization (≤ 1 day length of stay) is needed to better inform management paradigms and optimize triage.A retrospective review of the Kids' Inpatient Database (KID) was performed for all data reported between 2006 and 2012 for TBI patients aged ≤ 20 years. Univariate and multivariate regression analyses were performed to identify predictive factors of trauma severity and short hospitalization.A total of 220,777 pediatric TBI cases were identified, with the majority of cases being boys (66%) with a mean age of 11.5 years. Mean length of stay was 5.0 days, with 25% discharged within 1 day, and 83% routinely discharged home. In-hospital mortality occurred in 4% of cases. More severe TBI presentations were significantly and independently associated with older age, weekend admissions, hospital transfers, and in patients with chronic conditions and neurological issues (all P 0.01). There were 38% of admission that were short hospitalizations. Younger age, male gender, less chronic conditions, fall and assault etiologies, and with milder injury severity all significantly and independently predicted greater likelihood of short hospitalization.The severity of pediatric TBI admissions to the hospital can be impacted by a number of parameters. Furthermore, there exists a subset of clinical associations for short hospitalization admissions. Proactive identification of these parameters at time of presentation will assist in optimizing the management of pediatric TBI].

SCH Clinical and Sequencing Data

OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are rare tumors found throughout the body, with their clinical course in children still not completely understood. Correspondingly, this study aimed to determine survival outcomes and specific clinical predictors of survival in this population from a large national database. METHODS All patients with MPNSTs aged ≤ 18 years in the US National Cancer Database (NCDB) between 2005 and 2016 were retrospectively reviewed. Data were summarized, and overall survival was modeled using Kaplan-Meier and Cox regression analyses. RESULTS A total of 251 pediatric patients with MPNSTs (132 [53%] females and 119 [47%] males) were identified; the mean age at diagnosis was 13.1 years (range 1–18 years). There were 84 (33%) MPNSTs located in the extremities, 127 (51%) were smaller than 1 cm, and 22 (9%) had metastasis at the time of diagnosis. In terms of treatment, surgery was pursued in 187 patients (74%), chemotherapy in 116 patients (46%), and radiation therapy in 129 patients (61%). The 5-year overall survival rate was estimated at 52% (95% CI 45%–59%), with a median survival of 64 months (range 36–136 months). Multivariate regression revealed that older age (HR 1.10, p < 0.01), metastases at the time of diagnosis (HR 2.14, p = 0.01), and undergoing biopsy only (HR 2.98, p < 0.01) significantly and independently predicted a shorter overall survival. Chemotherapy and radiation therapy were not statistically significant. CONCLUSIONS In this study, the authors found that older patient age, tumor metastases at the time of diagnosis, and undergoing only biopsy significantly and independently predicted poorer outcomes. Only approximately half of patients survived to 5 years. These results have shown a clear survival benefit in pursuing maximal safe resection in pediatric patients with MPNSTs. As such, judicious workup with meticulous resection by an expert team should be considered the standard of care for these tumors in children.

PURPOSE: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the central nervous system by the World Health Organization (WHO). These tumors are rare and have not been well characterized in terms of clinical outcomes. We aimed to identify clinical predictors of mortality and tumor recurrence/progression by performing an individual patient data meta-analysis (IPDMA) of the literature. METHODS: A systematic literature review from 1970 to 2020 was performed, and individualized clinical data for patients diagnosed with DIA/DIG were extracted. Aggregated data were excluded from collection. Outcome measures of interest were mortality and tumor recurrence/progression, as well as time-to-event (TTE) for each of these. Participants without information on these outcome measures were excluded. Cox regression survival analyses were performed to determine predictors of mortality and tumor recurrence / progression. RESULTS: We identified 98 articles and extracted individual patient data from 188 patients. The cohort consisted of 58.9% males with a median age of 7 months. The majority (68.1%) were DIGs, while 24.5% were DIAs and 7.5% were non-specific desmoplastic infantile tumors; DIAs presented more commonly in deep locations (p = 0.001), with leptomeningeal metastasis (p = 0.001), and was associated with decreased probability of gross total resection (GTR; p = 0.001). Gender, age, and tumor pathology were not statistically significant predictors of either mortality or tumor recurrence/progression. On multivariate survival analysis, GTR was a predictor of survival (HR = 0.058; p = 0.007) while leptomeningeal metastasis at presentation was a predictor of mortality (HR = 3.27; p = 0.025). Deep tumor location (HR = 2.93; p = 0.001) and chemotherapy administration (HR = 2.02; p = 0.017) were associated with tumor recurrence/progression. CONCLUSION: Our IPDMA of DIA/DIG cases reported in the literature revealed that GTR was a predictor of survival while leptomeningeal metastasis at presentation was associated with mortality. Deep tumor location and chemotherapy were associated with tumor recurrence / progression.

Intracranial mixed vascular malformations (MVMs) are defined as any combination of a developmental venous anomaly (DVA), cerebral cavernous malformation (CCM), capillary telangiectasia (CTG), or arteriovenous malformation (AVM) within a single, contiguous lesion. However, most MVMs described in the literature contain only 2 pathologically discrete malformations; juxtaposition of 3 or more abnormalities in a single lesion remains exceedingly rare. We present the case of a 19-month-old female with new onset focal seizures and a 4-cm right basal ganglia lesion initially believed to be an embryonal neoplasm. She subsequently underwent gross total resection (GTR) of the lesion via a transsylvian-transinsular approach. Intraoperatively, the lesion appeared to be heterogenous and highly vascular, with areas of purplish-gray friable tissue. Pathology confirmed the lesion to be a MVM containing a CCM, CTG, and a DVA. This appears to be the first reported case of such a lesion confirmed on pathology in the literature.

BackgroundDespite the well-documented utility of responsive neurostimulation (RNS, NeuroPace) in adult epilepsy patients, literature on the use of RNS in children is limited.ObjectiveTo determine the real-world efficacy and safety of RNS in pediatric epilepsy patients.MethodsPatients with childhood-onset drug-resistant epilepsy treated with RNS were retrospectively identified at 5 pediatric centers. Reduction of disabling seizures and complications were evaluated for children (18 yr) and compared with prior literature pertaining to adult patients.ResultsOf 35 patients identified, 17 were

Minimally invasive magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has been proposed as an alternative to open epilepsy surgery, to address concerns regarding the risk of open surgery. Our primary hypothesis was that seizure freedom at 1 year after MRgLITT is noninferior to open surgery in children with drug-resistant epilepsy (DRE). The secondary hypothesis was that MRgLITT has fewer complications and shorter hospitalization than surgery. The primary objective was to compare seizure outcome of MRgLITT to open surgery in children with DRE. The secondary objective was to compare complications and length of hospitalization of the two treatments.This retrospective multicenter cohort study included children with DRE treated with MRgLITT or open surgery with 1-year follow-up. Exclusion criteria were corpus callosotomy, neurostimulation, multilobar or hemispheric surgery, and lesion with maximal dimension 60 mm. MRgLITT patients were propensity matched to open surgery patients. The primary outcome was seizure freedom at 1 year posttreatment. The difference in seizure freedom was compared using noninferiority test, with noninferiority margin of -10%. The secondary outcomes were complications and length of hospitalization.One hundred eighty-five MRgLITT patients were matched to 185 open surgery patients. Seizure freedom at 1 year follow-up was observed in 89 of 185 (48.1%) MRgLITT and 114 of 185 (61.6%) open surgery patients (difference = -13.5%, one-sided 97.5% confidence interval = -23.8% to ∞, pSeizure outcome of MRgLITT at 1 year posttreatment was inferior to open surgery. However, MRgLITT has the advantage of better safety profile and shorter hospitalization. The findings will help counsel children and parents on the benefits and risks of MRgLITT and contribute to informed decision-making on treatment options.

