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

OBJECTIVE: Dysregulation of γ-aminobutyric acidergic (GABAergic) transmission has been reported in lesional acquired epilepsies (gliomas, hippocampal sclerosis). We investigated its involvement in a developmental disorder, human focal cortical dysplasia (FCD), focusing on chloride regulation driving GABAergic signals. METHODS: In vitro recordings of 47 human cortical acute slices from 11 pediatric patients who received operations for FCD were performed on multielectrode arrays. GABAergic receptors and chloride regulators were pharmacologically modulated. Immunostaining for chloride cotransporter KCC2 and interneurons were performed on recorded slices to correlate electrophysiology and expression patterns. RESULTS: FCD slices retain intrinsic epileptogenicity. Thirty-six of 47 slices displayed spontaneous interictal discharges, along with a pattern specific to the histological subtypes. Ictal discharges were induced in proepileptic conditions in 6 of 8 slices in the areas generating spontaneous interictal discharges, with a transition to seizure involving the emergence of preictal discharges. Interictal discharges were sustained by GABAergic signaling, as a GABAA receptor blocker stopped them in 2 of 3 slices. Blockade of NKCC1 Cl- cotransporters further controlled interictal discharges in 9 of 12 cases, revealing a Cl- dysregulation affecting actions of GABA. Immunohistochemistry highlighted decreased expression and changes in KCC2 subcellular localization and a decrease in the number of GAD67-positive interneurons in regions generating interictal discharges. INTERPRETATION: Altered chloride cotransporter expression and changes in interneuron density in FCD may lead to paradoxical depolarization of pyramidal cells. Spontaneous interictal discharges are consequently mediated by GABAergic signals, and targeting chloride regulation in neurons may be considered for the development of new antiepileptic drugs. Ann Neurol 2019; 1-14 ANN NEUROL 2019;85:204-217.

Predictors of Outcome in Patients with Pediatric Intracerebral Hemorrhage: Development and Validation of a Modified Score.

Purpose To propose and validate a modified pediatric intracerebral hemorrhage (PICH) (mPICH) score and to compare its association with functional outcome to that of the original PICH score. Materials and Methods Data from prospectively included patients were retrospectively analyzed. Consecutive patients with nontraumatic PICH who had undergone clinical follow-up were included. The study population was divided into a development cohort (2008-2012, n = 100) and a validation cohort (2013-2016, n = 43). An mPICH score was developed after variables associated with poor outcome were identified at multivariate analysis (King's Outcome Scale for Childhood Head Injury score < 5a) in the development cohort. The accuracy of the score for prediction of poor outcome was evaluated (sensitivity, specificity). Discrimination and calibration of associations between the mPICH score and poor outcome cohorts were assessed (C statistics, Hosmer-Lemeshow test). Results The mPICH score assessed as follows: brain herniation, four points; altered mental status, three points; hydrocephalus, two points; infratentorial PICH, two points; intraventricular hemorrhage, one point; PICH volume greater than 2% of total brain volume, one point. An mPICH score greater than 5 was associated with severe disability or worse, with sensitivity of 97% (95% confidence interval [CI]: 83%, 100%) and specificity of 61% (95% CI: 49%, 73%). The C statistic was 0.81 (95% CI: 0.73, 0.89). In the validation cohort, sensitivity and specificity were 95.2% (95% CI: 76%, 99%) and 77% (95% CI: 55%, 92%), respectively. There was no significant difference between the observed and predicted risks of poor outcome (P = .46). Conclusion An mPICH score was developed as a simple clinical and imaging grading scale for acute prognosis in patients with PICH. © RSNA, 2017.

Loss of α1ß1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia.

Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the α1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble α1ß1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and nonsyndromic moyamoya.

Epileptic seizures in anaplastic gangliogliomas.

