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OBJECTIVE Distinguishing tumor recurrence from therapy-induced imaging changes (TIIC) on brain MRI in children treated for primary malignant brain tumors may be challenging. The authors aimed to assess the diagnostic ability of multimodal MRI in differentiating TIIC from tumor recurrence. METHODS The authors retrospectively included children with abnormal supratentorial brain MRI findings after treatment for primary malignant brain tumors (regardless of their localization) with complete resection and radiotherapy. A total of 18 patients with TIIC and 25 patients with tumor recurrence were compared, according to structural, apparent diffusion coefficient (ADC), and arterial spin labeling (ASL) imaging data accrued over time. TIIC were defined by a new MRI scan that was stable for at least 1 year or had regressed, or by histopathology findings in specimens obtained when the anomaly was surgically treated. RESULTS The time interval between completion of radiotherapy and the appearance of abnormal brain MRI findings was significantly shorter in the TIIC group compared with the tumor recurrence group (median 6 vs 35 months; p < 0.001). TIIC appeared as foci of increased T2-weighted signal intensity, without nodule, associated with variable contrast enhancement. Tumor recurrence appeared as a well-defined nodule with intermediate signal intensity on T2-weighted images with nodular contrast enhancement. Relative ADC values were significantly higher in the TIIC group (median 1.43 vs 0.88; p < 0.001). Relative ASL–cerebral blood flow (CBF) values were significantly lower in the TIIC group (median 0.27 vs 0.43; p = 0.04). On follow-up MRI, TIIC could progress, regress, or remain stable. In most instances (72%), they decreased in size or remained stable at 4 years of follow-up. CONCLUSIONS MRI features of TIIC include foci of increased signal intensity without a demonstrable nodule on T2-weighted images, high ADC values, and lower ASL-CBF values, whereas tumor recurrence appears as a well-defined nodule with low ADC values and higher ASL-CBF values.

OBJECTIVE Epidural hematoma (EDH) has rarely been studied specifically in infants. The objective of this study was to investigate the outcomes of patients aged < 18 months (infants) with EDH. METHODS The authors conducted a single-center retrospective study of 48 infants aged less than 18 months who underwent an operation for a supratentorial EDH in the last decade. Clinical, radiological, and biological variables were used in a statistical analysis to identify factors predictive of radiological and clinical outcome. RESULTS Forty-seven patients were included in the final analysis. Seventeen children (36%) had cerebral ischemia on postoperative imaging, either due to stroke (cerebral herniation) or by local compression. Factors associated with ischemia after multivariate logistic regression were the presence of an initial neurological deficit (76% vs 27%, p = 0.03), low platelet count (mean 192 vs 267 per mm3, p = 0.01), low fibrinogen level (mean 1.4 vs 2.2 g/L, p = 0.04) and long intubation time (mean 65.7 vs 10.1 hours, p = 0.03). Cerebral ischemia on MRI was predictive of a poor clinical outcome. CONCLUSIONS Infants with EDH have a low mortality rate but a high risk of cerebral ischemia, along with long-term neurological sequelae.

Background Focal cortical dysplasias (FCD) are a frequent cause of drug-resistant epilepsy in children but are often undetected on structural magnetic resonance imaging (MRI). We aimed to measure and validate the variation of resting state functional MRI (rs-fMRI) blood oxygenation level dependent (BOLD) metrics in surgically proven FCDs in children, to assess the potential yield for detecting and understanding these lesions. Methods We prospectively included pediatric patients with surgically proven FCD with inconclusive structural MRI and healthy controls, who underwent a ten-minute rs-fMRI acquired at 3T. Rs-fMRI data was pre-processed and maps of values of regional homogeneity (ReHo), degree centrality (DC), amplitude of low frequency fluctuations (ALFF) and fractional ALFF (fALFF) were calculated. The variations of BOLD metrics within the to-be-resected areas were analyzed visually, and quantitatively using lateralization indices. BOLD metrics variations were also analyzed in fluorodeoxyglucose-positron emission tomography (FDG-PET) hypometabolic areas. Results We included 7 patients (range: 3–15 years) and 6 aged-matched controls (range: 6–17 years). ReHo lateralization indices were positive in the to-be-resected areas in 4/7 patients, and in 6/7 patients in the additional PET hypometabolic areas. These indices were significantly higher compared to controls in 3/7 and 4/7 patients, respectively. Visual analysis revealed a good spatial correlation between high ReHo areas and MRI structural abnormalities (when present) or PET hypometabolic areas. No consistent variation was seen using DC, ALFF, or fALFF. Conclusion Resting-state fMRI metrics, noticeably increase in ReHo, may have potential to help detect MRI-negative FCDs in combination with other morphological and functional techniques, used in clinical practice and epilepsy-surgery screening.