The recent emphasis on surgery as an essential yet neglected component of global health care has drawn attention to the lack of pediatric neurosurgery in low- and middle-income countries (LMICs). Most LMICs have very few neurosurgeons able or willing to care for children, leaving few access to care for readily treatable conditions, like pediatric hydrocephalus and spina bifida. Herein, we review the role of pediatric neurosurgeons to improve hydrocephalus management and medical education in LMICs. A literature search on global pediatric neurosurgery was performed using the Pubmed database from the year 2000 to October 5th, 2021. The majority of current pediatric neurosurgical efforts focus on the management of hydrocephalus. Endoscopic third ventriculostomy (ETV) with or without choroid plexus cauterization (CPC) has emerged as an effective alternative to ventriculoperitoneal (VP) shunting for CSF diversion in LMICs. Neurosurgical programs in LMICs are most successful when twinning is used to pair the program with an established center in a high-income country (HIC). Multiple international pediatric neurosurgical efforts aim to provide medical expertise, infrastructure, and surgical education to LMICs. The next step in developing sustainable surgery programs in LMICs includes establishing local training programs. Existing global pediatric neurosurgery programs are most successful when partnered to an experienced center in a HIC. A lack of funding, resources, and training programs all pose barriers to increasing the pediatric neurosurgical capacity in LMICs. Future global neurosurgery efforts may look to other neurosurgical conditions with high burdens of disease in LMICs, like epilepsy.

OBJECTIVEUncontrolled epilepsy is associated with serious deleterious effects on the neurological development of infants and has been described as “catastrophic epilepsy.” Recently, there has been increased emphasis on early surgical interventions to preserve or rescue neurodevelopmental outcomes in infants with early intractable epilepsy. The enthusiasm for early treatments is often tempered by concerns regarding the morbidity of neurosurgical procedures in very young patients. Here, the authors report outcomes following the surgical management of infants (younger than 1 year).METHODSThe authors performed a retrospective review of patients younger than 1 year of age who underwent surgery for epilepsy at Miami (Nicklaus) Children’s Hospital and Jackson Memorial Hospital between 1994 and 2018. Patient demographics, including the type of interventions, were recorded. Seizure outcomes (at last follow-up and at 1 year postoperatively) as well as complications are reported.RESULTSThirty-eight infants (median age 5.9 months) underwent a spectrum of surgical interventions, including hemispherectomy (n = 17), focal resection (n = 13), and multilobe resections (n = 8), with a mean follow-up duration of 9.1 years. Hemimegalencephaly and cortical dysplasia were the most commonly encountered pathologies. Surgery for catastrophic epilepsy resulted in complete resolution of seizures in 68% (n = 26) of patients, and 76% (n = 29) had a greater than 90% reduction in seizure frequency. Overall mortality and morbidity were 0% and 10%, respectively. The latter included infections (n = 2), infarct (n = 1), and immediate reoperation for seizures (n = 1).CONCLUSIONSSurgical intervention for catastrophic epilepsy in infants remains safe, efficacious, and durable. The authors’ work provides the longest follow-up of such a series on infants to date and compares favorably with previously published series.

Background Cancer-related changes in sexual function (SF) negatively impact quality of life and intimate partner relationships. There is a lack of data regarding SF among patients who underwent radical cystectomy (RC). Aim To comparatively evaluate perioperative SF among patients who underwent RC. Methods A prospective cohort of 150 patients undergoing RC for bladder cancer and participating in an internal validation study at a single institution from 2016 to 2019 were eligible for analysis. The European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire–Bladder Cancer Muscle Invasive (EORTC QLQ–BLM 30) and Functional Assessment of Cancer Therapy–Bladder were administered; those completing the SF subscale of the EORTC QLQ–BLM 30 were included in final analysis. Analysis was performed using descriptive statistics and generalized linear modeling. Outcomes The primary outcome was interest or engagement in sexual activity within 4 weeks of survey completion, whereas the secondary outcome was a mean score on the EORTC QLQ–BLM 30 SF subscale. Results Overall, 132 of 150 (88%) of patients were eligible, of whom 82% were male, and the median age was 68.5 years. 53% reported at least a little interest in sexual activity, and 40% endorsed sexual activity within the last 4 weeks. The mean SF subscale score was 61.5 ± 25.2. Women had significantly worse mean scores of 72.9 ± 27.1 versus 59.1 ± 24.2 for men (P = .02). On multivariate analysis, both age and female gender were independently associated with higher SF domain scores. Clinical Implications A substantial portion of patients who underwent RC endorse being sexually active or express interest in sexually activity in the perioperative period. Given the recent increase in attention given to SF outcomes and quality of life, this work supports further efforts to explore this area and develop novel interventions to improve outcomes. Strengths and Limitations Strengths include rigorously collected, cross-sectional data using standardized methodology. Limitations include a relatively small sample size of female patients and unknown meaningful clinical difference. Conclusions A substantial portion of patients report sexual interest and activity in the perioperative period; however, female gender is associated with worse SF domain scores. These findings support further inquiry into this topic.

IntroductionVagus nerve stimulation (VNS) is a neuromodulation therapy that can reduce the seizure burden of children with medically intractable epilepsy. Despite the widespread use of VNS to treat epilepsy, there are currently no means to preoperatively identify patients who will benefit from treatment. The objective of the present study is to determine clinical and neural network-based correlates of treatment outcome to better identify candidates for VNS therapy.Methods and analysisIn this multi-institutional North American study, children undergoing VNS and their caregivers will be prospectively recruited. All patients will have documentation of clinical history, physical and neurological examination and video electroencephalography as part of the standard clinical workup for VNS. Neuroimaging data including resting-state functional MRI, diffusion-tensor imaging and magnetoencephalography will be collected before surgery. MR-based measures will also be repeated 12 months after implantation. Outcomes of VNS, including seizure control and health-related quality of life of both patient and primary caregiver, will be prospectively measured up to 2 years postoperatively. All data will be collected electronically using Research Electronic Data Capture.Ethics and disseminationThis study was approved by the Hospital for Sick Children Research Ethics Board (REB number 1000061744). All participants, or substitute decision-makers, will provide informed consent prior to be enrolled in the study. Institutional Research Ethics Board approval will be obtained from each additional participating site prior to inclusion. This study is funded through a Canadian Institutes of Health Research grant (PJT-159561) and an investigator-initiated funding grant from LivaNova USA (Houston, TX; FF01803B IIR).

