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

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

Cerebral Palsy (CP) represents a frequent cause of disability in childhood. Early in life, genetic disorders may present with motor dysfunction and diagnosed as CP. Establishing the primary, genetic etiology allows more accurate prognosis, genetic counselling, and planning for symptomatic interventions in homogeneous etiological groups. Deep brain stimulation (DBS) is recommended in refractory movement disorders, including isolated pediatric dystonias. For dystonia evolving in more complex associations in genetic CP, the effect of DBS is still understudied and currently only sporadically described.To report the effect of DBS applied to the globus pallidus pars interna (GPi) in children with complex movement disorders caused by pathogenic ADCY5 variants, diagnosed as dyskinetic CP previous to genetic diagnostic.We conducted a retrospective study on evolution of treatment with DBS in ADCY5-related disease. A standardized proforma including the different type of movement disorders and associated neurological signs was completed at each follow-up time, based on video recordings, as well as functional assessments used in children with CP.Four children (mean of age, 13 ± 2.9 years) received GPi-DBS. The same de novo pathogenic missense variant (c.1252CT, p.R418W) was identified in three out of four and a splice site variant (c.2088 + 2GT) in one subject. Developmental delay and overlapping features including axial hypotonia, chorea, dystonic attacks, myoclonus, and cranial dyskinesia were present. The median age at DBS was 9 years and follow-up with DBS, 2.6 years. We identified a pattern of clinical response with early suppression of dystonic attacks, followed by improvement of myoclonus and facial dyskinesia. Effect on chorea was delayed and more limited. Two patients gained notable functional benefit related to sitting, standing, gait, use of upper limbs and speech.ADCY5-related disease may benefit from GPi-DBS. The most significant clinical response relates to the early and sustained benefit on dystonic attacks and a variable but still positive response on the other hyperkinetic features. Genetic etiology of CP will contribute to further elucidate genotype-phenotype correlations and to refine DBS indication as network-related symptomatic interventions.

OBJECTIVE Chiari malformation type I (CM-I) is frequent in children and remains a surgical challenge. Several techniques have been described for posterior fossa decompression. No decision algorithm has been validated, and strategies are highly variable between institutions. The goal of this study was to define therapeutic guidelines that take into consideration patient specificities. METHODS The authors retrospectively collected data from patients who were < 18 years of age, were diagnosed with CM-I, and were treated surgically between 2008 and 2018 in 8 French pediatric neurosurgical centers. Data on clinical features, morphological parameters, and surgical techniques were collected. Clinical outcomes at 3 and 12 months after surgery were assessed by the Chicago Chiari Outcome Scale. The authors used a hierarchical clustering method to define clusters of patients by considering their anatomical similarities, and then compared outcomes between surgical strategies in each of these clusters. RESULTS Data from 255 patients were collected. The mean age at surgery was 9.6 ± 5.0 years, syringomyelia was reported in 60.2% of patients, the dura mater was opened in 65.0% of patients, and 17.3% of patients underwent a redo surgery for additional treatment. The mean Chicago Chiari Outcome Scale score was 14.4 ± 1.5 at 3 months (n = 211) and 14.6 ± 1.9 at 12 months (n = 157). The hierarchical clustering method identified three subgroups with potentially distinct mechanisms underlying tonsillar herniation: bony compression, basilar invagination, and foramen magnum obstruction. Each cluster matched with specific outcomes. CONCLUSIONS This French multicenter retrospective cohort study enabled the identification of three subgroups among pediatric patients who underwent surgery for CM-I, each of which was associated with specific outcomes. This morphological classification of patients might help in understanding the underlying mechanisms and providing personalized treatment.

This commentary provides an overview of the putamen as an established target site for gene therapy in treating aromatic l‐amino acid decarboxylase (AADC) deficiency and Parkinson’s disease, two debilitating neurological disorders that involve motor dysfunction caused by dopamine deficiencies. The neuroanatomy and the function of the putamen in motor control provide good rationales for targeting this brain structure. Additionally, the efficacy and safety of intraputaminal gene therapy demonstrate that restoration of dopamine synthesis in the putamen by using low doses of adeno‐associated viral vector serotype 2 to deliver the hAADC gene is well tolerated. This restoration leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency and improved uptake and conversion of exogenous l‐DOPA into dopamine in Parkinson’s patients., This Commentary provides an overview of putamen‐targeted gene therapies for treating aromatic l‐amino acid decarboxylase (AADC) deficiency and Parkinson’s disease.