To study longitudinal changes in tuber and whole-brain perfusion in children with tuberous sclerosis complex (TSC) using arterial spin labeling (ASL) perfusion MRI and correlate them with pathological EEG slow wave activity and neurodevelopmental outcomes.Retrospective longitudinal cohort study of 13 children with TSC, 3 to 6 serial ASL-MRI scans between 2 months and 7 years of age (53 scans in total), and an EEG examination performed within 2 months of the last MRI. Tuber cerebral blood flow (CBF) values were calculated in tuber segmentation masks, and tuber:cortical CBF ratios were used to study tuber perfusion. Logistic regression analysis was performed to identify which initial tuber characteristics (CBF value, volume, location) in the first MRI predicted tubers subsequently associated with EEG slow waves. Whole-brain and lobar CBF values were extracted for all patient scans and age-matched controls. CBF ratios were compared in patients and controls to study longitudinal changes in whole-brain CBF.Perfusion was reduced in tubers associated with EEG slow waves compared with other tubers. Low tuber CBF values around 6 months of age and large tuber volumes were predictive of tubers subsequently associated with EEG slow waves. Patients with severe developmental delay had more severe whole-brain hypoperfusion than those with no/mild delay, which became apparent after 2 years of age and were not associated with a higher tuber load.Dynamic changes in tuber and brain perfusion occur over time. Perfusion is significantly reduced in tubers associated with EEG slow waves. Whole-brain perfusion is significantly reduced in patients with severe delay.• Tubers associated with EEG slow wave activity were significantly more hypoperfused than other tubers, especially after 1 year of age. • Larger and more hypoperfused tubers at 6 months of age were more likely to subsequently be associated with pathological EEG slow wave activity. • Patients with severe developmental delay had more extensive and severe global hypoperfusion than those without developmental delay.

We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMG-K27M cell fitness. Gene expression studies afterVRK3knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG followingVRK3knock-down. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations,e.g.with the mitochondrial ClpP protease activator ONC201.

ContextEndocrine complications are common in pediatric brain tumor patients.ObjectiveTo 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.MethodsWe 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.ResultsAmong 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.ConclusionTumor 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.

ContextCraniopharyngioma is a benign brain tumor with frequent local recurrence or progression after treatment. GH replacement therapy (GHRT) is prescribed in children with GH deficiency resulting from childhood-onset craniopharyngioma.ObjectiveTo evaluate whether a shorter delay of GHRT initiation after childhood-onset craniopharyngioma completion therapy increased the risk of a new event (progression or recurrence).MethodsRetrospective, observational, monocenter study. We compared a cohort of 71 childhood-onset patients with craniopharyngiomas treated with recombinant human GH (rhGH). Twenty-seven patients were treated with rhGH at least 12 months after craniopharyngioma treatment (>12-month group) and 44 patients before 12 months (12-month group and in the ResultsIn the >12-month group, the 2- and 5-year event-free survivals were respectively 81.5% (95% CI, 61.1-91.9) and 69.4% (95% CI, 47.9-83.4) compared with 72.2% (95% CI, 56.3-83.1) and 69.8% (95% CI, 53.8-81.2) in the The median time for event was not statistically different.In univariate and multivariate analysis, the risk of craniopharyngioma new event was not associated with the GHRT time delay after craniopharyngioma treatment.ConclusionsNo association was found between GHRT time delay after childhood-onset craniopharyngioma treatment and an increased risk of recurrence or tumor progression, suggesting GH replacement therapy can be initiated 6 months after last treatment for craniopharyngiomas.