OBJECTIVE MRI is increasingly employed to assess intrauterine fetal anomalies. Central nervous system (CNS) anomalies are common structural conditions that warrant evaluation with fetal MRI and subsequent prenatal consultation with a pediatric neurosurgeon. As the use of fetal MRI increases, there is greater impetus to understand the most common CNS structural anomalies diagnosed in utero, as well as their natural histories. METHODS The authors performed a single-center retrospective review of fetal MRI evaluations performed between January 2012 and December 2020. Children who underwent both prenatal and postnatal neurosurgical evaluations of CNS anomalies were included. Specific CNS anomalies on fetal MRI, associated extra-CNS findings, and suspicion for genetic abnormality or syndromes were noted. Postnatal clinical status and interventions were assessed. RESULTS Between January 2012 and December 2020, a total of 469 fetal MRI evaluations were performed; of these, 114 maternal-fetal pairs had CNS anomalies that warranted prenatal consultation and postnatal pediatric neurosurgical follow-up. This cohort included 67 male infants (59%), with a mean ± SD follow-up of 29.8 ± 25.0 months after birth. Fetal MRI was performed at 27.3 ± 5.8 weeks of gestational age. The most frequently reported CNS abnormalities were ventriculomegaly (57%), agenesis or thinning of the corpus callosum (33%), Dandy-Walker complex (DWC) (21%), neuronal migration disorders (18%), and abnormalities of the septum pellucidum (17%). Twenty-one children (18%) required neurosurgical intervention at a mean age of 2.4 ± 3.7 months. The most common surgical conditions included myelomeningocele, moderate to severe ventriculomegaly, encephalocele, and arachnoid cyst. Corpus callosum agenesis or thinning was associated with developmental delay (p = 0.02) and systemic anomalies (p = 0.05). The majority of prenatal patients referred for DWC had Dandy-Walker variants that did not require surgical intervention. CONCLUSIONS The most common conditions for prenatal neurosurgical assessment were ventriculomegaly, corpus callosum anomaly, and DWC, whereas the most common surgical conditions were myelomeningocele, hydrocephalus, and arachnoid cyst. Only 18% of prenatal neurosurgical consultations resulted in surgical intervention during infancy. The majority of referrals for prenatal mild ventriculomegaly and DWC were not associated with developmental or surgical sequelae. Patients with corpus callosum abnormalities should be concurrently referred to a neurologist for developmental assessments.

OBJECTIVE The effect of congenital cardiac status on endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS) failure in hydrocephalic infants is unknown. Because cardiac status in infants can impact central venous pressure (CVP), it is possible that congenital heart disease (CHD) and congenital cardiac anomalies may render these cerebrospinal fluid diversion interventions more susceptible to failure. Correspondingly, the aim of this study was to determine how CHD and congenital cardiac anomalies may impact the failure of these initial interventions. METHODS A retrospective review of the Nationwide Inpatient Sample (NIS) database was conducted. Infants (aged < 1 year) with known congenital cardiac status managed with either ETV or VPS were included. Quantitative data were compared using either parametric or nonparametric methods, and failure rates were modeled using univariable and multivariable regression analyses. RESULTS A total of 18,763 infants treated with ETV or VPS for hydrocephalus were identified in our search, with ETV used to treat 7657 (41%) patients and VPS used to treat 11,106 (59%). There were 6722 (36%) patients who presented with CHD at admission, and a total of 25 unique congenital cardiac anomalies were detected across the cohort. Overall, the most common anomaly was patent ductus arteriosus (PDA) in 4990 (27%) patients, followed by atrial septal defect (ASD) in 2437 (13%) patients and pulmonary hypertension in 810 (4%) patients. With respect to initial intervention failure, 3869 (21%) patients required repeat surgical intervention during admission. This was significantly more common in the ETV group than the VPS group (36% vs 10%, p < 0.01). In both the ETV and VPS groups, CHD (p < 0.01), including all congenital cardiac anomalies, was an independent and significant predictor of failure. ASD (p < 0.01) and PDA (p < 0.01) both significantly predicted ETV failure, and PDA (p < 0.01) and pulmonary hypertension (p = 0.02) both significantly predicted VPS failure. CONCLUSIONS These results indicate that congenital cardiac status predicts ETV and VPS failure in patients with infantile hydrocephalus. The authors hypothesized that this finding was primarily due to changes in CVP; however, this may not be completely universal across both interventions and all congenital cardiac anomalies. Future studies about optimization of congenital cardiac status with ETV and VPS are required to understand the practical significance of these findings.

OBJECTIVE Quadrigeminal cistern arachnoid cysts (QACs) are congenital lesions that can cause pineal region compression and obstructive hydrocephalus when sufficiently large. Management of these cysts is controversial and rates of reintervention are high. Given the limited data on the management of QACs, the authors retrospectively reviewed 20 years of cases managed at their institution and performed a literature review on this topic. METHODS The authors performed a retrospective analysis of patients treated for QAC at their institution between 2001 and 2021. They also performed a literature review of studies published between 1980 and 2021 that reported at least 5 patients treated for QACs. Patient characteristics, radiographic findings, management course, and postoperative follow-up data were collected and analyzed. RESULTS A total of 12 patients treated for a QAC at the authors’ institution met the inclusion criteria for analysis. Median age was 9 months, mean cyst size was 5.1 cm, and 83% of patients had hydrocephalus. Initial treatment was endoscopic fenestration in 92% of these patients, 27% of whom had an endoscopic third ventriculostomy (ETV) performed concurrently. Reintervention was required in 42% of patients. Cases that required reintervention had a statistically significant lower median age at the initial intervention (5 months) than the cases that did not require reintervention (24.33 months; p = 0.018). There were no major complications. At a mean follow-up of 5.42 years, 83% of patients had improvement or resolution of their symptoms. A literature review revealed 7 studies that met the inclusion criteria, totaling 108 patients with a mean age of 8.8 years. Eighty-seven percent of patients had hydrocephalus at presentation. Ninety-two percent of patients were initially treated with endoscopic fenestration, 44% of whom underwent concurrent ETV. Complications occurred in 17.6% of cases, and reintervention was required in 30.6% of cases. The most frequent reason for reintervention was untreated or unresolved hydrocephalus after the initial procedure. CONCLUSIONS Endoscopic fenestration is the most common treatment for QACs. While generally safe and effective, there is a high rate of reintervention after initial treatment of QACs, which may be associated with a younger age at the first intervention. Additionally, identifying patients who require initial treatment of hydrocephalus is critically important, as the literature suggests that untreated hydrocephalus is a common cause of reintervention.

