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StiViPompe?: Stimulation du Vim dans la dystonie liée aux mutations ATP1A3 Contexte scientifiqueLes maladies liées aux mutations du gène ATP1A3 sont caractérisées par leur très importante diversité phénotypique, que ce soit en terme d’?ge de début, d’expression sémiologique, de sévérité ou de mode évolutif ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ITa5zwvB","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":12953,"uris":[""],"uri":[""],"itemData":{"id":12953,"type":"article-journal","container-title":"European Journal of Paediatric Neurology","DOI":"10.1016/j.ejpn.2017.12.009","ISSN":"10903798","issue":"2","journalAbbreviation":"European Journal of Paediatric Neurology","language":"en","page":"257-263","source":" (Crossref)","title":"ATP1A3-related disorders: An update","title-short":"ATP1A3-related disorders","volume":"22","author":[{"family":"Carecchio","given":"Miryam"},{"family":"Zorzi","given":"Giovanna"},{"family":"Ragona","given":"Francesca"},{"family":"Zibordi","given":"Federica"},{"family":"Nardocci","given":"Nardo"}],"issued":{"date-parts":[["2018",3]]}}}],"schema":""}1. Le syndrome ??dystonie et syndrome parkinsonien de début rapide?? (rapid-onset dystonia parkinsonism, RDP) est caractérisé par une dystonie d’installation brutale (en quelques heures à quelques jours), souvent associée à un syndrome parkinsonien (rigidité, bradykinésie). La dystonie s’installe généralement suite à un facteur déclenchant (stress émotionnel ou physique, prise d’alcool, infection, etc.), chez l’adolescent ou le jeune adulte ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"GuDjXNt2","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":12096,"uris":[""],"uri":[""],"itemData":{"id":12096,"type":"chapter","container-title":"Handbook of Clinical Neurology","ISBN":"978-0-444-52014-2","language":"en","note":"DOI: 10.1016/B978-0-444-52014-2.00040-9","page":"559-562","publisher":"Elsevier","source":" (Crossref)","title":"Rapid-onset dystonia-parkinsonism","URL":"","volume":"100","author":[{"family":"Geyer","given":"Howard L."},{"family":"Bressman","given":"Susan B."}],"accessed":{"date-parts":[["2019",6,16]]},"issued":{"date-parts":[["2011"]]}}}],"schema":""}2. La dystonie est souvent sévère, fixée, avec une implication importante de la région oro-faciale occasionnant des difficultés de parole, des troubles de l’alimentation et de la déglutition. Une dystonie peut survenir dans d’autres maladies liées à des mutations du gène ATP1A3, notamment chez des patients atteints d’hémiplégie alternante de l’enfant (alternating hemiplegia of childhood, AHC), souvent sous la forme d’accès dystoniques paroxystiques, longs (pouvant durer plusieurs heures) douloureux et très invalidants ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"PhXSfDCv","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":13168,"uris":[""],"uri":[""],"itemData":{"id":13168,"type":"article-journal","container-title":"Movement Disorders","DOI":"10.1002/mds.25659","ISSN":"08853185","issue":"1","journalAbbreviation":"Mov Disord.","language":"en","page":"153-154","source":" (Crossref)","title":"Intermediate form between alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism: Letters: New Observation","title-short":"Intermediate form between alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism","volume":"29","author":[{"family":"Sasaki","given":"Masayuki"},{"family":"Ishii","given":"Atsushi"},{"family":"Saito","given":"Yoshiaki"},{"family":"Hirose","given":"Shinichi"}],"issued":{"date-parts":[["2014",1]]}}}],"schema":""}3. Des chevauchements phénotypiques entre le RDP et l’AHC ont été rapportés?;?les pathologies liées aux mutations du gène ATP1A3 sont aujourd’hui considérées davantage comme un continuum que comme des entités totalement distinctes ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"SurBr28w","properties":{"formattedCitation":"\\super 4,5\\nosupersub{}","plainCitation":"4,5","noteIndex":0},"citationItems":[{"id":239,"uris":[""],"uri":[""],"itemData":{"id":239,"type":"article-journal","container-title":"Tremor and Other Hyperkinetic Movements","source":"Google Scholar","title":"Intermediate phenotypes of ATP1A3 mutations: phenotype–genotype correlations","title-short":"Intermediate phenotypes of ATP1A3 mutations","URL":"","volume":"5","author":[{"family":"Termsarasab","given":"Pichet"},{"family":"Yang","given":"Amy C."},{"family":"Frucht","given":"Steven J."}],"accessed":{"date-parts":[["2016",9,10]]},"issued":{"date-parts":[["2015"]]}}},{"id":4590,"uris":[""],"uri":[""],"itemData":{"id":4590,"type":"article-journal","container-title":"Pediatric Neurology","DOI":"10.1016/j.pediatrneurol.2014.09.015","ISSN":"08878994","issue":"1","language":"en","page":"56-64","source":"CrossRef","title":"The Expanding Spectrum of Neurological Phenotypes in Children With ATP1A3 Mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and Beyond","volume":"52","author":[{"family":"Sweney","given":"Matthew T."