Publications by authors named "Thomas Blauwblomme"

65 Publications

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

Stroke 2021 Sep 14:STROKEAHA120032690. Epub 2021 Sep 14.

Department of Pediatric Radiology UMR 1163, Institut Imagine, INSERM U1000, AP-HP, University hospital Necker-Enfants-malades, Paris, France. (J.F.H., G.B., B.K., F.G., L.G., N.B., V.D.R., F.B., O.N.).

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 inter-rater 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.
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http://dx.doi.org/10.1161/STROKEAHA.120.032690DOI Listing
September 2021

Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab097. Epub 2021 Jul 7.

Department of Pediatric and Adolescents Oncology, Gustave Roussy Cancer Institute, Paris Saclay University, Villejuif, France.

Background: Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth. We hereby report long-term follow-up of young patients treated with SMOi for recurrent medulloblastoma.

Methods: Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible.

Results: All patients with a somatic mutation responded to SMOi (6/8), including 2 prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for 3 patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radiotherapy was associated with very long disease control in 2 patients. The most severe adverse events were myalgia and growth plate fusion with metaphyseal sclerosis. Normal growth velocity was recovered for 1 patient although her final height was below estimated target height.

Conclusions: Targeting SMO in mutated is an interesting strategy for long-term responses. Combination of SMOi with chemotherapy or surgery and local radiotherapy is an appealing strategy to prevent early resistance and diminish SMOi exposure, especially in young patients. Inhibition of SHH pathway causes growth and development impairment but partial recovery of the growth velocity is possible.
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http://dx.doi.org/10.1093/noajnl/vdab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367281PMC
July 2021

Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions.

Acta Neuropathol Commun 2021 08 13;9(1):135. Epub 2021 Aug 13.

Department of Pediatric Neurosurgery, Necker Hospital, APHP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

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.
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http://dx.doi.org/10.1186/s40478-021-01238-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362233PMC
August 2021

Toward a transitional care from childhood and adolescence to adulthood in surgical neurooncology? A lesson from the Necker-Enfants Malades and the Sainte-Anne Hospitals collaboration.

J Neurosurg Pediatr 2021 Jul 30:1-7. Epub 2021 Jul 30.

1Service de Neurochirurgie, GHU Paris-Hôpital Sainte-Anne, Paris.

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.
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http://dx.doi.org/10.3171/2021.3.PEDS2141DOI Listing
July 2021

An integrative histopathological and epigenetic characterization of primary intracranial mesenchymal tumors, FET:CREB-fused broadening the spectrum of tumor entities in comparison with their soft tissue counterparts.

Brain Pathol 2021 Jul 27:e13010. Epub 2021 Jul 27.

Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne Hospital, Paris, France.

FET:CREB fusions have been described in a variety of tumors from various phenotypes. Recently, these fusion transcripts were reported in intracranial tumors, variably named intracranial mesenchymal myxoid tumors or angiomatoid fibrous histiocytomas. Controversy remains concerning the terminology for these tumors. Here, we report 11 cases of central nervous system mesenchymal tumors with proven FET:CREB fusion. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor or Sarcoma Classifier (v11b4/v12.2). However, by using unsupervised t-SNE and hierarchical clustering analyses, six of the cases constituted a distinct cluster. The remaining four tumors showed no obvious relation to any of the other referenced classes but were close to the clusters of extra-CNS angiomatoid fibrous histiocytomas (n = 1), clear cell sarcomas (n = 1), or solitary fibrous tumors (n = 2). Our findings confirm that intracranial FET:CREB-fused tumors do not represent a single molecular tumor entity, although most samples clustered close to each other, indicating the existence of a distinct epigenetic group that could potentially be partially masked by the low number of cases included. Further analyses are needed to characterize intracranial FET:CREB fused-defined tumors in more detail.
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http://dx.doi.org/10.1111/bpa.13010DOI Listing
July 2021

A CBF decrease in the left supplementary motor areas: New insight into postoperative pediatric cerebellar mutism syndrome using arterial spin labeling perfusion MRI.

J Cereb Blood Flow Metab 2021 Jul 14:271678X211031321. Epub 2021 Jul 14.