OBJECTIVEPrevious models have been utilized in other low- and middle-income countries (LMICs) to explore and assess the cost, sustainability, and effectiveness of infant hydrocephalus treatment. However, similar models have not been implemented in Haiti due to a paucity of data, epidemiology, and outcomes for hydrocephalus. Therefore, the authors utilized previously described economic modeling to estimate the annual cost and benefit of treating hydrocephalus in infants at a neurosurgery referral center, Hospital Bernard Mevs (HBM), in Port-au-Prince, Haiti.METHODSThe authors conducted a retrospective review of data obtained in all children treated for hydrocephalus at the HBM from 2008 to 2015. The raw data were pooled with previously described surgical outcomes for hydrocephalus in other LMICs. Modeling was performed to determine outcomes, neurosurgical costs, disability-adjusted life years (DALYs), and economic benefits of Haitian hydrocephalus treatment during this time frame. Standard account methodology was employed to calculate cost per procedure. Using these formulas, the net economic benefit and cost/DALY were determined for hydrocephalus treatment at HBM from 2008 to 2015.RESULTSOf the 401 patients treated during the study period, 158 (39.4%) met criteria for postinfectious hydrocephalus, 54 (13.5%) had congenital hydrocephalus, 38 (9.5%) had myelomeningocele, 19 (4.7%) had aqueductal stenosis, and 132 (33%) were not placed into a category. Overall, 317 individuals underwent surgical treatment of their hydrocephalus, averting 3077 DALYs. The total cost of the procedures was $754,000, and the cost per DALY ranged between $86 and $245. The resulting net economic benefit for neurosurgical intervention ranged from $2.5 to $5.5 million.CONCLUSIONSThis work demonstrates the substantial economic benefit of neurosurgical intervention for the treatment of pediatric hydrocephalus at a single hospital in Haiti. Based on DALYs averted, the need for additional centers offering basic neurosurgical services is apparent. A single center offering these services for several days each month was able to generate between $2.5 to $5.5 million in economic benefits, suggesting the need to develop neurosurgical capacity building in Haiti. Ultimately, prevention, screening, and early surgical treatment of these infants represent a public health and socioeconomic requisite for Haiti.

Carotid body tumors (CBTs) are rare paragangliomas, comprising 0.5% of all head and neck tumors, and 65% of head and neck paragangliomas. A majority of CBTs occur sporadically, while 15% are familial or hyperplastic in the setting of chronic hypoxia. They usually present as unilateral, well-circumscribed rubbery masses, arising at the level of the carotid bifurcation. A majority of CBTs are painless and therefore may evade diagnosis for months to years. Symptomatic lesions occur due to progressive cranial nerve IX, X, or XII dysfunction, manifesting as hoarseness, dysphagia, vertigo, coughing, or odynophagia. Other local symptoms include neck discomfort, pulsatile tinnitus, hearing loss, or carotid sinus syndrome. Appropriate workup includes a thorough physical exam followed by radiographic imaging, vascular studies, and biochemical workup with 24 h urinary catecholamine or metanephrine analysis. The management of these tumors, which involves standalone surgical resection or following embolization for larger and more vascular tumors, will also be discussed.

Intracranial mixed vascular malformations (MVMs) are defined as any combination of a developmental venous anomaly (DVA), cerebral cavernous malformation (CCM), capillary telangiectasia (CTG), or arteriovenous malformation (AVM) within a single, contiguous lesion. However, most MVMs described in the literature contain only 2 pathologically discrete malformations; juxtaposition of 3 or more abnormalities in a single lesion remains exceedingly rare. We present the case of a 19-month-old female with new onset focal seizures and a 4-cm right basal ganglia lesion initially believed to be an embryonal neoplasm. She subsequently underwent gross total resection (GTR) of the lesion via a transsylvian-transinsular approach. Intraoperatively, the lesion appeared to be heterogenous and highly vascular, with areas of purplish-gray friable tissue. Pathology confirmed the lesion to be a MVM containing a CCM, CTG, and a DVA. This appears to be the first reported case of such a lesion confirmed on pathology in the literature.

Neurenteric cysts (NECs) of the central nervous system (CNS) are uncommon congenital entities arising from embryonal elements. Intracranial NECs in the pediatric population are rare. The authors describe the presentation, radiographic imaging, and pathologic findings of an 11-year-old boy with a right oculomotor nerve NEC. A literature review was performed to identify additional cases of pediatric intracranial NECs published in the English language, over the past 30 years (1990–2020). The authors discuss the presentation, investigations, management, and prognosis of this interesting entity. We describe an 11-year-old boy who presented to neurosurgical attention with disconjugate gaze, anisocoria, and ptosis. Magnetic resonance imaging (MRI) demonstrated a lobulated, cystic, and peripherally enhancing mass involving the right oculomotor nerve. The patient underwent pterional craniotomy for drainage of the cyst and subtotal resection of the cyst wall. The tan-colored mass was displacing the basilar artery, compressing the cerebral peduncle, and adherent to the inferior surface of the tentorium. The lesion was within the oculomotor nerve and splitting the fibers, and the cystic contents were thick and mucinous. Histopathological examination of the specimen demonstrated a thin fibrous cyst wall with scattered inflammatory cells and lined by simple columnar epithelium containing mucin. The lining cells were immunoreactive with epithelial membrane antigen (EMA) and pan-keratin AE1/AE3. The diagnosis of a NEC was rendered. A comprehensive literature review of pediatric intracranial NECs yielded 46 additional lesions published in the literature, involving the skull base, posterior fossa, cerebral convexity, and cranial nerves. NECs present with local mass effect and less commonly, with aseptic meningitis or intracystic hemorrhage. Maximal safe GTR remains the mainstay management, although cyst drainage and marsupialization, cyst shunting, and fenestration of cystic contents into the ventricle or basal cisterns have been reported with variable success. CNS NECs are rare congenital entities; although they occur less frequently in the intracranial components compared to the spine, their diagnosis and management should be considered for intracranial cystic lesions. Maximal safe GTR is the mainstay treatment and frequently yields favorable outcomes.

OBJECTIVE Infantile intracranial aneurysms are exceedingly rare. The goal of this study was to evaluate an institutional case series of infantile intracranial aneurysms, as well as those reported in the contemporary literature, to determine their demographics, presentation, management, and long-term outcome. METHODS A comprehensive literature review from 1980 to 2020 was performed to identify individual cases of intracranial aneurysms in the infantile population ≤ 2 years of age. Additional cases from the authors’ institution were identified during the same time period. An individual participant data meta-analysis (IPDMA) was performed, abiding by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Patient demographic, radiographic, and clinical information was obtained. Descriptive statistical data were recorded, and multivariate logistic regression analyses were performed. RESULTS Patient data were obtained for 133 patients from 87 articles in the literature. Ten additional patients at the authors’ institution were also identified, for a total of 143 patients included in the IPDMA. The majority (72.7%) of this cohort consisted of idiopathic aneurysms, while 13.3% were posttraumatic pseudoaneurysms, 9.8% were infectious mycotic aneurysms, and 4.2% were aneurysms associated with a systemic connective tissue disorder or vasculitis. The mean age at presentation was 6.6 months. The majority of infants (97.9%) harbored only 1 aneurysm, and hemorrhage was the most common presenting feature (78.3%). The mean aneurysm size was 14.4 mm, and giant aneurysms ≥ 25 mm comprised 12.9% of the cohort. Most aneurysms occurred in the anterior circulation (80.9%), with the middle cerebral artery (MCA) being the most commonly affected vessel (51.8%). Management strategies included open surgical aneurysm ligation (54.0%), endovascular treatment (35.0%), surgical decompression without aneurysm treatment (4.4%), and medical supportive management only (13.9%). Surgical aneurysm ligation was more commonly performed for MCA and anterior cerebral artery aneurysms (p = 0.004 and p = 0.015, respectively), while endovascular techniques were favored for basilar artery aneurysms (p = 0.042). The mean follow-up period was 29.9 months; 12.4% of the cohort died, and 67.0% had a favorable outcome (Glasgow Outcome Scale score of 5). CONCLUSIONS This study is, to the authors’ knowledge, the largest analysis of infantile intracranial aneurysms to date. The majority were idiopathic aneurysms involving the anterior circulation. Surgical and endovascular techniques yielded equally favorable outcomes in this cohort. Long-term outcomes in the infantile population compared favorably to outcomes in adults.

