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OBJECTIVE Prior to 2019, the majority of patients at Children’s Hospital Colorado were admitted to the pediatric intensive care unit (PICU) following Chiari malformation (CM) decompression surgery. This study sought to identify the safety and efficacy of postoperative general ward management for these patients. METHODS After a retrospective baseline assessment of 150 patients, a quality improvement (QI) initiative was implemented, admitting medically noncomplex patients to the general ward postoperatively following CM decompression. Twenty-one medically noncomplex patients were treated during the QI intervention period. All patients were assessed for length of stay, narcotic use, time to ambulation, and postoperative complications. RESULTS PICU admission rates postoperatively decreased from 92.6% to 9.5% after implementation of the QI initiative. The average hospital length of stay decreased from 3.4 to 2.6 days, total doses of narcotic administration decreased from 12.3 to 8.7, and time to ambulation decreased from 1.8 to 0.9 days. There were no major postoperative complications identified that were unsuitable for management on a conventional pediatric medical/surgical nursing unit. CONCLUSIONS Medically noncomplex patients were safely admitted to the general ward postoperatively at Children’s Hospital Colorado after decompression of CM. This approach afforded decreased length of stay, decreased narcotic use, and decreased time to ambulation, with no major postoperative complications.

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

Stereoelectroencephalography (SEEG) has become increasingly employed as a critical component of epilepsy workups for patients with drug-resistant epilepsy when information from noninvasive studies is not conclusive and sufficient to guide epilepsy surgery. Although exceedingly rare, clinically significant hemorrhagic complications can be caused during SEEG implantation procedures. Intracranial hemorrhage (ICH) can be difficult to recognize due to the minimally invasive nature of SEEG. The authors describe their technique using a commercially available intraparenchymal intracranial pressure (ICP) monitor as a method for early intraoperative detection of ICH during SEEG implantation. Between May 2019 and July 2021, 18 pediatric patients underwent SEEG implantation at a single, freestanding children’s hospital with the use of an ICP monitor during the procedure. No patients experienced complications resulting from this technique. The authors have relayed their rationale for ICP monitor use during SEEG, the technical considerations, and the safety profile. In addition, they have reported an illustrative case in which the ICP monitor proved crucial in early detection of ICH during SEEG implantation.

Drug-resistant epilepsy (DRE) is a prevalent problem in children that can lead to abnormal development and various psychiatric comorbidities. Malformations of cortical development (MCD) include focal cortical dysplasia, tuberous sclerosis complex and hemimegalencephaly, which are the most common pathologies among children who undergo surgical resection for treatment of DRE. These disorders share many histopathological features, including dyslamination of the cerebral cortex and enlarged neuronal somata. Recently, genetic mutations in the mammalian target of rapamycin (mTOR) signaling cascade have been shown to underpin most MCDs. Rodent models, including the RhebCAmodel, recapitulate histologic and physiologic aspects of human DRE. However, there have been few studies characterizing the developmental time point of the histological changes seen in MCDs. In this study, we usein uteroelectroporation to upregulate the Rheb protein (directly upstream of mTOR) in a focal area of the neocortex. We demonstrate that mTOR dysregulation leads to focal dyslamination and increased neuronal size that is histologically similar to MCD, which correlates to spontaneous recurrent seizures. We used immunohistochemistry to investigate neuronal lamination at several time points during development between E18 and P21 and show early differences in lamination that persisted through development. Furthermore, the increased axonal length associated with mTOR upregulation occurs early in development. Our study provides a time frame for the initial development of abnormal neuronal migration and cellular growth that occurs in MCDs, and our data supports that these anatomical changes may contribute to the formation of epileptic networks.

