Sotorasib for Vascular Malformations Associated with KRAS G12C Mutation.

KRAS gain-of-function mutations are frequently observed in sporadic arteriovenous malformations. The mechanisms underlying the progression of such KRAS-driven malformations are still incompletely understood, and no treatments for the condition are approved. Here, we show the effectiveness of sotorasib, a specific KRAS G12C inhibitor, in reducing the volume of vascular malformations and improving survival in two mouse models carrying a mosaic Kras G12C mutation. We then administered sotorasib to two adult patients with severe KRAS G12C-related arteriovenous malformations. Both patients had rapid reductions in symptoms and arteriovenous malformation size. Targeting KRAS G12C appears to be a promising therapeutic approach for patients with KRAS G12C-related vascular malformations. (Funded by the European Research Council and others.).

Chloride deregulation and GABA depolarization in MTOR related malformations of cortical development.

Focal Cortical Dysplasia, Hemimegalencephaly and Cortical Tuber are pediatric epileptogenic malformations of cortical development (MCDs) frequently pharmaco-resistant and mostly surgically treated by the resection of epileptic cortex. Availability of cortical resection samples allowed significant mechanistic discoveries directly from human material. Causal brain somatic or germline mutations in the AKT/PI3K/DEPDC5/MTOR genes were identified. GABAa mediated paradoxical depolarization, related to altered chloride (Cl-) homeostasis, was shown to participate to ictogenesis in human pediatric MCDs. However, the link between genomic alterations and neuronal hyperexcitability is still unclear. Here we studied the post translational interactions between the mTOR pathway and the regulation of cation-chloride cotransporters (CCC), KCC2 and NKCC1, that are largely responsible for controlling intracellular Cl- and ultimately GABAergic transmission. For this study, 35 children (25 MTORopathies and 10 pseudo controls, diagnosed by histology plus genetic profiling) were operated for drug resistant epilepsy. Postoperative cortical tissues were recorded on multielectrode array (MEA) to map epileptic activities. CCC expression level and phosphorylation status of the WNK1/SPAK-OSR1 pathway was measured during basal conditions and after pharmacological modulation. Direct interactions between mTOR and WNK1 pathway components were investigated by immunoprecipitation. Membranous incorporation of MCD samples in Xenopus laevis oocytes enabled Cl- conductance and equilibrium potential (EGABA) for GABA measurement. Of the 25 clinical cases, half harbored a somatic mutation in the mTOR pathway, while pS6 expression was increased in all MCD samples. Spontaneous interictal discharges were recorded in 65% of the slices. CCC expression was altered in MCDs, with a reduced KCC2/NKCC1 ratio and decreased KCC2 membranous expression. CCC expression was regulated by the WNK1/SPAK-OSR1 kinases through direct phosphorylation of Thr906 on KCC2, that was reversed by WNK1 and SPAK antagonists (NEM and Staurosporine). mSIN1 subunit of MTORC2 was found to interact with SPAK-OSR1 and WNK1. Interactions between these key epileptogenic pathways could be reversed by the mTOR specific antagonist Rapamycin, leading to a dephosphorylation of CCCs and recovery of the KCC2/NKCC1 ratio. The functional effect of such recovery was validated by the restoration of the depolarizing shift in EGABA by rapamycin, measured after incorporation of MCD membranes to X. laevis oocytes, in line with a reestablishment of normal ECl-. Our study deciphers a protein interaction network through a phosphorylation cascade between MTOR and WNK1/SPAK-OSR1 leading to chloride cotransporters deregulation, increased neuronal chloride levels and GABAa dysfunction in malformations of Cortical Development, linking genomic defects and functional effects and paving the way to target epilepsy therapy.

Geometric growth of the normal human craniocervical junction from 0 to 18 years old.