Significance A noninvasive intranasal (i.n.) influenza vaccine can induce mucosal immune responses in respiratory tracts, preventing infection at the portal of virus entry. However, the absence of appropriate mucosal adjuvants at present hinders the development of such a vaccine. Here, we developed polyethyleneimine-functionalized two-dimensional graphene oxide nanoparticles (GP) that showed high antigen-loading capacities and superior immunoenhancing properties. Robust and broadly reactive immune responses were induced with i.n. immunization with GP-HA nanoparticles, conferring protection against homologous and heterologous viruses. With versatility and flexibility, GP nanoparticles can be easily adapted for constructing mucosal vaccines of different respiratory pathogens., Intranasal (i.n.) immunization is a promising vaccination route for infectious respiratory diseases such as influenza. Recombinant protein vaccines can overcome the safety concerns and long production phase of virus-based influenza vaccines. However, soluble protein vaccines are poorly immunogenic if administered by an i.n. route. Here, we report that polyethyleneimine-functionalized graphene oxide nanoparticles (GP nanoparticles) showed high antigen-loading capacities and superior immunoenhancing properties. Via a facile electrostatic adsorption approach, influenza hemagglutinin (HA) was incorporated into GP nanoparticles and maintained structural integrity and antigenicity. The resulting GP nanoparticles enhanced antigen internalization and promoted inflammatory cytokine production and JAWS II dendritic cell maturation. Compared with soluble HA, GP nanoparticle formulations induced significantly enhanced and cross-reactive immune responses at both systemic sites and mucosal surfaces in mice after i.n. immunization. In the absence of any additional adjuvant, the GP nanoparticle significantly boosted antigen-specific humoral and cellular immune responses, comparable to the acknowledged potent mucosal immunomodulator CpG. The robust immune responses conferred immune protection against challenges by homologous and heterologous viruses. Additionally, the solid self-adjuvant effect of GP nanoparticles may mask the role of CpG when coincorporated. In the absence of currently approved mucosal adjuvants, GP nanoparticles can be developed into potent i.n. influenza vaccines, providing broad protection. With versatility and flexibility, the GP nanoplatform can be easily adapted for constructing mucosal vaccines for different respiratory pathogens.

Objective To assess the extent and adequacy of pre-operative sexual function (SF) counseling in females undergoing radical cystectomy (RC) and develop educational material to improve identified deficits. Methods A 10-question survey was electronically delivered to all females who underwent RC at a single institution between 2015 and 2020. 23 of 145 patients responded (15.9%). In addition, women on the Bladder Cancer Advocacy Network (BCAN) patient discussion board were also queried. The primary outcome was the development of a patient educational handout based on patient perception of pre-operative SF counseling and self-reported changes in post-operative SF. Results 22 women, 84% of whom were sexually active, met the inclusion criteria. More than half (12/22, 54.5%) reported receiving no pre-operative counseling regarding possible SF changes while another 27.3% (6/22) received some counseling but desired more. Most women rated vaginal preservation as moderate to very important (17/22, 77.3%) and nearly all women noted at least one change in SF, most commonly dyspareunia (13/22, 59.1%). Most also desired more information regarding female sexual health. Separately, the BCAN discussion board was queried regarding patient preference for modality of pre-operative counseling. 77.8% (14/18) preferred a discussion with provider and 13/18 (72.2%) also wanted a written handout. Conclusions Sexual dysfunction is prevalent following RC in women and many desire more pre-operative counseling, regardless of disease stage or receipt of chemotherapy. These findings supported our development of interventions to improve pre-operative education as well as strategies to address post-operative SF changes, such as dyspareunia.

Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low and middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed SARS-CoV-2 specific receptor-binding domain (RBD) based vaccine in rhesus macaques. We formulated the RBD immunogen in alum, a licensed and an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted vaccine promoted better RBD binding and effector antibodies, higher CoV-2 neutralizing antibodies, improved Th1 biased CD4+T cell reactions, and increased CD8+ T cell responses when compared to the alum-alone adjuvanted vaccine. RBD+3M-052-alum induced a significant reduction of SARS-CoV-2 virus in respiratory tract upon challenge, accompanied by reduced lung inflammation when compared with unvaccinated controls. Anti-RBD antibody responses in vaccinated animals inversely correlated with viral load in nasal secretions and BAL. RBD+3M-052-alum blocked a post SARS-CoV-2 challenge increase in CD14+CD16++ intermediate blood monocytes, and Fractalkine, MCP-1, and TRAIL in the plasma. Decreased plasma analytes and intermediate monocyte frequencies correlated with reduced nasal and BAL viral loads. Lastly, RBD-specific plasma cells accumulated in the draining lymph nodes and not in the bone marrow, contrary to previous findings. Together, these data show that a yeast expressed, RBD-based vaccine+3M-052-alum provides robust immune responses and protection against SARS-CoV-2, making it a strong and scalable vaccine candidate.

Current strategies for improving protective response to influenza vaccines during immunosenescence do not adequately protect individuals over 65 years of age. Here, we used an aged mouse model to investigate the potential of co-delivery of influenza vaccine with the recently identified combination of a saponin adjuvant Quil-A and an activator of the STING pathway, 2’3 cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) via dissolving microneedle patches (MNPs) applied to skin. We demonstrate that synergy between the two adjuvant components is observed after their incorporation with H1N1 vaccine into MNPs as revealed by analysis of the immune responses in adult mice. Aged 21-month-old mice were found to be completely protected against live influenza challenge after vaccination with the MNPs adjuvanted with the Quil-A/cGAMP combination (5 µg each) and demonstrated significantly reduced morbidity compared to the observed responses in these mice vaccinated with unadjuvanted MNPs. Analysis of the lung lysates of the surviving aged mice post challenge revealed the lowest level of residual inflammation in the adjuvanted groups. We conclude that combining influenza vaccine with a STING pathway activator and saponin-based adjuvant in MNPs is a novel option for skin vaccination of the immunosenescent population, which is at high risk for influenza.

Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.

SARS-CoV-2 induced hypercytokinemia and inflammation are critically associated with COVID-19 disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type-I IFN antiviral responses and SARS-CoV-2-specific T-cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib treated animals had a rapid and remarkably potent suppression of lung macrophages production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection., Highlights • SARS-CoV-2 infected RMs mimic signatures of inflammation seen in COVID-19 patients • Baricitinib suppresses production of pro-inflammatory cytokines in lung macrophages • Baricitinib limits recruitment of neutrophils to the lung and NETosis • Baricitinib preserves innate antiviral and SARS-CoV-2-specific T-cell responses, Using a rhesus macaque infection model it is shown that baricitinib treatment started early after infection effectively resolves inflammatory signatures in airway macrophages, with decreased lung pathology and neutrophil infiltration.

