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Background/Context: High quality early education, preschool through third grade, has received significant attention as a vehicle for addressing academic disparities. Research–practice partnerships (RPPs) offer a promising strategy for improving early education and closing the gap between research and practice; however, RPPs in the early learning context are understudied, and there is little information about how teachers experience them. Purpose/Research Questions: Grounded in a framework of sensemaking theory and research on teachers’ beliefs and RPPs, this paper addresses the following questions: (1) How did an early education RPP attempt to build a meaningful and trusting partnership and amplify teacher voices? (2) How did teachers make sense of new knowledge within the context of the RPP and their practical wisdom? (3) To what degree were teachers reaffirming existing beliefs vs. questioning or adjusting current beliefs through their participation in the RPP? Research Design: This paper relies on qualitative data gathered as part of an interdisciplinary education neuroscience longitudinal RPP project between university researchers and educators in a California school district. The data analyzed for this paper included field notes and artifacts from RPP meetings and transcripts of teacher interviews. Conclusions/Recommendations: The RPP intentionally created opportunities for teachers to amplify their perspectives and interpretations. Within RPP meeting spaces, teachers reflected on their beliefs and practices in light of research conducted in their schools and, more generally, sometimes adjusting and other times reaffirming their views. The extent to which teachers incorporated new knowledge into their cognitive schemas varied based on the topic and how and where the information was presented. These findings yield important implications for research–practice partnerships and system change in early childhood education.

The education research community, both within the American Educational Research Association (AERA) and beyond, could and should play a critical role in fundamentally transforming educational institutions and systems. Given its complexity, transformative change in education is best undertaken as a collective endeavor. Yet for researchers to be a valuable resource in educational transformation, we will need to bridge knowledge across subfields that currently have limited interaction. Through two illustrative examples, we demonstrate the need to link knowledge on educational change with knowledge on how to create more equitable, anti-racist, and decolonized spaces for formal and informal learning. While operating in different spaces and initiated at different entry points, the two change efforts exemplify a common set of commitments and actionable pathways for achieving transformational change. This article is a call to action for researchers to join together in supporting educational transformation that fundamentally challenges the inequitable arrangements persisting in educational organizations characterized by systemic racism and colonialism. Bridging knowledge bases and being accountable to serve and support communities and their intersectional identities are essential to making deep, scalable changes in education that promote social justice.

OBJECTIVE The authors of this study evaluated the safety and efficacy of stereotactic laser ablation (SLA) for the treatment of drug-resistant epilepsy (DRE) in children. METHODS Seventeen North American centers were enrolled in the study. Data for pediatric patients with DRE who had been treated with SLA between 2008 and 2018 were retrospectively reviewed. RESULTS A total of 225 patients, mean age 12.8 ± 5.8 years, were identified. Target-of-interest (TOI) locations included extratemporal (44.4%), temporal neocortical (8.4%), mesiotemporal (23.1%), hypothalamic (14.2%), and callosal (9.8%). Visualase and NeuroBlate SLA systems were used in 199 and 26 cases, respectively. Procedure goals included ablation (149 cases), disconnection (63), or both (13). The mean follow-up was 27 ± 20.4 months. Improvement in targeted seizure type (TST) was seen in 179 (84.0%) patients. Engel classification was reported for 167 (74.2%) patients; excluding the palliative cases, 74 (49.7%), 35 (23.5%), 10 (6.7%), and 30 (20.1%) patients had Engel class I, II, III, and IV outcomes, respectively. For patients with a follow-up ≥ 12 months, 25 (51.0%), 18 (36.7%), 3 (6.1%), and 3 (6.1%) had Engel class I, II, III, and IV outcomes, respectively. Patients with a history of pre-SLA surgery related to the TOI, a pathology of malformation of cortical development, and 2+ trajectories per TOI were more likely to experience no improvement in seizure frequency and/or to have an unfavorable outcome. A greater number of smaller thermal lesions was associated with greater improvement in TST. Thirty (13.3%) patients experienced 51 short-term complications including malpositioned catheter (3 cases), intracranial hemorrhage (2), transient neurological deficit (19), permanent neurological deficit (3), symptomatic perilesional edema (6), hydrocephalus (1), CSF leakage (1), wound infection (2), unplanned ICU stay (5), and unplanned 30-day readmission (9). The relative incidence of complications was higher in the hypothalamic target location. Target volume, number of laser trajectories, number or size of thermal lesions, or use of perioperative steroids did not have a significant effect on short-term complications. CONCLUSIONS SLA appears to be an effective and well-tolerated treatment option for children with DRE. Large-volume prospective studies are needed to better understand the indications for treatment and demonstrate the long-term efficacy of SLA in this population.

OBJECTIVE Single-ventricle congenital heart disease (CHD) in pediatric patients with Glenn and Fontan physiology represents a unique physiology requiring the surgical diversion of the systemic venous return from the superior vena cava (Glenn) and then the inferior vena cava (Fontan) directly to the pulmonary arteries. Because many of these patients are on chronic anticoagulation therapy and may have right-to-left shunts, arrhythmias, or lymphatic disorders that predispose them to bleeding and/or clotting, they are at risk of experiencing neurological injury requiring intubation and positive pressure ventilation, which can significantly hamper pulmonary blood flow and cardiac output. The aim of this study was to describe the complex neurological and cardiopulmonary interactions of these pediatric patients after acute central nervous system (CNS) injury. METHODS The authors retrospectively analyzed the records of pediatric patients who had been admitted to a quaternary children’s hospital with CHD palliated to bidirectional Glenn (BDG) or Fontan circulation and acute CNS injury and who had undergone intubation and mechanical ventilation. Patients who had been admitted from 2005 to 2019 were included in the study. Clinical characteristics, surgical outcomes, cardiovascular and pulmonary data, and intracranial pressure data were collected and analyzed. RESULTS Nine pediatric single-ventricle patients met the study inclusion criteria. All had undergone the BDG procedure, and the majority (78%) were status post Fontan palliation. The mean age was 7.4 years (range 1.3–17.3 years). At the time of acute CNS injury, which included traumatic brain injury, intracranial hemorrhage, and cerebral infarct, the median time interval from the most recent cardiac surgical procedure was 3 years (range 2 weeks–11 years). Maintaining normocarbia to mild hypercarbia for most patients during intubation periods did not cause neurological deterioration, and hemodynamic profiles were more favorable as compared to periods of hypocarbia. Hypocarbia was associated with unfavorable hemodynamics but was necessary to decrease intracranial hypertension. Most patients were managed using low mean airway pressure (MAWP) in order to minimize the impact on preload and cardiac output. CONCLUSIONS The authors highlight the complex neurological and cardiopulmonary interactions with respect to partial pressure of arterial CO2 (PaCO2) and MAWP when pediatric CHD patients with single-ventricle physiology require mechanical ventilation. The study data demonstrated that tight control of PaCO2 and minimizing MAWP with the goal of early extubation may be beneficial in this population. A multidisciplinary team of pediatric critical care intensivists, cardiac intensivists and anesthesiologists, and pediatric neurosurgeons and neurologists are recommended to ensure the best possible outcomes.

