Interhemispheric Vertical Hemispherotomy: Technique, Outcome, and Pitfalls-A Bicentric Retrospective Case Series of 39 Cases.

BACKGROUND AND OBJECTIVES: When seizure onset affects a whole hemisphere, hemispheric disconnections are efficient and safe procedures. However, both lateral peri-insular hemispherotomy and vertical paramedian hemispherotomy approaches report a failure rate around 20%, which can be explained by residual connections giving rise to persistent seizures. In this study, we present the interhemispheric vertical hemispherotomy (IVH), a technical variation of the vertical paramedian hemispherotomy approach, that aims to increase seizure control avoiding residual connections while exposing the corpus callosum. METHODS: This is a retrospective study of IVH in two centers, with analysis of clinical and MRI data and outcomes. A detailed description of the technique is provided with a video. RESULTS: IVH was performed in 39 children. The mean age at surgery was 7.2 years, and etiologies were as follows: malformations of cortical development (n = 14), Rasmussen's encephalitis (n = 10), stroke (n = 10), post-traumatic (3), and Sturge-Weber Syndrome (2). Hemispheric disconnection was complete on postoperative MRI in 34 cases. There was no mortality, hydrocephalus occurred in one case, and subdural collection occurred in four cases. A second surgery was performed in four cases because of seizure relapse (n = 3) and/or incomplete disconnection on MRI (n = 4). With a mean follow-up of 3.2 years, International League Against Epilepsy class I epilepsy outcome was obtained for 37/39 patients. CONCLUSION: IVH is a safe and effective variation of the vertical approaches for hemispheric disconnection. It allows a good exposure and anatomic control of the corpus callosum, which is a frequent site of incomplete disconnection. IVH may be limited by the thalamic volume and the ventricular size, notably in hemimegalencephaly cases.

Assessment of Puberty and Hypothalamic-Pituitary-Gonadal Axis Function After Childhood Brain Tumor Treatment.

CONTEXT: Endocrine complications are common in pediatric brain tumor patients. OBJECTIVE: To describe hypothalamic-pituitary-gonadal axis (HPGA) function in patients treated in childhood for a primary brain tumor more than 5 years earlier, in order to identify risk factors for HPGA impairment. METHODS: We retrospectively included 204 patients diagnosed with a primary brain tumor before 18 years of age and monitored at the pediatric endocrinology unit of the Necker Enfants-Malades University Hospital (Paris, France) between January 2010 and December 2015. Patients with pituitary adenoma or untreated glioma were excluded. RESULTS: Among patients with suprasellar glioma not treated by radiotherapy, the prevalence of advanced puberty was 65% overall and 70% when the diagnosis occurred before 5 years of age. Medulloblastoma chemotherapy caused gonadal toxicity in 70% of all patients and in 87.5% of those younger than 5 years at diagnosis. In the group with craniopharyngioma, 70% of patients had hypogonadotropic hypogonadism, which was consistently accompanied by growth hormone deficiency. CONCLUSION: Tumor type, location, and treatment were the risk main factors for HPGA impairment. Awareness that onset can be delayed is essential to guide information of parents and patients, patient monitoring, and timely hormone replacement therapy.

Temporosylvian arachnoid cysts in children. Part 2: Postoperative neuropsychological and clinical improvement.