The craniocervical junction (CCJ) forms the bridge between the skull and the spine, a highly mobile group of joints that allows the mobility of the head in every direction. The CCJ plays a major role in protecting the inferior brainstem (bulb) and spinal cord, therefore also requiring some stability. Children are subjected to multiple constitutive or acquired diseases involving the CCJ: primary bone diseases such as in FGFR-related craniosynostoses or acquired conditions such as congenital torticollis, cervical spine luxation, and neurological disorders. To design efficient treatment plans, it is crucial to understand the relationship between abnormalities of the craniofacial region and abnormalities of the CCJ. This can be approached by the study of control and abnormal growth patterns. Here we report a model of normal skull base growth by compiling a collection of geometric models in control children. Focused analyses highlighted specific developmental patterns for each CCJ bone, emphasizing rapid growth during infancy, followed by varying rates of growth and maturation during childhood and adolescence until reaching stability by 18 years of age. The focus was on the closure patterns of synchondroses and sutures in the occipital bone, revealing distinct closure trajectories for the anterior intra-occipital synchondroses and the occipitomastoid suture. The findings, although based on a limited dataset, showcased specific age-related changes in width and closure percentages, providing valuable insights into growth dynamics within the first 2 years of life. Integration analyses revealed intricate relationships between skull and neck structures, emphasizing coordinated growth at different stages. Specific bone covariation patterns, as found between the first and second cervical vertebrae (C1 and C2), indicated synchronized morphological changes. Our results provide initial data for designing inclusive CCJ geometric models to predict normal and abnormal growth dynamics.

Specific brain MRI features of constitutional mismatch repair deficiency syndrome in children with high-grade gliomas.

BACKGROUND: Children with constitutional mismatch repair deficiency (CMMRD) syndrome have an increased risk of high-grade gliomas (HGG), and brain imaging abnormalities. This study analyzes brain imaging features in CMMRD syndrome children versus those with HGG without CMMRD. METHODS: Retrospective comparative analysis of brain imaging in 30 CMMRD children (20 boys, median age eight years, 22 with HGG), seven with Lynch syndrome (7 HGG), 39 with type 1 neurofibromatosis (NF1) (four with HGG) and 50 with HGG without MMR or NF1 pathogenic variant ("no-predisposition" patients). RESULTS: HGG in CMMRD and Lynch patients were predominantly hemispheric (versus midline) compared to NF1 and no-predisposition patients (91% and 86%, vs 25% and 54%, p = 0.004). CMMRD-associated tumors often had ill-defined boundaries (p = 0.008). All CMMRD patients exhibited at least one developmental venous anomaly (DVA), versus 14%, 10%, and 6% of Lynch, NF1, and no-predisposition patients (p < 0.0001). Multiple DVAs were observed in 83% of CMMRD patients, one NF1 patient (3%), and never in other groups (p < 0.0001). Cavernomas were discovered in 21% of CMMRD patients, never in other groups (p = 0.01). NF1-like focal areas of high T2-FLAIR signal intensity (FASI) were more prevalent in CMMRD patients than in Lynch or no-predisposition patients (50%, vs 20% and 0%, respectively, p < 0.0001). Subcortical and ill-limited FASI, possibly involving the cortex, were specific to CMMRD (p < 0.0001) and did not evolve in 93% of patients (13/14). CONCLUSION: Diffuse hemispherically located HGG associated with multiple DVAs, cavernomas, and NF1-like or subcortical FASI strongly suggests CMMRD syndrome compared to children with HGG in other contexts. CLINICAL RELEVANCE STATEMENT: The radiologic suggestion of CMMRD syndrome when confronted with HGGs in children may prompt genetic testing. This can influence therapeutic plans. Therefore, imaging features could potentially be incorporated into CMMRD testing recommendations. KEY POINTS: Using imaging to detect CMMRD syndrome early may improve patient care. CMMRD features include: hemispheric HGG with multiple developmental venous anomalies and NF1-like or subcortical areas with high T2-FLAIR intensity. We propose novel imaging features to improve the identification of potential CMMRD patients.

Imaging features to distinguish posterior fossa ependymoma subgroups.