Paediatric Neurosurgery Department, AP-HP, Hôpital Necker-Enfants Malades, Université de Paris, Paris, France.

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.
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http://dx.doi.org/10.1177/0271678X211031321DOI Listing
July 2021

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

Eur Radiol 2021 May 18. Epub 2021 May 18.

Pediatric Radiology Department, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 149 rue de Sèvres, F-75015, Paris, France.

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 μm/s vs 1741 μm/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).
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http://dx.doi.org/10.1007/s00330-021-07991-xDOI Listing
May 2021

Mortality and functional outcome after pediatric intracerebral hemorrhage: cohort study and meta-analysis.

J Neurosurg Pediatr 2021 Apr 9:1-7. Epub 2021 Apr 9.

1Service d'imagerie Morphologique et Fonctionnelle, GHU Paris Psychiatrie et Neurosciences, Hospitalier Sainte Anne, Institut de Psychiatrie et Neurosciences de Paris, UMR_S1266, INSERM, Université de Paris.

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.
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http://dx.doi.org/10.3171/2020.9.PEDS20608DOI Listing
April 2021

Acute surgical management of children with ruptured brain arteriovenous malformation.

J Neurosurg Pediatr 2021 Jan 22:1-9. Epub 2021 Jan 22.

1APHP, Necker Hospital.

Objective: Rupture of brain arteriovenous malformation (AVM) is the main etiology of intracerebral hemorrhage (ICH) in children. Ensuing intracranial hypertension is among the modifiable prognosis factors and sometimes requires emergency hemorrhage evacuation (HE). The authors aimed to analyze variables associated with HE in children with ruptured AVM.

Methods: This study was a single-center retrospective analysis of children treated for ruptured AVM. The authors evaluated the occurrence of HE, its association with other acute surgical procedures (e.g., nidal excision, decompressive hemicraniectomy), and clinical outcome. Variables associated with each intervention were analyzed using univariable and multivariable models. Clinical outcome was assessed at 18 months using the ordinal King's Outcome Scale for Childhood Head Injury.

Results: A total of 104 patients were treated for 112 episodes of ruptured AVM between 2002 and 2018. In the 51 children (45.5% of cases) who underwent HE, 37 procedures were performed early (i.e., within 24 hours after initial cerebral imaging) and 14 late. Determinants of HE were a lower initial Glasgow Coma Scale score (adjusted odds ratio [aOR] 0.83, 95% CI 0.71-0.97 per point increase); higher ICH/brain volume ratio (aOR 18.6, 95% CI 13-26.5 per percent increase); superficial AVM location; and the presence of a brain herniation (aOR 3.7, 95% CI 1.3-10.4). Concurrent nidal surgery was acutely performed in 69% of Spetzler-Martin grade I-II ruptured AVMs and in 25% of Spetzler-Martin grade III lesions. Factors associated with nidal surgery were superficial AVMs, late HE, and absent alteration of consciousness at presentation. Only 8 cases required additional surgery due to intracranial hypertension. At 18 months, overall mortality was less than 4%, 58% of patients had a favorable outcome regardless of surgical intervention, and 87% were functioning independently.

Conclusions: HE is a lifesaving procedure performed in approximately half of the children who suffer AVM rupture. The good overall outcome justifies intensive initial management.
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http://dx.doi.org/10.3171/2020.8.PEDS20479DOI Listing
January 2021

Hemorrhage Expansion After Pediatric Intracerebral Hemorrhage.

Stroke 2021 Jan 11;52(2):588-594. Epub 2021 Jan 11.

GHU Paris Psychiatrie et Neurosciences, Hospitalier Sainte Anne, Service d'imagerie Morphologique et Fonctionnelle, Institut de Psychiatrie et Neurosciences de Paris, Unité mixte de recherche S1266, Institut National de la Santé Et de la Recherche Médicale, Université de Paris, Paris, France (G.B., J.-F.H., B.K., F.G., L.G., O.N.).

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%; =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]; =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]; =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.
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http://dx.doi.org/10.1161/STROKEAHA.120.030592DOI Listing
January 2021

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

J Clin Immunol 2021 04 7;41(3):603-609. Epub 2021 Jan 7.

