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Most patients with COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), display neurological symptoms, and respiratory failure in certain cases could be of extra-pulmonary origin. Hypothalamic neural circuits play key roles in sex differences, diabetes, hypertension, obesity and aging, all risk factors for severe COVID-19, besides being connected to olfactory/gustative and brainstem cardiorespiratory centers. Here, human brain gene-expression analyses and immunohistochemistry reveal that the hypothalamus and associated regions express angiotensin-converting enzyme 2 and transmembrane proteinase, serine 2, which mediate SARS-CoV-2 cellular entry, in correlation with genes or pathways involved in physiological functions or viral pathogenesis. A post-mortem patient brain shows viral invasion and replication in both the olfactory bulb and the hypothalamus, while animal studies indicate that sex hormones and metabolic diseases influence this susceptibility.

Neuroinvasion by SARS-CoV-2 is now accepted. To investigate whether low testosterone levels observed in men with severe COVID-19 could be of central origin, we retrospectively analyzed blood samples from 60 male intensive-care patients and explored SARS-CoV-2 brain entry using animal and cellular models as well as adult COVID-19 patient and fetal human brains. Most hypotestosteronemic patients displayed hypogonadotropic hypogonadism or abnormal hypothalamic-pituitary-gonadal axis regulation. Neurons producing gonadotropin-releasing hormone (GnRH), the master molecule controlling fertility, expressed angiotensin-converting enzyme 2 and neuropilin-1, two host-cell factors mediating infection, and were infected and dying in all COVID-19 patient brains. Tanycytes - hypothalamic glia that regulate GnRH secretion - were also infected. Additionally, human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, richly expressed both the above host-cell susceptibility factors and formyl peptide receptor 2, a putative vomeronasal receptor that also appeared involved in SARS-CoV-2 pathogenesis in humans and mice. Finally, a fetal human GnRH cell line expressing all these receptors could be infected by a SARS-CoV-2-like pseudovirus. Together, our findings suggest that GnRH neurons, which may be implicated in brain development and aging in addition to reproduction, are particularly vulnerable to SARS-CoV-2 in both adults and fetuses/newborns, with potentially devastating long-term consequences.

Abdominal pseudocysts are common complications of ventriculoperitoneal shunt (VPS). We report the case of a 37-year-old woman treated by VPS for congenital obstructive hydrocephalus, who presented shunt dysfunction related to a voluminous abdominal cyst initially diagnosed as cerebrospinal fluid pseudocyst. The cyst was drained and the VPS was removed after endoscopic third ventriculocisternostomy (ETV). A few months later, a large new abdominal cyst appeared and was operated on. Diagnosis was rectified as massive ovarian mucinous cystadenoma. In any intra-abdominal cyst, differential diagnoses need considering to avoid mis-diagnosis in shunted patients, especially if the cyst is very large. The etiology of the hydrocephalus should also be investigated in case of shunt dysfunction. Even in case of longstanding shunt, ETV can be an alternative to shunt revision surgery in obstructive hydrocephalus, enabling VPS withdrawal and treatment of the hydrocephalus.

Background Idiopathic normal-pressure hydrocephalus (iNPH) is a treatable cause of gait and cognitive impairment. iNPH should be differentiated from ventriculomegaly secondary to brain atrophy to choose the best therapeutic option (ventriculoperitoneal shunt vs medical management). Objective To determine the diagnostic accuracy of automated sulcal morphometry to differentiate patients with iNPH from patients with ventriculomegaly of neurodegenerative origin. Methods Thirty-eight consecutive patients with iNPH (shunt responsive n = 31, nonresponsive n = 7), 35 with vascular cognitive disorder, and 25 age- and sex-matched healthy controls were prospectively included and underwent cognitive evaluation and 3T brain magnetic resonance imaging. Sulcal opening of 10 sulci of interest was retrospectively measured using an automated surface-based approach from the 3-dimensional T1-weighted images. Receiver-operating characteristic curve analyses determined the best parameter to identify iNPH patients. Results The best parameter to discriminate shunt-responsive iNPH from patients with vascular cognitive disorder and healthy controls was the ratio between calcarine sulcus and cingulate sulcus opening with an area under the curve of 0.94 (95% CI: 0.89, 0.99). A cut-off value of 0.95 provided the highest sensitivity (96.8%) and specificity (83.3%). Conclusion This preliminary study showed that automated sulcal morphometry may help the neurosurgeon to identify iNPH patients and to exclude other causes of ventriculomegaly.

OBJECTIVE To determine whether cervical vestibular evoked myogenic potentials (cVEMPs) are predictive of hearing preservation in patients undergoing vestibular schwannoma removal through middle fossa craniotomy approach. STUDY DESIGN Retrospective case study. SETTING Tertiary referral center. PATIENTS Eighteen patients who underwent a middle fossa craniotomy for vestibular schwannoma (stage I or II of Koos classification) with attempted hearing preservation from January 2008 to February 2016 were retrospectively reviewed. INTERVENTION Pre-surgical cVEMPs test, videonystagmography (caloric test), and magnetic resonance imaging (MRI) as well as a pre- and post-surgical audiometry test. MAIN OUTCOME MEASURES cVEMPs parameters including amplitude asymmetry ratio (AR), P13, and N23 latencies and peak-to-peak amplitude between P13 and N23 waves were calculated. Hearing data were classified according to the AAO-HNS hearing classes. The nerve of origin of the tumor was specified during surgery and the largest tumor diameter was measure on MRI axial plane on T2-CISS weighed images. RESULTS Preoperative amplitude asymmetry ratio was lower (n = 15, Mann-Whitney U test, p