Background and Purpose: Pediatric nontraumatic intracerebral hemorrhage accounts for half of stroke in children. Early diagnostic of the causative underlying lesion is the first step toward prevention of hemorrhagic recurrence. We aimed to investigate the performance of arterial spin labeling sequence (ASL) in the acute phase etiological workup for the detection of an arteriovenous shunt (AVS: including malformation and fistula), the most frequent cause of pediatric nontraumatic intracerebral hemorrhage. Methods: Children with a pediatric nontraumatic intracerebral hemorrhage between 2011 and 2019 enrolled in a prospective registry were retrospectively included if they had undergone ASL-magnetic resonance imaging before any etiological treatment. ASL sequences were reviewed using cerebral blood flow maps by 2 raters for the presence of an AVS. The diagnostic performance of ASL was compared with admission computed tomography angiography, other magnetic resonance imaging sequences including contrast-enhanced sequences and subsequent digital subtraction angiography. Results: A total of 121 patients with pediatric nontraumatic intracerebral hemorrhage were included (median age, 9.9 [interquartile range, 5.8–13]; male sex 48.8%) of whom 76 (63%) had a final diagnosis of AVS. Using digital subtraction angiography as an intermediate reference, visual ASL inspection had a sensitivity and a specificity of, respectively, 95.9% (95% CI, 88.5%–99.1%) and 79.0% (95% CI, 54.4%–94.0%). ASL had a sensitivity, specificity, and accuracy of 90.2%, 97.2%, and 92.5%, respectively for the detection of the presence of an AVS, with near perfect interrater agreement (κ=0.963 [95% CI, 0.912–1.0]). The performance of ASL alone was higher than that of other magnetic resonance imaging sequences, individually or combined, and higher than that of computed tomography angiography. Conclusions: ASL has strong diagnostic performance for the detection of AVS in the initial workup of intracerebral hemorrhage in children. If our findings are confirmed in other settings, ASL may be a helpful diagnostic imaging modality for patients with pediatric nontraumatic intracerebral hemorrhage. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: 3618210420, 2217698.

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.

Periodic discharges are a rare peculiar electroencephalogram pattern, occasionally associated with motor or other clinical manifestations, usually observed in critically ill patients. Their underlying pathophysiology remains poorly understood. Epileptic spasms in clusters and periodic discharges with motor manifestations share similar electroencephalogram pattern and some aetiologies of unfavourable prognosis such as subacute sclerosing panencephalitis or herpes encephalitis. Arterial spin labelling magnetic resonance imaging identifies localizing ictal and inter-ictal changes in neurovascular coupling, therefore assumed able to reveal concerned cerebral structures. Here, we retrospectively analysed ictal and inter-ictal arterial spin labelling magnetic resonance imaging in patients aged 6 months to 15 years (median 3 years 4 months) with periodic discharges including epileptic spasms, and compared these findings with those of patients with drug-resistant focal epilepsy who never presented periodic discharges nor epileptic spasms as well as to those of age-matched healthy controls. Ictal electroencephalogram was recorded either simultaneously with arterial spin labelling magnetic resonance imaging or during the close time lapse of patients’ periodic discharges, whereas inter-ictal examinations were performed during the patients’ active epilepsy but without seizures during the arterial spin labelling magnetic resonance imaging. Ictal arterial spin labelling magnetic resonance imaging was acquired in five patients with periodic discharges [subacute sclerosing panencephalitis (1), stroke-like events (3), West syndrome with cortical malformation (1), two of them also had inter-ictal arterial spin labelling magnetic resonance imaging]. Inter-ictal group included patients with drug-resistant epileptic spasms of various aetiologies (14) and structural drug-resistant focal epilepsy (8). Cortex, striatum and thalamus were segmented and divided in six functional subregions: prefrontal, motor (rostral, caudal), parietal, occipital and temporal. Rest cerebral blood flow values, absolute and relative to whole brain, were compared with those of age-matched controls for each subregion. Main findings were diffuse striatal as well as cortical motor cerebral blood flow increase during ictal examinations in generalized periodic discharges with motor manifestations (subacute sclerosing panencephalitis) and focal cerebral blood flow increase in corresponding cortical-striatal-thalamic subdivisions in lateralized periodic discharges with or without motor manifestations (stroke-like events and asymmetrical epileptic spasms) with straight topographical correlation with the electroencephalogram focus. For inter-ictal examinations, patients with epileptic spasms disclosed cerebral blood flow changes in corresponding cortical-striatal-thalamic subdivisions (absolute-cerebral blood flow decrease and relative-cerebral blood flow increase), more frequently when compared with the group of drug-resistant focal epilepsies, and not related to Vigabatrin treatment. Our results suggest that corresponding cortical-striatal-thalamic circuits are involved in periodic discharges with and without motor manifestations, including epileptic spasms, opening new insights in their pathophysiology and new therapeutical perspectives. Based on these findings, we propose a model for the generation of periodic discharges and of epileptic spasms combining existing pathophysiological models of cortical-striatal-thalamic network dynamics.