General Paediatrics- Infectious Diseases and Internal Medicine Department, Robert-Debré Hospital, AP-HP, Nord - Université de Paris, Paris, France.

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.
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http://dx.doi.org/10.1007/s10875-020-00952-xDOI Listing
April 2021

Etiology of intracerebral hemorrhage in children: cohort study, systematic review, and meta-analysis.

J Neurosurg Pediatr 2021 Jan 1:1-7. Epub 2021 Jan 1.

1Service d'imagerie Morphologique et Fonctionnelle, GHU Paris Psychiatrie et Neurosciences, Hospitalier Sainte Anne, Institut de Psychiatrie et Neurosciences de Paris (IPNP), UMR_S1266, INSERM, Université de Paris.

Objective: Understanding the etiological spectrum of nontraumatic pediatric intracerebral hemorrhage (pICH) is key to the diagnostic workup and care pathway. The authors aimed to evaluate the etiological spectrum of diseases underlying pICH.

Methods: Children treated at the authors' institution for a pICH were included in an inception cohort initiated in 2008 and retrospectively inclusive to 2000, which was analyzed in October 2019. They then conducted a systematic review of relevant articles in PubMed published between 1990 and 2019, identifying cohorts with pICH. Identified populations and patients from the authors' cohort were pooled in a multicategory meta-analysis.

Results: A total of 243 children with pICH were analyzed in the cohort study. The final primary diagnosis was an intracranial vascular lesion in 190 patients (78.2%), a complication of a cardiac disease in 17 (7.0%), and a coagulation disorder in 14 (5.8%). Hematological and cardiological etiologies were disproportionately more frequent in children younger than 2 years (p < 0.001). The systematic review identified 1309 children in 23 relevant records pooled in the meta-analysis. Overall, there was significant heterogeneity. The dominant etiology was vascular lesion, with an aggregate prevalence of 0.59 (95% CI 0.45-0.64; p < 0.001, Q = 302.8, I2 = 92%). In 18 studies reporting a detailed etiological spectrum, arteriovenous malformation was the dominant etiology (68.3% [95% CI 64.2%-70.9%] of all vascular causes), followed by cavernoma (15.7% [95% CI 13.0%-18.2%]).

Conclusions: The most frequent etiology of pICH is brain arteriovenous malformation. The probability of an underlying vascular etiology increases with age, and, conversely, hematological and cardiac causes are dominant causes in children younger than 2 years.
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http://dx.doi.org/10.3171/2020.7.PEDS20447DOI Listing
January 2021

Complete hemispherotomy leads to lateralized functional organization and lower level of consciousness in the isolated hemisphere.

Epilepsia Open 2020 Dec 24;5(4):537-549. Epub 2020 Sep 24.

Assistance Publique Hôpitaux de Paris Hôpital Necker-Enfants Malades Paris France.

Objective: To quantify whole-brain functional organization after complete hemispherotomy, characterizing unexplored plasticity pathways and the conscious level of the dissected hemispheres.

Methods: Evaluation with multimodal magnetic resonance imaging in two pediatric patients undergoing right hemispherotomy including complete callosotomy with a perithalamic section. Regional cerebral blood flow and fMRI network connectivity assessed the functional integrity of both hemispheres after surgery. The level of consciousness was tested by means of a support vector machine classifier which compared the intrinsic organization of the dissected hemispheres with those of patients suffering from disorders of consciousness.

Results: After hemispherotomy, both patients showed typical daily functionality. We found no interhemispheric transfer of functional connectivity in either patient as predicted by the operation. The healthy left hemispheres displayed focal blood hyperperfusion in motor and limbic areas, with preserved network-level organization. Unexpectedly, the disconnected right hemispheres showed sustained network organization despite low regional cerebral blood flow. Subcortically, functional connectivity was increased in the left thalamo-cortical loop and between the cerebelli. One patient further showed unusual ipsilateral right cerebello-cortical connectivity, which was explained by the mediation of the vascular system. The healthy left hemisphere had higher probability to be classified as in a minimally conscious state compared to the isolated right hemisphere.