Introduction Neurofibromatosis type 2 is characterized by the presence of bilateral vestibular schwannomas. However, other nervous system tumors may also occur. Therefore, the management of NF2 patients is complex and requires a multidisciplinary discussion in a specialized center. Materials and methods All recent articles concerning tumors other than vestibular schwannoma in NF2 disease were reviewed, using PubMed databases. Results Intracranial meningiomas occur in 50% of NF2 patients, and are often multiple. Surgery remains the main treatment and should be performed in cases of growing tumors. The role of antiangiogenic therapy is currently under evaluation and the role of radiosurgery still remains to be defined in NF2 disease. Spinal tumors occur in about half of NF2 patients. Surgery should be discussed when radiological tumor progression is demonstrated, even if spinal tumors are asymptomatic, in order to preserve neurological function and good quality of life. As regards lower cranial nerve schwannomas, radiosurgery appears to be a more appropriate treatment for growing tumor with a small volume in order to avoid post-operative complications, especially swallowing disorders. Facial nerve schwannomas may appear, on MRI, like vestibular schwannomas. The diagnosis should be suspected when the facial palsy is an early symptom during cerebello-pontine tumor progression. Trigeminal schwannomas are frequent in NF2 disease and fortunately they are often asymptomatic. Among major neurofibromatosis types, peripheral nerve sheath schwannomas are only present in patients with NF2 disease and schwannomatosis. Surgical resection is required when the cutaneous schwannomas is painful or when tumor progression is observed and causes symptoms. Conclusion Tumors other than vestibular schwannoma are also associated with a poor prognosis in NF2 patients. Surgery remains the main treatment in most cases. Each treatment decision in NF2 disease requires a complete evaluation of all cranial and spinal locations of the disease in order to establish surgical priorities and strategies.

The challenge of the neurosurgical management of gliomas lies in achieving a maximal resection without persistent functional deficit. Diffusion tensor imaging (DTI) allows non-invasive identification of white matter tracts and their interactions with the tumor. Previous DTI validation studies were compared with intraoperative cortical stimulation, but none was performed based on the tumor anatomopathological analysis. This preliminary study evaluates the correlation between the preoperative subcortical DTI tractography and histology in terms of fiber direction as well as potential tumor-related fiber disruption. Eleven patients harboring glial tumors underwent preoperative DTI images. Correlations were performed between the visual color-coded anisotropy (FA) map analysis and the tumor histology after “en bloc” resection. Thirty-one tumor areas were classified according to the degree of tumor infiltration, the destruction of myelin fibers and neurofilaments, the presence of organized white matter fibers, and their orientation in space. After histologic comparison, the DTI sensitivity and specificity to predict disrupted fiber tracts were respectively of 89% and 90%. The positive and negative predicted values of DTI were 80% and 95%. The DTI data were in line with the histologic myelin fiber orientation in 90% of patients. In our series, the prevalence of destructed fiber was 31%. Glioblastoma WHO grade IV harbored a higher proportion of destructed white matter tracts. Lower WHO grades were associated with higher preservation of subcortical fiber tracts. This DTI/histology study of “en bloc”–resected gliomas reported a high and reproducible concordance of the visual color-coded FA map with the histologic examination to predict subcortical fiber tract disruption. Our series brought consistency to the DTI data that could be performed routinely for glioma surgery to predict the tumor grade and the postoperative clinical outcomes.

International audience; No abstract available

Resume La survie d’un organisme repose sur sa capacite a communiquer de maniere rapide, efficace et reproductible avec les reseaux de cellules qui controlent la prise alimentaire et l’homeostasie energetique dans le cerveau. Pour cela, les facteurs hormonaux refletant l’etat de faim ou de satiete d’un individu doivent traverser la barriere hematoencephalique (BHE) pour atteindre les neurones effecteurs. Un defaut dans ce processus conduit invariablement a une perturbation du controle de la masse ponderale. Nous discutons ici de travaux recents montrant qu’un type particulier de cellules gliales nommees tanycytes joue un role important dans ce processus. Les corps cellulaires de ces cellules tapissent le plancher du troisieme ventricule et leurs extensions podales entrent en contact avec la surface piale du cerveau. Les tanycytes hypothalamiques regulent la plasticite de la BHE en fonction de l’etat nutritionnel de l’individu, et sont aussi impliques dans la capture des signaux metaboliques tels que la leptine dans la circulation sanguine et leur transport vers le liquide cephalorachidien. Le blocage du transport des facteurs metaboliques peripheriques dans le cerveau a travers les tanycytes pourrait constituer un evenement physiopathologique conduisant a l’hormonoresistance centrale chez les patients obeses.

International audience; The hypothalamus contains integrative systems that support life, including physiological processes such as food intake, energy expenditure and reproduction. Here, we show that anorexia nervosa patients, contrary to normal weight and constitutionally lean individuals, respond with a paradoxical reduction in hypothalamic levels of glutamate/glutamine (Glx) upon feeding. This reversal of the Glx response is associated with decreased wiring in the arcuate nucleus and increased connectivity in the lateral hypothalamic area, which are involved in the regulation on a variety of physiological and behavioral functions including the control of food intake and energy balance. The identification of distinct hypothalamic neurochemical dysfunctions and associated structural variations in anorexia nervosa paves the way for the development of new diagnostic and treatment strategies in conditions associated with abnormal body mass index and a maladaptive response to negative energy balance.

International audience; BACKGROUNDHearing response following an osteodural decompression of the internal auditory canal (IAC) is controversial.OBJECTIVETo evaluate the course of auditory brainstem responses (ABRs) and the early hearing response during the first year following IAC decompression for small to medium-sized vestibular schwannomas occurring in neurofibromatosis type 2 (NF2).METHODSRetrospective chart review of middle fossa craniotomy for IAC osteodural decompression in NF2-related vestibular schwannomas.RESULTSTwelve NF2 patients were operated on from 2011 to 2016 for IAC decompression. All had NF2 according to the Manchester criteria. All had a progressive change of their ABRs documented from the diagnosis of NF2 over a mean period of 6.25 [0.36;10.9] yr. Treatment was proposed to stop hearing progression based on the speech discrimination scores (SDSs; n = 4) or for hearing maintenance (n = 8). In patients with prior hearing progression, hearing responses were observed in 3 of the 4 patients during the first year. One patient kept on progressing. In the hearing maintenance group, the SDSs remained stable. SDSs improved from 85% [20-100] to 92.5% [60-100] on average (n = 12) and from 55% [20-80] to 77.5% [50-100] in the hearing progression group (n = 4). ABRs improved in 4 patients following decompression.CONCLUSIONIAC decompression allows early objective hearing responses in select patients. We suggest that the procedure should be offered to patients with hearing progression based on their SDSs and/or associated progressive increases in their wave III and V latencies on ABRs.