Background Primary central nervous system tumors (PCNST) among adolescents and young adults (AYA, 15–39 y) have rarely been reported. We present a nationwide report of PCNST histologically confirmed in the French AYA population between 2008 and 2013. Methods Patients were identified through the French Brain Tumor Database (FBTDB), a national dataset that includes prospectively all histologically confirmed cases of PCNST in France. Patients aged 15 to 39 years with histologically confirmed PCNST diagnosed between 2008 and 2013 were included. For each of the 143 histological subtypes of PCNST, crude rates, sex, surgery, and age distribution were provided. To enable international comparisons, age-standardized incidence rates were adjusted to the world-standard, European, and USA populations. Results For 6 years, 9661 PCNST (males/females: 4701/4960) were histologically confirmed in the French AYA population. The overall crude rate was 8.15 per 100 000 person-years. Overall, age-standardized incidence rates were (per 100 000 person-years, population of reference: world/Europe/USA): 7.64/8.07/8.21, respectively. Among patients aged 15–24 years, the crude rate was 5.13 per 100 000. Among patients aged 25–39 years, the crude rate was 10.10 per 100 000. Age-standardized incidence rates were reported for each of the 143 histological subtypes. Moreover, for each histological subtype, data were detailed by sex, age, type of surgery (surgical resection or biopsy), and cryopreserved samples. Conclusion These data represent an exhaustive report of all histologically confirmed cases of PCNST with their frequency and distribution in the French AYA population in 2008–2013. For the first time in this age group, complete histological subtypes and rare tumor identification are detailed.

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.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5–37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden’s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

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BACKGROUND: Status dystonicus (SD) is a life-threatening condition. OBJECTIVE AND METHODS: In a dystonia cohort who developed status dystonicus, we analyzed demographics, background dystonia phenomenology and complexity, trajectory previous to-, via status dystonicus episodes, and evolution following them. RESULTS: Over 20 years, 40 of 328 dystonia patients who were receiving DBS developed 58 status dystonicus episodes. Dystonia was of pediatric onset (95%), frequently complex, and had additional cognitive and pyramidal impairment (62%) and MRI alterations (82.5%); 40% of episodes occured in adults. Mean disease duration preceding status dystonicus was 10.3 \textpm 8 years. Evolution time to status dystonicus varied from days to weeks; however, 37.5% of patients exhibited progressive worsening over years. Overall, DBS was efficient in resolving 90% of episodes. CONCLUSION: Status dystonicus is potentially reversible and a result of heterogeneous conditions with nonuniform underlying physiology. Recognition of the complex phenomenology, morphological alterations, and distinct patterns of evolution, before and after status dystonicus, will help our understanding of these conditions. \textcopyright 2018 International Parkinson and Movement Disorder Society.

International audience; BackgroundPositional skull deformities (PSD) are becoming a daily health concern for craniofacial surgeons. Several reports have indicated that cerebrospinal fluid (CSF) space increases on computed tomography (CT) scans of infants suffering from PSD, suggesting a potential causal link. Here, we describe a semi-automatic method to estimate total brain and CSF volumes quantitatively. We tested the potential correlation between total CSF volume and the occurrence of PSD.MethodsA single-center retrospective study was carried out using 79 CT scans of PSD and 60 CT scans of control subjects. The endocranium was segmented automatically using a three-dimensional deformable surface model, and the brain was segmented using a semi-automatic threshold-based method. Total CSF volume was estimated based on the difference between endocranial and brain volumes.ResultsAutomatic segmentation of the endocranium was possible in 75 CT scans. Semi-automatic brain and CSF volume evaluations were performed in 40 CT scans of infants with PSD (18 = occipital plagiocephaly, 11 = fronto-occipital plagiocephaly, and 11 = posterior brachycephaly) and in six control CT scans. Endocranial and total CSF volumes were not significantly different between patients with PSD and controls. The occipital plagiocephaly group had an enlarged brain volume compared with that in patients in the other groups.ConclusionsTotal CSF volume did not change in infants with PSD, and the results do not support a role for volume changes in CSF in the etiology of PSD. Macrocephaly in patients with occipital plagiocephaly may be a specific etiological factor compared with that in other PSDs.Keywords