Several variations of functional disconnection surgery have been described for the treatment of lateralized, hemispheric, drug-resistant epilepsy in children. The purpose of this study is to investigate the existing literature regarding patient selection, approach, and outcomes after hemispherotomy. A systematic review of the English literature through February 2019 was performed in accordance with the PRISMA statement. The articles were classified by level of evidence and summarized in an evidentiary table. Seizure outcomes, functional outcomes, surgical techniques, complications, and patient selection were critically analyzed. A total of 173 papers were reviewed, of which 37 met criteria of inclusion and exclusion. Thirteen studies were classified as level III evidence, the remaining reached level IV. Vertical and lateral hemispherotomy achieve similar rates of seizure freedom and functional outcomes, though parasagittal and interhemispheric approaches may have shorter operative times and less blood loss. Etiology, bilateral MRI abnormalities, and nonlateralizing EEG did not predict worse seizure or functional outcomes. Both vertical and lateral hemispherotomy approaches result in durable, reproducible benefits to epilepsy severity and functional status in appropriately selected pediatric patients.

Heterozygous pathogenic variants in DNM1 cause developmental and epileptic encephalopathy (DEE) due to a dominant-negative mechanism impeding vesicular fission. Thus far, pathogenic variants in DNM1 have been studied using a canonical transcript that includes the alternatively spliced exon 10b. However, after performing RNA sequencing in thirty-nine pediatric brain samples, we find the primary transcript expressed in the brain includes the downstream exon 10a instead. Using this information, we evaluated genotype-phenotype correlations of variants affecting exon 10a and identified a cohort of eleven previously unreported individuals. Eight individuals harbor a recurrent de novo splice site variant, NG_029726.1(NM_001288739.1):c.1197-8G>A, which affects exon 10a and leads to DEE consistent with the classical DNM1 phenotype. We find this splice site variant leads to disease through an unexpected dominant-negative mechanism. Functional testing reveals an in-frame upstream splice acceptor causing insertion of two amino acids predicted to impair oligomerization-dependent activity. This is supported by neuropathological samples showing accumulation of synaptic vesicles adherent to the plasma membrane consistent with impaired vesicular fission. Two additional individuals with missense variants affecting exon 10a, p.(Arg399Trp) and p.(Gly401Asp), had a similar DEE phenotype. In contrast, a single individual with a missense variant affecting exon 10b, p.(Pro405Leu), which is less expressed in the brain, had a correspondingly less severe presentation. Thus, we implicate variants affecting exon 10a as causing the severe DEE typically associated with DNM1-related disorders. We highlight the importance of considering relevant isoforms for disease-causing variants, as well as the possibility of splice site variants acting through a dominant-negative mechanism.

Background Suppurative intracranial complications of sinusitis are rare events in children and can lead to harmful neurologic sequelae and significant morbidity. We sought to review the presentation and management of patients admitted at our hospital with these conditions. Methods This was a retrospective study of pediatric patients admitted to a quaternary children’s hospital from 2007 to 2019 for operative management of sinusitis with intracranial extension. Clinical characteristics, including surgical and microbiological data, were collected and analyzed. Results Fifty-four patients were included; the median age was 11.0 years, and there was a male predominance. Eighty-nine percent of patients had prior healthcare visits for the current episode of sinusitis; 46% of patients had an abnormal neurologic exam on admission. Epidural abscess and subdural empyema were the most common complications, and subdural empyema was associated with repeat surgical intervention. The dominant pathogens were Streptococcus anginosus group organisms (74%). The majority of patients completed treatment parenterally, with a median duration of therapy of 35 days. Neurological sequelae, including epilepsy or ongoing focal deficits, occurred in 22% of patients. History of seizure or an abnormal neurological exam at admission were associated with neurological sequelae. Conclusions Clinicians should consider intracranial complications of sinusitis in patients with symptoms of sinusitis for >1 week. Patients should undergo urgent neuroimaging, as neurosurgical intervention is essential for these patients. Subdural empyema was associated with repeat neurosurgical intervention. Neurological sequelae occurred in 22% of patients, and new onset seizure or an abnormal neurological exam at admission were associated with neurological sequelae.

OBJECTIVEIntracerebral convection-enhanced delivery (CED) has been limited to short durations due to a reliance on externalized catheters. Preclinical studies investigating topotecan (TPT) CED for glioma have suggested that prolonged infusion improves survival. Internalized pump-catheter systems may facilitate chronic infusion. The authors describe the safety and utility of long-term TPT CED in a porcine model and correlation of drug distribution through coinfusion of gadolinium.METHODSFully internalized CED pump-catheter systems were implanted in 12 pigs. Infusion algorithms featuring variable infusion schedules, flow rates, and concentrations of a mixture of TPT and gadolinium were characterized over increasing intervals from 4 to 32 days. Therapy distribution was measured using gadolinium signal on MRI as a surrogate. A 9-point neurobehavioral scale (NBS) was used to identify side effects.RESULTSAll animals tolerated infusion without serious adverse events. The average NBS score was 8.99. The average maximum volume of distribution (Vdmax) in chronically infused animals was 11.30 mL and represented 32.73% of the ipsilateral cerebral hemispheric volume. Vdmax was achieved early during infusions and remained relatively stable despite a slight decline as the infusion reached steady state. Novel tissue TPT concentrations measured by liquid chromatography mass spectroscopy correlated with gadolinium signal intensity on MRI (p = 0.0078).CONCLUSIONSProlonged TPT-gadolinium CED via an internalized system is safe and well tolerated and can achieve a large Vdmax, as well as maintain a stable Vd for up to 32 days. Gadolinium provides an identifiable surrogate for measuring drug distribution. Extended CED is potentially a broadly applicable and safe therapeutic option in select patients.