Resume L’hydrocephalie chronique de l’adulte se caracterise par une triade clinique associant des troubles de la marche, une deterioration neuro-cognitive et une incontinence urinaire. Les signes apparaissent de facon insidieuse chez un patient de plus de 40 ans. Le diagnostic radiologique est fait sur une IRM cerebrale qui retrouve un elargissement ventriculaire, des anomalies de la repartition du liquide cerebro-spinal (LCS) des espaces sous-arachnoidiens (elargissement des scissures laterales mais rarefaction du LCS au vertex) et un flux du LCS aqueducal augmente ; en cas d’hydrocephalie obstructive sur une stenose decompensee de l’aqueduc, ce flux est nul et le plancher du troisieme ventricule est abaisse. Des tests complementaires (PL depletive d’au moins 40 mL de LCS ou un test de perfusion) permettent de confirmer l’indication chirurgicale a une derivation ventriculo-peritoneale (en cas d’hydrocephalie communicante) ou a une ventriculo-cisternostomie (en cas d’hydrocephalie obstructive). Une amelioration clinique est retrouvee chez 80 % des patients si l’indication chirurgicale est bien posee, faisant de cette pathologie une des seules causes de demence curable.

Internal variation among spheno-orbital meningiomas (SOM) is surgically challenging. Optic canal invasion management is discussed. This retrospective study includes 70 patients with SOM who underwent surgery between 1995 and 2012. Preoperative ophthalmological, neurological and aesthetic clinical signs were collected. All patients benefitted from repeated tomography and magnetic resonance imaging (MRI). The surgical team consisted of a neurosurgeon and a plastic surgeon. In the majority of cases, resection was followed by bone reconstruction using an autologous iliac crest graft. The extent of resection was evaluated on the dural and osseous sides. Early clinical outcomes, long-term follow-up, recurrence and adjuvant therapies were reported. The mean age was 52 years old, and 91 % of the patients were women. Initial symptoms primarily included proptosis (65 %), decreased visual acuity (39 %) and soft tissue tumefaction (16 %). We classified 40 cases as the internal variety when considering the inner third of the greater wing of the sphenoid, optic canal, anterior clinoid process or cavernous sinus. The remaining cases were described as the external variety. The complete resection rates for the internal and external varieties were 12 % and 61 %, respectively (P

Objectives/Hypothesis To determine the long-term growth rate of vestibular schwannoma (VS) in neurofibromatosis type 2 (NF2) patients based on volumetric measurements. Study Design Retrospective review. Methods We retrospectively reviewed magnetic resonance imaging (MRI) scans acquired from patients with NF2 from 1999 to 2013. Patients with an annual radiologic follow-up over at least 3 consecutive years were included. Volumetric VS growth was prospectively measured using a three-dimensional imaging workstation and through manual contouring of the lesion. Time to tumor progression was assessed according to the Response Evaluation in Neurofibromatosis and Schwannomatosis Tumor Measurement Group. Results Eighteen patients presenting with a total of 26 VSs were included. The mean age at diagnosis was 26.1 years (range, 7 to 49 years). One hundred five MRI scans were analyzed during a median radiological follow-up of 5.6 years (range, 3 to 12 years). The annual volume and diameter growth rates were respectively 218.3 mm3/yr (range, −10 to 1,250 mm3/yr) and 0.9 mm/yr (range, −0.5 to 4.5 mm/yr). Time to tumor progression was 3 years (median survival). There was a weak correlation between volumetric and linear measurements (P < .0001, linear regression, n = 26, r2 = 0.58). Among the 26 VSs, 76.9% (20/26) showed progression (VS growth more than 20%), 19.2% were stable, and 3.9% (1/26) exhibited shrinkage (spontaneous regression of more than 20% of the initial volume). Conclusions This study helps to assess the long-term growth profile of VS in a population of NF2 patients with untreated VS. These data could help to better acknowledge VS natural growth history. Level of Evidence 4 Laryngoscope, 2016

In the case of ventriculomegaly in the elderly, it is often difficult to differentiate between communicating chronic hydrocephalus (CCH) and brain atrophy. The aim of this study is to describe the MRI criteria of CCH, defined by a symptomatic patient with ventriculomegaly and that improved after shunt placement.Magnetic resonance imaging was prospectively evaluated in 90 patients with ventriculomegaly. Patients were classified into three groups: patients without clinical signs of CCH (control, n = 47), patients with CCH treated by shunt placement with clinical improvement (responders, n = 36), and patients with CCH treated using a shunt without clinical improvement (nonresponders, n = 7). MRI parameters of the two groups of interest (responders vs. controls) were compared.Compared with controls, Evans' index (p = 0.029), ventricular area (p0.01), and volume (p = 0.0001) were higher in the responders. In this group, the callosal angle was smaller (p ≤ 0.0001) and the aqueductal stroke volume (SVa) of CSF was higher (p ≤ 0.0001) than in controls. On the ROC curves, the optimal cut-off values for differentiating between responders and controls were a ventricular area33.5 cmOn suspicion of CCH, a large ventricular area, a small callosal angle, and an increased aqueductal stroke volume are important MRI arguments that can be associated with the clinical evaluation and dynamic testing of CSF to confirm the indication for a shunt.

Cerebrospinal fluid (CSF) and blood flows have a strong relationship during a cardiac cycle. Idiopathic intracranial hypertension (IIH) is a pathology that seems to present hemodynamic and hydrodynamic disturbance. The aim of this study was to establish CSF and blood interaction in IIH.We retrospectively studied cerebral hydrodynamic and hemodynamic flows by phase-contrast MRI (PCMRI) in 13 IIH subjects (according Dandy's criteria) and 16 controls. We analyzed arterial peak flow, pulsatility index, and resistive index in arterial and venous compartments (PFart, PIart, RIart, PFvein, PIvein, RIvein) and measured arteriovenous and CSF peak flow and stroke volume (PFav, SVWe found no significant difference between IIH and control groups in arterial and venous parameters. Arteriovenous flow analysis showed higher PFav and SVAlthough no significant change was found in arterial and venous flows, we showed that a small phase shift of venous outflow might cause an increase in the arteriovenous pulsatility and an increasing brain expansion during the cardiac cycle. This arteriovenous flow increase would result in an increase of CSF flushing through the foramen magnum and an increased ICP.

