Thomas Roujeau

Stereotactic biopsy of diffuse pontine lesions in children

OBJECT Empirical radiotherapy is the current treatment for children with diffuse pontine lesions that have imaging characteristics of an infiltrative malignant astrocytoma. The use of chemotherapeutic agents is, however, currently under investigation in the treatment of these tumors. To be included into a trial, patients need a definitive histological diagnosis. The authors present their prospective study of the stereotactic biopsy of these lesions during a 4-year period. METHODS A suboccipital, transcerebellar approach was used to obtain biopsy samples in 24 children. RESULTS Two patients suffered deficits. Both had a transient (< 2 months) new cranial nerve palsy; one of these patients also experienced an exacerbation of a preoperative hemiparesis. No patient died during the perioperative period. A histological diagnosis was made in all 24 patients as follows: 22 had a malignant infiltrative astrocytoma, one had a low-grade astrocytoma, and one had a pilocytic astrocytoma. The diagnosis of the latter two patients affected the initial treatment after the biopsy. CONCLUSIONS The findings of this study imply that stereotactic biopsy sampling of a diffuse pontine tumor is a safe procedure, is associated with minimal morbidity, and has a high diagnostic yield. A nonmalignant tumor was identified in two of the 24 patients in whom the imaging findings were characteristic of a malignant infiltrative astrocytoma. With the advent of new treatment protocols, stereotactic biopsy sampling, which would allow specific tumor characterization of diffuse pontine lesions, may become standard.

Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas

Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we have carried out integrated molecular profiling of a large series of samples obtained with stereotactic biopsy at diagnosis. While chromosomal imbalances did not distinguish DIPG and supratentorial tumors on CGHarrays, gene expression profiling revealed clear differences between them, with brainstem gliomas resembling midline/thalamic tumours, indicating a closely-related origin. Two distinct subgroups of DIPG were identified. The first subgroup displayed mesenchymal and pro-angiogenic characteristics, with stem cell markers enrichment consistent with the possibility to grow tumor stem cells from these biopsies. The other subgroup displayed oligodendroglial features, and appeared largely driven by PDGFRA, in particular through amplification and/or novel missense mutations in the extracellular domain. Patients in this later group had a significantly worse outcome with an hazard ratio for early deaths, ie before 10 months, 8 fold greater that the ones in the other subgroup (p = 0.041, Cox regression model). The worse outcome of patients with the oligodendroglial type of tumors was confirmed on a series of 55 paraffin-embedded biopsy samples at diagnosis (median OS of 7.73 versus 12.37 months, p = 0.045, log-rank test). Two distinct transcriptional subclasses of DIPG with specific genomic alterations can be defined at diagnosis by oligodendroglial differentiation or mesenchymal transition, respectively. Classifying these tumors by signal transduction pathway activation and by mutation in pathway member genes may be particularily valuable for the development of targeted therapies.

Mortality in Children With Severe Head Trauma: Predictive Factors and Proposal for a New Predictive Scale

BACKGROUND Traumatic brain injury is a public health problem around the world, and recognition of systemic sources of secondary brain lesions is crucial to improve outcome. OBJECTIVE To identify the main predictors of mortality and to propose a grading scale to measure the risk of death. METHODS This retrospective study was based on medical records of children with severe traumatic brain injury who were hospitalized at a level I pediatric trauma center between January 2000 and December 2005. Multiple logistic regression analysis was done to identify independent factors related to mortality. A receiver-operating characteristics curve was performed to verify the accuracy of the multiple logistic regression, and associations that increased mortality were verified. RESULTS We identified 315 children with severe head injury. Median Glasgow Coma Scale score was 6, and median Pediatric Trauma Score was 4. Global mortality rate was 30%, and deaths occurred despite adequate medical management within the first 48 hours in 79% of the patients. Age<2 years (P=.02), Glasgow Coma Scale≤5 (P<10), accidental hypothermia (P=.0002), hyperglycemia (P=.0003), and coagulation disorders (P=.02) were all independent factors predicting mortality. A prognostic scale ranging from 0 to 6 that included these independent factors was then calculated for each patient and resulted in mortality rates ranging from 1% with a score of 6 to 100% with a score of 0. CONCLUSION Independent and modifiable mortality predictors could be identified and used for a new grading scale correlated with the risk of mortality in pediatric traumatic brain injury.BACKGROUND: Traumatic brain injury is a public health problem around the world, and recognition of systemic sources of secondary brain lesions is crucial to improve outcome. OBJECTIVE: To identify the main predictors of mortality and to propose a grading scale to measure the risk of death. METHODS: This retrospective study was based on medical records of children with severe traumatic brain injury who were hospitalized at a level I pediatric trauma center between January 2000 and December 2005. Multiple logistic regression analysis was done to identify independent factors related to mortality. A receiver-operating characteristics curve was performed to verify the accuracy of the multiple logistic regression, and associations that increased mortality were verified. RESULTS: We identified 315 children with severe head injury. Median Glasgow Coma Scale score was 6, and median Pediatric Trauma Score was 4. Global mortality rate was 30%, and deaths occurred despite adequate medical management within the first 48 hours in 79% of the patients. Age < 2 years (P = .02), Glasgow Coma Scale ≤ 5 (P < 10−5), accidental hypothermia (P = .0002), hyperglycemia (P = .0003), and coagulation disorders (P = .02) were all independent factors predicting mortality. A prognostic scale ranging from 0 to 6 that included these independent factors was then calculated for each patient and resulted in mortality rates ranging from 1% with a score of 6 to 100% with a score of 0. CONCLUSION: Independent and modifiable mortality predictors could be identified and used for a new grading scale correlated with the risk of mortality in pediatric traumatic brain injury.