Intrusion Detection Systems (IDS) generate a high volume of alerts that security analysts do not have the resources to explore fully. Modelling attacks, especially the coordinated campaigns of Advanced Persistent Threats (APTs), in a visually-interpretable way is a useful approach for network security. Graph models combine multiple alerts and are well suited for visualization and interpretation, increasing security effectiveness. In this paper, we use feature embeddings, learned from network event logs, and community detection to construct and segment alert graphs of related alerts and networks hosts. We posit that such graphs can aid security analysts in investigating alerts and may capture multiple aspects of an APT attack. The eventual goal of this approach is to construct interpretable attack graphs and extract causality information to identify coordinated attacks.

Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients (n = 8) diagnosed histologically as DIG/DIGA. Two of these cases clustered with other tumor entities, and were excluded from analysis. The remaining 16 cases were confirmed to be DIG/DIA by histology and by DNA methylation profiling. Somatic BRAF gene mutations were discovered in 7 instances (43.8%); 4 were BRAFV600E mutations, and 3 were BRAFV600D mutations. Three instances of malignant transformation were found, and sequencing of the recurrence demonstrated a new TP53 mutation in one case, new ATRX deletion in one case, and in the third case, the original tumor harbored an EML4–ALK fusion, also present at recurrence. DIG/DIA are distinct pathologic entities that frequently harbor BRAFV600 mutations. Complete surgical resection is the ideal treatment, and overall prognosis is excellent. While, the small sample size and incomplete surgical records limit a definitive conclusion about the risk of tumor recurrence, the risk appears quite low. In rare cases with wild-type BRAF, malignant progression can be observed, frequently with the acquisition of other genetic alterations. Implications: DIG/DIA are a distinct molecular entity, with a subset frequently harboring either BRAFV600E or BRAFV600D mutations. Mol Cancer Res; 16(10); 1491–8. ©2018 AACR.

Spontaneous intracranial hypotension (SIH) has a wide range of clinical presentations. Cases of SIH that result in severe neurologic compromise have only very rarely been described.We describe our experience with a 70-year-old male who presented with a history of postural headache and imaging that demonstrated bilateral subdural hematomas. The patient's condition subsequently deteriorated and he became comatose despite an epidural blood patch and craniotomy to drain the subdural hematoma. We utilized a strategy of intraventricular saline infusion to normalize intracranial pressure. The patient ultimately required direct surgical ligation of a spinal perineural cyst before making a full recovery.Given the rarity of SIH presenting with severe neurologic deterioration and the unique treatment strategies required to manage this condition we conducted a review of the literature and discussed the management of the most severe complications of SIH. Keywords: Spontaneous intracranial hypotension, Neurosurgery, Subdural hematoma

Background/Objective Multilevel spondylolysis is a rare cause of progressive lower back pain, and patients who fail conservative management are treated surgically. Direct repair methods can maintain mobility and lead to decreased morbidity compared with spinal fusion in single-level spondylolysis. In this paper, we present a patient with nonadjacent multilevel spondylolysis who underwent the “smiley face” technique of direct multilevel repair without fusion using 3-dimensional intraoperative spinal navigation. Methods Bilateral spondylolysis at L3 and L5 with associated spondylolisthesis in a 50-year-old male was repaired using the “smiley face” technique. Patient-reported outcomes, including the Oswestry Disability Index (ODI) and visual analog scale scores for back and leg pain, were assessed preoperatively along with 6 weeks and 4 months postoperatively. Results Postoperative computed tomography imaging showed precise screw insertion and rod placement along with stable hardware alignment in follow-up imaging. The patient's ODI and lower back visual analog scale scores decreased from 25 to 8 and 7.5 to 4, respectively, correlating to an excellent outcome on ODI. Conclusion Direct repair and avoidance of fusion is possible and can provide good functional outcomes in patients with nonadjacent multilevel spondylolysis and associated spondylolisthesis.

When noninvasive modalities fail to adequately localize the seizure onset zone (SOZ) in children with medically refractory epilepsy, invasive interrogation with stereo-electroencephalography (SEEG) or subdural electrodes may be required. Our center utilizes SEEG for invasive monitoring in a carefully selected population of children, many of whom have seizures despite a prior surgical resection. We describe the cohort of patients who underwent SEEG in the first 5 years of its employment in our institution, almost half of which had a history of a failed epilepsy surgery.We retrospectively reviewed the records of the first 44 consecutive children who underwent SEEG at Nicklaus Children's Hospital (Miami, Florida), a large, level 4 epilepsy referral center. Patient demographic, clinical, radiographic, and electrophysiological information was collected prospectively. Student's t-test was used for sampling of means and analysis of variance (ANOVA) for evaluation of variance beyond 2 means; chi-square test of independence was used to assess the relationship between categorical variables.There were 44 patients in this cohort, of whom 17 (38.6 %) were male. The mean age of seizure onset was 6.2 years. Twenty-one patients (47.7 %) had previously failed an epilepsy surgery. Patients with a history of prior epilepsy surgery failure were older at SEEG implantation (17.6 vs. 13.7 years; p = 0.043), were more likely to have SEEG for identification of resection margins (9 vs. 4; p = 0.034), and had fewer electrodes placed (5.9 vs. 7.5; p = 0.016). No difference was seen in complication rates between groups with only 3/297 electrodes placed associated with complications, all of which were minor. Post-SEEG, 29 (65.9 %) patients underwent focal resection, 7 patients had VNS insertion, 3 underwent RNS placement, and 5 had no further intervention. The majority of patients that underwent resection in both groups experienced an improvement in seizures (Engel class I-III), reported by 13/15 (86.7 %) in those naive to surgery and 10/14 (71.4 %) in those with prior surgical failure. Seizure-freedom was much lower in those with prior epilepsy surgery, seen in only 4/14 (28.6 %) versus 8/15 (53.3 %).Our data supports current literature on SEEG as a safe and effective method of electrophysiological evaluation in children naive to surgery and adds that it is a safe technique in children with a history of failed epilepsy surgery. There was no difference in complication rates, which were1 % in both groups. A favorable outcome was seen in the majority of patients in both groups; the seizure freedom rate, however, was much lower in those with prior epilepsy surgery.

OBJECTIVEEndoscopic third ventriculostomy (ETV)/choroid plexus cauterization (CPC) has become an increasingly common technique for the treatment of infant hydrocephalus. Both flexible and rigid neuroendoscopy can be used, with little empirical evidence directly comparing the two. Therefore, the authors used a propensity score–matched cohort and survival analysis to assess the comparative efficacy of flexible and rigid neuroendoscopy.METHODSIndividual data were collected through retrospective review of infants younger than 2 years of age, treated at 1 of 2 hospitals: 1) Boston Children's Hospital, exclusively utilizing flexible neuroendoscopy, and 2) Nicklaus Children's Hospital-Jackson Memorial Hospital, exclusively utilizing rigid neuroendoscopy. Patient characteristics and postoperative outcomes were assessed. A propensity score model was developed to balance patient characteristics in the case mix.RESULTSA propensity score model for neuroendoscope type was developed with 5 independent variables: chronological age, sex, hydrocephalus etiology, prior CSF diversion, and prepontine scarring. Propensity score decile-adjusted and 1-to-1 nearest-neighbor matching analysis revealed that compared with flexible neuroendoscopy, rigid neuroendoscopy had an ETV/CPC failure odds ratio (OR) of 1.43 (p = 0.31) and 1.31 (p = 0.47), respectively, compared with an unadjusted OR of 2.40 (p = 0.034). Furthermore, in a Cox regression analysis controlled by propensity score, rigid neuroendoscopy had a hazard ratio (HR) of 1.10 (p = 0.70), compared with an unadjusted HR of 1.61 (p = 0.031).CONCLUSIONSAlthough unadjusted analysis suggested worse ETV/CPC outcomes for infants treated by rigid neuroendoscopy, much of the difference could be attributed to the case mix and other predictors of outcome. A larger sample observational study or randomized controlled trials are required to provide evidence-based guidelines on ETV/CPC technique.

