In patients with pharmaco-resistant focal epilepsies investigated with intracranial electroencephalography (iEEG), direct electrical stimulations of a cortical region induce cortico-cortical evoked ...potentials (CCEP) in distant cerebral cortex, which properties can be used to infer large scale brain connectivity. In 2013, we proposed a new probabilistic functional tractography methodology to study human brain connectivity. We have now been revisiting this method in the F-TRACT project (f-tract.eu) by developing a large multicenter CCEP database of several thousand stimulation runs performed in several hundred patients, and associated processing tools to create a probabilistic atlas of human cortico-cortical connections. Here, we wish to present a snapshot of the methods and data of F-TRACT using a pool of 213 epilepsy patients, all studied by stereo-encephalography with intracerebral depth electrodes. The CCEPs were processed using an automated pipeline with the following consecutive steps: detection of each stimulation run from stimulation artifacts in raw intracranial EEG (iEEG) files, bad channels detection with a machine learning approach, model-based stimulation artifact correction, robust averaging over stimulation pulses. Effective connectivity between the stimulated and recording areas is then inferred from the properties of the first CCEP component, i.e. onset and peak latency, amplitude, duration and integral of the significant part. Finally, group statistics of CCEP features are implemented for each brain parcel explored by iEEG electrodes. The localization (coordinates, white/gray matter relative positioning) of electrode contacts were obtained from imaging data (anatomical MRI or CT scans before and after electrodes implantation). The iEEG contacts were repositioned in different brain parcellations from the segmentation of patients' anatomical MRI or from templates in the MNI coordinate system. The F-TRACT database using the first pool of 213 patients provided connectivity probability values for 95% of possible intrahemispheric and 56% of interhemispheric connections and CCEP features for 78% of intrahemisheric and 14% of interhemispheric connections. In this report, we show some examples of anatomo-functional connectivity matrices, and associated directional maps. We also indicate how CCEP features, especially latencies, are related to spatial distances, and allow estimating the velocity distribution of neuronal signals at a large scale. Finally, we describe the impact on the estimated connectivity of the stimulation charge and of the contact localization according to the white or gray matter. The most relevant maps for the scientific community are available for download on f-tract. eu (David et al., 2017) and will be regularly updated during the following months with the addition of more data in the F-TRACT database. This will provide an unprecedented knowledge on the dynamical properties of large fiber tracts in human.
Purpose To compare arterial spin labeling (ASL) data between low- and high-grade brain tumors in children to establish a cutoff to distinguish low- from high-grade neoplasms and to assess potential ...correlations between cerebral blood flow (CBF) and quantitative histologic microvascular data. Materials and Methods Approval was obtained from the regional review board. ASL data obtained in 129 children between 2011 and 2015 were retrospectively analyzed. CBF and relative CBF in the most perfused area of each neoplasm and contrast enhancement were quantified with a semiquantitative ratio. The correlation between CBF and microvascular density was analyzed in specimens stained with anti-CD34. Results were controlled in two validation cohorts with 1.5- and 3.0-T magnetic resonance (MR) imaging. Results Mean CBF was significantly higher for high-grade than for low-grade hemispheric (116 mL/min/100 g interquartile range {IQR}, 73-131 mL/min/100 g vs 29 mL/min/100 g IQR, 23-35 29 mL/min/100 g, P < .001), thalamic (87 mL/min/100 g IQR, 73-100 mL/min/100 g vs 36 mL/min/100 g IQR, 30-40 mL/min/100 g, P = .016), and posterior fossa (59 mL/min/100 g IQR, 45-91 mL/min/100 g vs 33 mL/min/100 g IQR, 25-40 mL/min/100 g, P < .001) tumors. With a cutoff of 50 mL/min/100 g, sensitivity and specificity were 90% (95% confidence interval CI: 68, 100) and 93% (95% CI: 66, 100), respectively, for hemispheric tumors; 100% (95% CI: 48, 100) and 80% (95% CI: 28, 100), respectively, for thalamic tumors; and 65% (95% CI: 51, 78) and 94% (95% CI: 80, 99), respectively, for posterior fossa tumors. In posterior fossa tumors, additional use of the CBF-to-contrast enhancement ratio yielded sensitivity and specificity of 96% (95% CI: 87, 100) and 97% (95% CI: 84, 100), respectively. Use of a simple algorithm based on these values yielded an accuracy of 93% (95% CI: 87, 97). Validation sets yielded similar results, with grading accuracy of 88% (95% CI: 62, 98) with 1.5-T MR imaging and 77% (95% CI: 46, 95) with 3.0-T MR imaging. CBF was strongly correlated with microvascular density (R = 0.66, P < .001). Conclusion High-grade pediatric brain tumors display higher CBF than do low-grade tumors, and they may be accurately graded by using these values. CBF is correlated with tumor microvascular density.