OBJECTIVE: The authors' objective was to study clinical, imaging, and neuropsychological changes in children who underwent surgery for a temporal arachnoid cyst (TAC). METHODS: Thirty-four children were prospectively assessed similarly at diagnosis and postoperatively (mean 14 months) with clinic visits, images, cognitive tests, and parental questionnaires on mood/behavior and executive functions. The scores were compared pre- and postoperatively for the entire cohort and individually. The scores of 25 children were also compared with a control group of 23 healthy age-matched children. Parents were administered an outcome questionnaire on average 4 years postoperatively. RESULTS: The 34 children selected for surgery had signs of raised intracranial pressure (74%) and/or selective neuropsychological disorders presumably linked to cyst location (learning difficulties in 65%, cognitive difficulties in 56%, and mood/behavior difficulties in 47%). The majority of patients had a convex cyst (85%) and underwent microsurgical fenestration (85%). The TAC volume decreased ≥ 50% for 59% of children. On the Wechsler Intelligence Scale, the entire cohort significantly improved on Full Scale IQ and verbal and perceptual nonverbal indexes. Individually, nearly half of the children (47%) highly increased their scores (≥ 15 points) on at least one IQ index and 26% on at least two indexes. Language, working memory, episodic memory, and executive functions were also significantly improved. Improvements were more pronounced in patients with a preoperative heterogeneous profile with isolated lower scores and a left-sided cyst. Parental questionnaires showed reduction in anxiety, aggressiveness, social problems, and daily life executive disorders. Preschool-aged children improved significantly in language and verbal IQ, as did middle/high school-aged children in many domains. Individual analyses revealed improvement in 76% of cases. Cognitive scores were lower for patients preoperatively than for controls and were no longer significantly different postoperatively in verbal fluency, visual memory, and working memory. Four years later, 97% of parents described an improvement in their child, correlated with cognitive improvements. CONCLUSIONS: Among children with a TAC, some have no clinical signs or neuropsychological difficulties, and others may show signs of raised intracranial pressure and/or specific neuropsychological disorders that impact daily life and require significant and long-lasting rehabilitation. In these cases, consideration may be given to surgical decompression. It is interesting to note that 76% of this surgically treated cohort improved regardless of the child's age, particularly in patients with selective disorders and an impact on daily life. However, a larger number of children will need to be investigated before the true benefit of such treatment can be known.

Temporosylvian arachnoid cysts in children. Part 1: Cognitive profile of children with a temporal cyst and impact of the cyst in daily life. A prospective study in 100 consecutive children.

OBJECTIVE: The aim of this study was to determine the cognitive profile of children with a temporal arachnoid cyst (TAC) and its impact on daily life. METHODS: The authors prospectively analyzed the cognitive and psychological profiles of 100 consecutive children relative to age and cyst characteristics (side, cyst size, and cyst shape: convex or nonconvex) and their outcome 4 years later. RESULTS: Mean IQs were normal but with high heterogeneity on Full Scale IQ (FSIQ; range 59-150); 29% of children had at least one Wechsler index below the norm, in particular, Processing Speed and Working Memory Indexes. Impairments were observed in language for 31% of children, as well as in verbal memory (28%), visual memory (23%), executive function (21%), and visual attention (24%). Half of the children (50%) needed rehabilitation for learning difficulties, and 26% had academic difficulties. The parental questionnaire BRIEF (Behavior Rating Inventory of Executive Function) revealed significant executive dysfunctions in daily life for 22% of the children. One-third of the patients (34%) required psychotherapy for anxiety or social disorders, with higher rates in patients with a right-sided cyst and older children. Cyst size had very little neuropsychological impact. Convex cysts were significantly associated with worse performance than nonconvex cysts on all Wechsler indexes and FSIQ, and in language, verbal memory, attention, and visuospatial skills. Children with a convex cyst had significantly more executive and behavior difficulties in daily life and more psychotherapy than other children. The effect of cyst shape was independent of Galassi type and cyst side. Children with a ruptured cyst or an incidentally discovered cyst usually had a good cognitive level. Four years later, children without initial disorders remained stable, whereas those with difficulties who did not undergo surgery needed more rehabilitation and school adaptations. CONCLUSIONS: This large cohort study revealed a varied profile of children with a TAC: at initial assessment, 50% had neuropsychological difficulties and needed rehabilitation and/or psychotherapy for learning or behavior difficulties, and 50% had no difficulties, which may explain the debate about this pathology. Patients with neuropsychological difficulties had a heterogeneous profile with normal intelligence but selective cognitive and/or behavior disorders that may have a long-term impact on their quality of life, particularly those with a right-sided cyst. A neuropsychological evaluation is not always necessary for a cyst discovered incidentally, but early evaluation is essential in patients with academic, learning, or psychological disorders. When assessment shows selective disorders presumably linked to cyst location, surgery may be considered, particularly for convex cysts, as this study revealed more effects in association with cyst shape than with cyst size and significantly poorer performance with a convex cyst.

High Prevalence of Early Endocrine Disorders After Childhood Brain Tumors in a Large Cohort.