AIM: Prevalence and predictors of epileptic seizures are unknown in the malignant variant of ganglioglioma. METHODS: In a retrospective exploratory dataset of 18 supratentorial anaplastic World Health Organization grade III gangliogliomas, we studied: (i) the prevalence and predictors of epileptic seizures at diagnosis; (ii) the evolution of seizures during tumor evolution; (iii) seizure control rates and predictors of epilepsy control after oncological treatments. RESULTS: Epileptic seizures prevalence progresses throughout the natural course of anaplastic gangliogliomas: 44% at imaging discovery, 67% at histopathological diagnosis, 69% following oncological treatment, 86% at tumor progression, and 100% at the end-of-life phase. The medical control of seizures and their refractory status worsened during the tumor's natural course: 25% of uncontrolled seizures at histopathological diagnosis, 40% following oncological treatment, 45.5% at tumor progression, and 45.5% at the end-of-life phase. Predictors of seizures at diagnosis appeared related to the tumor location (i.e. temporal and/or cortical involvement). Prognostic parameters of seizure control after first-line oncological treatment were temporal tumor location, eosinophilic granular bodies, TP53 mutation, and extent of resection. Prognostic parameters of seizure control at tumor progression were a history of epileptic seizures at diagnosis, seizure control after first-line oncological treatment, eosinophilic granular bodies, and TP53 mutation. CONCLUSION: Epileptic seizures are frequently observed in anaplastic gangliogliomas and both prevalence and medically refractory status worsen during the tumor's natural course. Both oncological and antiepileptic treatments should be employed to improve the control of epileptic seizures and the quality of life of patients harboring an anaplastic ganglioglioma.

Arterial Spin Labeling to Predict Brain Tumor Grading in Children: Correlations between Histopathologic Vascular Density and Perfusion MR Imaging.

Purpose To compare arterial spin labeling (ASL) data between low- and high-grade brain tumors in children to establish a cutoff to distinguish low- from high-grade neoplasms and to assess potential correlations between cerebral blood flow (CBF) and quantitative histologic microvascular data. Materials and Methods Approval was obtained from the regional review board. ASL data obtained in 129 children between 2011 and 2015 were retrospectively analyzed. CBF and relative CBF in the most perfused area of each neoplasm and contrast enhancement were quantified with a semiquantitative ratio. The correlation between CBF and microvascular density was analyzed in specimens stained with anti-CD34. Results were controlled in two validation cohorts with 1.5- and 3.0-T magnetic resonance (MR) imaging. Results Mean CBF was significantly higher for high-grade than for low-grade hemispheric (116 mL/min/100 g [interquartile range {IQR}, 73-131 mL/min/100 g] vs 29 mL/min/100 g [IQR, 23-35 29 mL/min/100 g], P < .001), thalamic (87 mL/min/100 g [IQR, 73-100 mL/min/100 g] vs 36 mL/min/100 g [IQR, 30-40 mL/min/100 g], P = .016), and posterior fossa (59 mL/min/100 g [IQR, 45-91 mL/min/100 g] vs 33 mL/min/100 g [IQR, 25-40 mL/min/100 g], P < .001) tumors. With a cutoff of 50 mL/min/100 g, sensitivity and specificity were 90% (95% confidence interval [CI]: 68, 100) and 93% (95% CI: 66, 100), respectively, for hemispheric tumors; 100% (95% CI: 48, 100) and 80% (95% CI: 28, 100), respectively, for thalamic tumors; and 65% (95% CI: 51, 78) and 94% (95% CI: 80, 99), respectively, for posterior fossa tumors. In posterior fossa tumors, additional use of the CBF-to-contrast enhancement ratio yielded sensitivity and specificity of 96% (95% CI: 87, 100) and 97% (95% CI: 84, 100), respectively. Use of a simple algorithm based on these values yielded an accuracy of 93% (95% CI: 87, 97). Validation sets yielded similar results, with grading accuracy of 88% (95% CI: 62, 98) with 1.5-T MR imaging and 77% (95% CI: 46, 95) with 3.0-T MR imaging. CBF was strongly correlated with microvascular density (R = 0.66, P < .001). Conclusion High-grade pediatric brain tumors display higher CBF than do low-grade tumors, and they may be accurately graded by using these values. CBF is correlated with tumor microvascular density. © RSNA, 2016 Online supplemental material is available for this article.

Spinal lipoma of the filum terminale: review of 174 consecutive patients.

PURPOSE: 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. METHODS: 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). RESULTS: 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 < 0.001). Surgery improved symptoms in 50 % of patients at 2.1-year follow-up period. Of 85 asymptomatic patients, all except one remained asymptomatic postoperatively and none of the symptomatic patients deteriorated. The presence of associated malformations and the conus level did not affect surgical outcome. Postoperative complications developed in nine patients (5.2 %): seven transient local problems, one definitive urological deterioration, and one transient respiratory problem. CONCLUSIONS: Surgery for LFT was a simple and safe procedure. It improved half of symptomatic patients and stopped the deterioration of the others. Even if only one of the asymptomatic patients deteriorated at maximum follow-up, the role of prophylactic surgery remains a point of discussion.

Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes.

Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequencing, whilst global gene expression profiling and chromosomal imbalances were determined by microarrays. A full description of the MRI findings at diagnosis and at relapse was integrated with the molecular profiling data and clinical outcome. All DIPG but one were found to harbour either a somatic H3-K27M mutation and/or loss of H3K27 trimethylation. We also discovered a novel K27M mutation in HIST2H3C, and a lysine-to-isoleucine substitution (K27I) in H3F3A, also creating a loss of trimethylation. Patients with tumours harbouring a K27M mutation in H3.3 (H3F3A) did not respond clinically to radiotherapy as well, relapsed significantly earlier and exhibited more metastatic recurrences than those in H3.1 (HIST1H3B/C). H3.3-K27M-mutated DIPG have a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature with PDGFRA activation, while H3.1-K27M-mutated tumours exhibit a mesenchymal/astrocytic phenotype and a pro-angiogenic/hypoxic signature supported by expression profiling and radiological findings. H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets.

Pediatric infratentorial ganglioglioma.

PURPOSE: Pediatric infratentorial gangliogliomas are exceedingly rare tumors; thus, the factors affecting their outcome are poorly understood and their optimal management has still to be defined. METHODS: We reviewed the literature on pediatric gangliogliomas with a focus on those located in the posterior fossa to study treatment and outcome data. We added to this review some of our clinical cases. RESULTS: We found 100 and 80 cases of brainstem and cerebellar pediatric ganglioglioma, respectively, in our literature review. The surgical management varied from biopsy to gross total resection, and adjuvant treatment was given after incomplete resection or at time of progression. A gross total resection should be attempted to remove the contrast enhancing part of the tumor, which may be possible in most of the cerebellar gangliogliomas and some of the brainstem lesions. The cervicomedullary ganglioglioma seems to be the most infiltrative and least amenable to complete resection. Chemotherapy has a limited role and BRAF mutation was reported in 38 to 54 % of cases. The use of radiotherapy exposes the patient to a risk of malignant transformation and should be reserved for unresectable tumors which progress. CONCLUSION: Pediatric posterior fossa gangliogliomas are rare and challenging tumors due to their frequent infiltrative component involving the brainstem. To date, adjuvant therapy has a limited role that may evolve with time thanks to the use of targeted therapies against BRAF mutation. The surgical resection of well-defined contrast enhancing parts should be attempted even in staged surgeries and balanced with the risks of neurological deterioration.

Biopsy in a series of 130 pediatric diffuse intrinsic Pontine gliomas.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

High-dose busulfan-thiotepa with autologous stem cell transplantation followed by posterior fossa irradiation in young children with classical or incompletely resected medulloblastoma.

BACKGROUND: The aim of the study is to evaluate the outcome of young children with high risk localized medulloblastomas (newly diagnosed classical or incompletely resected) treated by high-dose busulfan-thiotepa with autologous stem cell rescue (ASCT) followed by focal radiation therapy (RT). PROCEDURE: Between September 1994 and January 2010, 19 children younger than 5 years old at diagnosis fulfilling the above inclusion criteria were treated at the Institute Gustave Roussy. After conventional chemotherapy, they received busulfan at a dose of 600 mg/m(2) and thiotepa at a dose of 900 mg/m(2) followed by ASCT. Focal RT was delivered at least 70 days after ASCT. RESULTS: The median follow-up was 40.5 months (range, 14.5-191.2 months). The 3-year event-free survival (EFS) and OS were 68% (95% CI 45-84%) and 84% (95% CI 61-94%), respectively. Acute toxicity consisted mainly in hepatic veno-occlusive disease (6/19 patients) and bone marrow aplasia (all patients). No toxic death occurred. The Full Scale Intellectual Quotient tended to decrease over time at a mean rate of 0.9 point per year from the date of diagnosis. CONCLUSIONS: This intensive treatment resulted in a high overall survival rate in young children with newly diagnosed non-metastatic classic or incompletely resected MB. In spite of a high incidence of hepatic veno-occlusive disease (32%), the acute toxicity was manageable. Delayed neuropsychological side effects remain main concerns. These results should to be confirmed in a larger cohort.

Craniovertebral junction anomalies in achondroplastic children.

The natural history of CVJ stenosis in achondroplastic children is only partially known. Achondroplastic children have a foramen magnum that is significatively smaller at birth, and it does not follow the normal growth during the first 18 months of life, leading to CVJ stenosis and, for the most severe of them, to neurological and developmental impairment and delay and even sudden death due to cervicomedullary narrowing. We reviewed our experience based on 37 patients operated for cervicomedullary decompression between 1970 and 2010 and performed a literature review. The indication for surgery should be taken on very strict clinical and radiological parameters as well as sleep studies. Under those criteria, surgical decompression of CVJ leads to neurological and developmental improvement, despite non-negligible mortality and morbidity.