Hemispheric disconnection in the form of hemispherectomy or hemispherotomy is the most effective way of treating intractable hemispheric epilepsy. Anatomical hemispherectomy approaches have largely been abandoned in most cases due to a higher risk of superficial hemosiderosis, intraoperative blood loss, hydrocephalus, prolonged hospital stay, and mortality compared to the variety of tissue-sparing hemispherotomy techniques. Disconnective hemispherotomy approaches utilize the lateral ventricle as a key component of the surgical corridor. Without a lateral ventricle, disconnective surgery becomes significantly challenging, typically leading to a hemispherectomy. The authors present the case of a patient with severe hemispheric dysplasia without a lateral ventricle on the pathologic side and detail a novel surgical technique for a prone, occipital interhemispheric, tissue-sparing, purely disconnective aventricular hemispherotomy with an excellent surgical outcome.

Monkeys can learn the implied ranking of pairs of images drawn from an ordered set, despite never seeing all of the images simultaneously and without explicit spatial or temporal cues. We recorded the activity of posterior parietal cortex (including lateral intraparietal area LIP) neurons while monkeys learned 7-item transitive inference (TI) lists with 2 items presented on each trial. Behavior and neuronal activity were significantly influenced by the ordinal relationship of the stimulus pairs, specifically symbolic distance (the difference in rank) and joint rank (the sum of the ranks). Symbolic distance strongly predicted decision accuracy and learning rate. An effect of joint rank on performance was found nested within the symbolic distance effect. Across the population of neurons, there was significant modulation of firing correlated with the relative ranks of the two stimuli presented on each trial. Neurons exhibited selectivity for stimulus rank during learning, but not before or after. The observed behavior is poorly explained by associative or reward mechanisms, and appears more consistent with a mental workspace model in which implied serial order is mapped within a spatial framework. The neural data suggest that posterior parietal cortex supports serial learning by representing information about the ordinal relationship of the stimuli presented during a given trial.

Corpus callosotomy is a palliative surgical option for patients with refractory epilepsy and frequent drop attacks, decreasing seizure frequency and severity by disconnecting the cerebral hemispheres. Though often successful, open surgery is not without risk. Corpus callosotomy by MRI-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to the standard open procedure. This report aims to present an illustrative case and systematically review the current literature on the surgical technique. A systematic review of the English literature through January 2019 was performed. Articles were searched by title utilizing the following key word combinations: “laser” and “callosotomy”, “callosotomy” and “ablation”, “laser” and “corpus”, “callosotomy” and “thermal”, and “stereotactic” and callosotomy”. The articles recovered were then classified by level of evidence and summarized. Fifteen papers were reviewed, of which 6 met inclusion and exclusion criteria. All included studies were classified as level IV evidence. There was a total of 13 patients ranging from 13 months to 44 years old (mean 23.5 years old). The number of laser fibers utilized ranged from 1 to 3. Engel class I was achieved in 5 patients, II in 4, III in 2, IV in 1. Reported patient follow up was 4–39.7 months (mean 15.43). Corpus callosotomy utilizing MRI-guided laser interstitial thermal therapy results in improvement in seizure frequency and severity with minimal complications. Prospective trials are needed to compare its seizure control and long-term outcomes to that of standard open callosotomy.

OBJECTIVEThe lack of a continuous, noninvasive modality for monitoring intracranial pressure (ICP) is a major obstacle in the care of pediatric patients with hydrocephalus who are at risk for intracranial hypertension. Intracranial hypertension can lead to cerebral ischemia and brain tissue hypoxia. In this study, the authors evaluated the use of near-infrared spectroscopy (NIRS) to measure regional cerebral oxygen saturation (rSO2) in symptomatic pediatric patients with hydrocephalus concerning for elevated ICP.METHODSThe authors evaluated the NIRS rSO2 trends in pediatric patients presenting with acute hydrocephalus and clinical symptoms of intracranial hypertension. NIRS rSO2 values were recorded hourly before and after neurosurgical intervention. To test for significance between preoperative and postoperative values, the authors constructed a linear regression model with the rSO2 values as the outcome and pre- and postsurgery cohorts as the independent variable, adjusted for age and sex, and used the generalized estimating equation method to account for within-subject correlation.RESULTSTwenty-two pediatric patients underwent NIRS rSO2 monitoring before and after CSF diversion surgery. The mean durations of NIRS rSO2 recording pre- and postoperatively were 13.95 and 26.82 hours, respectively. The mean pre- and postoperative rSO2 values were 73.84% and 80.65%, respectively, and the adjusted mean difference estimated from the regression model was 5.98% (adjusted p < 0.0001), suggestive of improved cerebral oxygenation after definitive neurosurgical CSF diversion treatment. Postoperatively, all patients returned to baseline neurological status with no clinical symptoms of elevated ICP.CONCLUSIONSCerebral oxygenation trends measured by NIRS in symptomatic pediatric hydrocephalus patients with intracranial hypertension generally improve after CSF diversion surgery.

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents(1,2) and they are dysregulated in multiple human neurological disorders(3–5). Little is known about molecular characteristics of adult human hippocampal imGCs and even their existence is under debate(1,6–8). Here we performed single-nucleus RNA-sequencing (snRNA-seq) aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus during infant, child, adolescent, adult, and aging stages. We identified common molecular hallmarks of human imGCs across the lifespan and discovered age-dependent transcriptional dynamics unique to human imGCs that suggest changes in cellular functionality, niche interactions, and disease relevance, in contrast to those in mice9. We also found a decreased number of imGCs with altered gene expression in Alzheimer’s disease (AD). Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a significant number of imGCs in the adult human hippocampus via low frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in AD.