CONTEXT: Endocrine complications are common in pediatric brain tumor patients. OBJECTIVE: We aimed to describe the endocrine follow-up of patients with primary brain tumors. METHODS: This is a noninterventional observational study based on data collection from medical records of 221 patients followed at a Pediatric Endocrinology Department. RESULTS: Median age at diagnosis was 6.7 years (range, 0-15.9), median follow-up 6.7 years (0.3-26.6), 48.9% female. Main tumor types were medulloblastoma (37.6%), craniopharyngioma (29.0%), and glioma (20.4%). By anatomic location, 48% were suprasellar (SS) and 52% non-suprasellar (NSS). Growth hormone deficiency (GHD) prevalence was similar in both groups (SS: 83.0%, NSS: 76.5%; P = 0.338), appearing at median 1.8 years (-0.8 to 12.4) after diagnosis; postradiotherapy GHD appeared median 1.6 years after radiotherapy (0.2-10.7). Hypothyroidism was more prevalent in SS (76.4%), than NSS (33.9%) (P < 0.001), as well as ACTH deficiency (SS: 69.8%, NSS: 6.1%; P < 0.001). Early puberty was similar in SS (16%) and NSS (12.2%). Hypogonadotropic hypogonadism was predominant in SS (63.1%) vs NSS (1.3%), P < 0.001, and postchemotherapy gonadal toxicity in NSS (29.6%) vs SS (2.8%), P < 0.001. Adult height was lower for NSS compared to target height (-1.0 SD, P < 0.0001) and to SS patients (P < 0.0001). Thyroid nodules were found in 13/45 patients (28.8%), including 4 cancers (4.8-11.5 years after radiotherapy). Last follow-up visit BMI was higher in both groups (P = 0.0001), and obesity incidence was higher for SS (46.2%) than NSS (17.4%). CONCLUSION: We found a high incidence of early-onset endocrine disorders. An endocrine consultation and nutritional evaluation should be mandatory for all patients with a brain tumor, especially when the tumor is suprasellar or after hypothalamus/pituitary irradiation.

Role of neoadjuvant chemotherapy in metastatic medulloblastoma: a comparative study in 92 children.

BACKGROUND: Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed. METHODS: Two therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy between 2002 and 2015: surgery at diagnosis (n = 54, group A) and surgery delayed after carboplatin and etoposide-based neoadjuvant therapy (n = 38, group B). Treatment strategies were similar in both groups. RESULTS: The rate of complete tumor excision was significantly higher in group B than in group A (93.3% vs 57.4%, P = 0.0013). Postoperative complications, chemotherapy-associated side effects, and local progressions were not increased in group B. Neoadjuvant chemotherapy led to a decrease in the primary tumor size in all patients; meanwhile 4/38 patients experienced a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after neoadjuvant chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up). CONCLUSION: Preoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival. KEY POINTS: 1. Preoperative chemotherapy increases the rate of complete tumor removal.2. No additional risk (toxic or disease progression) is linked to the delayed surgery.3. Preoperative chemotherapy could have a positive impact on the neuropsychological outcome of patients.

Microsurgical, endoscopic, and shunt management of pediatric temporosylvian arachnoid cysts: a comparative study.

OBJECTIVE: Arachnoid cysts (ACs) are most frequently located in the middle cranial fossa. Some patients are asymptomatic whereas others exhibit signs of increased intracranial pressure, seizures, or cognitive and behavioral symptoms. When ACs do require treatment, the optimal surgical technique remains controversial. This study was conducted to assess the most effective surgical treatment for these cysts. METHODS: The authors retrospectively reviewed 240 temporal intracranial ACs managed over a 25-year period in their pediatric neurosurgical unit. Pre- and posttreatment results were clinically and radiologically assessed. RESULTS: A majority of male patients (74.6%) with an overall median age of 6.9 years were included. The mean cyst size was 107 cm3; the Galassi classification showed 99 (41.3%) type I, 77 (32.1%) type II, and 64 (26.7%) type III cysts. Forty-four ACs (18.3%) were diagnosed after rupture. Surgical management was performed by microsurgery (28.3%), endoscopic cyst fenestration (14.6%), cystoperitoneal shunting (CPS; 16.2%), or subdural shunting (10%). Furthermore, 74 children (30.8%) did not undergo operations. After a mean follow-up of 4.1 years, the mean percentage decrease in cyst volume and the overall rate of clinical improvement did not significantly differ. The endoscopy group had earlier complications and a shorter event-free survival (EFS) time (EFS at 3 years = 67.7%, vs 71.5% and 90.5% for CPS and microsurgery, respectively; p < 0.007) and presented with more subdural hematomas compared to the microsurgery group (p < 0.005). The microsurgery group also showed a tendency for longer cystocisternostomy permeability than the endoscopy group. CONCLUSIONS: Concerning the management of unruptured symptomatic temporal ACs, microsurgery appears to be the most effective treatment, with longer EFS and fewer complications compared to shunting or endoscopy.