The foramen magnum in isolated and syndromic brachycephaly.

BACKGROUND: Though the foramen magnum (FM) is often altered in complex craniosynostosis, no study analysed the FM dimensions in patients with brachycephaly specifically. PATIENTS AND METHODS: We measured the FM area, sagittal and transverse diameters on preoperative CT scans in patients with bicoronal synostosis (n = 40) and age-matched control group (n = 18). Our study included 16 children with FGFR3 p.Pro250Arg mutation (mean age 6.1 months), 10 with TWIST-1 mutation (mean age7.6 months) and 14 patients with isolated bicoronal synostosis (mean age 6.1). RESULTS: We observed a significantly smaller FM area in FGFR3 group compared to control group and isolated brachycephaly group (p = 0.001 and p = 0.038, respectively). The mean FM area in FGFR3 group was 426.13 mm(2) (p = 0.001), while in TWIST-1 group was 476.34 mm(2) (p = 0.103), and in isolated brachycephaly group 489.43 mm(2) (p = 0.129) compared to control group: 528.90 mm(2). The posterior segment of the sagittal diameter of the FM and its width as well as the bi-interoccipital synchondrosis diameters were significantly smaller in FGFR3 group compared to control group. In TWIST-1 group, the only altered dimension was the FM anterior segment of the sagittal diameter (p = 0.008). We did not observe any significant alteration of FM in patients with isolated brachycephaly compared to control group. DISCUSSION AND CONCLUSIONS: The FM area is significantly altered in FGFR3-related brachycephaly, whereas in patients with Saethre-Chotzen syndrome (TWIST-1 mutation) the mean FM area is similar to control group. This study confirms the importance of FGFRs on FM growth whereas TWIST-1 seems to have a minor role.

Interhemispheric Vertical Hemispherotomy: Technique, Outcome, and Pitfalls-A Bicentric Retrospective Case Series of 39 Cases.

BACKGROUND AND OBJECTIVES: When seizure onset affects a whole hemisphere, hemispheric disconnections are efficient and safe procedures. However, both lateral peri-insular hemispherotomy and vertical paramedian hemispherotomy approaches report a failure rate around 20%, which can be explained by residual connections giving rise to persistent seizures. In this study, we present the interhemispheric vertical hemispherotomy (IVH), a technical variation of the vertical paramedian hemispherotomy approach, that aims to increase seizure control avoiding residual connections while exposing the corpus callosum. METHODS: This is a retrospective study of IVH in two centers, with analysis of clinical and MRI data and outcomes. A detailed description of the technique is provided with a video. RESULTS: IVH was performed in 39 children. The mean age at surgery was 7.2 years, and etiologies were as follows: malformations of cortical development (n = 14), Rasmussen's encephalitis (n = 10), stroke (n = 10), post-traumatic (3), and Sturge-Weber Syndrome (2). Hemispheric disconnection was complete on postoperative MRI in 34 cases. There was no mortality, hydrocephalus occurred in one case, and subdural collection occurred in four cases. A second surgery was performed in four cases because of seizure relapse (n = 3) and/or incomplete disconnection on MRI (n = 4). With a mean follow-up of 3.2 years, International League Against Epilepsy class I epilepsy outcome was obtained for 37/39 patients. CONCLUSION: IVH is a safe and effective variation of the vertical approaches for hemispheric disconnection. It allows a good exposure and anatomic control of the corpus callosum, which is a frequent site of incomplete disconnection. IVH may be limited by the thalamic volume and the ventricular size, notably in hemimegalencephaly cases.

Assessment of Puberty and Hypothalamic-Pituitary-Gonadal Axis Function After Childhood Brain Tumor Treatment.

CONTEXT: Endocrine complications are common in pediatric brain tumor patients. OBJECTIVE: To 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. METHODS: We 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. RESULTS: Among 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. CONCLUSION: Tumor 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.

Hypothalamic-pituitary lesions in pediatric patients: endocrine symptoms often precede neuro-ophthalmic presenting symptoms.