Significance: Complete hemispherotomy leads to a lateralized whole-brain organization, with the remaining hemisphere claiming most of the brain's energetic reserves supported by subcortical structures. Our results further underline the contribution of nonneuronal vascular signals on contralateral connectivity, shedding light on the nature of network organization in the isolated tissue. The disconnected hemisphere is characterized by a level of consciousness which is necessary but insufficient for conscious processing, paving the way for more specific inquiries about its role in awareness in the absence of behavioral output.
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http://dx.doi.org/10.1002/epi4.12433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733653PMC
December 2020

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Am J Med Genet A 2021 01 7;185(1):15-25. Epub 2020 Oct 7.

Department of Paediatric Neurology, University Hospital of Wales, Cardiff, UK.

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.
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http://dx.doi.org/10.1002/ajmg.a.61907DOI Listing
January 2021

Endoscopic aqueductal stenting in the management of pediatric hydrocephalus.

J Neurosurg Pediatr 2020 Jul 3:1-7. Epub 2020 Jul 3.

1Department of Pediatric Neurosurgery, Hôpital Necker, Assistance Publique Hôpitaux de Paris, Université de Paris, France; and.

Objective: Pediatric 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.

Methods: A 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.

Results: Seventeen 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.

Conclusions: The 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.
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http://dx.doi.org/10.3171/2020.4.PEDS20144DOI Listing
July 2020

Hydrocephalus in children with ruptured cerebral arteriovenous malformation.

J Neurosurg Pediatr 2020 May 22:1-5. Epub 2020 May 22.

1APHP, Necker Hospital, Université de Paris.

Objective: Hydrocephalus is a strong determinant of poor neurological outcome after intracerebral hemorrhage (ICH). In children, ruptured brain arteriovenous malformations (bAVMs) are the dominant cause of ICH. In a large prospective cohort of pediatric patients with ruptured bAVMs, the authors analyzed the rates and predictive factors of hydrocephalus requiring acute external ventricular drainage (EVD) or ventriculoperitoneal shunt (VPS).

Methods: The authors performed a single-center retrospective analysis of the data from a prospectively maintained database of children admitted for a ruptured bAVM since 2002. Admission clinical and imaging predictors of EVD and VPS placement were analyzed using univariate and multivariate statistical models.

Results: Among 114 patients (mean age 9.8 years) with 125 distinct ICHs due to ruptured bAVM, EVD and VPS were placed for 55/125 (44%) hemorrhagic events and 5/114 patients (4.4%), respectively. A multivariate nominal logistic regression model identified low initial Glasgow Coma Scale (iGCS) score, hydrocephalus on initial CT scan, the presence of intraventicular hemorrhage (IVH), and higher modified Graeb Scale (mGS) score as strongly associated with subsequent need for EVD (all p < 0.001). All children who needed a VPS had initial hydrocephalus requiring EVD and tended to have higher mGS scores.

Conclusions: In a large cohort of pediatric patients with ruptured bAVM, almost half of the patients required EVD and 4.4% required permanent VPS. Use of a low iGCS score and a semiquantitative mGS score as indicators of the IVH burden may be helpful for decision making in the emergency setting and thus improve treatment.
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http://dx.doi.org/10.3171/2020.3.PEDS19680DOI Listing
May 2020

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

Neuro Oncol 2020 11;22(11):1686-1695

Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Paris-Saclay University, Villejuif, France.

Background: Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been assessed.

Methods: Two therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy between 2002 and 2015: surgery at diagnosis (n = 54, group A) and surgery delayed after carboplatin and etoposide-based neoadjuvant therapy (n = 38, group B). Treatment strategies were similar in both groups.

Results: The rate of complete tumor excision was significantly higher in group B than in group A (93.3% vs 57.4%, P = 0.0013). Postoperative complications, chemotherapy-associated side effects, and local progressions were not increased in group B. Neoadjuvant chemotherapy led to a decrease in the primary tumor size in all patients; meanwhile 4/38 patients experienced a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after neoadjuvant chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up).