Gamma-aminobutyric acidergic transmission underlies interictal epileptogenicity in pediatric focal cortical dysplasia.

OBJECTIVE: Dysregulation of γ-aminobutyric acidergic (GABAergic) transmission has been reported in lesional acquired epilepsies (gliomas, hippocampal sclerosis). We investigated its involvement in a developmental disorder, human focal cortical dysplasia (FCD), focusing on chloride regulation driving GABAergic signals. METHODS: In vitro recordings of 47 human cortical acute slices from 11 pediatric patients who received operations for FCD were performed on multielectrode arrays. GABAergic receptors and chloride regulators were pharmacologically modulated. Immunostaining for chloride cotransporter KCC2 and interneurons were performed on recorded slices to correlate electrophysiology and expression patterns. RESULTS: FCD slices retain intrinsic epileptogenicity. Thirty-six of 47 slices displayed spontaneous interictal discharges, along with a pattern specific to the histological subtypes. Ictal discharges were induced in proepileptic conditions in 6 of 8 slices in the areas generating spontaneous interictal discharges, with a transition to seizure involving the emergence of preictal discharges. Interictal discharges were sustained by GABAergic signaling, as a GABAA receptor blocker stopped them in 2 of 3 slices. Blockade of NKCC1 Cl- cotransporters further controlled interictal discharges in 9 of 12 cases, revealing a Cl- dysregulation affecting actions of GABA. Immunohistochemistry highlighted decreased expression and changes in KCC2 subcellular localization and a decrease in the number of GAD67-positive interneurons in regions generating interictal discharges. INTERPRETATION: Altered chloride cotransporter expression and changes in interneuron density in FCD may lead to paradoxical depolarization of pyramidal cells. Spontaneous interictal discharges are consequently mediated by GABAergic signals, and targeting chloride regulation in neurons may be considered for the development of new antiepileptic drugs. Ann Neurol 2019; 1-14 ANN NEUROL 2019;85:204-217.

Diagnostics of pediatric supratentorial RELA ependymomas: integration of information from histopathology, genetics, DNA methylation and imaging.

Ependymoma with RELA fusion has been defined as a novel entity of the revised World Health Organization 2016 classification of tumors of the central nervous system (CNS), characterized by fusion transcripts of the RELA gene and consequent pathological activation of the NFkB pathway. These tumors represent the majority of supratentorial ependymomas in children. The validation of diagnostic tools to identify this clinically relevant ependymoma entity is essential. Here, we have used interphase fluorescent in situ hybridization (FISH) for C11orf95 and RELA, immunohistochemistry (IHC) for p65-RelA and the recently developed DNA methylation-based classification besides conventional histopathology, and compared the precision of the methods in 40 supratentorial pediatric brain tumors diagnosed as ependymomas in the past years. Reverse transcription PCR (RT-PCR) and RNA sequencing were performed to explore discordant cases. Furthermore, we integrated imaging and clinical features as additional layers of information. The concordance between nuclear RelA expression by IHC and RELA FISH was 100%. Concordance between IHC and DNA methylation profiling, and between FISH and DNA methylation profiling was also high (96.4% and 95.2%, respectively). Thirty-four out of 40 (85%) cases were confirmed by integrated diagnoses as ependymal tumors, including 22 RELA-fused ependymomas (71% of ependymal tumors), two YAP1-fused ependymomas (6%), six non-RELA/non-YAP1 ependymomas (18%) and four ependymal/subependymal mixed tumors (12%). Ependymal/subependymal mixed tumors had an excellent clinical outcome despite the presence of histopathological signs of malignancy, suggesting that these tumors should not be diagnosed as classic ependymomas. DNA methylation profiling helped in the differential diagnosis of RELA-fused ependymomas. IHC and FISH, which are available in the majority of pathology laboratories, are valuable tools to identify RELA-fused ependymomas.