Resume Les kystes arachnoidiens supra-sellaires (KASS) de l’enfant sont consideres comme rares, mais leur incidence augmente du fait de l’amelioration des diagnostics prenataux. Nous presentons 15 KASS de decouverte antenatale entre 2005 et 2015. Les dossiers ont ete revus retrospectivement en precisant les caracteristiques radiologiques, les modalites de traitement, les resultats et le suivi a long terme. Le suivi moyen etait de 71 mois. Les formes hautes (KASS-1) regroupaient 2 cas (13 %) presentant une hydrocephalie. Nous avons observe 8 (53 %) formes basses (KASS-2) avec dilatation de la citerne interpedonculaire sans hydrocephalie. Les formes asymetriques (KASS-3) concernaient les 5 (33,5 %) patients restants. Six patients (40 %) ont ete traites par ventriculo-kysto-cisternostomie, dont 1 par fœtoscopie, 1 (6,5 %) par derivation ventriculo-peritoneale, 2 (13,5 %) par abord pterional et 6 (40 %) ont simplement ete suivis. Les suites chirurgicales ont ete favorables initialement dans 9 cas (100 %), 1 patient (13 %) a du etre retraite ulterieurement. Les patients non operes etaient tous de type 2 et n’ont presente aucune modification radiologique. A long terme, 1 patient (6,5 %) avait des perturbations endocriniennes, 1 un retard de developpement, 2 (13,5 %) des alterations neuropsychologiques mineures et 1 une comitialite. Le suivi antenatal combine par IRM et echographie permet distinguer trois sous-types de KASS. Les KASS-1 et KASS-3 sont d’excellent pronostic apres traitement dans la periode perinatale. Les KASS-2 peuvent beneficier d’une simple surveillance et restent en majorite asymptomatiques. Cette classification permet une meilleure estimation pronostique ainsi qu’une meilleure decision therapeutique.

International audience; INTRODUCTION:Brain mapping through a direct cortical and subcortical electrical stimulation during an awake craniotomy has gained an increasing popularity as a powerful tool to prevent neurological deficit while increasing extent of resection of hemispheric diffuse low-grade gliomas in adults. However, few case reports or very limited series of awake surgery in children are currently available in the literature.METHODS:In this paper, we review the oncological and functional differences between pediatric and adult populations, and the methodological specificities that may limit the use of awake mapping in pediatric low-grade glioma surgery.RESULTS:This could be explained by the fact that pediatric low-grade gliomas have a different epidemiology and biologic behavior in comparison to adults, with pilocytic astrocytomas (WHO grade I glioma) as the most frequent histotype, and with WHO grade II gliomas less prone to anaplastic transformation than their adult counterparts. In addition, aside from the issue of poor collaboration of younger children under 10 years of age, some anatomical and functional peculiarities of children developing brain (cortical and subcortical myelination, maturation of neural networks and of specialized cortical areas) can influence direct electrical stimulation methodology and sensitivity, limiting its use in children.CONCLUSIONS:Therefore, even though awake procedure with cortical and axonal stimulation mapping can be adapted in a specific subgroup of children with a diffuse glioma from the age of 10 years, only few pediatric patients are nonetheless candidates for awake brain surgery.

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, France, between 2002 and 2015: surgery at diagnosis (n=54; group A) and surgery delayed after carboplatin and etoposide-based preoperative 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% versus 57.4%, p=0.0013). Post-operative complications, chemotherapy-associated side effects and local progressions were not increased in group B. Preoperative chemotherapy led to a decrease in the primary tumor size in all patients, 4/38 patients experiencing meanwhile 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 preoperative 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.

A female newborn was presented to the neurosurgery department at 3 weeks of age with a subcutaneous scalp bulge (figure 1A). Figure 1 (A) Extracranial transilluminant collection. (B) Coronal, T2-weighted MRI of the cranium showing a leak through the metopic suture suggesting a dural defect, a subaponeurotic pseudomeningocele and bilateral brain lesions. She was born at 40 weeks of gestation by vacuum extraction in another hospital. A frontal caput succedaneum was present at birth, and a cephalhaematoma developed next to the sagittal suture during the following hours. …

International audience

International audience; Background: Exacerbation of hyperkinesia is a life-threatening complication of dyskinetic movement disorders, which can lead to multi-organ failure and even to death. GNAO1 has been recently identified to be involved in the pathogenesis of early infantile epileptic encephalopathy and movement disorders. Patients with GNAO1 mutations can present with a severe, progressive hyperkinetic movement disorder with prolonged life-threatening exacerbations, which are refractory to most anti-dystonic medication. Objective: The objective was to investigate the evolution of symptoms and the response to deep brain stimulation of the globus pallidus internus (GPi-DBS) in patients with different GNAO1 mutations. Methods: We report six patients presenting with global motor retardation, reduced muscle tone and recurrent episodes of severe, life-threatening hyperkinesia with dystonia, choreoathetosis, and ballism since early childhood. Five of them underwent GPi-DBS. Results: The genetic workup revealed mutations in GNAO1 for all six patients. These encompass a new splice site mutation (c.723 + 1G > T) in patient 1, a new missense mutation (c.610G > C; p.Gly204Arg) in patient 2, a heterozygous mutation (c.625 > T; p.Arg209Cys) in patients 3 and 4, and a heterozygous mutation (c.709G > A; p.Glu237Lys) in patients 5 and 6. By intervention with GPi-DBS the severe paroxysmal hyperkinetic exacerbations could be stopped in five patients. One patient is still under evaluation for neuromodulation. Conclusion In complex movement disorders of unsolved etiology clinical WES can rapidly streamline pathogenic genes. We identified two novel GNAO1 mutations. GPi-DBS can be an effective and life-saving treatment option for patients with GNAO1 mutations and has to be considered early.