OBJECTIVES: Posterior fossa ependymoma group A (EPN_PFA) and group B (EPN_PFB) can be distinguished by their DNA methylation and give rise to different prognoses. We compared the MRI characteristics of EPN_PFA and EPN_PFB at presentation. METHODS: Preoperative imaging of 68 patients with posterior fossa ependymoma from two centers was reviewed by three independent readers, blinded for histomolecular grouping. Location, tumor extension, tumor volume, hydrocephalus, calcifications, tissue component, enhancement or diffusion signal, and histopathological data (cellular density, calcifications, necrosis, mitoses, vascularization, and microvascular proliferation) were compared between the groups. Categorical data were compared between groups using Fisher's exact tests, and quantitative data using Mann-Whitney tests. We performed a Benjamini-Hochberg correction of the p values to account for multiple tests. RESULTS: Fifty-six patients were categorized as EPN_PFA and 12 as EPN_PFB, with median ages of 2 and 20 years, respectively (p = 0.0008). The median EPN_PFA tumoral volume was larger (57 vs 29 cm3, p = 0.003), with more pronounced hydrocephalus (p = 0.002). EPN_PFA showed an exclusive central position within the 4th ventricle in 61% of patients vs 92% for EPN_PFB (p = 0.01). Intratumor calcifications were found in 93% of EPN_PFA vs 40% of EPN_PFB (p = 0.001). Invasion of the posterior fossa foramina was mostly found for EPN_PFA, particularly the foramina of Luschka (p = 0.0008). EPN_PFA showed whole and homogeneous tumor enhancement in 5% vs 75% of EPN_PFB (p = 0.0008). All mainly cystic tumors were EPN_PFB (p = 0.002). The minimal and maximal relative ADC was slightly lower in EPN_PFA (p = 0.02 and p = 0.01, respectively). CONCLUSION: Morphological characteristics from imaging differ between posterior fossa ependymoma subtypes and may help to distinguish them preoperatively. CLINICAL RELEVANCE STATEMENT: This study provides a tool to differentiate between group A and group B ependymomas, which will ultimately allow the therapeutic strategy to be adapted in the early stages of patient management. KEY POINTS: • Posterior fossa ependymoma subtypes often have different imaging characteristics. • Posterior fossa ependymomas group A are commonly median or lateral tissular calcified masses, with incomplete enhancement, affecting young children and responsible for pronounced hydrocephalus and invasion of the posterior fossa foramina. • Posterior fossa ependymomas group B are commonly median non-calcified masses of adolescents and adults, predominantly cystic, and minimally invasive, with total and homogeneous enhancement.

A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation.

Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumour type is now classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System (CNS) tumours. However, the H3.3-K27M subgroup still appears clinically and molecularly heterogeneous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tended to have a better prognosis. To better study the role of these co-driver alterations, we assembled a large paediatric and adult cohort of 29 tumours H3K27-altered with co-occurring activating mutation in BRAF or FGFR1 as well as 31 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylation analysis. Interestingly, unsupervised t-distributed Stochastic Neighbour Embedding (tSNE) analysis of DNA methylation profiles regrouped BRAFV600E and all but one FGFR1MUT DMG in a unique methylation cluster, distinct from the other DMG subgroups and also from ganglioglioma (GG) or high-grade astrocytoma with piloid features (HGAP). This new DMG subtype harbours atypical radiological and histopathological profiles with calcification and/or a solid tumour component both for BRAFV600E and FGFR1MUT cases. The analyses of a H3.3-K27M BRAFV600E tumour at diagnosis and corresponding in vitro cellular model showed that mutation in H3-3A was the first event in the oncogenesis. Contrary to other DMG, these tumours occur more frequently in the thalamus (70% for BRAFV600E and 58% for FGFR1MUT) and patients have a longer overall survival with a median above three years. In conclusion, DMG, H3 K27 and BRAF/FGFR1 co-altered represent a new subtype of DMG with distinct genotype/phenotype characteristics, which deserve further attention with respect to trial interpretation and patient management.

Pediatric spinal pilocytic astrocytomas form a distinct epigenetic subclass from pilocytic astrocytomas of other locations and diffuse leptomeningeal glioneuronal tumours.

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.