Transcriptomic and epigenetic profiling of 'diffuse midline gliomas, H3 K27M-mutant' discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location.

Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the updated WHO classification grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histones H3 tail.Two hundred and fifteen patients younger than 18 years old with centrally-reviewed pediatric high-grade gliomas (pHGG) were included in this study. Comprehensive transcriptomic (n = 140) and methylation (n = 80) profiling was performed depending on the material available, in order to assess the biological uniqueness of this new entity compared to other midline and hemispheric pHGG.Tumor classification based on gene expression (GE) data highlighted the similarity of K27M DMG independently of their location along the midline. T-distributed Stochastic Neighbor Embedding (tSNE) analysis of methylation profiling confirms the discrimination of DMG from other well defined supratentorial tumor subgroups. Patients with diffuse intrinsic pontine gliomas (DIPG) and thalamic DMG exhibited a similarly poor prognosis (11.1 and 10.8 months median overall survival, respectively). Interestingly, H3.1-K27M and H3.3-K27M primary tumor samples could be distinguished based both on their GE and DNA methylation profiles, suggesting that they might arise from a different precursor or from a different epigenetic reorganization.These differences in DNA methylation profiles were conserved in glioma stem-like cell culture models of DIPG which mimicked their corresponding primary tumor. ChIP-seq profiling of H3K27me3 in these models indicate that H3.3-K27M mutated DIPG stem cells exhibit higher levels of H3K27 trimethylation which are correlated with fewer genes expressed by RNAseq. When considering the global distribution of the H3K27me3 mark, we observed that intergenic regions were more trimethylated in the H3.3-K27M mutated cells compared to the H3.1-K27M mutated ones.H3 K27M-mutant DMG represent a homogenous group of neoplasms compared to other pediatric gliomas that could be further separated based on the type of histone H3 variant mutated and their respective epigenetic landscapes. As these characteristics drive different phenotypes, these findings may have important implication for the design of future trials in these specific types of neoplasms.

Pediatric Chordomas: Results of a Multicentric Study of 40 Children and Proposal for a Histopathological Prognostic Grading System and New Therapeutic Strategies.

Pediatric chordomas are rare malignant neoplasms, and few data are available for optimizing therapeutic strategies and outcome. This study aimed at evaluating how best to manage them and to identify prognostic factors. This multicentric retrospective study included 40 children diagnosed with chordomas between 1966 and 2012. Clinical, radiological, and histopathological data, treatment modalities, and outcomes were reviewed. The median age was 12 years old. Most chordomas were histologically classical forms (45.5%) and were mostly located at the skull base (72.5%). The overall survival (OS) was 66.6% and 58.6%, and progression-free survival (PFS) was 55.7% and 52% at 5 and 10 years, respectively. Total resection was correlated with a better outcome (p = 0.04 for OS and PFS, log-rank). A histopathological/immunohistochemical grading system recently crafted for adults was applied. In a multivariate analysis, it significantly correlated with outcome (PFS and OS, p = 0.004), and the loss of BAF47 immunoexpression appeared to be a significant independent prognostic factor (PFS, p = 0.033). We also identified clinical and histopathological parameters that correlated with prognosis. A new grading system combined with the quality of surgical resection could help classify patients to postpone radiotherapy in case of low risk. Targeted therapy and reirradiation at recurrence may be considered as potential therapeutic strategies.

Predictors of Outcome in Patients with Pediatric Intracerebral Hemorrhage: Development and Validation of a Modified Score.