International audience; Intracranial empyema is a rare but serious complication of sinusitis in children. Myelodysplastic/myeloproliferative syndromes (MMS), including juvenile myelomonocytic leukemia (JMML), can lead to immunosuppression, thus favouring infections. We report the case of a sphenoid sinogenic retro-clival extradural empyema in a 14-year-old female patient associated with JMML. Treatment consisted in an endonasal transphenoidal drainage of the empyema associated with intravenous antibiotherapy. The patient was thereafter enrolled in chemotherapeutic treatment with Azacitidine. The disease progressed to blast phase, indicating bone marrow graft. This is the first reported case of an endocranial complication of bacterial sinusitis associated with MMS in a child.

Part of special issue: Lysosome (2018); International audience

International audience; Background : Congenital bilateral vocal cord paralysis is a rare occurrence. Approximately half the cases areassociated with a major comorbidity, usually neurological, neuromuscular or malformative. Case presentation : In a male newborn, respiratory distress syndrome and stridor were observed immediatelyfollowing birth. The cause was bilateral vocal cord paralysis in the adducted position. Neuroradiologicalinvestigation revealed a unilateral discontinuity between the upper pons and the right medulla oblongata. Hypoplasia of the right posterior hemiarches of C1-C2and the right exo-occipital bone was observed, as wasa small clivus. MR angiography showed the absence of the distal right vertebral artery, with hypoplasia andparietal irregularities of the proximal segments. Respiratory autonomy was not obtained despite endoscopiclaser cordotomy, corticosteroid therapy and nasal continuous positive airway pressure. The infant died at theage of 4 weeks after treatment was limited to comfort care. Conclusions : A medullary lesion is an exceptional cause of congenital bilateral vocal cord paralysis. The strictlyunilateral neurological and vascular defect and the absence of associated intracranial or extracranial malformationmake this clinical case unique and suggest a disruptive mechanism. This case also highlights the help provided byadvanced neuroimaging techniques, i.e. fibre tracking using diffusion tensor imaging, in the decision-making process.

Diffuse intrinsic pontine glioma (DIPG) is the most severe pediatric solid tumor, with no significant improvement in the past 50 years. Possible reasons for failure to make therapeutic progress include poor understanding of the underlying molecular biology due to lack of tumor material.We performed a prospective analysis of children with typical appearance of DIPG who had a stereotactic biopsy in our unit since 2002. Technical approach, complications, histopathological results, and samples processing are exposed. The literature on this subject is discussed.Reviewing our own 130 cases of DIPG biopsies and previous published data, these procedures appear to have a diagnostic yield and morbidity rates similar to those reported for other brain locations (3.9 % of transient morbidity in our series). In addition, the quality and the quantity of the material obtained allow to (1) confirm the diagnosis, (2) reveal that WHO grading was useless to predict outcome, and (3) perform an extended molecular screen, including biomarkers study and the development of preclinical models. Recent studies reveal that DIPG may comprise more than one biological entity and a unique oncogenesis involving mutations never described in other types of cancers, i.e., histones H3 K27M and activin receptor ACVR1.Stereotactic biopsies of DIPG can be considered as a safe procedure in well-trained neurosurgical teams and could be incorporated in protocols. It is a unique opportunity to integrate DIPG biopsies in clinical practice and use the biology at diagnosis to drive the introduction of innovative targeted therapies, in combination with radiotherapy.

No treatment is available for early-onset forms of metachromatic leukodystrophy (MLD), a lysosomal storage disease caused by autosomal recessive defect in arylsulfatase A (ARSA) gene causing severe demyelination in central and peripheral nervous systems. We have developed a gene therapy approach, based on intracerebral administration of AAVrh.10-hARSA vector, coding for human ARSA enzyme. We have previously demonstrated potency of this approach in MLD mice lacking ARSA expression. We describe herein the preclinical efficacy, safety, and biodistribution profile of intracerebral administration of AAVrh.10-hARSA to nonhuman primates (NHPs). NHPs received either the dose planned for patients adjusted to the brain volume ratio between child and NHP (1×dose, 1.1×10(11) vg/hemisphere, unilateral or bilateral injection) or 5-fold this dose (5×dose, 5.5×10(11) vg/hemisphere, bilateral injection). NHPs were subjected to clinical, biological, and brain imaging observations and were euthanized 7 or 90 days after injection. There was no toxicity based on clinical and biological parameters, nor treatment-related histological findings in peripheral organs. A neuroinflammatory process correlating with brain MRI T2 hypersignals was observed in the brain 90 days after administration of the 5×dose, but was absent or minimal after administration of the 1×dose. Antibody response to AAVrh.10 and hARSA was detected, without correlation with brain lesions. After injection of the 1×dose, AAVrh.10-hARSA vector was detected in a large part of the injected hemisphere, while ARSA activity exceeded the normal endogenous activity level by 14-31%. Consistently with other reports, vector genome was detected in off-target organs such as liver, spleen, lymph nodes, or blood, but not in gonads. Importantly, AAVrh.10-hARSA vector was no longer detectable in urine at day 7. Our data demonstrate requisite safe and effective profile for intracerebral AAVrh.10-hARSA delivery in NHPs, supporting its clinical use in children affected with MLD.