Pediatric patients presenting with intramedullary spinal cord lesions often require specific diagnoses to guide their treatment plans. Though results from magnetic resonance imaging and lumbar puncture may narrow the differential diagnosis, these tests cannot always provide a definitive diagnosis. In such cases, spinal cord biopsy may be undertaken to provide a specific histopathologic diagnosis for guiding treatment. Data from the adult population show 24% of spinal cord biopsies can be nondiagnostic and the procedure may carry a 21% complication rate. Therefore, spinal cord biopsy may portend a similar high risk-to-benefit ratio in the pediatric population. Here, we review spinal cord biopsy cases scheduled for diagnosis, and not debulking, at a high volume pediatric referral center during a seventeen-year period. We report our experience with five patients who met our inclusion criteria. Due to the rarity of the procedure, statistically significant factors associated with improved diagnostic yield or peri-operative complication could not be identified. A definitive diagnosis which guided the post-operative treatment plan was obtained in four of our five patients. None of our patients developed post-operative motor deficits. However, these patients were susceptible to the same risks of open spine surgery, such as wound infections and spinal deformities. Our case series shows that intramedullary spinal cord biopsies may provide tissue for obtaining histopatholgic diagnoses. However, the potential risks of complication, and the possibility of obtaining nondiagnostic tissue, should be discussed with patients, families and their medical treatment teams.

The molecular diversity of glia in the human hippocampus and their temporal dynamics over the lifespan remain largely unknown. Here, we performed single-nucleus RNA sequencing to generate a transcriptome atlas of the human hippocampus across the postnatal lifespan. Detailed analyses of astrocytes, oligodendrocyte lineages, and microglia identified subpopulations with distinct molecular signatures and revealed their association with specific physiological functions, age-dependent changes in abundance, and disease relevance. We further characterized spatiotemporal heterogeneity of GFAP-enriched astrocyte subpopulations in the hippocampal formation using immunohistology. Leveraging glial subpopulation classifications as a reference map, we revealed the diversity of glia differentiated from human pluripotent stem cells and identified dysregulated genes and pathological processes in specific glial subpopulations in Alzheimer's disease (AD). Together, our study significantly extends our understanding of human glial diversity, population dynamics across the postnatal lifespan, and dysregulation in AD and provides a reference atlas for stem-cell-based glial differentiation.

OBJECTIVE Stereoelectroencephalography (SEEG) has become widespread in the United States during the past decade. Many pediatric neurosurgeons practicing SEEG may not have had experience with this technique during their formal training, and the literature is mostly limited to single-center series. As a result, implementation of this relatively new technique may vary at different institutions. The authors hypothesized that aspects of SEEG experience, techniques, and outcomes would vary widely among programs across the country. METHODS An electronic survey with 35 questions addressing the categories of training and experience, technique, electrode locations, and outcomes was sent to 128 pediatric epilepsy surgeons who were potential SEEG users. RESULTS Sixty-one pediatric fellowship-trained epilepsy surgeons in the United States responded to the survey. Eighty-nine percent were actively using SEEG in their practice. Seventy-two percent of SEEG programs were in existence for less than 5 years, and 68% were using SEEG for > 70% of their invasive monitoring. Surgeons at higher-volume centers operated on younger patients (p < 0.001). Most surgeons (70%) spent 1–3 hours per case planning electrode trajectories. Two-thirds of respondents reported a median implant duration of 5–7 days, but 16% reported never having an implant duration > 5 days, and 16% reported having had implants stay in place for > 4 weeks. The median response for the median number of electrodes initially implanted was 12 electrodes, although 19% of respondents reported median implants of 5–8 electrodes and 17% reported median implants of 15–18 electrodes. Having a higher volume of SEEG cases per year was associated with a higher median number of electrodes implanted (p < 0.001). Most surgeons found SEEG helpful in defining an epileptic network and reported that most of their SEEG patients undergo focal surgical treatment. CONCLUSIONS SEEG has been embraced by the pediatric epilepsy surgery community. Higher case volume is correlated with a tendency to place more electrodes and operate on younger patients. For most parameters addressed in the survey, responses from surgeons clustered around a norm, though additional findings of substantial variations highlight differences in implementation and philosophy among pediatric epilepsy programs.

ALK (Anaplastic lymphoma kinase) fusion proteins are oncogenic and have been seen in various tumors. PPP1CB-ALK fusions are rare but have been reported in a few patients with low- or high-grade gliomas. However, little is known regarding the mechanism of fusion formation and genomic break points of this fusion. We performed genomic characterization of a PPP1CB-ALK fusion with fusion gene amplification in a congenital glioblastoma. The PPP1CB-ALK consists of exons 1-5 of PPP1CB and exons 20-29 of ALK. The genomic translocation breakpoints were determined by real-time quantitative PCR (RT-qPCR) and Sanger sequencing of genomic DNA. Next generation sequencing, RT-qPCR and fluorescence in situ hybridization analyses demonstrated PPP1CB-ALK amplification. Copy number analyses of genes between PPP1CB and ALK using RT-qPCR suggest that the PPP1CB-ALK is likely the result of local chromothripsis followed by episomal amplification. Transcriptome sequencing demonstrated high-level SOX2 expression and predicted WNT/β-catenin pathway activation, suggesting possible therapeutic approaches.

Conjoined twins who are classified as craniopagus (joined at the cranium) have a rare congenital anomaly. Despite advances in surgical techniques and critical care, the rate of complications and death is still high among twins with total fusion in which the superior sagittal sinus is shared. Here, we describe total-fusion craniopagus twins who at 10 months of age underwent successful surgical separation performed by a multidisciplinary team. Computer-aided design and modeling with a three-dimensional printer, custom-designed cranial distraction and constriction devices, and intraoperative navigation techniques were used. These techniques allowed for separation of the twins at an early age and harnessed the regenerative capacity of their young brains.