ESES is a developmental epileptic disorder directly responsible for progressive encephalopathy and neurocognitive regression. The natural history, indications for surgical intervention, and predictors for favorable seizure and neuropsychological outcome remain unclear. We performed a retrospective review of children who underwent resective or disconnective surgery for ESES between January 2009 and July 2016 at a large tertiary pediatric center. Information on the patients' demographics, seizure semiology, radiographic and electrographic findings, and surgical management was collected. The primary outcome was seizure freedom at last follow-up visit, and secondary outcomes were neuropsychological improvement and electrographic ESES resolution. We identified 11 children who underwent surgery for ESES. The mean ages were 3.2 years for seizure onset, 7.1 years for formal ESES diagnosis, and 9.4 years for surgery. Seizure etiologies included cortical malformations (four patients), encephalomalacia and gliosis from prior hemorrhage or tumor resections (three patients), developmental porencephaly (one patient), and Rasmussen's encephalitis (one patient); the etiology was unknown in two children. Preoperatively, nine children had motor deficits, seven had speech and language delay, and three had visual field defects. All children had seizures and neuropsychological regression prior to surgical consideration. Focal cortical resections were performed in seven children, and hemispherectomies in four. Post-operatively, nine children experienced decreased seizure frequency, eight had neuropsychological improvement, and nine had resolution of electrographic ESES. Patients with poor surgical outcomes had more significant pre-operative comorbidities, in addition to bilateral ESES activity. In this case series, surgery for a carefully selected group of children with ESES is safe and feasible, yielding rates of seizure freedom and neuropsychological improvement that compare favorably with previous reports for antiepileptic drugs, benzodiazepines, and steroids. As we gain greater understanding into the management of ESES, surgery is an increasingly useful tool for patients with mild or moderate neurodevelopmental delay, focal epileptogenic foci, and hemi-ESES electrographic findings.

Carotid body tumors (CBTs) are rare paragangliomas, comprising 0.5% of all head and neck tumors, and 65% of head and neck paragangliomas. A majority of CBTs occur sporadically, while 15% are familial or hyperplastic in the setting of chronic hypoxia. They usually present as unilateral, well-circumscribed rubbery masses, arising at the level of the carotid bifurcation. A majority of CBTs are painless and therefore may evade diagnosis for months to years. Symptomatic lesions occur due to progressive cranial nerve IX, X, or XII dysfunction, manifesting as hoarseness, dysphagia, vertigo, coughing, or odynophagia. Other local symptoms include neck discomfort, pulsatile tinnitus, hearing loss, or carotid sinus syndrome. Appropriate workup includes a thorough physical exam followed by radiographic imaging, vascular studies, and biochemical workup with 24 h urinary catecholamine or metanephrine analysis. The management of these tumors, which involves standalone surgical resection or following embolization for larger and more vascular tumors, will also be discussed.

OBJECTIVE Vagus nerve stimulation (VNS) is a common treatment for medically intractable epilepsy, but response rates are highly variable, with no preoperative means of identifying good candidates. This study aimed to predict VNS response using structural and functional connectomic profiling. METHODS Fifty-six children, comprising discovery (n = 38) and validation (n = 18) cohorts, were recruited from 3 separate institutions. Diffusion tensor imaging was used to identify group differences in white matter microstructure, which in turn informed beamforming of resting-state magnetoencephalography recordings. The results were used to generate a support vector machine learning classifier, which was independently validated. This algorithm was compared to a second classifier generated using 31 clinical covariates. RESULTS Treatment responders demonstrated greater fractional anisotropy in left thalamocortical, limbic, and association fibers, as well as greater connectivity in a functional network encompassing left thalamic, insular, and temporal nodes (p

Databases were searched to identify studies published over the past 10 years that addressed the utility of patient-reported outcomes (PROs) in patients receiving chimeric antigen receptor (CAR) T cell therapy in patients with hematological malignancies. Among 280 records, three articles covering 206 patients were eligible. The data were prospectively collected at multiple time points. The compliance rates were 70% to 94%. There was an inverse relationship between fatigue and social function among adults. The quality of life (QoL) improvement and ability to complete PROs were linked to disease status. About 40% of adults reported at least some cognitive difficulties, with a detrimental impact on mental and physical health status. In adults, the most commonly reported cognitive impairment was memory difficulties. Depression was associated with cognitive difficulties. Younger adults were at higher risk of long-term poor mental health, anxiety, and depression. For pediatric and adolescent patients, emotional dysfunction improves over time. QoL status improved over time; yet, severe cytokine release syndrome and neurotoxicity caused delayed improvement. Information regarding whether the PROs were integrated into medical records and clinical guidelines is lacking. Utilizing PROs in patients on CAR T cell therapy seems feasible and informative. Studies utilizing larger sample sizes and using validated PRO tools at different time points remain unmet needs.

Background The management of drug-resistant epilepsy in children with Tuberous Sclerosis Complex (TSC) is challenging because of the multitude of treatment options, wide range of associated costs, and uncertainty of seizure outcomes. The most cost-effective approach for children whose epilepsy has failed to improve with first-line medical therapy is uncertain. Methods A review of MEDLINE from 1990 to 2015 was conducted. A cost-utility analysis, from a third-party payer perspective, was performed for children with drug-resistant epilepsy that had failed to improve with 2 antiseizure drugs (ASDs) and that was amenable to resective epilepsy surgery, across a time-horizon of 5 years. Four strategies were included: (1) resective epilepsy surgery, (2) vagus nerve stimulator (VNS) implantation, (3) ketogenic diet, and (4) addition of a third ASD (specifically, carbamazepine). The incremental cost per quality-adjusted life year (QALY) gained was analyzed. Results Given a willingness-to-pay (WTP) of $100,000 per QALY, the addition of a third ASD ($6600 for a gain of 4.14 QALYs) was the most cost-effective treatment strategy. In a secondary analysis, if the child whose epilepsy had failed to improve with 3 ASDs, ketogenic diet, addition of a fourth ASD, and resective epilepsy surgery were incrementally cost-effective treatment strategies. Vagus nerve stimulator implantation was more expensive yet less effective than alternative strategies and should not be prioritized. Conclusions The addition of a third ASD is a universally cost-effective treatment option in the management of children with drug-resistant epilepsy that has failed to improve with 2 ASDs. For children whose epilepsy has failed to improve with 3 ASDs, the most cost-effective treatment depends on the health-care resources available reflected by the WTP.