Purpose To propose and validate a modified pediatric intracerebral hemorrhage (PICH) (mPICH) score and to compare its association with functional outcome to that of the original PICH score. Materials and Methods Data from prospectively included patients were retrospectively analyzed. Consecutive patients with nontraumatic PICH who had undergone clinical follow-up were included. The study population was divided into a development cohort (2008-2012, n = 100) and a validation cohort (2013-2016, n = 43). An mPICH score was developed after variables associated with poor outcome were identified at multivariate analysis (King's Outcome Scale for Childhood Head Injury score < 5a) in the development cohort. The accuracy of the score for prediction of poor outcome was evaluated (sensitivity, specificity). Discrimination and calibration of associations between the mPICH score and poor outcome cohorts were assessed (C statistics, Hosmer-Lemeshow test). Results The mPICH score assessed as follows: brain herniation, four points; altered mental status, three points; hydrocephalus, two points; infratentorial PICH, two points; intraventricular hemorrhage, one point; PICH volume greater than 2% of total brain volume, one point. An mPICH score greater than 5 was associated with severe disability or worse, with sensitivity of 97% (95% confidence interval [CI]: 83%, 100%) and specificity of 61% (95% CI: 49%, 73%). The C statistic was 0.81 (95% CI: 0.73, 0.89). In the validation cohort, sensitivity and specificity were 95.2% (95% CI: 76%, 99%) and 77% (95% CI: 55%, 92%), respectively. There was no significant difference between the observed and predicted risks of poor outcome (P = .46). Conclusion An mPICH score was developed as a simple clinical and imaging grading scale for acute prognosis in patients with PICH. © RSNA, 2017.

Cerebral blood flow changes after radiation therapy identifies pseudoprogression in diffuse intrinsic pontine gliomas.

Background: The interval between progression and death in diffuse intrinsic pontine glioma (DIPG) is usually <6 months. However, reports of longer patient survival following radiotherapy, in the presence of radiological signs of progression, suggest that these cases may be comparable to pseudoprogression observed in adult glioblastoma. Our aim was to identify such cases and compare their multimodal MRI features with those of patients who did not present the same evolution. Methods: Multimodal MRIs of 43 children treated for DIPG were retrospectively selected at 4 timepoints: baseline, after radiotherapy, during true progression, and at the last visit. The patients were divided into 2 groups depending on whether they presented conventional MRI changes that mimicked progression. The apparent diffusion coefficient, arterial spin labeling cerebral blood flow (ASL-CBF), and dynamic susceptibility contrast perfusion relative cerebral blood volume (DSCrCBV) and flow (DSCrCBF) values were recorded for each tumor voxel, avoiding necrotic areas. Results: After radiotherapy, 19 patients (44%) showed radiological signs that mimicked progression: 16 survived >6 months following so-called pseudoprogression, with a median of 8.9 months and a maximum of 35.6 months. All 43 patients exhibited increased blood volume and flow after radiotherapy, but the 90th percentile of those with signs of pseudoprogression had a greater increase of ASL-CBF (P < 0.001). Survival between the 2 groups did not differ significantly. During true progression, DSCrCBF and DSCrCBV values increased only in patients who had not experienced pseudoprogression. Conclusions: Pseudoprogression is a frequent phenomenon in DIPG patients. This condition needs to be recognized before considering treatment discontinuation. In this study, the larger increase of the ASL-CBF ratio after radiotherapy accurately distinguished pseudoprogression from true progression.

Multimodal Magnetic Resonance Imaging of Treatment-Induced Changes to Diffuse Infiltrating Pontine Gliomas in Children and Correlation to Patient Progression-Free Survival.

PURPOSE: To use multimodal magnetic resonance imaging (MRI) to quantify treatment-induced changes in the whole volume of diffuse infiltrating pontine gliomas and correlate them with progression-free survival (PFS). METHODS AND MATERIALS: This prospective study included 22 children aged 3.3 to 14.7 years (median, 5.9 years). Multimodal MRI was performed at 3 distinct time points: before treatment, the first week following radiation therapy (RT), and 2 months after RT. The imaging protocol included morphologic, multi b-value diffusion; arterial spin labeling; and dynamic susceptibility contrast-enhanced perfusion. Morphologic and multimodal data-lesion volume, diffusion coefficients, relative cerebral blood flow, and relative cerebral blood volume (rCBV)-were recorded at the 3 aforementioned time points. The Wilcoxon test was used to compare each individual parameter variation between time points, and its correlation with PFS was assessed by the Spearman test. RESULTS: Following RT, the tumors' solid component volume decreased by 40% (P<.001). Their median diffusion coefficients decreased by 20% to 40% (P<.001), while median relative cerebral blood flow increased by 60% to 80% (P<.001) and median rCBV increased by 70% (P<.001). PFS was positively correlated with rCBV measured immediately after RT (P=.003), and in patients whose rCBV was above the cutoff value of 2.46, the median PFS was 4.6 months longer (P=.001). These indexes tended to return to baseline 2 months after RT. Lesion volume before or after RT was not correlated with survival. CONCLUSIONS: Multimodal MRI provides useful information about diffuse infiltrating pontine gliomas' response to treatment; rCBV increases following RT, and higher values are correlated with better PFS. High rCBV values following RT should not be mistaken for progression and could be an indicator of response to therapy.