Objectives The purpose of this study was to determine the effect of the Accreditation Council for Graduate Medical Education Milestones on the assessment of neurological surgery residents. The authors sought to determine the feasibility, acceptability, and utility of this new framework in making judgments of progressive competence, its implementation within programs, and the influence on curricula. Residents were also surveyed to elicit the effect of Milestones on their educational experience and professional development. Design, Setting, and Participants In 2015, program leadership and residents from 21 neurological surgery residency programs participated in an online survey and telephone interview in which they reflected on their experiences with the Milestones. Survey data were analyzed using descriptive statistics. Interview transcripts were analyzed using grounded theory. Results Response themes were categorized into 2 groups: outcomes of the Milestones implementation process, and facilitators and barriers. Because of Milestones implementation, participants reported changes to the quality of the assessment process, including the ability to identify struggling residents earlier and design individualized improvement plans. Some programs revised their curricula based on training gaps identified using the Milestones. Barriers to implementation included limitations to the adoption of a developmental progression model in the context of rotation block schedules and misalignment between progression targets and clinical experience. The shift from time-based to competency-based evaluation presented an ongoing adjustment for many programs. Organized preparation before clinical competency committee meetings and diverse clinical competency committee composition led to more productive meetings and perceived improvement in promotion decisions. Conclusions The results of this study can be used by program leadership to help guide further implementation of the Milestones and program improvement. These results also help to guide the evolution of Milestones language and their implementation across specialties.

OBJECTIVE: To demonstrate that a novel non-invasive index of intracranial pressure (ICP) derived from diffuse optics-based techniques is associated with intracranial hypertension. STUDY DESIGN: We compared non-invasive and invasive ICP measurements in infants with hydrocephalus. Infants born term and preterm were eligible for inclusion if clinically determined to require cerebrospinal fluid (CSF) diversion. Ventricular size was assessed preoperatively via ultrasound measurement of the fronto-occipital (FOR) and fronto-temporal (FTHR) horn ratios. Invasive ICP was obtained at the time of surgical intervention with a manometer. Intracranial hypertension was defined as invasive ICP ≥15 mmHg. Diffuse optical measurements of cerebral perfusion, oxygen extraction, and non-invasive ICP were performed preoperatively, intraoperatively, and postoperatively. Optical and ultrasound measures were compared with invasive ICP measurements, and their change in values after CSF diversion were obtained. RESULTS: We included 39 infants; 23 had intracranial hypertension. No group difference in ventricular size was found by FOR (p=0.93) or FTHR (p=0.76). Infants with intracranial hypertension had significantly higher non-invasive ICP (p=0.02) and oxygen extraction fraction (p=0.01) compared with infants without intracranial hypertension. Increased cerebral blood flow (p=0.005) and improved oxygen extraction fraction (P < .001) after CSF diversion were only observed in infants with intracranial hypertension. CONCLUSIONS: Non-invasive diffuse optical measures (including a non-invasive ICP index) were associated with intracranial hypertension. The findings suggest impaired perfusion from intracranial hypertension was independent of ventricular size. Hemodynamic evidence of the benefits of CSF diversion was seen in infants with intracranial hypertension. Non-invasive optical techniques hold promise for aiding the assessment of CSF diversion timing.

Monkeys are able to learn the implied ordering of pairs of images drawn from an ordered set, without ever seeing all of the images simultaneously and without explicit spatial or temporal cues. The learning of implied order differs from learning of explicit visual or motor sequences. We recorded the activity of parietal neurons in rhesus macaques while they learned 7-item TI lists when only 2 items were presented on each trial. Behavior and ensemble neuronal activity were significantly influenced by the ordinal relationship of the stimulus pairs, specifically symbolic distance (the difference in rank) and joint ranks (the sum of the ranks). Symbolic distance strongly predicted decision accuracy, and learning was consistently faster as symbolic distance increased. An effect of joint rank on performance was also found nested within the symbolic distance effect. Across the population of neurons, there was significant modulation of firing correlated with the relative ranks of the two stimuli presented on each trial. Neurons exhibited selectivity for stimulus rank during learning, but not before or after. The observed behavior during learning is best explained by a virtual workspace model, not by associative or reward mechanisms. The neural data support a role for posterior parietal cortex in representing several variables that contribute to serial learning, particularly information about the ordinal ranks of the stimuli presented during a given trial. Thus, parietal cortex appears to belong to a neural substrate for learning and representing abstract relationships in a virtual workspace.

Children with myelomeningocele (MMC) are at increased risk of developing neuromuscular scoliosis and spinal cord re-tethering (Childs Nerv Syst 12:748-754, 1996; Neurosurg Focus 16:2, 2004; Neurosurg Focus 29:1, 2010). Some centers perform prophylactic untethering on asymptomatic MMC patients prior to scoliosis surgery because of concern that additional traction on the cord may place the patient at greater risk of neurologic deterioration peri-operatively. However, prophylactic untethering may not be justified if it carries increased surgical risks. The purpose of this study was to determine if prophylactic untethering is necessary in asymptomatic children with MMC undergoing scoliosis surgery. A multidisciplinary, retrospective cohort study from seven children’s hospitals was performed including asymptomatic children with MMC

Objective Interictal spikes are a characteristic feature of invasive electroencephalography (EEG) recordings in children with refractory epilepsy. Spikes frequently co-occur across multiple brain regions with discernable latencies, suggesting that spikes can propagate through distributed neural networks. The purpose of this study was to examine the long-term reproducibility of spike propagation patterns over hours to days of interictal recording. Methods Twelve children (mean age 13.1 years) were retrospectively studied. A mean ± standard deviation (SD) of 47.2 ± 40.1 hours of interictal EEG recordings were examined per patient (range 17.5-166.5 hours). Interictal recordings were divided into 30-minute segments. Networks were extracted based on the frequency of spike coactivation between pairs of electrodes. For each 30-minute segment, electrodes were assigned a "Degree Preference (DP)" based on the tendency to appear upstream or downstream within propagation sequences. The consistency of DPs across segments ("DP-Stability") was quantified using the Spearman rank correlation. Results Regions exhibited highly stable preferences to appear upstream, intermediate, or downstream in spike propagation sequences. Across networks, the mean ± SD DP-Stability was 0.88 ± 0.07, indicating that propagation patterns observed in 30-minute segments were representative of the patterns observed in the full interictal window. At the group level, regions involved in seizure generation appeared more upstream in spike propagation sequences. Significance Interictal spike propagation is a highly reproducible output of epileptic networks. These findings shed new light on the spatiotemporal dynamics that may constrain the network mechanisms of refractory epilepsy.