The COVID-19 pandemic and the containment and mitigation measures taken were feared to be associated with increased child abuse.To investigate the trend of abusive head trauma (AHT) incidence and severity in infants during the COVID-19 pandemic.In a time-series analysis of a longitudinal, population-based, cohort study, all consecutive cases of AHT in infants younger than 12 months old referred between January 2017 and December 2021 to Necker Hospital for Sick Children, the single regional pediatric neurosurgery center for the Paris metropolitan area, were included. AHT was defined as 1 or more subdural hemorrhage and a positive multidisciplinary evaluation after a social, clinical, biological, and radiological workup. Data were analyzed from January to March 2022.The primary outcome was the monthly incidence of AHT, which was analyzed using Poisson regression modeling. Secondary outcomes included mortality and severe morbidity and were studied with logistic and linear regressions. The monthly incidence of neurosurgical interventions for hydrocephalus was used as a control series.Among the 99 included infants with AHT (median [IQR] age, 4 [3-6] months; 64 boys [65%]), 86 of 99 (87%) had bridging vein thrombosis, 74 of 99 (75%) had retinal hemorrhages, 23 of 72 (32%) had fractures, 26 of 99 (26%) had status epilepticus, 20 of 99 (20%) had skin injuries, 53 of 99 (54%) underwent neurosurgical interventions, and 13 of 99 (13%) died. Compared with the prepandemic period (2017-2019), AHT incidence was stable in 2020 (adjusted incidence rate ratio, 1.02; 95% CI, 0.59-1.77) and then significantly increased in 2021 (adjusted incidence rate ratio, 1.92; 95% CI, 1.23-2.99). The severity of AHT worsened in 2021 in terms of mortality (odds ratio 9.39; 95% CI, 1.88-47.00). Other secondary outcomes and the control series were not significantly modified.In this cohort study, a marked increase in AHT incidence and severity occurred during the COVID-19 pandemic in the Paris metropolitan area. These results suggest the need for clinical awareness and preventive actions.

OBJECTIVE Transitional care in surgical neurooncology is poorly studied. However, this period is pivotal, since it allows the patient to be empowered in his or her disease management. Here, the authors describe the experience of the Necker-Enfants Malades and the Sainte-Anne Hospital collaboration. METHODS The mixed transitional consultations started in September 2019 in a dedicated space for transitional care, named the “La Suite” department, located in the Necker-Enfants Malades Hospital, Paris, France. The authors organized planned consultations to schedule the clinical and radiological follow-up in the adult neurosurgical department but also emergency consultations to manage tumor recurrence in young adult patients. Transitional care was performed jointly by pediatric and adult neurosurgeons who have developed clinical and research skills in the field of surgical neurooncology. Neuropathological analysis was performed by a neuropathologist who is specialized in pediatric and adult neurooncology. RESULTS Fourteen patients benefited from a mixed transitional consultation. All of them accepted to start their management in an adult neurosurgical environment. Eleven patients (78.6%) for whom the disease was controlled benefited from a planned consultation. Three patients (21.4%) required rapid neurosurgical management for a tumor recurrence (n = 2) or for a new primary CNS tumor (n = 1) and benefited from an emergency consultation. CONCLUSIONS For adult patients harboring a brain tumor during childhood or adolescence, the authors suggest that neurosurgeons specialized in adult surgical neurooncology with a full knowledge in pediatric neurooncology will combine the required skills to optimize care management for these patients within a dedicated multidisciplinary organization framework.

OBJECTIVE The clinical outcome of pediatric intracerebral hemorrhage (pICH) is rarely reported in a comprehensive way. In this cohort study, systematic review, and meta-analysis of patients with pICH, the authors aimed to describe the basic clinical outcomes of pICH. METHODS Children who received treatment for pICH at the authors’ institution were prospectively enrolled in the cohort in 2008; data since 2000 were retrospectively included, and data through October 2019 were analyzed. The authors then searched PubMed and conducted a systematic review of relevant articles published since 1990. Data from the identified populations and patients from the cohort study were pooled into a multicategory meta-analysis and analyzed with regard to clinical outcomes. RESULTS Among 243 children screened for inclusion, 231 patients were included. The median (IQR) age at ictus was 9.6 (4.6–12.5) years, and 128 patients (53%) were male. After a median (IQR) follow-up of 33 (13–63) months, 132 patients (57.4%) had a favorable clinical outcome, of whom 58 (44%) had no residual symptoms. Nineteen studies were included in the meta-analysis. Overall, the proportion of children with complete recovery was 27% (95% CI 19%–36%; Q = 49.6; I2 = 76%); of those with residual deficits, the complete recovery rate was 48.1% (95% CI 40%–57%; Q = 75.3; I2 = 81%). When pooled with the cohort study, the aggregate case-fatality rate at the last follow-up was 17.3% (95% CI 12%–24%; Q = 101.6; I2 = 81%). CONCLUSIONS Here, the authors showed that 1 in 6 children died after pICH, and the majority of children had residual neurological deficits at the latest follow-up. Results from the cohort study also indicate that children with vascular lesions as the etiology of pICH had significantly better clinical functional outcomes.