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

In the current study, we performed whole-cell current clamp recordings from human cortical neurons in layer 2/3 of the human neocortex in order to characterize the diversity of L2/3 human neocortical neurons in epileptic foci with various etiologies in order to begin to elucidate the underlying mechanisms of hyperexcitability which are still mostly unknown. We differentiated neuronal subtypes based on their firing patterns and AHP kinetics or epilepsy subtype (malformation of cortical development (MCD) vs. other (non-MCD)). We found that L2/3 pyramidal neurons have diverse firing properties and action potential kinetics, with some neurons looking remarkably similar to LTS interneurons. We also saw that L2/3 pyramidal neurons could be split into those with fast AHPs and those without, medium AHPs (mAHPs). Based on these parameters, we were unable to significantly differentiate neurons based on firing properties indicating that AHP component kinetics alone do not dictate L2/3 pyramidal neuron firing in human epileptic cortical slices. We also report significant differences in intrinsic properties between MCD and non-MCD and control L2/3 pyramidal neurons and are the first to characterize that wash on of the proconvulsant drug, 4-aminopyridine (4-AP), leads to increased AP duration, less firing rate (FR) accommodation, and slowed down AHPs. Overall, the present study is the first to characterize the large variability of L2/3 human neocortical pyramidal neurons, to compare between L2/3 pyramidal neurons within the epileptic foci between MCD and non-MCD cases, to use control tissue from tumor patients without incidence of seizure, and to determine the influence of 4-AP on L2/3 pyramidal neuron intrinsic properties.

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT3-mTOR-signaling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n=16), focal cortical dysplasia type I and related phenotypes (n=48), focal cortical dysplasia type II (n=44), or focal cortical dysplasia type III (n=15) classified using imaging and pathological findings. We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel, and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1, and NIPBL, genes associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a very small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that FCD types I, II, and III, are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

OBJECTIVEPediatric adamantinomatous craniopharyngiomas (ACPs) are histologically benign brain tumors that confer significant neuroendocrine morbidity. Previous studies have demonstrated that injury to the hypothalamus is associated with worsened quality of life and a shorter lifespan. This insight helps many surgeons define the goals of surgery for patients with ACP. Puget and colleagues proposed a 3-tiered preoperative and postoperative grading system based on the degree of hypothalamic involvement identified on MRI. In a prospective cohort from their institution, the authors found that use of the system to guide operative goals was associated with decreased morbidity. To date, however, the Puget system has not been externally validated. Here, the authors present an interrater reliability study that assesses the generalizability of this system for surgeons planning initial operative intervention for children with craniopharyngiomas.METHODSA panel of 6 experts, consisting of pediatric neurosurgeons and pediatric neuroradiologists, graded 30 preoperative and postoperative MRI scans according to the Puget system. Interrater reliability was calculated using Fleiss’ κ and Krippendorff’s α statistics.RESULTSInterrater reliability in the preoperative context demonstrated moderate agreement (κ = 0.50, α = 0.51). Interrater reliability in the postoperative context was 0.27 for both methods of statistical evaluation.CONCLUSIONSInterrater reliability for the system as defined is moderate. Slight refinements of the Puget MRI grading system, such as collapsing the 3 grades into 2, may improve its reliability, making the system more generalizable.

Background Pediatric cervical spine injuries (CSI) are rare but potentially devastating sequelae of blunt trauma. Existing protocols to evaluate children at risk for CSI frequently incorporate computed topography (CT) and magnetic resonance imaging (MRI); however, the clinical value of performing both remains unclear. Methods Single-center retrospective review of pediatric trauma patients who underwent both CT and MRI of the cervical spine between 2001 and 2015. Based on radiographic findings, CT and MRI results were grouped into one of three categories: no injury, stable injury, or unstable injury. Radiographic instability was defined by disruption of two or more contiguous spinal columns while radiographic stability was defined by any other acute cervical spine abnormality on imaging. Clinical instability was defined by the need for surgical intervention (halo or spinal fusion), with the remaining patients, including children discharged in a cervical collar, considered clinically stable. Results In total, 221 children met inclusion criteria, with a median age of 9 (interquartile range, 3-14). The Glasgow Coma Scale (GCS) score of the cohort was 9 (interquartile range, 4-15). Thirty-three (14.9%) children had clinically unstable injuries, requiring surgical intervention. Among the 160 (72.4%) children with no injury on CT, MRI identified no injury in 84 (52.5%) cases, a stable injury in 76 (47.5%) cases, and an unstable injury in none. Among the 21 children with stable injuries on CT, MRI findings were concordant in 17 (81.0%) cases. In four (19.0%) cases, a spinal column injury was identified on CT and appeared to be stable, but later deemed unstable on MRI. Forty (18.1%) patients had an unstable injury on CT with 100% MRI concordance. Conclusion In pediatric trauma patients suspected of having a CSI, a normal cervical spine CT is sufficient to rule out a clinically significant CSI as no child with a normal cervical CT was found to be radiographically or clinically unstable. Level of evidence Diagnostic Test, level III.