Cranial spring hardware is generally removed 3 months after placement for spring-mediated cranioplasty. Spring removal is performed as an outpatient procedure under general anesthesia in approximately 15 minutes through the incision locations of the index procedure. Herein, the authors provide a multimedia demonstration of cranial spring hardware removal after spring-mediated cranioplasty for sagittal craniosynostosis. The video can be found here: https://vimeo.com/511179695

Spring-mediated cranioplasty is a useful treatment modality for correcting scaphocephalic head shape in sagittal craniosynostosis because it is less invasive than whole-vault cranioplasty and offers durable morphologic outcomes. Herein, the authors provide a multimedia demonstration of alternative operative approaches for spring-mediated cranioplasty for sagittal craniosynostosis. The video can be found here: https://vimeo.com/511256259

Background Resident attitudes toward the Accreditation Council for Graduate Medical Education (ACGME) likely influence the ACGME's effectiveness in its role of ensuring compliance with its requirements. Beyond perceptions of duty hour limits and their enforcement, there is a lack of data on resident perceptions of the ACGME and its role. Objective We explored resident attitudes toward the ACGME and developed recommendations for improved outreach to the resident community to improve perceptions. Methods A multi-specialty, nationally representative group of residents and fellows conducted a 3-part structured exercise that (1) described current trainee impressions of the ACGME; (2) evaluated the value of the ACGME engaging residents; and (3) recommended ways to improve communication between the ACGME and residents. Results Most residents are only vaguely familiar with the role of the ACGME and generally have a negative impression regarding ACGME accreditation functions. This contrasts with the attitudes of the residents more closely involved with the ACGME through its Review Committees. There is value in engaging residents in the mission of the ACGME, and outreach efforts across multiple modalities could more closely align ACGME values and resident impressions of the organization and its role. Conclusions A multifaceted effort to engage residents in the mission and goals of the ACGME would augment both ACGME and trainee efforts to improve graduate medical education.

OBJECTIVECraniopharyngioma represents up to 10% of pediatric brain tumors. Although these lesions are benign, attempts at gross-total resection (GTR) can lead to serious complications. More conservative approaches have emerged but require adjuvant radiation. Endoscopic endonasal surgery (EES) aimed at GTR has the potential to result in fewer complications, but there has been limited comparison to open surgery. The authors performed a review of these two approaches within their institution to elucidate potential benefits and complication differences.METHODSThe authors performed a retrospective review of pediatric patients undergoing resection of craniopharyngioma at their institution between 2001 and 2017. Volumetric analysis of tumor size and postoperative ischemic injury was performed. Charts were reviewed for a number of outcome measures.RESULTSA total of 43 patients with an average age of 8.2 years were identified. Open surgery was the initial intervention in 15 and EES in 28. EES was performed in patients 3–17 years of age. EES has been the only approach used since 2011. In the entire cohort, GTR was more common in the EES group (85.7% vs 53.3%, p = 0.03). Recurrence rate (40% vs 14.2%, p = 0.13) and need for adjuvant radiation (20.0% vs 10.7%, p = 0.71) were higher in the open surgical group, although not statistically significant. Pseudoaneurysm development was only observed in the open surgical group. Volumetric imaging analysis showed a trend toward larger preoperative tumor volumes in the open surgical group, so a matched cohort analysis was performed with the largest tumors from the EES group. This revealed no difference in residual tumor volume (p = 0.28), but the volume of postoperative ischemia was still significantly larger in the open group (p = 0.004). Postoperative weight gain was more common in the open surgical group, a statistically significant finding in the complete patient group that trended toward significance in the matched cohort groups. Body mass index at follow-up correlated with volume of ischemic injury in regression analysis of the complete patient cohort (p = 0.05).CONCLUSIONSEES was associated with similar, if not better, extent of resection and significantly less ischemic injury than open surgery. Pseudoaneurysms were only seen in the open surgical group. Weight gain was also less prevalent in the EES cohort and appears be correlated with extent of ischemic injury at time of surgery.

Syrinx has been reported in 25–85 % of children with Chiari malformation type I (CMI), and it is most commonly cervical in location. As a result, cervical MRI is routinely included in an evaluation for CMI. Isolated thoracic syrinx without involvement of the cervical cord in this population is uncommon but clinically important because its presence may influence the decision to operate, surgical techniques employed, or interpretation of follow-up imaging. The purpose of this study was to determine the incidence of isolated thoracic syrinx in a large group of children evaluated for CMI. We retrospectively reviewed all patients under 21 years of age who were evaluated for CMI at Columbia University/Morgan Stanley Children’s Hospital of New York from 1998 to 2013. All patients underwent MRI of the entire spine as part of the CMI evaluation, regardless of whether surgery was planned. The proportion of patients exhibiting isolated thoracic syrinx was determined. Presenting signs, symptoms, and imaging findings were then studied in an attempt to identify any clinical features associated with isolated thoracic syrinx. We identified 266 patients evaluated over the study period. One-hundred thirty-two patients (50 %) presented with a syrinx, and 12 patients (4.5 % of all patients evaluated and 9.1 % of all patients with a syrinx) had an isolated thoracic syrinx. Demographic variables, clinical presentation, and extent of tonsillar ectopia showed great heterogeneity in this group, and no factor was consistently associated with isolated thoracic syrinx. Isolated thoracic syrinx is an uncommon but clinically significant finding in children with CMI. Our data demonstrate that the presence of a CMI-related thoracic syrinx cannot be reliably predicted clinically and is therefore likely to be missed in patients who do not undergo complete spinal cord imaging. MRI of the entire spinal cord should be considered for all children undergoing initial evaluation for CMI.