Conclusion: Preoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival.

Key Points: 1. Preoperative chemotherapy increases the rate of complete tumor removal.2. No additional risk (toxic or disease progression) is linked to the delayed surgery.3. Preoperative chemotherapy could have a positive impact on the neuropsychological outcome of patients.
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http://dx.doi.org/10.1093/neuonc/noaa083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846143PMC
November 2020

Intracranial chondromas: A histopathologic and molecular study of three cases.

Clin Neuropathol 2020 Jul/Aug;39(4):171-178

Aims: Meningeal chondromas constitute a small fraction of central nervous system tumors, with only 61 cases reported in the literature. Somatic mutations of genes have been described in enchondromas, and, in soft-tissue chondromas, rearrangements of the 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 mutations, and FISH analysis of the locus were performed.

Results: Immunohistochemical analyses of all cases were negative for IDH1R132H and HMGA2 proteins. Molecular analyses failed to reveal mutations, and FISH analyses did not evidence any 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.
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http://dx.doi.org/10.5414/NP301238DOI Listing
April 2021

First Line Onyx Embolization in Ruptured Pediatric Arteriovenous Malformations : Safety and Efficacy.

Clin Neuroradiol 2021 Mar 4;31(1):155-163. Epub 2019 Dec 4.

Pediatric Radiology, Necker Children Hospital, Paris, France.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1007/s00062-019-00861-6DOI Listing
March 2021

Nontraumatic Pediatric Intracerebral Hemorrhage.

Stroke 2019 12 22;50(12):3654-3661. Epub 2019 Oct 22.

From the Pediatric Radiology Department, Necker Enfants Malades (NEM), INSERM UMR1266, Sainte-Anne (G.B., J.F.H., O.N.).

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http://dx.doi.org/10.1161/STROKEAHA.119.025783DOI Listing
December 2019

Management of Gorham Stout disease with skull-base defects: Case series of six children and literature review.

Int J Pediatr Otorhinolaryngol 2019 Sep 5;124:152-156. Epub 2019 Jun 5.

AP-HP, Hôpital Necker-Enfants Malades, Department of Paediatric Otolaryngology, Paris Descartes University, 149 Rue de Sèvres, 75015, Paris, France.

Background: Gorham-Stout disease (GSD) is a rare lymphatic disorder which results in bone destruction. Defects of the skull base are difficult to manage, we describe cases to better understand the disease and discuss treatment.

Methods: Retrospective study including all patients treated for GSD skull-base defects. Medical records, clinical, imaging and treatment data were studied. A systematic review of the literature included case reports of the diseases for further analysis.

Results: 6 patients (5 males, 1 female) were included. Mean age at diagnosis was 3.5 years (range 0-10). Follow-up was of 5.2 years. Patients were divided into Naso-temporal (NT) and Vertebro-temporal (VT) groups following anatomical location. NT patients (4 patients) all had petrous defects extending anteriorly, including sphenoid, ethmoidal and mandibular defects. They all had cerebro-spinal fluid leak (CSF) and recurrent meningitis (range from 3 to 7). Two of those patients had sequelae including deafness, paralysis and epilepsy. VT patients (2 patients) all had temporal, occipital bone and cervical vertebrae defects. None had CSF leaks but both died from medullar compression (preceded by tetraparesis in one case). Overall, five out of six patients had type I Chiari malformation. Interferon seemed to be the most efficient medical treatment. Surgery included petrectomy, endonasal surgery for CSF leak management and neurosurgery for medullar management but could not guarantee long-term effects.

Conclusion: Main issues in skull base defects are CSF leaks and medullar compressions. Surgical treatment is necessary in both cases but can only be satisfactory if general medical treatment can stabilise the disease.
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http://dx.doi.org/10.1016/j.ijporl.2019.06.002DOI Listing
September 2019

Long-term Outcomes of Cerebral Aneurysms in Children.

Pediatrics 2019 06 8;143(6). Epub 2019 May 8.

Pediatric Radiology, Necker Hospital for Sick Children, Université Paris Descartes, Paris, France.