Endoscopic third ventriculostomy/choroid plexus cauterization (ETV/CPC) has gained popularity in its treatment of infantile hydrocephalus over the past decade. In this manuscript, we perform a systematic review and meta-analysis to determine the efficacy and safety of ETV/CPC, and to compare the procedural outcomes between North American and sub-Saharan African cohorts. Systematic review was performed using four electronic databases and bibliographies of relevant articles, with no language or date restrictions. Cohort studies of participants undergoing ETV/CPC that reported outcome were included using MOOSE guidelines. The outcome was time to repeat CSF diversion or death. Forest plots were created for pooled mean and its 95 % CI of outcome and morbidity. Of 78 citations, 11 retrospective reviews (with 524 total participants) were eligible. Efficacy was achieved in 63 % participants at follow-up periods between 6 months and 8 years. Adverse events and mortality was reported in 3.7 and 0.4 % of participants, respectively. Publication bias was detected with respect to efficacy and morbidity of the procedure. A large discrepancy in success was identified between ETV/CPC in six studies from sub-Saharan Africa (71 %), compared to three studies from North America (49 %). The reported success of ETV/CPC for infantile hydrocephalus is higher in sub-Saharan Africa than developed nations. Large long-term prospective multi-center observational studies addressing patient-important outcomes are required to further evaluate the efficacy and safety of this re-emerging procedure.

Tumoral calcinosis is an uncommon condition characterized by the calcification of periarticular soft tissue. In uremic patients the disease is secondary to metabolic disturbances in predisposed patients. The authors report the case of a 73-year-old woman who presented with a new painful cervical mass while undergoing continuous ambulatory peritoneal dialysis for long-standing end-stage renal disease (ESRD). A CT scan of the neck showed a lobulated, calcified mass in the left paraspinal soft tissue at C2–3. This mass affected the facet joint and also extended into the neural foramen but did not cause any neurological compromise. Due to the patient's significant medical comorbidities, resection was deferred and the patient was followed in the clinic. Subsequent repeat imaging has shown a significant decrease in the size of the mass. In the context of ESRD, a diagnosis of uremic tumoral calcinosis (UTC) was made. The authors conducted a search of the PubMed and EMBASE databases and identified 7 previously reported cases of UTC of the cervical spine. They present a summary of these cases and discuss the etiology, diagnosis, and management of the condition. Although the metabolic disturbances seen in patients undergoing dialysis can lead to tumoral calcinosis, most reported cases involve large joints such as the shoulder or the hip; however, the spine can also be affected and should be considered in the differential diagnosis of patients with uremia as it can mimic aggressive bone-forming neoplasms.

Influenza infection typically initiates at respiratory mucosal surfaces. Induction of immune responses at the sites where pathogens initiate replication is crucial for the prevention of infection. We studied the adjuvanticity of GPI-anchored CCL28 co-incorporated with influenza HA-antigens in chimeric virus-like particles (cVLPs), in boosting strong protective immune responses through an intranasal (i.n.) route in mice. We compared the immune responses to that from influenza VLPs without CCL28, or physically mixed with soluble CCL28 at systemic and various mucosal compartments. The cVLPs containing GPI-CCL28 showed in-vitro chemotactic activity towards spleen and lung cells expressing CCR3/CCR10 chemokine receptors. The cVLPs induced antigen specific endpoint titers and avidity indices of IgG in sera and IgA in tracheal, lung, and intestinal secretions, significantly higher (4–6 fold) than other formulations. Significantly higher (3–5 fold) hemagglutination inhibition titers and high serum neutralization against H3N2 viruses were also detected with CCL28-containing VLPs compared to other groups. The CCL28-containing VLPs showed complete and 80% protection, when vaccinated animals were challenged with A/Aichi/2/1968/H3N2 (homologous) and A/Philippines/2/1982/H3N2 (heterologous) viruses, respectively. Thus, GPI-anchored CCL28 in influenza VLPs act as a strong immunostimulator at both systemic and mucosal sites, boosting significant cross-protection in animals against heterologous viruses across a large distance.

Background Value in healthcare is reflected by patient-centered outcomes of care per health dollar expended. Although liposomal bupivacaine is more expensive, it has been shown to provide prolonged analgesia (up to 72 hours). Objective This study aimed to evaluate whether the addition of liposomal bupivacaine to standard bupivacaine could decrease opioid intake and improve pain control after laparotomy for gynecologic surgery compared with standard bupivacaine alone in an enhanced recovery after surgery pathway. Study Design A prospective randomized controlled single-blinded trial of wound infiltration with liposomal bupivacaine plus 0.25% bupivacaine (study arm) vs 0.25% bupivacaine (control arm) was performed at a National Cancer Institute–designated tertiary referral cancer center. Participants were patients aged ≥18 years undergoing exploratory laparotomy for a gynecologic indication. All patients were treated on an enhanced recovery pathway including local wound infiltration before closure. In this study, 266 mg of liposomal bupivacaine (free base; equal to 300 mg bupivacaine HCL)+150 mg of bupivacaine mixed in the same syringe was used in the study arm, and 150 mg of bupivacaine was used in the control arm. The primary outcome was the proportion of patients who were opioid-free within 48 hours after surgery. Secondary outcomes included number of opioid-free days from postoperative day 0 to postoperative day 3, days to first opioid administration, morphine equivalent daily dose, and patient-reported outcomes collected with the MD Anderson Symptom Inventory. The MD Anderson Symptom Inventory was administered as a preoperative baseline, daily while hospitalized, and at least weekly for 8 weeks after discharge. All outcomes were prespecified before data collection. Results In this study, 102 patients were evaluated. Among them, 16.7% of patients in the study arm received no opioids up to 48 hours compared with 14.8% in the control arm (P=.99). There were no significant differences in the amount of intraoperative opioids administered or days to first opioid use. There was no significant difference between the 2 arms in median cumulative morphine equivalent daily dose (21.3 [study arm] vs 33.8 [control arm]; P=.36) or between the groups in morphine equivalent daily dose per individual day. There were no significant differences in patient-reported pain or interference with walking between the 2 arms or other patient-reported outcomes. Conclusion Within an enhanced recovery after surgery pathway, adding liposomal bupivacaine to 0.25% bupivacaine wound infiltration did not decrease the proportion of patients who were opioid-free within 48 hours after surgery, did not decrease opioid intake, or did not improve patient’s self-reported pain and functional recovery compared with standard bupivacaine.

Influenza is a persistent threat to public health. Here we report that double-layered peptide nanoparticles induced robust specific immunity and protected mice against heterosubtypic influenza A virus challenges. We fabricated the nanoparticles by desolvating a composite peptide of tandem copies of nucleoprotein epitopes into nanoparticles as cores and cross-linking another composite peptide of four tandem copies of influenza matrix protein 2 ectodomain epitopes to the core surfaces as a coating. Delivering the nanoparticles via dissolvable microneedle patch-based skin vaccination further enhanced the induced immunity. These peptide-only, layered nanoparticles demonstrated a strong antigen depot effect and migrated into spleens and draining (inguinal) lymph nodes for an extended period compared with soluble antigens. This increased antigen-presentation time correlated with the stronger immune responses in the nanoparticle-immunized group. The protection conferred by nanoparticle immunization was transferable by passive immune serum transfusion and depended partially on a functional IgG receptor FcγRIV. Using a conditional cell depletion, we found that CD8+ T cells were involved in the protection. The immunological potency and stability of the layered peptide nanoparticles indicate applications for other peptide-based vaccines and peptide drug delivery.