OBJECTThe long-term consequences of atlantoaxial (AA) and occipitocervical (OC) fusion and instrumentation in young children are unknown. Anecdotal reports have raised concerns regarding altered growth and alignment of the cervical spine after surgical intervention. The purpose of this study was to determine the long-term effects of these surgeries on the growth and alignment of the maturing spine.METHODSA multiinstitutional retrospective chart review was conducted for patients less than or equal to 6 years of age who underwent OC or AA fusion with rigid instrumentation at 9 participating centers. All patients had at least 3 years of clinical and radiographic follow-up data and radiographically confirmed fusion. Preoperative, immediate postoperative, and most recent follow-up radiographs and/or CT scans were evaluated to assess changes in spinal growth and alignment.RESULTSForty children (9 who underwent AA fusion and 31 who underwent OC fusion) were included in the study (mean follow-up duration 56 months). The mean vertical growth over the fused levels in the AA fusion patients represented 30% of the growth of the cervical spine (range 10%–50%). Three different vertical growth patterns of the fusion construct developed among the 31 OC fusion patients during the follow-up period: 1) 16 patients had substantial growth (13%–46% of the total growth of the cervical spine); 2) 9 patients had no meaningful growth; and 3) 6 patients, most of whom presented with a distracted atlantooccipital dislocation, had a decrease in the height of the fused levels (range 7–23 mm). Regarding spinal alignment, 85% (34/40) of the patients had good alignment at follow-up, with straight or mildly lordotic cervical curvatures. In 1 AA fusion patient (11%) and 5 OC fusion patients (16%), we observed new hyperlordosis (range 43°–62°). There were no cases of new kyphosis or swan-neck deformity, evidence of subaxial instability, or unintended subaxial fusion. No preoperative predictors of these growth patterns or alignment were evident.CONCLUSIONSThese results demonstrate that most young children undergoing AA and OC fusion with rigid internal fixation continue to have good cervical alignment and continued growth within the fused levels during a prolonged follow-up period. However, some variability in vertical growth and alignment exists, highlighting the need to continue close long-term follow-up.

Background Progressive independence in patient care activities is imperative for residents' readiness for practice and patient safety of those cared for by graduates of residency programs. However, establishing a standardized system of progressive independence is an ongoing challenge in graduate medical education. Objective We aggregated trainees' perspectives on progressive independence, developed a model of the ideal state, and suggested actionable improvements. Methods A multispecialty, nationally representative group of trainees conducted a structured exercise that (1) described the attributes of an ideal system of graduated responsibility; (2) compared the current system to that ideal; (3) developed benchmarks to reinforce best practices; and (4) identified approaches to motivate programs to adopt best practices. Results At the core of an ideal model of graduated responsibility is a well-structured curriculum and assessment of individual learners using educational milestones and patient outcomes. The ideal model also includes robust faculty development and emphasizes faculty mentorship. To address legal and financial restrictions that pose barriers to progressive independent, objective outcome criteria like the milestones could be used to ask payers to alter payment restrictions for work performed by senior trainees, providing financial incentives for programs to encourage appropriate independent practice. Recognition of high-performing programs at the national level could motivate others to adopt best practices. Conclusions A multifaceted approach, incorporating robust 2-way feedback about skill level and autonomy between residents and faculty, along with improved faculty development in this area, is needed to optimize residents' attainment of progressive independence. There are incentives to move programs and institutions toward this optimal model.

We present a patient with prednisone-induced spinal epidural lipomatosis (SEL) and relatively acute neurologic deterioration followed by rapid recovery after surgical decompression. SEL is a rare disease characterized by hypertrophy of epidural fat, most commonly associated with exogenous steroid use. To our knowledge, an analysis of the dynamics of steroid dose related to time to onset has never been performed, or of patient presentation features with respect to patient outcome. We retrospectively reviewed the literature for English language series and case reports of SEL associated with prednisone use from 1975-2013. Data were compiled for 41 patients regarding the prescribed dose of prednisone and length of treatment, as well as the severity of symptoms on the Ranawat scale, time to onset, time to recovery, and degree of recovery of neurological symptoms. Fisher's exact test and analysis of variance were used for comparing proportions, and p values

Objective To assess whether early changes in enhancing tumor volume (eTV) and relative cerebral blood volume (rCBV) 1 month after convection-enhanced delivery of topotecan in patients with recurrent malignant glioma correlated with 6-month disease progression status. Methods Sixteen patients were enrolled in a Phase Ib trial of convection-enhanced delivery of topotecan for recurrent malignant glioma. Each patient was evaluated with serial follow-up magnetic resonance imaging at baseline and at 4- to 8-week intervals. Changes at 1 month compared with baseline in eTV and rCBV were evaluated as potential predictors of 6-month progression status, classified as either progressive disease or nonprogressive disease. Relationships between percent changes in eTV and rCBV at 1 month with the probability of progressive disease at 6 months were estimated by the use of logistic regression analysis. Receiver operating characteristic curves for varying percent change thresholds in eTV and rCBV were evaluated by the use of 6-month progressive disease as the reference. Results There was a significant difference in the percent change in rCBV at 1 month in patients with progressive disease compared with those with nonprogressive disease at 6 months (+12% vs. −29%, P = 0.02). Logistic regression analysis demonstrated on average that a 10% increase in rCBV at 1 month after convection-enhanced delivery of topotecan was associated with 1.7 times the odds of developing progressive disease at 6 months (95% confidence interval [CI] 1.0–2.9 P = 0.05). Receiver operating characteristic analysis for determining progressive disease at 6 months showed a greater area under the curve with rCBV (0.867; 95% CI 0.66–1.00) than with change in enhancing tumor volume (0.767; 95% CI 0.51–1.00). Conclusion In this selected population of patients with recurrent malignant glioma treated with convection-enhanced delivery of topotecan, early changes in rCBV at 4 weeks after therapy may help predict progression status at 6 months.

Proneural glioblastoma is defined by an expression pattern resembling that of oligodendrocyte progenitor cells and carries a distinctive set of genetic alterations. Whether there is a functional relationship between the proneural phenotype and the associated genetic alterations is unknown. To evaluate this possible relationship, we performed a longitudinal molecular characterization of tumor progression in a mouse model of proneural glioma. In this setting, the tumors acquired remarkably consistent genetic deletions at late stages of progression, similar to those deleted in human proneural glioblastoma. Further investigations revealed that p53 is a master regulator of the transcriptional network underlying the proneural phenotype. This p53-centric transcriptional network and its associated phenotype were observed at both the early and late stages of progression, and preceded the proneural-specific deletions. Remarkably, deletion of p53 at the time of tumor initiation obviated the acquisition of later deletions, establishing a link between the proneural transcriptional network and the subtype-specific deletions selected during glioma progression. Cancer Res; 74(5); 1440–51. ©2014 AACR.