Clinico-Radio-Histo-Molecular and Neurocognitive Characteristics of Diffuse Gliomas in Adolescent and Young Adults: A Comprehensive Review.

BACKGROUND: Diffuse gliomas are the most frequent neoplasms in adolescent and young adults (AYAs), especially high-grade gliomas, which have the highest mortality rate. Recent histo-molecular advances are in favour of specialized therapeutic management of AYA patients, which we have analysed in this comprehensive review of the literature. SUMMARY: A literature search was conducted to identify all studies concerning diffuse gliomas and AYAs (15-39 years). We assessed epidemiology, clinical and imaging findings, histo-molecular characteristics, neurosurgical and neuro-oncological management, prognosis, and health-related quality of life. KEY MESSAGES: Diffuse gliomas remain the most frequent brain tumours in the AYA population. Symptoms mainly depend on the tumour location, which varies due to histo-molecular profiles. Specific imaging patterns of histo-molecular subtypes of diffuse gliomas are identified; however, no specific pattern related to the age group has been identified. The literature review favours optimizing the extent of surgical resection for diffuse gliomas, whichever the grade, and suggests a dedicated management for these patients. It seems more relevant to consider the treatment according to the histo-molecular profile of the diffuse glioma rather than the age group. Clinical trials will allow AYA patients to benefit from innovative therapies that could improve their outcome. This literature review suggests the need for a close and long-term psychological follow-up for AYA patients with brain tumour during the transitional care, during adulthood, as well as for their family members. Collaborative efforts are needed between paediatric and adult neurosurgical and neuro-oncological teams, to move forward in the therapeutic management of AYA patients harbouring diffuse gliomas.

The longitudinal evolution of cerebral blood flow in children with tuberous sclerosis assessed by arterial spin labeling magnetic resonance imaging may be related to cognitive performance.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. KEY POINTS: • 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.

A brain atlas of axonal and synaptic delays based on modelling of cortico-cortical evoked potentials.

Epilepsy presurgical investigation may include focal intracortical single-pulse electrical stimulations with depth electrodes, which induce cortico-cortical evoked potentials at distant sites because of white matter connectivity. Cortico-cortical evoked potentials provide a unique window on functional brain networks because they contain sufficient information to infer dynamical properties of large-scale brain connectivity, such as preferred directionality and propagation latencies. Here, we developed a biologically informed modelling approach to estimate the neural physiological parameters of brain functional networks from the cortico-cortical evoked potentials recorded in a large multicentric database. Specifically, we considered each cortico-cortical evoked potential as the output of a transient stimulus entering the stimulated region, which directly propagated to the recording region. Both regions were modelled as coupled neural mass models, the parameters of which were estimated from the first cortico-cortical evoked potential component, occurring before 80 ms, using dynamic causal modelling and Bayesian model inversion. This methodology was applied to the data of 780 patients with epilepsy from the F-TRACT database, providing a total of 34 354 bipolar stimulations and 774 445 cortico-cortical evoked potentials. The cortical mapping of the local excitatory and inhibitory synaptic time constants and of the axonal conduction delays between cortical regions was obtained at the population level using anatomy-based averaging procedures, based on the Lausanne2008 and the HCP-MMP1 parcellation schemes, containing 130 and 360 parcels, respectively. To rule out brain maturation effects, a separate analysis was performed for older (>15 years) and younger patients (<15 years). In the group of older subjects, we found that the cortico-cortical axonal conduction delays between parcels were globally short (median = 10.2 ms) and only 16% were larger than 20 ms. This was associated to a median velocity of 3.9 m/s. Although a general lengthening of these delays with the distance between the stimulating and recording contacts was observed across the cortex, some regions were less affected by this rule, such as the insula for which almost all efferent and afferent connections were faster than 10 ms. Synaptic time constants were found to be shorter in the sensorimotor, medial occipital and latero-temporal regions, than in other cortical areas. Finally, we found that axonal conduction delays were significantly larger in the group of subjects younger than 15 years, which corroborates that brain maturation increases the speed of brain dynamics. To our knowledge, this study is the first to provide a local estimation of axonal conduction delays and synaptic time constants across the whole human cortex in vivo, based on intracerebral electrophysiological recordings.