Decompressive craniectomy (DC) is a lifesaving procedure but is associated to several post-operative complications, namely cerebrospinal fluid (CSF) dynamics impairment. The aim of this multicentric study was to evaluate the incidence of such CSF alterations after DC and review their impact on the overall outcome. We performed a retrospective multicentric study to analyze the CSF disorders occurring in children aged from 0 to 17 years who had undergone a DC for traumatic brain injury (TBI) in the major Departments of Pediatric Neurosurgery of France between January 2006 and August 2016. Out of 150 children, ranging in age between 7 months and 17 years, mean 10.75 years, who underwent a DC for TBI in 10 French pediatric neurosurgical centers. Sixteen (6 males, 10 females) (10.67%) developed CSF disorders following the surgical procedure and required an extrathecal CSF shunting. External ventricular drainage increased the risk of further complications, especially cranioplasty infection (p = 0.008). CSF disorders affect a minority of children after DC for TBI. They may develop early after the DC but they may develop several months after the cranioplasty (8 months), consequently indicating the necessity of clinical and radiological close follow-up after discharge from the neurosurgical unit. External ventricular drainage and permanent CSF shunt placement increase significantly the risk of cranioplasty infection.

Summary Background Mucopolysaccharidosis type IIIB syndrome (also known as Sanfilippo type B syndrome) is a lysosomal storage disease resulting in progressive deterioration of cognitive acquisition after age 2–4 years. No treatment is available for the neurological manifestations of the disease. We sought to assess the safety and efficacy of a novel intracerebral gene therapy. Methods Local regulatory authorities in France allowed inclusion of up to four children in this phase 1/2 study. Treatment was 16 intraparenchymal deposits (four in the cerebellum) of a recombinant adenoassociated viral vector serotype 2/5 (rAAV2/5) encoding human α-N-acetylglucosaminidase (NAGLU) plus immunosuppressive therapy. We assessed tolerance, neurocognitive progression, brain growth, NAGLU enzymatic activity in CSF, and specific anti-NAGLU immune response for 30 months after surgery. This trial is registered with EudraCT, number 2012-000856-33, and the International Standard Clinical Trial Registry, number ISRCTN19853672. Findings Of seven eligible children, the four youngest, from France (n=2), Italy (n=1), and Greece (n=1), aged 20, 26, 30, and 53 months, were included between February, 2012, and February, 2014. 125 adverse events were recorded, of which 117 were treatment emergent and included six classified as severe, but no suspected unexpected serious adverse drug reactions were seen. Vector genomes were detected in blood for 2 days after surgery. Compared with the natural history of mucopolysaccharidosis type III syndromes, neurocognitive progression was improved in all patients, with the youngest patient having function close to that in healthy children. Decrease in developmental quotient was −11·0 points in patient one, −23·0 in patient two, −29·0 in patient three, and −17·0 in patient four, compared with −37·7 in the natural history of the disease. NAGLU activity was detected in lumbar CSF and was 15–20% of that in unaffected children. Circulating T lymphocytes that proliferated and produced tumour necrosis factor α upon ex-vivo exposure to NAGLU antigens were detectable at 1–12 months and 3–12 months, respectively, but not at 30 months in three of four patients. Interpretation Intracerebral rAVV2/5 was well tolerated and induced sustained enzyme production in the brain. The initial specific anti-NAGLU immune response that later subsided suggested acquired immunological tolerance. The best results being obtained in the youngest patient implies a potential window of opportunity. Longer follow-up is needed to further assess safety outcomes and persistence of improved cognitive development. Funding Association Francaise Contre les Myopathies, Vaincre les Maladies Lysosomales, Institut Pasteur, and UniQure.