Convection-enhanced delivery (CED) for the treatment of malignant gliomas is a technique that can deliver chemotherapeutic agents directly into the tumor and the surrounding interstitium through sustained, low-grade positive-pressure infusion. This allows for high local concentrations of drug within the tumor while minimizing systemic levels that often lead to dose-limiting toxicity. Diffuse intrinsic pontine gliomas (DIPGs) are universally fatal childhood tumors for which there is currently no effective treatment. In this report the authors describe CED of the topoisomerase inhibitor topotecan for the treatment of DIPG in 2 children. As part of a pilot feasibility study, the authors treated 2 pediatric patients with DIPG. Stereotactic biopsy with frozen section confirmation of glial tumor was followed by placement of bilateral catheters for CED of topotecan during the same procedure. The first patient underwent CED 210 days after initial diagnosis, after radiation therapy and at the time of tumor recurrence, with a total dose of 0.403 mg in 6.04 ml over 100 hours. Her Karnofsky Performance Status (KPS) score was 60 before CED and 50 posttreatment. Serial MRI initially demonstrated a modest reduction in tumor size and edema, but the tumor progressed and the patient died 49 days after treatment. The second patient was treated 24 days after the initial diagnosis prior to radiation with a total dose of 0.284 mg in 5.30 ml over 100 hours. Her KPS score was 70 before CED and 50 posttreatment. Serial MRI similarly demonstrated an initial modest reduction in tumor size. The patient subsequently underwent fractionated radiation therapy, but the tumor progressed and she died 120 days after treatment. Topotecan delivered by prolonged CED into the brainstem in children with DIPG is technically feasible. In both patients, high infusion rates (> 0.12 ml/hr) and high infusion volumes (> 2.8 ml) resulted in new neurological deficits and reduction in the KPS score, but lower infusion rates (< 0.04 ml/hr) were well tolerated. While serial MRI showed moderate treatment effect, CED did not prolong survival in these 2 patients. More studies are needed to improve patient selection and determine the optimal flow rates for CED of chemotherapeutic agents into DIPG to maximize safety and efficacy. Clinical trial registration no.: NCT00324844.

Recent preclinical studies suggest that treating glioblastoma (GBM) with a combination of targeted chemotherapy and radiotherapy may enhance the anti-tumor effects of both therapies. However, the effects of these treatments on glioma growth and progression are poorly understood.In this study, we have tested the effects of combination therapy in a mouse glioma model that utilizes a PDGF-IRES-Cre-expressing retrovirus to infect adult glial progenitors in mice carrying conditional deletions of Pten and p53. This model produces tumors with the histological features of GBM with 100% penetrance, making it a powerful system to test novel treatments. Sunitinib is an orally active, small molecule inhibitor of multiple receptor tyrosine kinases critical for tumor growth and angiogenesis, including PDGF receptors. We investigate the addition of Sunitinib to radiotherapy, and use bioluminescence imaging to characterize the effects of treatment on glioma growth and progression.Treating our PDGF-driven mouse model with either Sunitinib or high-dose radiation alone delayed tumor growth and had a modest but significant effect on survival, while treating with low-dose radiation alone failed to control glioma growth and progression. The addition of Sunitinib to low-dose radiation caused a modest, but significant delay in tumor growth. However, no significant survival benefit was seen as tumors progressed in 100% of animals. Histological analysis revealed a reduction in vascular proliferation and a marked increase in brain invasion. An additional study combining Sunitinib with high-dose radiation revealed a fatal toxicity despite individual monotherapies being well tolerated.These results show that the addition of Sunitinib to radiotherapy fails to significantly alter survival in GBM despite enhancement of the effects of radiation. Furthermore, an enhanced risk of toxicity associated with combined therapy must be considered in the design of future clinical studies.

Convection-enhanced delivery of chemotherapeutics for the treatment of malignant glioma is a technique that delivers drugs directly into a tumor and the surrounding interstitium through chronic, low grade positive-pressure infusion. This allows for high local concentrations of drug while overcoming the limitations imposed by toxicity and the blood-brain barrier in systemic therapies that prevent the use of many potentially effective drugs. To examine the safety profile of a conventional chemotherapeutic agent, topotecan, via convection-enhanced delivery in the treatment of recurrent malignant gliomas and, secondarily, to assess radiographic response and survival. We performed a prospective, dose-escalation Phase Ib study of the topoisomerase-I inhibitor, topotecan, given by convection-enhanced delivery in patients with recurrent malignant gliomas. Significant anti-tumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A maximum tolerated dose was established for future phase II studies. Topotecan by convection-enhanced delivery has significant anti-tumor activity at concentrations that are non-toxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent Phase II and Phase III trials.

The pineal region can harbor highly diverse histologic tumor subtypes. Because optimal therapeutic strategies vary with tumor type, an accurate diagnosis is the foundation of enlightened management decisions. Either stereotactic biopsy or open surgery is essential for securing tissue for pathologic examination. Biopsy has the advantage of ease and minimal invasiveness but is associated with more sampling errors than open surgery. The emergence of endoscopic techniques and stereotactic radiosurgery provide complementary options to improve pineal tumor management, and will assume greater importance in the neurosurgeon's armamentarium.

Evaluation of: Nagaraj S, Schrum AG, Cho HI et al.: Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J. Immunol. 184, 3106–3116 (2010). CD8 T-cell inhibition by myeloid-derived suppressor cells (MDSCs) is one of the presumed methods by which tumors evade the immune system, although the mechanism remains unclear. This paper provides a new insight into the inhibitory interactions between MDSCs and T cells and the mechanisms by which this occurs. The authors demonstrated that tumor-mediated CD8 T-cell suppression via MDSCs causes T cells to be suppressed only for the T-cell receptor (TCR) specific for the tumor-derived antigen while remaining responsive to antigens activating other TCRs in the same cell. They further show that the specific TCR complex is nitrated by the MDSC, which reduces the physical interaction of TCRs with CD3ζ and CD8 and results in lower levels of several TCR-related molecules, including phosphorylated CD3ζ, and reduces activation, proliferation and IFN-γ production in response to the specific antigen of the TCR only. This article will move the field of tumor immunology forward by identifying potential therapeutic targets as well as advancing a mechanistic knowledge to guide further research.