Deep brain stimulation for Huntington's disease: long-term results of a prospective open-label study

UNLABELLED OBJECT.: To date, experience of globus pallidus internus (GPi) deep brain stimulation (DBS) in the treatment of Huntingtons 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 Huntingtons 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.

Magnetic resonance-based deep brain stimulation technique: a series of 478 consecutive implanted electrodes with no perioperative intracerebral hemorrhage.

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.

Intracerebral Gene Therapy Using AAVrh.10-hARSA Recombinant Vector to Treat Patients with Early-Onset Forms of Metachromatic Leukodystrophy: Preclinical Feasibility and Safety Assessments in Nonhuman Primates

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.

Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial

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 Française Contre les Myopathies, Vaincre les Maladies Lysosomales, Institut Pasteur, and UniQure.

Cerebral localization of Rosai–Dorfman disease in a child

Rosai-Dorfman disease (RDD) is a rare idiopathic histiocytic disorder that only occasionally involves the central nervous system (CNS). Previous cases of RDD involving the CNS were generally seen in adults. Pediatric cases of RDD are rare, and the disease in these cases typically has an indolent clinical course. In this report, the authors describe a pediatric case of intracranial RDD with rapid clinical and radiological progression. A previously healthy 13-year-old girl presented with a 15-day history of progressive left-sided headaches, vomiting, and fever. On examination she was pyrexial but otherwise normal. Neuroimaging results demonstrated an extraaxial left frontal lesion with peripheral enhancement. A bur hole was drilled over the lesion to obtain a tissue sample and de-bulk the lesion. The initial histological results showed a nonspecific inflammatory lesion. Postoperatively, the patient was asymptomatic, and neuroimaging results confirmed a significant reduction in the size of the lesion. Repeated neuroimaging 3 months later, however, revealed a large recurrence of the lesion, which was removed macroscopically by a craniotomy. Histological analysis of the tissue confirmed the RDD diagnosis. At the latest follow-up (12 months) the patient had remained asymptomatic with no evidence of recurrence on neuroimaging. This is the first reported case of intracranial RDD with an aggressive clinical course.

Medulloblastomas: update on a heterogeneous disease.

Purpose of review Medulloblastoma is the main primitive neuroectodermal tumour of the posterior fossa in childhood. The classical therapeutic approach consists of surgical resection, followed by craniospinal irradiation. Because of the good overall survival (75%), the main recent research efforts focus on refining the most relevant prognostic stratification and in decreasing the long-term sequelae. Recent findings Thanks to the better understanding of the heterogeneity of medulloblastomas, clinical, histological and biological markers have been clearly identified and allow risk-adapted strategies. A subset of tumours of early childhood (<3–5 years), frequently associated with a Sonic Hedgehog signalling, might be cured without irradiation. In older children, several trials have demonstrated the safety of reduced craniospinal irradiation in standard risk tumours. Furthermore, the evidence of an excellent prognosis associated with a subset of tumours characterized by an activation of the WNT pathway leads to forthcoming de-escalating strategies. Reducing long-term sequelae also relies on new surgical approaches aiming at reducing the cerebellar injuries. Tremendous efforts have also been made in defining the most adapted irradiation doses and fields. Intensity-modulated radiotherapy and proton beam therapy might also influence the long-term neurological and endocrine defects of the patients. Summary Histological and biological characteristics clearly define various prognostic groups within medulloblastomas; confirming the overall good outcome and reducing long-term sequelae are the main focus of current clinical trials.

Epilepsy associated with shaken baby syndrome

ObjectThe 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.Materials and methodsWe have retrospectively reviewed the clinical and electrophysiological findings in a series of 404 children hospitalised with SBS.ResultsIn 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.ConclusionsThe 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.