The diffuse intrinsic pontine gliomas (DIPGs) are now defined by the type of histone H3 mutated at lysine 27. We aimed to correlate the multimodal MRI features of DIPGs, H3K27M mutant, with their histological and molecular characteristics. Twenty-seven treatment-naive children with histopathologically confirmed DIPG H3K27M mutant were prospectively included. MRI performed prior to biopsy included multi-b-value diffusion-weighted imaging, ASL, and dynamic susceptibility contrast (DSC) perfusion imaging. The ADC and cerebral blood flow (CBF) and blood volume (CBV) were measured at the biopsy site. We assessed quantitative histological data, including microvascular density, nuclear density, and H3K27M-positive nuclear density. Gene expression profiling was also assessed in the samples. We compared imaging and histopathological data according to histone subgroup. We correlated MRI quantitative data with histological data and gene expression. H3.1K27M mutated tumors showed higher ADC values (median 3151 μm2/s vs 1741 μm2/s, p = 0.003), and lower perfusion values (DSC-rCBF median 0.71 vs 1.43, p = 0.002, and DSC-rCBV median 1.00 vs 1.71, p = 0.02) than H3.3K27M ones. They had similar microvascular and nuclear density, but lower H3K27M-positive nuclear density (p = 0.007). The DSC-rCBV was positively correlated to the H3K27M-positive nuclear density (rho = 0.74, p = 0.02). ADC values were not correlated with nuclear density nor perfusion values with microvascular density. The expression of gated channel activity–related genes tended to be inversely correlated with ADC values and positively correlated with DSC perfusion. H3.1K27M mutated tumors have higher ADC and lower perfusion values than H3.3K27M ones, without direct correlation with microvascular or nuclear density. This may be due to tissular edema possibly related to gated channel activity–related gene expression. • H3.1K27M mutant DIPG had higher apparent diffusion coefficient (p = 0.003), lower α (p = 0.048), and lower relative cerebral blood volume (p = 0.02) than H3.3K27M mutant DIPG at their biopsy sites. • Biopsy samples obtained within the tumor’s enhancing portion showed higher microvascular density (p = 0.03) than samples obtained outside the tumor’s enhancing portion, but similar H3K27M-positive nuclear density (p = 0.84). • Relative cerebral blood volume measured at the biopsy site was significantly correlated with H3K27M-positive nuclear density (rho = 0.74, p = 0.02).

Pediatric spinal low-grade glioma (LGG) and glioneuronal tumours are rare, accounting for less 2.8–5.2% of pediatric LGG. New tumour types frequently found in spinal location such as diffuse leptomeningeal glioneuronal tumours (DLGNT) have been added to the World Health Organization (WHO) classification of tumours of the central nervous system since 2016, but their distinction from others gliomas and particularly from pilocytic astrocytoma (PA) are poorly defined. Most large studies on this subject were published before the era of the molecular diagnosis and did not address the differential diagnosis between PAs and DLGNTs in this peculiar location. Our study retrospectively examined a cohort of 28 children with LGGs and glioneuronal intramedullary tumours using detailed radiological, clinico-pathological and molecular analysis. 25% of spinal PAs were reclassified as DLGNTs. PA and DLGNT are nearly indistinguishable in histopathology or neuroradiology. 83% of spinal DLGNTs presented first without leptomeningeal contrast enhancement. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that spinal PAs formed a unique methylation cluster distinct from reference midline and posterior fossa PAs, whereas spinal DLGNTs clustered with reference DLGNT cohort. FGFR1 alterations were found in 36% of spinal tumours and were restricted to PAs. Spinal PAs affected significantly younger patients (median age 2 years old) than DLGNTs (median age 8.2 years old). Progression-free survival was similar among the two groups. In this location, histopathology and radiology are of limited interest, but molecular data (methyloma, 1p and FGFR1 status) represent important tools differentiating these two mitogen-activated protein kinase (MAPK) altered tumour types, PA and DLGNT. Thus, these molecular alterations should systematically be explored in this type of tumour in a spinal location.