16th International Conference on Intracranial Pressure and Neuromonitoring (ICP), Cambridge, MA, JUN 28-JUL 02, 2016; International audience; Objective: In the case of ventriculomegaly in the elderly, it is often difficult to differentiate between communicating chronic hydrocephalus (CCH) and brain atrophy. The aim of this study is to describe the MRI criteria of CCH, defined by a symptomatic patient with ventriculomegaly and that improved after shunt placement. Materials and methods: Magnetic resonance imaging was prospectively evaluated in 90 patients with ventriculomegaly. Patients were classified into three groups: patients without clinical signs of CCH (control, n = 47), patients with CCH treated by shunt placement with clinical improvement (responders, n = 36), and patients with CCH treated using a shunt without clinical improvement (nonresponders, n = 7). MRI parameters of the two groups of interest (responders vs. controls) were compared. Results: Compared with controls, Evans' index (p = 0.029), ventricular area (p < 0.01), and volume (p = 0.0001) were higher in the responders. In this group, the callosal angle was smaller (p = 0.0001) and the aqueductal stroke volume (SVa) of CSF was higher (p = 0.0001) than in controls. On the ROC curves, the optimal cut-off values for differentiating between responders and controls were a ventricular area >33.5 cm(2), a callosal angle 136.5 mu L/R-R. In multivariate analysis, responders remained associated with SVa and callosal angle, with a c-statistic of 0.90 (95%CI, 0.83-0.98). Conclusion: On suspicion of CCH, a large ventricular area, a small callosal angle, and an increased aqueductal stroke volume are important MRI arguments that can be associated with the clinical evaluation and dynamic testing of CSF to confirm the indication for a shunt.

Discipline Clinique. Introduction et but de l’etude L’hypothalamus contient differents systemes neuronaux coordonnant la prise alimentaire, la depense energetique ou encore la reproduction. De nombreuses approches en imagerie par resonance magnetique cerebrale chez l’Homme ont emerge dans l’etude des troubles du comportement alimentaire comme l’anorexie mentale (AM), principalement dans des zones corticales. Aucune d’entre elles n’a encore porte sur une etude fonctionnelle de l’AM a l’echelle ultrastructurelle des noyaux hypothalamiques. Materiel et methodes Notre etude explore ainsi la connectivite fonctionnelle et structurelle des noyaux hypothalamiques en IRM multimodale in vivo chez des patientes presentant une AM restrictive comparativement a des temoins ajustes en poids (maigreur constitutive) et des temoins normoponderaux. Ces 30 volontaires ont beneficie de sequences anatomiques, de spectroscopie en resonance magnetique et de sequences de diffusion avec algorithme de tractographie, a jeun et apres prise alimentaire calibree. Les variations neurobiochimiques a l’echelle hypothalamique et la connectivite structurelle a l’echelle de chaque noyau hypothalamique ont pu etre etudiees. Resultats et analyse statistique Nous avons mis en evidence une activite basale du reseau glutamatergique exacerbee avant prise alimentaire qui decroit paradoxalement apres prise alimentaire, a contrario des sujets controle. Cette reponse inverse de neurotransmission est associee a un nombre de fibres nerveuses passant par le noyau arque plus faible chez les AM mais egalement a une connectivite accrue de l’aire hypothalamique laterale, deux regions fortement impliquees dans le controle de la prise alimentaire. Conclusion Cette etude en imagerie cerebrale non invasive met en lumiere differents dysfonctionnements hypothalamiques et ouvre la porte a de nouvelles strategies a la fois diagnostiques et therapeutiques dans cette pathologie severe aux traitements limites et au pronostic sombre.

Introduction Le defi de la prise en charge neurochirurgicale des tumeurs gliales consiste a realiser une ablation tumorale aussi complete que possible sans deficit fonctionnel postoperatoire. La technique de tenseur de diffusion (DTI) permet l’identification non-invasive des fibres de substance blanche et leurs rapports avec la tumeur. Cependant, il reste soumis a de nombreuses limitations techniques et sa fiabilite en tant qu’outil de planification pre- et peroperatoire est remise en question. La plupart des etudes de validation ont ete realisees en comparaison avec la stimulation corticale peroperatoire, mais aucune n’a ete realisee sur l’analyse anatomopathologique de la tumeur pour evaluer l’integrite des fibres de la substance blanche dans l’environnement tumoral. L’objectif de l’etude est donc d’evaluer la faisabilite d’une correlation anatomo-radiologique entre le DTI et l’analyse histologique des tumeurs gliales. Materiel et methodes 12 patients atteints de tumeurs gliales de grade II a IV ont beneficie d’une IRM avec sequence de DTI preoperatoire. Les fibres de substance blanche detruites et infiltrees ont ete identifiees a l’aide de la carte d’anisotropie fractionnelle a codage colorimetrique directionnel (carte RVB) par evaluation visuelle. Les correlations DTI et histologiques ont ete realisees sur 31 regions, classees selon le degre d’infiltration tumorale, la destruction des fibres de myeline et des neurofilaments, la presence de fibres de substance blanche organisee et leur orientation dans l’espace. Resultats Les correlations observees entre le DTI et les analyses histologiques concernant l’orientation et la destruction des fibres sont elevees. Selon le niveau de myeline intacte evalue a l’aide de l’histologie et des fibres detectees sur les images DTI, une concordance est observee pour 23 a 26 des 31 zones etudiees. La concordance directionnelle des faisceaux est egalement observee chez 9 patients sur les 10 presentant des fibres organisees en DTI. Conclusion Cette etude a demontre qu’il est possible d’obtenir une correlation entre les images DTI et l’etude histologique des fibres de myeline dans les tumeurs gliales et a confirme qu’une analyse visuelle de la carte RVB peut etre une methode utile pour evaluer l’infiltration de substance blanche dans les tumeurs gliales. Cependant, d’autres etudes sont necessaires pour evaluer la correlation avec les donnees cliniques afin de determiner le seuil de destruction auquel le faisceau perd sa fonction ( Fig. 1 ).