Object To date, experience of globus pallidus internus (GPi) deep brain stimulation (DBS) in the treatment of Huntington's disease (HD) has been limited to a small number of case reports. The aim of this study was to analyze long-term motor outcome of a cohort of HD patients treated with GPi DBS. Methods Seven patients with pharmacologically resistant chorea and functional impairment were included in a prospective open-label study from 2008 to 2011. The main outcome measure was the motor section of the Unified Huntington's Disease Rating Scale. The primary end point was reduction of chorea. Results Patients underwent MRI-guided bilateral GPi implantation. The median duration of follow-up was 3 years. A significant reduction of chorea was observed in all patients, with sustained therapeutic effect; the mean improvement on the chorea subscore was 58.34% at the 12-month follow-up visit (p = 0.018) and 59.8% at the 3-year visit (p = 0.040). Bradykinesia and dystonia showed a nonsignificant trend toward progressive worsening related to disease evolution and partly to DBS. The frequency of stimulation was 130 Hz for all patients. DBS-induced bradykinesia was managed by pulse-width reduction or bipolar settings. Levodopa mildly improved bradykinesia in 4 patients. Regular off-stimulation tests confirmed a persistent therapeutic effect of DBS on chorea. Conclusions GPi DBS may provide sustained chorea improvement in selected HD patients with pharmacologically resistant chorea, with transient benefit in physical aspects of quality of life before progression of behavioral and cognitive disorders. DBS therapy did not improve dystonia or bradykinesia. Further studies including quality of life measures are needed to evaluate the impact of DBS in the long-term outcome of HD.

Mucopolysaccharidosis type IIIA is a severe degenerative disease caused by an autosomal recessive defect of a gene encoding a lysosomal heparan-N-sulfamidase, the N-sulfoglycosamine sulfohydrolase (SGSH), the catalytic site of which is activated by a sulfatase-modifying factor (SUMF1). Four children (Patients 1-3, aged between 5.5 and 6 years; Patient 4 aged 2 years 8 months) received intracerebral injections of an adeno-associated viral vector serotype rh.10-SGSH-IRES-SUMF1 vector in a phase I/II clinical trial. All children were able to walk, but their cognitive abilities were abnormal and had declined (Patients 1-3). Patients 1-3 presented with brain atrophy. The therapeutic vector was delivered in a frameless stereotaxic device, at a dose of 7.2×10(11) viral genomes/patient simultaneously via 12 needles as deposits of 60 μl over a period of 2 hr. The vector was delivered bilaterally to the white matter anterior, medial, and posterior to the basal ganglia. Immunosuppressive treatment (mycophenolate mofetil and tacrolimus) was initiated 15 days before surgery and maintained for 8 weeks (mycophenolate mofetil) or throughout follow-up (tacrolimus, with progressive dose reduction) to prevent elimination of transduced cells. Safety data collected from inclusion, during the neurosurgery period and over the year of follow-up, showed good tolerance, absence of adverse events related to the injected product, no increase in the number of infectious events, and no biological sign of toxicity related to immunosuppressive drugs. Efficacy analysis was necessarily preliminary in this phase I/II trial on four children, in the absence of validated surrogate markers. Brain atrophy evaluated by magnetic resonance imaging seemed to be stable in Patients 1 and 3 but tended to increase in Patients 2 and 4. Neuropsychological evaluations suggested a possible although moderate improvement in behavior, attention, and sleep in Patients 1-3. The youngest patient was the most likely to display neurocognitive benefit.

Resume Nous rapportons le cas d’une adolescente de 14 ans ayant presente une hypokinesie ventriculaire gauche symptomatique dans les suites de la rupture d’une malformation arterio-veineuse cerebelleuse. La cardiomyopathie de type tako-tsubo doit etre connue des pediatres, car les circonstances declenchant l’affection, un facteur emotionnel ou une atteinte du systeme nerveux central, peuvent se rencontrer dans l’enfance. Elle est responsable d’une dysfonction ventriculaire qui predomine a l’apex et dans la region medio-ventriculaire gauche, donnant un aspect caracteristique a l’echocardiographie. Un traitement symptomatique peut etre transitoirement necessaire en cas d’hypotension arterielle, de trouble du rythme ou d’insuffisance cardiaque. Son evolution generalement favorable autorise a delivrer une information rassurante et a limiter les explorations etiologiques sur le muscle cardiaque.