Background: Our aim was to report the long-term clinical and imaging outcomes of ≤15-year-old children treated for ruptured or symptomatic cerebral aneurysms and to identify prognostic factors for clinical outcome, recurrence, and rebleeding.

Methods: We retrospectively identified all pediatric cases of cerebral aneurysm from 2000 to 2015 and then prospectively evaluated long-term occlusion using brain MRI and clinical outcome measures: outcome was considered favorable if King's Outcome Scale for Childhood Head Injury score was ≥5. We performed univariate analysis and logistic binary regression to identify variables associated with clinical and imaging outcomes.

Results: Fifty-one children (aged 8.5 ± 1.1 years [mean ± SD], with 37 ruptured and 14 symptomatic aneurysms) were included, and endovascular treatments (84%) or microsurgical procedures (16%) were performed. Despite a 19.6% death rate, at a mean follow-up of 8.3 years, 35 children (68.6%) had a favorable outcome. Annual bleeding and aneurysm recurrence rates were 1.4% ± 1.1% and 2.6% ± 1.8%, respectively. Cerebral ischemia, whether initial or delayed within the first month, was predictive of poor clinical outcome in multivariate analysis (odds ratio: 25; 95% confidence interval: 0.43-143; < .0001), whereas aneurysm size >5 mm was the only factor associated with recurrence (odds ratio: 14.6; 95% confidence interval: 2.4-86.1; = .003).

Conclusions: Two-thirds of studied ≤15-year-old children suffering from ruptured or symptomatic cerebral aneurysms had long-term favorable outcome. Annual bleeding and aneurysm recurrence rates have shown to be low after endovascular or surgical treatment. Long-term imaging follow-up helps to depict aneurysm recurrence or de novo aneurysm formation and to prevent rebleeding.
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http://dx.doi.org/10.1542/peds.2018-3036DOI Listing
June 2019

A novel de novo PDGFRB variant in a child with severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis.

Am J Med Genet A 2019 07 19;179(7):1304-1309. Epub 2019 Apr 19.

Laboratory of embryology and genetics of malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.

The spectrum of clinical consequences of variants in the Platelet derived growth factor receptor beta (PDGFRB) gene is wide. Missense variants leading to variable loss of signal transduction in vitro have been reported in the idiopathic basal ganglia calcification (IBGC) syndrome Type 4. In contrast, gain-of-function variants have been reported in infantile myofibromatosis, Penttinen syndrome, and Kosaki overgrowth syndrome. Here, we report a patient harboring a novel postzygotic variant in PDGFRB (c.1682_1684del, p.[Arg561_Tyr562delinsHis]) and presenting severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis. This observation expands the phenotype associated with PDGFRB variants and illustrates the wide clinical spectrum linked to dysregulation of PDGFRB.
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http://dx.doi.org/10.1002/ajmg.a.61151DOI Listing
July 2019

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

J Neurosurg Pediatr 2019 03 22:1-9. Epub 2019 Mar 22.

OBJECTIVE: Arachnoid cysts (ACs) are most frequently located in the middle cranial fossa. Some patients are asymptomatic whereas others exhibit signs of increased intracranial pressure, seizures, or cognitive and behavioral symptoms. When ACs do require treatment, the optimal surgical technique remains controversial. This study was conducted to assess the most effective surgical treatment for these cysts. METHODS: The authors retrospectively reviewed 240 temporal intracranial ACs managed over a 25-year period in their pediatric neurosurgical unit. Pre- and posttreatment results were clinically and radiologically assessed. RESULTS: A majority of male patients (74.6%) with an overall median age of 6.9 years were included. The mean cyst size was 107 cm3; the Galassi classification showed 99 (41.3%) type I, 77 (32.1%) type II, and 64 (26.7%) type III cysts. Forty-four ACs (18.3%) were diagnosed after rupture. Surgical management was performed by microsurgery (28.3%), endoscopic cyst fenestration (14.6%), cystoperitoneal shunting (CPS; 16.2%), or subdural shunting (10%). Furthermore, 74 children (30.8%) did not undergo operations. After a mean follow-up of 4.1 years, the mean percentage decrease in cyst volume and the overall rate of clinical improvement did not significantly differ. The endoscopy group had earlier complications and a shorter event-free survival (EFS) time (EFS at 3 years = 67.7%, vs 71.5% and 90.5% for CPS and microsurgery, respectively; p < 0.007) and presented with more subdural hematomas compared to the microsurgery group (p < 0.005). The microsurgery group also showed a tendency for longer cystocisternostomy permeability than the endoscopy group. CONCLUSIONS: Concerning the management of unruptured symptomatic temporal ACs, microsurgery appears to be the most effective treatment, with longer EFS and fewer complications compared to shunting or endoscopy.
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http://dx.doi.org/10.3171/2018.12.PEDS18484DOI Listing
March 2019