Inasmuch as the neurohormone melatonin is synthetically derived from serotonin (5-HT), a close interrelationship between both has long been suspected. The present study reveals a hitherto unrecognized cross-talk mediated via physical association of melatonin MT2 and 5-HT2C receptors into functional heteromers. This is of particular interest in light of the "synergistic" melatonin agonist/5-HT2C antagonist profile of the novel antidepressant agomelatine. A suite of co-immunoprecipitation, bioluminescence resonance energy transfer, and pharmacological techniques was exploited to demonstrate formation of functional MT2 and 5-HT2C receptor heteromers both in transfected cells and in human cortex and hippocampus. MT2/5-HT2C heteromers amplified the 5-HT-mediated Gq/phospholipase C response and triggered melatonin-induced unidirectional transactivation of the 5-HT2C protomer of MT2/5-HT2C heteromers. Pharmacological studies revealed distinct functional properties for agomelatine, which shows "biased signaling." These observations demonstrate the existence of functionally unique MT2/5-HT2C heteromers and suggest that the antidepressant agomelatine has a distinctive profile at these sites potentially involved in its therapeutic effects on major depression and generalized anxiety disorder. Finally, MT2/5-HT2C heteromers provide a new strategy for the discovery of novel agents for the treatment of psychiatric disorders.

International audience; The adult brain contains niches of neural stem cells that continuously add new neurons to selected circuits throughout life. Two niches have been extensively studied in various mammalian species including humans, the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus. Recently, studies conducted mainly in rodents have identified a third neurogenic niche in the adult hypothalamus. In order to evaluate whether a neural stem cell niche also exists in the adult hypothalamus in humans, we performed multiple immunofluorescence labeling to assess the expression of a panel of neural stem/progenitor cell (NPC) markers (Sox2, nestin, vimentin, GLAST, GFAP) in the human hypothalamus and compared them with the mouse, rat and a non-human primate species, the grey mouse lemur (Microcebus murinus). Our results show that the adult human hypothalamus contains four distinct populations of cells that express the five NPC markers: i) a ribbon of small stellate cells that lines the third ventricular wall behind a hypocellular gap, similar to that found along the lateral ventricles, ii) ependymal cells, iii) tanycytes, which line the floor of the third ventricle in the tuberal region, and iv) a population of small stellate cells in the suprachiasmatic nucleus. In the mouse, rat and mouse lemur hypothalamus, co-expression of NPC markers is primarily restricted to tanycytes, and these species lack a ventricular ribbon. Our work thus identifies four cell populations with the antigenic profile of NPCs in the adult human hypothalamus, of which three appear specific to humans.

International audience; BACKGROUND: Ruptured arteriovenous malformations (rAVM) are life-threatening diseases.OBJECTIVE: To evaluate the outcome of patients with grade 1 SPM rAVM after microsurgical treatment.METHODS: We retrospectively included 64 consecutive operated patients with a grade 1 SPM rAVM in our institution between 2002 and 2012. Complications related to the surgical procedure were recorded. All patients were re-evaluated 3months after treatment using the modified Rankin Scale score (mRS). Persistent neurological disorders were evaluated 1year after bleeding. Conventional cerebral angiography was performed for each patient immediately after surgical treatment and 1year later.RESULTS: The mean age at diagnosis was 30.8 years. Initial WFNS score was grade 1 in 25 patients, grade 2 in 11 patients, grade 3 in 10 patients, grade 4 in 9 patients and grade 5 in 9 patients. No remnant was left and a new surgery was performed only in a single patient who was initially operated-on under emergency conditions with limited preoperative investigations due to a poor clinical grade. Early postoperative complications related to the surgical procedure were recorded in 7 patients. The mRS score 3months after treatment was ≤2 in 53 patients (83%). Persistent neurological disorders were recorded in 40 patients (62.5%). High initial WFNS score (>2) and the hydrocephalus were significantly associated (P2).CONCLUSIONS: Grade 1 rAVM is a life-threatening disease concerning in most cases young patients. Long-term morbidity is often related to the hemorrhagic brain damage and rarely to the AVM resection.

International audience; Purpose. - Medial lobe temporal structures and more specifically the hippocampus play a decisive role in episodic memory. Most of the memory functional magnetic resonance imaging (fMRI) studies evaluate the encoding phase; the retrieval phase being performed outside the MRI. We aimed to determine the ability to reveal greater hippocampal fMRI activations during retrieval phase. Materials and methods. - Thirty-five epileptic patients underwent a two-step memory fMRI. During encoding phase, subjects were requested to identify the feminine or masculine gender of faces and words presented, in order to encourage stimulus encoding. One hour after, during retrieval phase, subjects had to recognize the word and face. We used an event-related design to identify hippocampal activations. Results. - There was no significant difference between patients with left temporal lobe epilepsy, patients with right temporal lobe epilepsy and patients with extratemporal lobe epilepsy on verbal and visual learning task. For words, patients demonstrated significantly more bilateral hippocampal activation for retrieval task than encoding task and when the tasks were associated than during encoding alone. Significant difference was seen between face-encoding alone and face retrieval alone. Conclusions. - This study demonstrates the essential contribution of the retrieval task during a fMRI memory task but the number of patients with hippocampal activations was greater when the two tasks were taken into account. (C) 2018 Published by Elsevier Masson SAS.

The causes of mortality in neurofibromatosis type 2 (NF2) patients are poorly studied in the literature. Our study aimed to fit this gap by analyzing the main causes of death in this population.This study is the retrospective review of prospectively collected data of 80 patients with NF2 disease followed in Lille University Hospital between 1987 and 2011. Demographical data, diagnosis criteria, and cause of death were recorded.There were 45 men and 35 women, with a mean age at diagnosis of 27.2 years (range: 6-73 years; SD: ± 15.4). Sixty-eight patients met Manchester criteria and the others had an identified mutation in the NF2 gene which confirmed the diagnosis. Of all patients, we noted 7 deaths. The mean age at diagnosis of dead patients was 26 years. The mean age of death was 38.9 years. The causes of death were suicide in 1 patient, hematoma after surgical removal of grade IV vestibular schwannoma in 1 patient, aspiration pneumonia after swallowing disturbances in 3 patients, intracranial hypertension related to growth of multiple meningiomas in 1 patient, and brachial plexus sarcoma grade 3 in the last patient.NF2 is a serious disease that can quickly be life-threatening. The presence of lower cranial nerves schwannomas is a poor prognostic factor, and radiosurgery should be considered for their treatment, as surgical removal often worsens the swallowing disturbances. A psychological support should also be provided.