OBJECTIVE: To evaluate whether analyses of clinical and endocrine presenting symptoms could help to shorten the time to diagnosis of hypothalamic-pituitary lesions in children. STUDY DESIGN: A retrospective, single-center, cohort study of 176 patients (93 boys), aged 6 years (range, 0.2-18 years), with hypothalamic-pituitary lesions was performed. RESULTS: The lesions were craniopharyngioma (n = 56), optic pathway glioma (n = 54), suprasellar arachnoid cyst (n = 25), hamartoma (n = 22), germ cell tumor (n = 12), and hypothalamic-pituitary astrocytoma (n = 7). The most common presenting symptoms were neurologic (50%) and/or visual complaints (38%), followed by solitary endocrine symptoms (28%). Precocious puberty led to diagnosis in 19% of prepubertal patients (n = 131), occurring earlier in patients with hamartoma than in patients with optic-pathway glioma (P < .02). Isolated diabetes insipidus led to diagnosis for all germ-cell tumors. For 122 patients with neuro-ophthalmic presenting symptoms, the mean symptom interval was 0.5 year (95% CI, 0.4-0.6 year), although 66% of patients had abnormal body mass index or growth velocity, which preceded the presenting symptom interval onset by 1.9 years (95% CI, 1.5-2.4 years) (P < .0001) and 1.4 years (95% CI, 1-1.8 years) (P < .0001), respectively. Among them, 41 patients were obese before diagnosis (median 2.2 years [IQR, 1-3 years] prior to diagnosis) and 35 of them had normal growth velocity at the onset of obesity. The sensitivity of current guidelines for management of childhood obesity failed to identify 61%-85% of obese children with an underlying hypothalamic-pituitary lesion in our series. CONCLUSIONS: Endocrine disorders occurred in two-thirds of patients prior to the onset of the neuro-ophthalmic presenting symptom but were missed. Identifying them may help to diagnose hypothalamic-pituitary lesions earlier.

Interval between onset of symptoms and diagnosis of medulloblastoma in children: distribution and determinants in a population-based study.

Hospital-based studies have reported long delays in the diagnosis of paediatric brain tumours. Our objective was to describe the duration between onset of symptoms and diagnosis of medulloblastoma in children and study their clinical determinants in a population-based study. This retrospective cohort study included all paediatric medulloblastoma from a region of France from 1990 to 2005. The median interval from symptom onset until diagnosis for these 166 patients was 65 days and did not decrease during the study period. The most frequent manifestations were: vomiting (88%), headaches (79%), psychomotor regression (60% of children under 3 years), psychological symptoms (27%), strabismus (26%), and asthenia (25%). For one third of the children under 3 years, the diagnosis was made only after life-threatening signs of intracranial hypertension appeared. The prediagnosis interval was significantly longer (median 91 vs. 60 days, p = 0.001) in children with psychological symptoms (27%). Causes for intervals that exceeded the median (65 days) included inconsistent (25%) or late (36%) combination of headaches and vomiting, a period of spontaneous symptom remission (14%-20%), no (24%) or late (57%) neurological signs, psychological symptoms (35%), and a normal neurological examination (27%). Time to medulloblastoma diagnosis in children remains fairly long, despite advances in imaging. Primary-care physicians must be suspicious not only of suggestive neurological signs, but also of non-specific symptoms that persist or are multiple. A meticulous neurological examination and cerebral imaging for such patients might facilitate earlier diagnosis.

The growth of the foramen magnum in Crouzon syndrome.

BACKGROUND: Though the craniovertebral junction is often abnormal in children with Crouzon's syndrome, no study had measured accurately the size of their foramen magnum (FM). PATIENTS AND METHODS: We compared the FM size (area, diameters) on computed tomography examination in 21 children with a genetically confirmed Crouzon's syndrome prior to any surgery and in 23 control children without craniofacial abnormalities. We extrapolated the growth pattern in both groups. RESULTS: We found a statistically significant smaller FM area (p=0.0228), FM sagittal diameter (p=0.0287), and FM sagittal posterior diameter (p=0.0023) in children with Crouzon's syndrome. No differences were detected with regard to the transversal diameter. Hydrocephalus in children with Crouzon's syndrome was associated with a small FM area (p=0.05), small sagittal diameter (p=0.023), small sagittal posterior diameter (p=0.0173), and reduced transversal diameter (p=0.03985). No association of the aforementioned findings was found with the position of the cerebellar tonsils or the lambdoid suture functional state (open or fused). Comparable results were observed among the two genetic forms (exon 8 or 10 mutations). Concerning the growth pattern, a first phase of rapid increase and a second phase of slow increase could be recognized in all the measurements in both populations, though with some significant differences. DISCUSSION AND CONCLUSIONS: The growth of FM follows a biphasic pattern in both Crouzon's and control children. The sagittal diameter and the global size of the FM are mostly affected in children with Crouzon's syndrome. The small FM, especially its posterior part, is likely to play a key role in the physiopathology of hydrocephalus.