RSNA, 2016 Online supplemental material is available for this article.
Summary
Hemispherectomy is a complex multistep procedure with a steep learning curve. Several surgical approaches have been developed, but each requires considerable practice to master. Four ...experienced pediatric neurosurgeons, who participated in the 2014 Gothenburg Pediatric Epilepsy Surgery Meeting, provided succinct technical summaries of four hemispherectomy approaches: modified functional hemispherectomy, peri‐insular hemispherotomy, parasagittal hemispherotomy, and endoscopic‐assisted hemispherotomy. No clinical or outcome data are included. Our intention is to reduce the slope and length of the learning curve for surgeons and to improve the understanding of the technical details of hemispherectomy surgery by nonsurgeonmembers of epilepsy teams.
Abstract
Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosis and ...the precise anatomic origin of brain tumors in the Rosa26-Cre
ERT2
::Smarcb1
flox/flox
model. This cross-species analysis points to an extra-cerebral origin for MYC tumors. Additionally, we clearly distinguish SHH ATRT emerging from the cerebellar anterior lobe (CAL) from those emerging from the basal ganglia (BG) and intra-ventricular (IV) regions. Molecular characteristics point to the midbrain-hindbrain boundary as the origin of CAL SHH ATRT, and to the ganglionic eminence as the origin of BG/IV SHH ATRT. Single-cell RNA sequencing on SHH ATRT supports these hypotheses. Trajectory analyses suggest that
SMARCB1
loss induces a de-differentiation process mediated by repressors of the neuronal program such as
REST
, ID and the NOTCH pathway.
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-H3K27M cell fitness. Gene expression studies after
VRK3
knockdown 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 following
VRK3
knockdown. 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.
The co-occurrence of moyamoya vasculopathy and extra-optic pathway tumors is rare in neurofibromatosis type 1 (NF1), with only four cases described in the literature. Brain surgery in these patients ...may be challenging because of the risk of brain infarction after skin and dural incision. Given its percutaneous and minimally invasive nature, laser interstitial thermal therapy (LITT) is an ideal option for the treatment of brain tumors in these patients. Here, we report on two patients with NF1 and moyamoya syndrome (MMS) treated for a brain glioma with LITT, after cerebral revascularization.
The first patient, with familial NF1, underwent bilateral indirect revascularization with multiple burr holes (MBH) for symptomatic MMS. Two years later, she was diagnosed with a left temporal tumor, with evidence of radiologic progression over 10 months. The second patient, also with familial NF1, developed unilateral MMS when he was 6 years old and was treated with MBH. At the age of 15 years, MRI showed a right cingular lesion, growing on serial MRIs. Both patients underwent LITT with no perioperative complications; they are progression free at 10 and 12 months, respectively, and the tumors have decreased in volume.
While the association of extra-optic neoplasm and moyamoya angiopathy is seldom reported in NF1, tumor treatment is challenging in terms of both avoiding stroke and achieving oncological control. Here, we show in 2 cases, that LITT could be a safe and effective option in these rare conditions.
Diffuse Instrinsic Pontine Glioma is the most aggressive form of High Grade Gliomas in children. The lack of biological material and the absence of relevant models have hampered the development of ...new therapeutics. Their extensive infiltration of the brainstem renders any surgical resection impossible and until recently biopsies were considered not informative enough and therefore not recommended. Thus, most models were derived from autopsy material. We aimed to develop relevant
DIPG models that mimic this specific disease and its molecular diversity from tumor material obtained at diagnosis. Eight patient-derived orthotopic xenograft models were obtained after direct stereotactic injection of a mixed cell suspension containing tumor cells and stromal cells in the brainstem or thalamus of nude mice and serially passaged thereafter. In parallel, we developed 6 cell-derived xenograft models after orthotopic injection of tumor-initiating cells cultured from stereotactic biopsies. Cells were modified to express luciferase to enable longitudinal tumor growth monitoring, and fluorescent reporter proteins to trace the tumor cells in the brain. These models do not form a tumor mass, they are invasive, show the H3K27 trimethylation loss
and the tumor type diversity observed in patients in terms of histone H3 mutations and lineage markers. Histological and MRI features at 11.7 Tesla show similarities with treatment naïve human DIPG, and in this respect, both direct and indirect orthotopic xenograft looked alike. These DIPG models will therefore constitute valuable tools for evaluating new therapeutic approaches in this devastating disease.