Spinal lipoma of the filum terminale (LFT) is a congenital lumbosacral anomaly that can cause tethered cord syndrome. Purposes of this study are to clarify preoperative characteristics of LFT, to elucidate surgical effects, and to discuss the rationale of prophylactic surgery for LFT. Medical data of 174 children (2008–2014) who underwent section of LFT were prospectively recorded for prevalence of symptoms, skin stigmas, and associated malformations, motivator of diagnosis, conus level, and surgical outcome. Mean age at surgery was 4.1 ± 4.2 years (37 days to 17.7 years). Ninety-four children (54.0 %) had skin stigmas and 60 (34.5 %) had certain perineal malformations. Seventy-nine children (45.4 %) were symptomatic. The most common motivator for diagnosis was skin stigmas (44.3 %), followed by associated malformations (33.3 %), and symptoms (20.1 %). The age at surgery was significantly older in symptomatic patients than in asymptomatic patients (p

Brain stem glioma accounts for 6–9% of brain tumors in children. Tumor progression may lead to CSF pathway obstruction and development of hydrocephalus. We retrospectively reviewed charts of patients consecutively treated in our institution with diffuse intrinsic pontine glioma in order to assess incidence of hydrocephalus, its management, and its impact on overall survival. All patients had brain stem glioma not amenable to surgery. Cases with exophytic brain stem glioma were excluded. Fifty-one children were treated from January 2005 to December 2010 for brain stem glioma in the Pediatric Neurosurgery Department of Necker Enfants Malades, Paris, France. Hydrocephalus occurred in 11 of them (22%). They were six boys and five girls; the average and median time from tumor diagnosis to onset of hydrocephalus were 5.3 and 3.2 months, respectively, while average and median time from onset of hydrocephalus to death were 5.3 and 2.8 months, respectively. Hydrocephalus was treated in nine patients by a ventriculoperitoneal (VP) shunt and in two patients by an endoscopic third ventriculostomy. Because of early failure, a VP shunt was implanted in one child. The overall 1-year survival rate was 33%. Survival rate of patients with such obstructive hydrocephalus was not significantly different from patients harboring brain stem glioma who did not develop hydrocephalus. Furthermore, hydrocephalus was not related to terminal tumor progression. Considering both risks and benefit of treatment, VP shunt could be proposed, on the base of our experience, as the first option in spite of the apparently obstructive nature of the hydrocephalus associated to a brain stem tumor.

Introduction Even if decompressive craniectomy is a lifesaving procedure, it may be associated to several postoperative complications, namely cerebrospinal fluid (CSF) dynamics impairment. Material and methods We performed a retrospective multicentric study analysis of CSF disorders in children aged from 0 to 17 years undergoing a DC during the hospitalization for TBI between January 2006 and August 2016 in the major departments of pediatric neurosurgery of France. Results Hundred and fifty children underwent a DC for TBI between January 2006 and August 2016. The incidence of CSF disorders was 10, 67%. One main factor appeared statistically related to shunt placement: previous EVD placement. Shunt placement increased the risk of further complications especially cranioplasty infection (P = 0.008). Conclusion CSF disorders may develop several months after DC and its occurrence increases significantly the risk of complications of the cranioplasty. Clinical and radiological close follow-up is mandatory after discharge from the neurosurgical unit.

Objective The aim of this study was to determine the safety of a deep brain stimulation technique consisting of a combination of routine general anesthesia, magnetic resonance imaging direct targeting, and a single penetration technique in a large population of patients undergoing operation for movement disorders. Methods One hundred ninety-four patients treated with deep brain stimulation between 1996 and 2007 were assessed via a computerized database for intra- and perioperative events. Most patients were young; only 62 of them were older than 40 years (mean age, 31.1 years). General anesthesia was induced in all cases before placement of a magnetic resonance imaging-compatible stereotactic frame. Electrode implantation was done under radioscopic control via a rigid immobile cannula using a single cerebral perforation. No perioperative microelectrode recording or neurostimulation testing was used. Systematic postoperative magnetic resonance imaging was performed before frame removal. Results A total of 478 electrodes were implanted in 220 procedures: 426 for dystonic-dyskinetic syndromes and 52 for Parkinson disease. The mean number of parenchymal penetrations per patient was 2.5 for the dystonic-dyskinetic syndrome group and 2.08 for the Parkinson disease group. Postimplantation magnetic resonance imaging detected no perioperative intraparenchymal hemorrhages. Conclusion We consider that the risk of hemorrhagic complication is multifactorial but closely related to the chosen technique.