Background and Purpose: Significant hemorrhage expansion (sHE) is a known predictor of poor outcome after an intracerebral hemorrhage (ICH) in adults but remains poorly reported in children. In a large inception cohort, we aimed to explore the prevalence of sHE, its associations with clinical outcomes, and its clinical-imaging predictors in children. Methods: Children admitted between January 2000 and March 2020 at a quaternary care pediatric hospital were screened for inclusion. Sample was restricted to children with 2 computed tomography scans within 72 hours of ICH onset, and a minimal clinical follow-up of months. sHE was defined as an increase from baseline ICH volume by 6 cc or 33% on follow-up computed tomography. Clinical outcome was assessed at 12 months with the King’s Outcome Scale for Childhood Head Injury score and defined as favorable for scores ≥5. Results: Fifty-two children met inclusion criteria, among which 8 (15%) demonstrated sHE, and 18 (34.6%) any degree of expansion. Children with sHE had more frequent coagulation disorders (25.0% versus 2.3%; P =0.022). After multivariable adjustment, only the presence of coagulation disorders at baseline remained independently associated with sHE (adjusted odds ratio, 14.4 [95% CI, 1.04–217]; P =0.048). sHE was independently associated with poor outcome (King’s Outcome Scale for Childhood Head Injury P =0.043). Conclusions: sHE is a frequent phenomenon after admission for a pediatric ICH and more so in children with coagulation defects. As sHE was strongly associated with poorer clinical outcomes, these data mandate a baseline coagulation work up and questions the need for protocolized repeat head computed tomography in children admitted for pediatric ICH.

Background: Choroid plexectomy was first performed around 1910. Later, the technique evolved into subtotal choroid plexus cauterization (CPC) but was largely abandoned following the invention of the ventriculoperitoneal shunt. Over time, with improved understanding of the pathophysiology of hydrocephalus and improvement in endoscopic techniques and equipment, the procedure of CPC was reintroduced. However, little is known about the biomolecular consequences of ablation of a significant portion of the choroid plexus on metabolic brain homeostasis, neurogenesis, and neuroimmunology. Summary: The physiological functions of choroid plexus in neurogenesis and neuroimmunology and its role in diseases, such as AD and MS, should alert to possible as yet to be determined consequences. Studies, both in children and in adults, are needed not only on the success in hydrodynamic stabilization of hydrocephalus but also on the long-term outcome, especially premature neurodegeneration and inflammatory changes and on compensatory metabolic mechanisms. Key Messages: The value of CPC for treatment of hydrocephalus in medically underserved areas should be remembered, yet when alternative treatment options are available, we cannot responsibly advocate against or for the use of CPC. Therefore, perhaps a more detailed discussion of risks and benefits of a CPC with parents would be best to include the possible implications in brain development and function.

BACKGROUND AND PURPOSE: Whether architectural characteristics of ruptured brain AVMs vary across the life span is unknown. We aimed to identify angioarchitectural features associated with brain AVMs ruptured early in life. MATERIALS AND METHODS: Patients with ruptured brain AVMs referred to 2 distinct academic centers between 2000 and 2018 were pooled and retrospectively analyzed. Imaging was retrospectively reviewed for angioarchitectural characteristics, including nidus size, location, Spetzler-Martin grade, venous drainage, and arterial or nidal aneurysm. Angioarchitecture variations across age groups were analyzed using uni- and multivariable models; then cohorts were pooled and analyzed using Kaplan-Meier and Cox models to determine factors associated with earlier rupture. RESULTS: Among 320 included patients, 122 children (mean age, 9.8 ± 3.8 years) and 198 adults (mean age, 43.3 ± 15.7 years) were analyzed. Pediatric brain AVMs were more frequently deeply located (56.3% versus 21.2%, P