Paediatric low-grade astrocytomas of the fourth ventricle are rare tumours, generally revealed by hydrocephalus. However, some patients present with a history of severe anorexia. It might be a harbinger, which if recognized, could lead to earlier diagnosis. We decided to examine our database in order to evaluate the incidence and signification of anorexia in this context. Retrospective monocentric study of cases of low-grade astrocytomas of the fourth ventricle operated between 1991 and 2012 in our paediatric neurosurgery department. We particularly observed the clinical presentation and long-term clinical, oncological and radiological evolution. Non-parametrical tests were used (Mann–Whitney, Fisher). We reviewed 34 cases, 31 pilocytic astrocytomas and 3 diffuse astrocytomas, 16 boys and 18 girls, (M/F ratio 0.89). Mean age at diagnosis was 8 years old. Seven presented with notable anorexia, the average BMI in this group was ≤2 standard deviation (SD); with clinical signs evolving for 11.5 months. Twenty-seven children had no anorexia; average BMI in this group was +1 SD, with clinical evolution for 6 months on an average of p

Neural stem and precursor cells persist postnatally throughout adulthood and are capable of responding to numerous endogenous and exogenous signals by modifying their proliferation and differentiation. Whereas adult neurogenesis has been extensively studied in the dentate gyrus of the hippocampal formation and in the subventricular zone adjacent to the wall of the lateral ventricles, we and others have recently reported constitutive adult neurogenesis in other brain structures, including the hypothalamus. In this study, we used immunohistochemistry to study the expression of the neuroblast marker doublecortin (DCX), and compared its expression pattern in adult ovine, mouse, and human hypothalamic tissues. Our results indicate that DCX-positive cells resembling immature and developing neurons occur in a wide range of hypothalamic nuclei in all three species, although with different distribution patterns. In addition, the morphology of DCX-positive cells varied depending on their location. DCX-positive cells near the third ventricle had the morphology of very immature neuroblasts, a round shape with no processes, whereas those located deeper in the parenchyma such as in the ventromedial nucleus were fusiform and showed a bipolar morphology. Extending this observation, we showed that among the cohort of immature neurons entering the ventromedial nucleus, some appeared to undergo maturation, as revealed by the partial colocalization of DCX with markers of more mature neurons, e.g., human neuronal protein C and D (HuC/D). This study provides further confirmation of the existence of an adult hypothalamic neurogenic niche and argues for the potential existence of a migratory path within the hypothalamus.

Resume Introduction Le but de cette etude etait d’analyser l’epidemiologie, le traitement et le pronostic des hemangioblastomes (HGB) du systeme nerveux central (SNC) diagnostiques dans le cadre de la maladie de von Hippel-Lindau (VHL). Methode Nous avons revu une serie de 19 patients traites dans notre service (1996–2008). L’analyse a porte sur les caracteristiques cliniques et radiologiques pre- et postoperatoires, la recherche de lesions peripheriques, le pronostic clinique (modified Rankin scale [mRS], score de McCormick) et l’evolution a long terme. Resultats La symptomatologie revelatrice etait frequemment l’hypertension intracrânienne pour les lesions cerebelleuses (7/15) et un deficit sensitivo-moteur pour les lesions de la moelle allongee (2/5) ou de la moelle spinale (5/11). Les sites preferentiels etaient cerebelleux (15/31) ou spinaux (11/31). Des localisations multiples et des lesions viscerales etaient retrouvees chez deux tiers des patients. L’exerese etait complete dans plus de trois quarts des cas. La mortalite postoperatoire etait de 16 %. Le mRS final etait ≤ 1 dans 17 des 20 localisations infratentorielles et le score de McCormick final ≤ 2 dans toutes les localisations spinales. A distance, deux tiers des patients presentaient une recidive clinique ou une nouvelle localisation evolutive. Conclusion La maladie de VHL doit etre evoquee lorsqu’un HGB survient avant 30 ans, qu’il est de localisation spinale, qu’il est associe a d’autres localisations du SNC ou a des lesions peripheriques typiques.

Neurofibromatosis 2 (NF2) is a genetically inherited tumor predisposition syndrome. It predisposes to the development of multiple tumors of the central nervous system including schwannomas, meningiomas and ependymomas. Bilateral vestibular schwannomas (VS) are pathognomonic for the disease. In childhood, non-auditory symptoms often mark the onset of the NF2, such as facial palsy, peripheral neuropathy, and neurosurgical emergencies. In this article, we describe the case of a 6-year-old child presenting with an ischemic brain-stem stroke, who was later diagnosed with NF2. We report the clinical and genetic findings and review the previous literature on vasculopathy reported in association with NF2, with a focus on the symptoms presenting at disease onset. For our case patient, an unpublished germline mutation resulting in frameshift (c.876_877insT) was identified on blood screening. We report our full multidisciplinary assessment with vascular angiography, volumetric MRI and audiometry. Vasculopathy is not currently included in the criteria traditionally used for diagnosis of NF2. We suggest that vascular stroke in childhood may be considered a presenting symptom for NF2.

L’hydrocephalie chronique de l’adulte se caracterise par une triade clinique associant des troubles de la marche, une deterioration neurocognitive et une incontinence urinaire. Le diagnostic radiologique est fait sur une IRM cerebrale qui retrouve un elargissement ventriculaire, des anomalies de la repartition du liquide cerebro-spinal (LCS) des espaces sous-arachnoidiens (elargissement des scissures laterales mais rarefaction du LCS au vertex), un angle calleux diminue et un flux du LCS aqueducal augmente dans les hydrocephalies communicantes ; en cas d’hydrocephalie obstructive sur une stenose decompensee de l’aqueduc, ce flux est nul et le plancher du troisieme ventricule est abaisse. Des tests complementaires (ponction lombaire depletive d’au moins 40 mL de LCS, drainage lombaire externe ou test de perfusion mesurant un index de resistance a l’ecoulement du LCS) permettent de confirmer au cas par cas, lors d’une discussion pluridisciplinaire associant un neurologue, un neuroradiologue et un neurochirurgien, une indication a un traitement chirurgical ; le poids des eventuelles co-morbidites sera discute collegialement. En cas d’hydrocephalie communicante, c’est une derivation ventriculoperitoneale (DVP) ou ventriculo-atriale (DVA) qui sera indiquee. L’intervention dure une heure environ, sous anesthesie generale ; un catheter ventriculaire est insere dans l’atrium ventriculaire ou la corne frontale puis est connecte a une valve qui regulera le debit ou la pression d’ouverture du systeme. Le catheter distal se termine dans la cavite peritoneale (DVP) ou dans l’oreillette droite (DVA). Les risques sont moderes (infection, hematome intracrânien ou malposition du materiel). En cas d’hydrocephalie obstructive, c’est une ventriculocisternostomie endoscopique qui sera proposee. L’amelioration clinique survient dans les semaines qui suivent l’intervention chez plus de 80 % des patients. Le suivi est clinique et radiologique, avec des radiographies de valve verifiant le bon positionnement du materiel et une IRM qui montre habituellement une legere diminution de la taille des ventricules.