The optimal surgical management of sylvian arachnoid cysts is debated. We present our experience in children who were treated endoscopically, focusing on the limits and complications of this approach.Seventeen children with a temporo-sylvian arachnoid cyst have been treated using a purely temporal endoscopic approach.In all but one case, the recognition of anatomical landmarks was obtained at the insertion of the endoscope. In one child, the orientation and opening of the basal cisterns were more difficult due to the thickness and opacity of the membranes. Nevertheless, it was possible to perform the cysto-cisternostomy endoscopically in all children with several stomies in 13. In one child, a venous bleeding occurred. There were no other intraoperative complications. There were no postoperative cerebrospinal fluid leaks. In two patients, a symptomatic subdural collection developed which required a transient subdural-peritoneal shunt. No subdural collection was noted on a delayed follow-up (mean, 23 months). Preoperative symptoms related to the mass effect exerted by the cyst resolved in all children. Two children presented a recurrence, 12 and 20 months after endoscopic surgery, respectively. At the redo-endoscopy, the stomies were found to be closed. Their reopening resulted in the disappearance of the symptoms.An endoscopic approach can be used safely in the management of sylvian arachnoid cysts. An effective opening of the deep arachnoid membranes into the basal cisterns could be performed in all patients with the resolution of the preoperative symptoms. However, the long-term efficacy of the stoma needs to be assessed.

This study aims to describe the characteristics of severe head injuries in children less than 6 years old, victims of falls from windows, and identify the main predictive factors of mortality in this population.A cross-sectional study was designed through data derived from medical records of less than 6-year-old children victims of falls from windows presenting with a severe head injury defined by an initial Glasgow coma scale (GCS)or =8, hospitalized at a Pediatric Trauma center level III, between January 2000 and December 2005. Statistical analysis used univariate analysis and multiple logistic regressions.We identified 58 severe head injuries in children victims of falls from windows. The mean age was 2.8 +/- 1.4 years, with a male prevalence (64%); 48% of patients had a GCSor =5; 62.1% had a Pediatric Trauma Score (PTS)or =3 at hospital admission. The mortality rate was 41% (24/58) and most of them (88%; 21/24) died within 48 h. An increased death rate was noted in children admitted with hypoxemia (p = 0.001), low systolic blood pressure (p = 0.002), hypothermia (p = 0.0001), GCSor =5 (p = 10(-5)), PTSor =3 (p = 0.008), hyperglycemia (p = 0.023), coagulation disorders (p = 0.02), and initial intracranial pressureor =20 mmHg (p = 0.03). Initial hypothermia, hyperglycemia, and coagulation disorders were the only independent predictive factors of mortality.Severe head injuries resulting from falls from windows carry a high risk of mortality in less than 6-year-old children. Hypothermia, hyperglycemia, and coagulation's disorders are independent predictive factors of mortality. Early deaths could be considered as direct consequences of uncontrollable brain lesions.

No recent studies are available which consider the epidemiology and outcome of paediatric intracranial empyema (PICE). We retrospectively studied all PICE cases admitted in our institution from 1993 to 2006. Outcome was assessed using the Glasgow Outcome Scale (GOS) at 24 months. Aetiology, clinical features, therapeutic considerations and risk factors of poor outcome were analysed according to age. Data from 38 patients were studied; 33/38 presented with subdural empyema (SDE) and 5/38 with extradural empyema (EDE); 10/38 were infants

Epilepsy surgery has gained a large role in the treatment of intractable seizures in the last few decades because of the development of operative techniques and better identification of the cerebral anomalies using electrophysiological recordings and neuroimaging. A series of 419 children, aged from five months to 15 years, with epilepsy (medically refractory in 85.5% of them) associated with focal cortical lesions, who underwent surgery between 1986 and 2006 was analyzed to identify the factors that correlated with outcome. Mean follow-up was 5.2 years. According to Engel's classification; 75.8% of the children were seizure-free. When the lesion was well defined, correlations between clinical data, radiological features and electrophysiological features, suggesting a zone of seizure onset around (or even in) the lesion, was the best guarantee of achieving good seizure control by lesionectomy. Nevertheless, seizure outcome was also determined by other factors: the duration of the epilepsy and the surgery. Persistence of seizures was found to be significantly associated with the preoperative duration of epilepsy, the completeness of the lesional resection and de novo brain damage induced by the surgical procedure itself. Early surgery must be considered in children because of the benefits of seizure control on the developing brain and the risk of secondary epileptogenesis.

The shaken baby syndrome (SBS) is an important cause of developmental delay in infants. Epileptic seizures are a common feature of this syndrome. The aim if this study is to analyse the impact of the early and late seizures disorder. We have retrospectively reviewed the clinical and electrophysiological findings in a series of 404 children hospitalised with SBS. In the acute phase, clinical epileptic seizures of various semiologies were found in 73% of the infants. Only 11% of the children had a normal EEG on admission. A poor outcome was found in 88% of the children in case of persisting EEG anomalies despite anti-epileptic treatment with 48% mortality in these patients. The development of refractory epilepsy was also associated with a poor outcome in this series. In fact 96% of the children with seizure recurrence had behavioural problems. The early recognition and subsequent management of these seizures is vital to prevent further neurological injury. Delayed or recurrent epileptic seizures may occur with a different semiology to the seizures in the acute phase and are also associated with a poor prognosis.