OBJECTIVEPediatric patients with long-term shunts may experience specific complications related to the segregation of the supra- and infratentorial spaces along with different pressure regimens, leading to either mesencephalic syndromes during shunt dysfunction or isolated fourth ventricle (IFV). An accepted treatment to reestablish normal CSF pathways and reequilibrate the transtentorial pressures is endoscopic aqueductal stenting (EAS) to avoid restenosis. In the present paper, the authors studied children treated with EAS during the last decade for both IFV and obstructive hydrocephalus, evaluated its impact on the course of the disease, and identified prognostic factors for EAS success.METHODSA noninterventional retrospective study of routinely acquired data was performed, including all hydrocephalic children undergoing EAS between 2011 and 2019 at Hôpital Necker, Paris, France. The following variables were analyzed: etiology of hydrocephalus; number of surgeries before and after stent placement; indication for EAS; type of stent connection (i.e., connected or not to a ventriculoperitoneal shunt); and the stent position. Stent failure was defined as the need to perform further shunt revision. Univariate and multivariate analyses were run to identify factors associated with stent failure.RESULTSSeventeen patients with a mean age at stent placement of 6 years (SD 6.5 years, range 1 month–18 years) and with a mean follow-up after EAS of 47.5 months (SD 33.7 months, range 5–120 months) were included in the analysis. The etiology of hydrocephalus was as follows: obstructive tumoral (41%), posthemorrhagic (35%), postinfectious (12%), and dysraphism related (12%). The indication for EAS was IFV (47%), rostral midbrain dysfunction syndrome (35%), prevention of secondary aqueductal stenosis after debulking surgery (12%), or primary aqueductal stenosis (6%). No transient or permanent neurological deficits related to the procedure were observed. After EAS, 10 patients did not require further surgeries (59%), and for the others the number of hydrocephalus-related surgeries significantly decreased after stenting. In univariate analysis posthemorrhagic etiology and prevention of aqueductal stenosis were identified as predictors of a good outcome, whereas in multivariate analysis posthemorrhagic hydrocephalus was found to predict a favorable outcome.CONCLUSIONSThe results confirm EAS as a first-line treatment for IFV and suggest its efficacy in changing the history of hydrocephalic patients who have undergone multiple operations and who experience rostral midbrain dysfunction syndrome, as well as efficacy in the prevention of aqueductal stenosis in selected cases of obstructive tumoral hydrocephalus.

Aims Meningeal chondromas constitute a small fraction of central nervous system tumors, with only 61 cases reported in the literature. Somatic mutations of IDH1/2 genes have been described in enchondromas, and, in soft-tissue chondromas, rearrangements of the HMGA2 gene have been reported. The aim of our study was to perform molecular analyses of 3 additional cases and to do a complete review of the literature to better characterize this rare entity. Materials and methods Here, we report 3 cases of primitive meningeal chondromas in children and young adults. Immunohistochemical analyses for HMGA2 and IDH1R132H, molecular analyses of IDH1/2 mutations, and FISH analysis of the HMGA2 locus were performed. Results Immunohistochemical analyses of all cases were negative for IDH1R132H and HMGA2 proteins. Molecular analyses failed to reveal IDH1/2 mutations, and FISH analyses did not evidence any HMGA2 rearrangements. Similarly to what is reported in the literature, the 3 meningeal chondromas in this study were benign tumors with no recurrence after complete resection with a follow-up of 85, 46, and 89 months. Conclusion Meningeal chondroma is rare. It affects predominantly young adults and has a good outcome. No molecular alterations have currently been described in this entity.

Brain arteriovenous malformations (bAVM) are the main cause of pediatric intracerebral hemorrhage (pICH). Embolization with Onyx (ev3, Irvine, CA, USA) in children with ruptured bAVM has been infrequently reported. The aim of this study was to assess the safety and efficacy profile of Onyx embolization as first line endovascular treatment of ruptured pediatric bAVMs. Children with non-traumatic pICH due to bAVM rupture at a pediatric quaternary care center were prospectively enrolled in a registry and retrospectively analyzed between 2013 and 2018. Clinical and demographic data, treatment modalities and clinical imaging follow-up were retrieved, and detailed procedural data were retrospectively assessed by two investigators. The safety (procedural morbidity and mortality) and efficacy (obliteration and interval rebleeding) were evaluated. In this study 29 children treated for a bAVM by Onyx embolization were included (14 girls, 48%; median age 11.1 years, interquartile range, IQR 8.1–12.7 years) with a total of 72 endovascular sessions (median of 2 sessions per patient IQR 1–3). The AVMs were deeply located in 23 patients (79%). No systemic complications occurred, and no child experienced embolization-related persistent neurological deficits. Non-clinically relevant complications were observed during five procedures, unrelated to Onyx. After a mean follow-up of 31 months from rupture complete obliteration rates were 100%, 89%, 29%, 14% in bAVM Spetzler Martin grades I, II, III and IV–V, respectively. It was found that Onyx embolization is safe and represents a good option for an initial treatment approach, in a sequential treatment strategy for pediatric ruptured brain AVMs. Younger age may not be an argument to deny Onyx embolization.