Abnormal Spontaneous Blood Oxygenation Level Dependent Fluctuations in Children with Focal Cortical Dysplasias: Initial Findings in Surgically Confirmed Cases.

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.

Reliability of fast-spin echo T2-weighted three-dimensional sequences to predict endoscopic third ventriculocisternostomy patency in children.

PURPOSE: Clinical and radiological assessment of endoscopic third ventriculocisternostomy (ETV) patency can be challenging in children. The objective of our study was thus to test the accuracy and interrater reliability of 3D fast-spin echo (FSE) T2-weighted sequences to assess the patency of ETV. METHODS: We included all the consecutive children who underwent surgery for ETV over a two-year period and selected the children who presented ETV dysfunction and matched them with children without dysfunction. We evaluated the Kappa interrater reliability of three experienced physicians for prediction of ETV patency using solely the flow void sign in 3D FSE T2-weighted sequences. RESULTS: Nineteen children underwent surgery for ETV dysfunction and 12 children without dysfunction were matched. Sensitivity was 0.79, 0.89 and 0.84 and specificity was 1 for all raters. None of the patent ETV was wrongly considered to be dysfunctional. Fleiss' kappa was 0.871 (p < 0.001). The interrater reliability was excellent with respect to the patency or not of the ETV. CONCLUSION: FSE T2-weighted sequence is a simple and reproducible tool that can be widely used in daily practice to assess the patency of ETV. Interrater reliability of this sequence is high and accessibility in outpatient setting is acceptable.

Arterial Spin Labeling for the Etiological Workup of Intracerebral Hemorrhage in Children.

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.

The genomic landscape of dysembryoplastic neuroepithelial tumours and a comprehensive analysis of recurrent cases.

AIMS: Dysembryoplastic neuroepithelial tumour (DNT) is a glioneuronal tumour that is challenging to diagnose, with a wide spectrum of histological features. Three histopathological patterns have been described: specific DNTs (both the simple form and the complex form) comprising the specific glioneuronal element, and also the non-specific/diffuse form which lacks it, and has unclear phenotype-genotype correlations with numerous differential diagnoses. METHODS: We used targeted methods (immunohistochemistry, fluorescence in situ hybridisation and targeted sequencing) and large-scale genomic methodologies including DNA methylation profiling to perform an integrative analysis to better characterise a large retrospective cohort of 82 DNTs, enriched for tumours that showed progression on imaging. RESULTS: We confirmed that specific DNTs are characterised by a single driver event with a high frequency of FGFR1 variants. However, a subset of DNA methylation-confirmed DNTs harbour alternative genomic alterations to FGFR1 duplication/mutation. We also demonstrated that a subset of DNTs sharing the same FGFR1 alterations can show in situ progression. In contrast to the specific forms, "non-specific/diffuse DNTs" corresponded to a heterogeneous molecular group encompassing diverse, newly-described, molecularly distinct entities. CONCLUSIONS: Specific DNT is a homogeneous group of tumours sharing characteristics of paediatric low-grade gliomas: a quiet genome with a recurrent genomic alteration in the RAS-MAPK signalling pathway, a distinct DNA methylation profile and a good prognosis but showing progression in some cases. The "non-specific/diffuse DNTs" subgroup encompasses various recently described histomolecular entities, such as PLNTY and diffuse astrocytoma, MYB or MYBL1 altered.

Is the Choroid Plexus Needed?

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.

Hemorrhage Expansion After Pediatric Intracerebral Hemorrhage.

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 <5A, odds ratio, 5.77 [95% CI, 1.01-38.95]; 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.

Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies.

Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.

Radiogenomics of diffuse intrinsic pontine gliomas (DIPGs): correlation of histological and biological characteristics with multimodal MRI features.

OBJECTIVES: 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. METHODS: Twenty-seven treatment-naïve 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. RESULTS: 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. CONCLUSIONS: 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. KEY POINTS: • 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).

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.