Epilepsy surgery may be a curative therapy for patients with drug‐resistant epilepsies when focal lesions or foci are identified. Genetic testing is not yet routinely included in many presurgical ...evaluation programs although recent evidence support that finding a germline genetic mutation could help to better delineate the patient candidacy to surgery and provide valuable information on the expected surgery outcome. In this study, we report nine patients presenting drug‐resistant focal epilepsy enrolled in presurgical evaluation. We show how the identification of genetic pathogenic variant in epilepsy known genes led to the interruption of the presurgical work‐up and ruled out surgery in 7 of them. We observed that the co‐existence of some recurrent clinical characteristics as early seizures' onset, frequent precipitating factors including fever, and developmental delay or intellectual disability may be useful markers for germline genetic pathogenic variants. In this group, genetic assessment should be mandatory during presurgical work up, mainly in patients with negative magnetic resonance imaging (MRI) or doubtful structural lesions. The integration of next generation targeted sequencing into the presurgical evaluation can improve the selection of candidates for resective surgery and fosters a personalized medicine approach with a better outcome.
Plaine Language
Genetic testing is not yet systematically included in the pre‐surgical assessment of patients with drug‐resistant focal epilepsies. In this study, through the description of nine patients, we underline how the integration of genomics into the presurgical work up can help in evaluating the patient candidacy to surgery and provide valuable information on expected surgery outcome.
To use multimodal magnetic resonance imaging (MRI) to quantify treatment-induced changes in the whole volume of diffuse infiltrating pontine gliomas and correlate them with progression-free survival ...(PFS).
This prospective study included 22 children aged 3.3 to 14.7 years (median, 5.9 years). Multimodal MRI was performed at 3 distinct time points: before treatment, the first week following radiation therapy (RT), and 2 months after RT. The imaging protocol included morphologic, multi b-value diffusion; arterial spin labeling; and dynamic susceptibility contrast-enhanced perfusion. Morphologic and multimodal data-lesion volume, diffusion coefficients, relative cerebral blood flow, and relative cerebral blood volume (rCBV)-were recorded at the 3 aforementioned time points. The Wilcoxon test was used to compare each individual parameter variation between time points, and its correlation with PFS was assessed by the Spearman test.
Following RT, the tumors' solid component volume decreased by 40% (P<.001). Their median diffusion coefficients decreased by 20% to 40% (P<.001), while median relative cerebral blood flow increased by 60% to 80% (P<.001) and median rCBV increased by 70% (P<.001). PFS was positively correlated with rCBV measured immediately after RT (P=.003), and in patients whose rCBV was above the cutoff value of 2.46, the median PFS was 4.6 months longer (P=.001). These indexes tended to return to baseline 2 months after RT. Lesion volume before or after RT was not correlated with survival.
Multimodal MRI provides useful information about diffuse infiltrating pontine gliomas' response to treatment; rCBV increases following RT, and higher values are correlated with better PFS. High rCBV values following RT should not be mistaken for progression and could be an indicator of response to therapy.
Objective
Preceding oxygen glucose deprivation (OGD) and ongoing seizures have both been reported to increase neuronal chloride concentration (Cl−i), which may contribute to anticonvulsant failure by ...reversing the direction of chloride currents at inhibitory GABAA synapses.
Methods
The effects of OGD on Cl−i, seizure activity, and anticonvulsant efficacy were studied in a chronically epileptic in vitro preparation.
Results
Seizures initially increased during OGD, followed by suppression. On reperfusion, seizure frequency and Cl−i progressively increased, and phenobarbital efficacy was reduced. Bumetanide (10 μmol/L) and furosemide (1 mmol/L) prevented or reduced the OGD induced Cl−i increase. Phenobarbital efficacy was enhanced by bumetanide (10 μmol/L). Furosemide (1 mmol/L) suppressed recurrent seizures.
Interpretation
Cl−i increases after OGD and is associated with worsened seizure activity, reduced efficacy of GABAergic anticonvulsants, and amelioration by antagonists of secondary chloride transport.
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