Hydrocephalus treatment in children: long-term outcome in 975 consecutive patients.

OBJECTIVE Hydrocephalus remains one of the more common pathologies managed in pediatric neurosurgical units. Endoscopic third ventriculostomy (ETV) has an advantage over ventriculoperitoneal shunting as it enables patients to remain device free. Multiple shunt devices with various valve designs exist, with no one valve proven to be superior to another. The aim of this study was to describe the management of hydrocephalus and its long-term outcome. METHODS The authors retrospectively reviewed the medical records of all patients who had been treated for hydrocephalus at the Hôpital Necker-Enfants Malades in the period from 1985 to 1995. RESULTS Nine hundred seventy-five children had been treated for hydrocephalus. The mean follow-up was 11 ± 7.4 years (mean ± standard deviation). The most common cause of hydrocephalus was tumor related (32.3%), followed by malformative (24.5%) and inflammatory (20.9%) causes. Two hundred eighty patients underwent ETV as the first-line treatment. The procedure was effective in controlling hydrocephalus due to posterior fossa tumors and aqueductal stenosis. Six hundred ninety-five children had initial shunt insertion, with the majority receiving an Orbis-Sigma valve (OSV). The overall OSV shunt survival was 70% at 1 year, 58% at 10 years, and 49% at 20 years. The most common cause for mechanical shunt failure was obstruction (50.7%). Overall shunt survival was statistically different between the OSV and the differential-pressure valve (p = 0.009). CONCLUSIONS Endoscopic third ventriculostomy is effective in the management of childhood hydrocephalus. Its success is directly related to the underlying pathology. In the long term, the OSV has significantly higher event-free shunt survival than the classic differential-pressure valve systems.

Long-term Outcome After Multiple Burr Hole Surgery in Children With Moyamoya Angiopathy: A Single-Center Experience in 108 Hemispheres.

BACKGROUND: Multiple burr hole (MBH) surgery is a simple, safe, and effective indirect technique of revascularization in moyamoya angiopathy (MM). However, it is not yet recognized as a first-line treatment. OBJECTIVE: To assess the long-term outcome and perioperative complications in a large single-center cohort of children with MM who underwent burr hole surgery. METHODS: This study is a retrospective analysis of children who underwent surgery for MM in a national reference center for pediatric stroke between 1999 and 2015. Sixty-four children (108 hemispheres, median age 7 years) were consecutively treated. The indication for revascularization was previous stroke or transient ischemic attack (TIA) or rapidly progressive disease on brain magnetic resonance imaging (MRI) and digital subtraction angiography. Children were followed with clinical examinations, telephone interviews, and MRI with any clinical recurrence of stroke or TIA used as the primary endpoint. Surgical mortality and morbidity were documented. RESULTS: Sixty-four patients were operated (bilateral MBH n = 39, unilateral procedure n = 25). At a mean follow-up of 4.2 years and 270.6 patient years, 89.1% of patients had not suffered any recurrent stroke or TIA. A second surgery was required in 5 cases after unilateral revascularization, and in 3 cases after bilateral MBH. Mortality associated with the procedure was 0. Postoperative Matsushima angiographic grading was the only predictive factor of ischemic recurrence ( P = .036). CONCLUSION: In pediatric MM, MBH compares favorably to other indirect or direct revascularization techniques in children in the prevention of stroke or TIA.

Epileptic seizures in anaplastic gangliogliomas.