Scaphocephaly correction with retrocoronal and prelambdoid craniotomies (Renier's "H" technique).

OBJECTIVE: The aim of this paper is to describe the surgical technique, originally devised by Dr. Renier which is currently used to treat children with scaphocephaly under 6 months of age at the Craniofacial Unit of Hopital Necker Enfants Malades (French National Referral Center for Faciocraniosynostosis), focusing on its advantages and limitations.

Changes in intracranial CSF distribution after ETV.

OBJECTIVE: The aim of this prospective study was to analyze the changes in cerebrospinal fluid (CSF) distribution after endoscopic third ventriculocisternostomy (ETV). METHODS: Twenty-two hydrocephalic children (eight boys, aged 3 months to 17 years) candidates for ETV were studied by preoperative brain magnetic resonance (MR) and repeated post-ETV MRs at established time intervals. A volumetric analysis of CSF distribution after ETV was performed using a specific software. RESULTS: Fifteen children had an uneventful follow-up, whereas four required a second ETV due to a secondary closure of the stoma, one died of acute intracranial hypertension, and two needed an extrathecal shunt. A progressive reduction in the volume of the ventricles was found in case of successful ETV during the follow-up period. The ventricular volumes were reduced in average of 76 % of the initial volume at day 3, 69 % at 2 weeks, 42 % at 2 months, and 40 % at 6 months. This finding was associated with an enlargement of subarachnoid spaces which increased in case of successful ETV (192 % of initial volume at day 3; 210 % at day 15; 428 % at 2 months; and 468 % at 6 months). In case of secondary closure of the stoma, the distribution of intra- and extraventricular CSF tended to go back to the preoperative status. CONCLUSION: Volume variations of the ventricles and the subarachnoid spaces are a good indicator of the efficacy of the ETV.

Temporosylvian arachnoid cysts in children. Part 2: Postoperative neuropsychological and clinical improvement.

OBJECTIVE: The authors' objective was to study clinical, imaging, and neuropsychological changes in children who underwent surgery for a temporal arachnoid cyst (TAC). METHODS: Thirty-four children were prospectively assessed similarly at diagnosis and postoperatively (mean 14 months) with clinic visits, images, cognitive tests, and parental questionnaires on mood/behavior and executive functions. The scores were compared pre- and postoperatively for the entire cohort and individually. The scores of 25 children were also compared with a control group of 23 healthy age-matched children. Parents were administered an outcome questionnaire on average 4 years postoperatively. RESULTS: The 34 children selected for surgery had signs of raised intracranial pressure (74%) and/or selective neuropsychological disorders presumably linked to cyst location (learning difficulties in 65%, cognitive difficulties in 56%, and mood/behavior difficulties in 47%). The majority of patients had a convex cyst (85%) and underwent microsurgical fenestration (85%). The TAC volume decreased ≥ 50% for 59% of children. On the Wechsler Intelligence Scale, the entire cohort significantly improved on Full Scale IQ and verbal and perceptual nonverbal indexes. Individually, nearly half of the children (47%) highly increased their scores (≥ 15 points) on at least one IQ index and 26% on at least two indexes. Language, working memory, episodic memory, and executive functions were also significantly improved. Improvements were more pronounced in patients with a preoperative heterogeneous profile with isolated lower scores and a left-sided cyst. Parental questionnaires showed reduction in anxiety, aggressiveness, social problems, and daily life executive disorders. Preschool-aged children improved significantly in language and verbal IQ, as did middle/high school-aged children in many domains. Individual analyses revealed improvement in 76% of cases. Cognitive scores were lower for patients preoperatively than for controls and were no longer significantly different postoperatively in verbal fluency, visual memory, and working memory. Four years later, 97% of parents described an improvement in their child, correlated with cognitive improvements. CONCLUSIONS: Among children with a TAC, some have no clinical signs or neuropsychological difficulties, and others may show signs of raised intracranial pressure and/or specific neuropsychological disorders that impact daily life and require significant and long-lasting rehabilitation. In these cases, consideration may be given to surgical decompression. It is interesting to note that 76% of this surgically treated cohort improved regardless of the child's age, particularly in patients with selective disorders and an impact on daily life. However, a larger number of children will need to be investigated before the true benefit of such treatment can be known.