Postoperative pediatric cerebellar mutism syndrome (pCMS), characterized mainly by delayed onset transient mutism is a poorly understood complication that may occur after pediatric medulloblastoma (MB) resection. Our aim was to investigate postoperative changes in whole-brain cerebral blood flow (CBF) at rest in pCMS patients using arterial spin labeling (ASL) perfusion imaging. This study compared preoperative and postoperative T2-weighted signal abnormalities and CBF using a voxel-wise, whole-brain analysis in 27 children undergoing MB resection, including 11 patients who developed mutism and 16 who did not. Comparison of postoperative T2 signal abnormalities between patients who developed pCMS (mean age 7.0 years) and those who did not showed that pCMS (mean age 8.9 years) patients were significantly more likely to present with T2-weighted hyperintensities in the right dentate nucleus (DN) (p = 0.02). Comparison of preoperative and postoperative CBF in patients with pCMS showed a significant postoperative CBF decrease in the left pre-supplementary motor area (pre-SMA) (p = 0.007) and SMA (p = 0.009). In patients who did not develop pCMS, no significant differences were observed. Findings provide evidence of an association between pCMS, injury to the right DN, and left pre-SMA/SMA hypoperfusion, areas responsible for speech. This supports the relevance of CBF investigations in pCMS.

The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “Supratentorial-ependymoma, C11orf95-fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.

Resume L’accident vasculaire cerebral (AVC) pediatrique affecte un millier d’enfants chaque annee en France. Les objectifs de l’imagerie, l’IRM etant l’examen de phase aigue a privilegier, sont d’etablir un diagnostic precoce de l’existence et de la nature des lesions du parenchyme cerebral, de fournir une information precise sur l’etat des structures arterielles, mais aussi de la perfusion cerebrale, afin de proposer la meilleure attitude therapeutique. En cas d’AVC ischemique, faute d’essais therapeutiques dedies, le traitement recommande chez l’adulte est souvent adapte chez l’enfant. Il peut comporter, jusque 24 h apres le debut des symptomes, sur des criteres d’imagerie precis et apres une discussion pluridisciplinaire au cas par cas, l’extraction percutanee du thrombus occlusif (thrombectomie mecanique) d’une artere proximale. L’imagerie interventionnelle (neuroradiologie interventionnelle, NRI) doit egalement pouvoir proposer des solutions therapeutiques en cas d’AVC hemorragique de l’enfant dont la rupture d’une malformation vasculaire cerebrale est responsable une fois sur deux. Identifiee en imagerie, la malformation responsable de l’AV, anevrisme ou MAV, devra etre obliteree dans les meilleurs delais (embolisation).

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.

PURPOSE Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40NS SNV/Mb, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.

Medulloblastoma (MB), the most frequent embryonic tumor of the cerebellum is classified into four molecular subgroups (WNT group, SHH group, group 3 and group 4). Although the vast majority of MB are sporadic, predisposing genetic diseases have been described in rare WNT MB and more frequently in the SHH group. In a recent pediatric series of SHH-MB, germline alterations of the ELP1 gene have been described in 14% of cases, making this gene the most frequent genetic predisposition in MB. We have investigated the potential interest of ELP1 immunostaining on a large cohort of 132 MB. A complete loss of ELP1 staining was observed in 12 SHH MB (among 57 total SHH MB: 21%). The loss of ELP1 immunostaining was well correlated with the presence of a bi-allelic alteration of the gene except for one case for which the MB had a loss of ELP1 protein expression demonstrated by immunohistochemistry (IHC) and confirmed by whole proteome analysis, although no obvious genetic alteration in the coding sequence of ELP1 could be found. Molecular analysis of a large “molecular” cohort of 266 MB from French centers for which somatic ELP1 was sequenced allows to identify 12 additional MB with bi-allelic ELP1 genetic alterations. Our results demonstrate the benefit of the ELP1 IHC as an accurate and reliable tool to screen ELP1-deficient MB. This new immunohistochemical tool will now be advantageously used to screen SHH MB upfront for genetic alteration in ELP1, and will subsequently help orientating these patients towards genetic counseling.

PURPOSE: Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS: A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS: Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION: CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.

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.