Grade 2 meningiomas are a real problem in therapeutic management because of their tendency to reoccur. The most effective treatment is surgery. The role of adjuvant radiotherapy in this disease is still disputed due to its uncertain effect on progression-free survival. To show that early adjuvant radiotherapy is an effective treatment in patients with grade 2 meningiomas. A retrospective study was performed on all patients operated on for grade 2 meningioma in our center between 1994 and 2011. For every patient, we recorded the age at diagnosis, sex, background of neurofibromatosis type 2 (NF2) or meningiomatosis, location of meningioma, quality of tumor resection and whether the patient received early postoperative radiotherapy. These prognosis factors were studied using statistical tests. We included 167 patients (94 women, 73 men, sex ratio = 1.28); the mean age at diagnosis was 53.8 years. Twenty-seven patients received early adjuvant radiotherapy after surgery. Patients who received early postoperative radiotherapy had a significantly longer progression-free survival (8.2 years) than patients without radiotherapy (5.7 years, p = 0.04). In multivariate analysis, quality of tumor resection and early postoperative radiotherapy decrease the risk of recurrence of meningioma (p

In spite of the few clinical studies regarding the occurrence of intracranial meningiomas, their prognosis in neurofibromatosis type 2 (NF2) has not been accurately assessed and their management remains controversial. This study aims to compare NF2 patients with intracranial meningiomas to those without, and consequently to identify prognostic factors in attempt to improve the management of these tumors.This retrospective study includes a total of 80 NF2 patients followed at Lille Hospital Center between 1987 and 2011. The diagnosis of NF2 was confirmed either because the patient met the Manchester criteria or by the presence of genetic mutation. Clinical, radiological and genetic data were retrospectively recorded and analyzed. Patients underwent annual cranial and spinal MRI. Both location and size of each tumor were reported.The mean follow-up period was 8.8 years (range 1-24 years; SD: ±0.8) and the mean age at diagnosis was 27.2 years (range 6-73 years; SD: ±1.7). Among all patients, 34 harbored intracranial meningiomas. Patients with intracranial meningiomas had a higher number of intracranial schwannomas, spinal tumors and cutaneous tumors (p0.05). They underwent more surgical procedures (p0.012). Twenty five intracranial meningiomas were surgically removed in 17 patients. The decision to perform surgery was taken in 10 cases for symptomatic tumors and in 15 cases for growing asymptomatic tumors determined by radiology. The histological analysis found a high rate of fibroblastic, transitional or grade 2 meningiomas preferentially located at the cerebri falx.Intracranial meningiomas are common in NF2. They are associated with poor prognosis factors. Clinical and radiological monitoring could lead to early treatment of these tumors both when clinical symptoms are present and in case of proven radiological evolution, and thus trying to maintain a favorable functional prognosis for as long as possible.

Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway for the central control of reproduction. The coordinated and timely activation of these hypothalamic neurons, which determines sexual development and adult reproductive function, lies under the tight control of a complex array of excitatory and inhibitory transsynaptic inputs. In addition, research conducted over the past 20 years has unveiled the major contribution of glial cells to the control of GnRH neurons. Glia use a variety of molecular and cellular strategies to modulate GnRH neuronal function both at the level of their cell bodies and at their nerve terminals. These mechanisms include the secretion of bioactive molecules that exert paracrine effects on GnRH neurons, juxtacrine interactions between glial cells and GnRH neurons via adhesive molecules and the morphological plasticity of the glial coverage of GnRH neurons. It now appears that glial cells are integral components, along with upstream neuronal networks, of the central control of GnRH neuronal function. This review attempts to summarize our current knowledge of the mechanisms used by glial cells to control GnRH neuronal activity and secretion.

Non-syndromic coronal synostoses oxycephaly and brachycephaly (NSCSOB) are rare. Their natural history, surgical management, and outcome are debated. We reviewed the available literature on NSCSOB. In addition, we reviewed retrospectively our experience with cases of NSCSOB, managed and operated by our joint craniofacial team since 1984. Newborns underwent perifrontal craniectomy, while infants and older children underwent fronto-orbital advancement with frontoparietal remodeling. Cases with delayed onset of faciosynostosis were excluded. Some cases of NSCSOB present at birth or even prenatally with gross dysmorphism and severe brachycephaly; others present later in life with harmonious restriction of intracranial volume and are at risk for development and vision. Some NSCSOB evolve from initially unisutural synostoses. We treated 61 cases, operated aged 1.4 to 106.7 months, 30 with brachycephaly and 31 with oxycephaly. Twelve of these (19.7 %), had been treated initially for sagittal or unicoronal synostosis, and evolved into NSCSOB. Intracranial hypertension was present initially in 28 (45.9 %), with ophthalmological consequences in 13 (21.3 %) and mental retardation in 6 (9.6 %). No patient had hydrocephalus; only two had asymptomatic Chiari malformation. The mean postoperative follow-up was 113.6 months. At last control, 21 patients had developmental delay and 5 had visual impairment. NSCSOB are a complex entity. They have in common a high risk of severe intracranial hypertension and rare hydrodynamic complications. Genetic screening is necessary to assert their non-syndromic nature. Prolonged follow-up of all craniosynostoses is necessary because unisutural synostoses can evolve into NSCSOB, and NSCSOB can evolve into craniofaciosynostosis.