AIM: Prevalence and predictors of epileptic seizures are unknown in the malignant variant of ganglioglioma. METHODS: In a retrospective exploratory dataset of 18 supratentorial anaplastic World Health Organization grade III gangliogliomas, we studied: (i) the prevalence and predictors of epileptic seizures at diagnosis; (ii) the evolution of seizures during tumor evolution; (iii) seizure control rates and predictors of epilepsy control after oncological treatments. RESULTS: Epileptic seizures prevalence progresses throughout the natural course of anaplastic gangliogliomas: 44% at imaging discovery, 67% at histopathological diagnosis, 69% following oncological treatment, 86% at tumor progression, and 100% at the end-of-life phase. The medical control of seizures and their refractory status worsened during the tumor's natural course: 25% of uncontrolled seizures at histopathological diagnosis, 40% following oncological treatment, 45.5% at tumor progression, and 45.5% at the end-of-life phase. Predictors of seizures at diagnosis appeared related to the tumor location (i.e. temporal and/or cortical involvement). Prognostic parameters of seizure control after first-line oncological treatment were temporal tumor location, eosinophilic granular bodies, TP53 mutation, and extent of resection. Prognostic parameters of seizure control at tumor progression were a history of epileptic seizures at diagnosis, seizure control after first-line oncological treatment, eosinophilic granular bodies, and TP53 mutation. CONCLUSION: Epileptic seizures are frequently observed in anaplastic gangliogliomas and both prevalence and medically refractory status worsen during the tumor's natural course. Both oncological and antiepileptic treatments should be employed to improve the control of epileptic seizures and the quality of life of patients harboring an anaplastic ganglioglioma.

Diazoxide in Children With Obesity After Hypothalamic-Pituitary Lesions: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: The objective was to evaluate the safety and efficacy of diazoxide (DZX) for decreasing obesity with hyperinsulinemia in patients treated for hypothalamic-pituitary lesions during childhood. DESIGN: This was a double-blind, placebo-controlled trial in parallel groups using a centralized randomization process (PEDIAC). SETTING: This was a single-center study. PATIENTS: Among the 40 patients included, 35 fulfilled the study requirements. INTERVENTIONS: Interventions included six-month treatment with DZX (4 mg/kg/d) or placebo. MAIN OUTCOME MEASURES: The primary outcome was relative weight change at 2 months. Secondary outcomes were changes in absolute weight, plasma insulin concentrations, glucose peak after oral glucose tolerance test (OGTT), and glycosylated hemoglobin after 2 months. RESULTS: Eighteen participants were randomized to the DZX group; three withdrew their consent or were excluded after the occurrence of diabetes mellitus at days 10, 10, and 35, respectively; and two dropped out because of protocol non-compliance at day 10. No statistically significant differences in baseline characteristics were observed among the 13 DZX patients and the 17 placebo patients. The relative weight changes at 2 months in the DZX and placebo groups were -0.9 and -0.5%, respectively (P = nonsignificant). No statistically significant differences were observed between the groups concerning the change in absolute weight or glycosylated hemoglobin after 2 months, but the plasma glucose concentrations (basal and after OGTT) were significantly greater in the patients receiving DZX treatment vs those receiving the placebo, whereas the plasma increases in insulin after OGTT were lower. CONCLUSIONS: The 2-month treatment with DZX was not associated with a significant change in weight compared with placebo; however, it was associated with the occurrence of diabetes mellitus in three of 18 patients.

Clinical, Imaging, Histopathological and Molecular Characterization of Anaplastic Ganglioglioma.

Anaplastic ganglioglioma (AGG) is a rare and malignant variant of ganglioglioma. According to the World Health Organization classification version 2016, their histopathological grading criteria are still ill-defined. The aim of the present study was to assess the clinical, imaging, histopathological, and molecular characteristics and outcomes of AGGs in a large consecutive and retrospective adult and pediatric case series. Eighteen patients with AGGs (13 adults and 5 children) were identified (14 de novo and 4 secondary) from a cohort of 222 gangliogliomas (GG) (8%) treated at our institution between 2000 and 2015. AGGs represented a very aggressive disease with poor outcome (median progression-free survival, 10 months; median overall survival, 27 months). They were located in the temporal lobe only in 22% and presented with seizures (44%) or increased intracranial pressure (44%) at diagnosis. Concerning histopathological and molecular data, they shared morphological characteristics and BRAF V600E mutation (39%) with their benign counterparts but also showed hTERT promoter mutation (61%), p53 accumulation (39%), ATRX loss (17%), or p.K27M H3F3A mutation (17%). AGGs are malignant neoplasms requiring aggressive oncological treatment. In the perspective of targeted therapies, AGGs should be screened for BRAF V600E, hTERT, ATRX, and mutations of histone genes.