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

Ann Neurol 2019 02 17;85(2):204-217. Epub 2019 Jan 17.

INSERM U1129, Infantile Epilepsies and Brain Plasticity, Paris Descartes University, PRES Sorbonne Paris Cité, Paris, France.

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 GABA 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.
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http://dx.doi.org/10.1002/ana.25403DOI Listing
February 2019

Transient ischemia facilitates neuronal chloride accumulation and severity of seizures.

Ann Clin Transl Neurol 2018 Sep 5;5(9):1048-1061. Epub 2018 Jul 5.

Department of Neurology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts 02114.

Objective: Preceding oxygen glucose deprivation (OGD) and ongoing seizures have both been reported to increase neuronal chloride concentration ([Cl]), which may contribute to anticonvulsant failure by reversing the direction of chloride currents at inhibitory GABA synapses.

Methods: The effects of OGD on [Cl], 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] progressively increased, and phenobarbital efficacy was reduced. Bumetanide (10 mol/L) and furosemide (1 mmol/L) prevented or reduced the OGD induced [Cl] increase. Phenobarbital efficacy was enhanced by bumetanide (10 mol/L). Furosemide (1 mmol/L) suppressed recurrent seizures.

Interpretation: [Cl] 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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http://dx.doi.org/10.1002/acn3.617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144438PMC
September 2018

Probabilistic functional tractography of the human cortex revisited.

Neuroimage 2018 11 17;181:414-429. Epub 2018 Jul 17.

Epilepsy Monitoring Unit, Department of Neurology, Hospital del Mar-IMIM, Barcelona, Spain.

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.
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http://dx.doi.org/10.1016/j.neuroimage.2018.07.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150949PMC
November 2018

Temporomandibular joint anomalies in pediatric craniofacial Gorham-Stout disease.

J Craniomaxillofac Surg 2018 Aug 9;46(8):1179-1184. Epub 2018 May 9.

Assistance Publique - Hôpitaux de Paris, Service de chirurgie maxillofaciale et plastique, Hôpital Universitaire Necker - Enfants Malades, Sorbonne Paris Cité, Université Paris Descartes, Paris, France. Electronic address:

Purpose: Gorham-Stout disease (GS) is a rare and little understood bone disease that leads to the progressive replacement of the affected bone by fibrous tissues. The mandible is the most commonly affected craniofacial bone, but there is no report to date of temporomandibular joint (TMJ) lesions in this condition. We aimed to characterize the involvement of the TMJ in this uncommon bone disorder.

Material And Methods: We retrospectively included all patients managed for craniofacial forms of GS in our pediatric institution over a period of 12 years. We collected clinical data on TMJ function and radiological data from computed tomography and magnetic resonance imaging.

Results: Four pediatric patients were managed for craniofacial forms of GS between 2005 and 2017. All patients presented with various radiological lesions of the TMJs, including osteolytic lacunae of the condylar head, condylar head flattening and thinning of the glenoid cavity. Only one patient presented with functional TMJ impairment.

Conclusion: The TMJ appears to be radiology affected in pediatric craniofacial forms of GS. Nevertheless, TMJ lesions, even when radiologically severe, rarely impair TMJ function. TMJ structure and function should be systematically assessed in craniofacial forms of GS, and, in the case of joint lesions, a regular follow-up of TMJ function should be considered.
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http://dx.doi.org/10.1016/j.jcms.2018.05.014DOI Listing
August 2018
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