Introduction The outlook of pediatric hydrocephalus has spectacularly improved over the past decades; however, the adult outcome is still poorly documented. Determining the healthcare profile of these patients is important in order to organize the management of this growing population. We decided to review our pediatric hydrocephalus database for pediatric patients treated for hydrocephalus and followed up into adulthood. Methods Our institution has a virtual monopoly for pediatric hydrocephalus, serving a four-million-plus population; the transition to adult care is also managed in the same institution. We retrospectively reviewed patients younger than 18 treated for hydrocephalus since 1980 and followed up beyond the age of 20. Results We reviewed 456 patients, with a mean initial age of 55.6 months, and followed up for a mean of 24.2 years. In 81 patients (17.8%), the last shunt operation occurred after 20 years; 22 of these (4.9% of the total) having never been revised earlier. Sixteen patients (3.5%) could be weaned of their shunt. Thirteen patients died in adult age, 5 of these dying of shunt-related causes. The most prominent sequels were motor (46.5%) and cognitive (47.6%); only 82 patients (18.0%) had no sequel at all. Intelligence quotient values were ≥80 in 54.5% of tested patients; however, schooling was normal in only 41.4%, and only 33.7% was employed in the competitive labor market. Conclusion Adults treated for hydrocephalus in childhood require a life-long follow-up. Late mortality is low but not null, morbidity is high, and many patients require shunt surgery during adulthood. The transition from child to adult neurosurgery needs to be organized for these vulnerable patients.

Background and purpose Haemophilia is a well-known X-linked recessive bleeding disorder related to a deficiency of factor VIII. The aim of the paper is to point out the role of an early diagnosis in cases of intracranial bleeding, especially in neonates and to highlight the bad prognosis. Methods Three patients were included in the study from our prospective data. All had severe factor VIII deficiency (less than 1%). Results The first of them was a newborn without familial history of haemophilia which presented with hypotonia and seizures after a delivery with vacuum. CT showed a subdural haematoma and MRI multiple ischemic lesions. Two months later, he died from a new intracranial haemorrhagic episode resistent to infusion of factor VIII related to development of an anti-factor VIII antiboby. The second neonate had no familial history more and experienced hypothermia and areactive mydriasis because of an acute subdural haematoma. He died eight days later of ischemic lesions in spite of a craniotomy. The third was a 5-month-old boy with a familial history. Physical examination revealed lethargy, seizure and a recent cranial perimeter increase. He underwent a craniotomy with a good result. Conclusion The authors stress the need for immediate factor VIII infusion and appropriate neurosurgical work-up. The rapid medical management is mandatory if morbidity and mortality are to be minimized.

International audience; Gaining new insights into the anatomy of the human hypothalamus is crucial for the development of new treatment strategies involving functional stereotactic neurosurgery. Here, using anatomical comparisons between histology and magnetic resonance images of the human hypothalamus in the coronal plane, we show that discrete gray and white hypothalamic structures are consistently identifiable by MRI. Macroscopic and microscopic images were used to precisely annotate the MRI sequences realized in the coronal plane in twenty healthy volunteers. MRI was performed on a 1.5 T scanner, using a protocol including T1-weighted 3D fast field echo, T1-weighted inversion-recovery, turbo spin echo and T2-weighted 2D fast field echo imaging. For each gray matter structure as well as for white matter bundles, the different MRI sequences were analyzed in comparison to each other. The anterior commissure and the fornix were often identifiable, while the mammillothalamic tract was more difficult to spot. Qualitative analyses showed that MRI could also highlight finer structures such as the paraventricular nucleus, the ventromedial nucleus of the hypothalamus and the infundibular (arcuate) nucleus, brain nuclei that play key roles in the regulation of food intake and energy homeostasis. The posterior hypothalamic area, a target for deep brain stimulation in the treatment of cluster headaches, was readily identified, as was the lateral hypothalamic area, which similar to the aforementioned hypothalamic nuclei, could be a putative target for deep brain stimulation in the treatment of obesity. Finally, each of the identified structures was mapped to Montreal Neurological Institute (MNI) space.

The lateral ventricles are the C-shaped cavities of the telencephalon. Embryology of theses cavities is recalled as well as the immediate relationship of the frontal horn, the body, the atrium and the temporal and occipital horns.

Central neurocytoma is the second most frequent tumor in our series of 284 lateral ventricle tumors (12%). Mean age was 32.6 years. There was a male predominance (20/35). Most frequent clinical signs were neuropsychological disturbances and intracranial hypertension. On imaging, these tumors concentrate central calcifications in more than half of cases. Main locations were frontal horn and corpus of lateral ventricle (82%). Uneventful postoperative course was recorded in 52% of cases. Immunoreactivity against neuron-specific enolase (NSE), synaptophysin, S 100 protein, Microtubul Associated Protein de type 2 (MAP 2) and calcineurin confirms the neuronal nature of the neoplasm. This tumor has a good prognosis. Local control after surgery is obtained in 68% of cases. Gamma knife surgery seems to be useful in cases of little volume with tumoral remnants or recurrence, when radiological appearance is well circumscribed and round-shaped.

Twenty-seven cases of ependymoma were collected in the French multicentric study dedicated to lateral ventricle tumors. The mean age of patients was 31,5 years. All patients underwent surgery, with complete resection of the tumor in 76% of cases. Histologic examination disclosed 23 grade 2 ependymomas and four grade 3 ependymomas. Postoperative mortality was 7%. Four patients underwent radiotherapy, and five chemotherapy. Local recurrence of the tumor occurred in seven cases, with a mean delay of 48 months. Disseminated disease within the central nervous system was found in only one patient. Median survival in all the 27 patients was 181 months, and median progression-free survival was 106 months. The relevant series of the literature are reviewed in order to precise the prognostic factors of ependymomas and therapeutic strategies.

Subependymoma is a benign lesion, slow-growing neoplasm, representing 0.2 to 0.7 % of intracranial tumors. They are often clinically silent, incidentally discovered at autopsy. These symptoms are related to big volume. They are attached to the septum pellucidum, leading to hydrocephalus by Monro foramen obstruction. Overall mean age at diagnosis is 39 years with more males than females. At CT-scan, subependymoma shows a slightly low attenuation compared to gray matter. There is no or mild enhancement following contrast injection. On MR T1-weighted imaging, subependymoma is isointense and hyperintense on MR T2-weighted imaging. Intramural calcifications and cystic components are noted in 20 to 30 % of patients. Peritumoral oedema is absent. Immunohistochemicals studies show intense positivity for S-100 and GFAP. The treatment is surgical with an excellent prognosis.

The lateral ventricle is a deep-seated cavity, overlayed by a cortical mantle which contains eloquent areas, especially on the dominant hemisphere, and surrounded by the optic radiations. The surgical approach requires a thorough preoperative reflexion based on magnetic resonance imaging, in order to understand the site of origin and the vascular pedicles of the tumor. Surgical approaches to the frontal horn, temporal horn and atrium are successively described.