},{"family":"Newcomb","given":"Tara M."},{"family":"Swoboda","given":"Kathryn J."}],"issued":{"date-parts":[["2015",1]]}}}],"schema":""}4,5. Les IRM cérébrales réalisées chez ces patients ne retrouvent pas de lésions. A ce jour, il n’existe pas de traitement curatif des maladies liées aux mutations du gène ATP1A3. Les traitements symptomatiques ont souvent un effet limité et/ou non démontré. Cependant, notre expérience clinique et la collection rétrospective de données suggère que la flunarizine pourrait réduire la fréquence et/ou la sévérité des accès paroxystiques (dont les accès dystoniques) chez certains patients ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"0VJ4u7GE","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":12970,"uris":[""],"uri":[""],"itemData":{"id":12970,"type":"article-journal","abstract":"Background: Alternating Hemiplegia of Childhood (AHC) is a severe disorder. Several drugs have been administered as prophylaxis for paroxysmal attacks, however, no therapy is completely e?ective.\nMethods: Our aim is to review the pharmacological data related to the prophylactic and acute treatment of a cohort of 30 patients (16 M, 14 F, age range 5–42 years) and to correlate them with the clinical and genetic data collected through the Italian Biobank and Clinical Registry for AHC.\nResults: Flunarizine was the most commonly used long-term treatment in the cohort; it reduced duration and frequency of attacks in 50% of patients and decreased intensity in 32.1%. In younger patients, ?unarizine seemed signi?cantly more e?ective in reducing intensity. We found no correlation between the e?ectiveness of ?unarizine and genotype, or between developmental outcome and duration of treatment. In particular, 3 of our patients a?ected by E815K mutation presented rapid neurological deterioration despite ongoing treatment. Among the other administered prophylactic therapies, few proved to be e?ective (benzodiazepines, niaprazine, acetazolamide, melatonin, olanzapine, ketogenic diet). No clear rationale exists regarding their use, but these therapies may work by reducing the triggering factors.\nConclusions: The presented data are retrospective, but they are aimed at ?lling a gap given the rarity of the disease and the lack of randomized and controlled studies. Besides their usefulness in clarifying the pathophysiology of the disease, prospective studies involving larger cohorts of ATP1A3 mutated AHC patients are needed to provide a rationale for testing other molecules.","container-title":"Brain and Development","DOI":"10.1016/j.braindev.2017.02.001","ISSN":"03877604","issue":"6","journalAbbreviation":"Brain and Development","language":"en","page":"521-528","source":" (Crossref)","title":"Alternating Hemiplegia of Childhood: Pharmacological treatment of 30 Italian patients","title-short":"Alternating Hemiplegia of Childhood","volume":"39","author":[{"family":"Pisciotta","given":"Livia"},{"family":"Gherzi","given":"Marcella"},{"family":"Stagnaro","given":"Michela"},{"family":"Calevo","given":"Maria Grazia"},{"family":"Giannotta","given":"Melania"},{"family":"Vavassori","given":"Maria Rosaria"},{"family":"Veneselli","given":"Edvige"},{"family":"De Grandis","given":"Elisa"}],"issued":{"date-parts":[["2017",6]]}}}],"schema":""} 6. Nous avons réalisé le seul essai thérapeutique contr?lé dans cette maladie en testant l’effet de la triheptanoine mais le résultat en a été négatif ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"JB4X2T1j","properties":{"formattedCitation":"\\super 7\\nosupersub{}","plainCitation":"7","noteIndex":0},"citationItems":[{"id":12949,"uris":[""],"uri":[""],"itemData":{"id":12949,"type":"article-journal","abstract":"Background: Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations.\nMethods: We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects.\nResults: In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated.\nConclusions: Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting. Trial registration: The study has been registered with (NCT002408354) the 03/24/2015.","container-title":"Orphanet Journal of Rare Diseases","DOI":"10.1186/s13023-017-0713-2","ISSN":"1750-1172","issue":"1","journalAbbreviation":"Orphanet J Rare Dis","language":"en","page":"160","source":" (Crossref)","title":"A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood","volume":"12","author":[{"family":"Hainque","given":"Elodie"},{"family":"Caillet","given":"Samantha"},{"family":"Leroy","given":"Sandrine"},{"family":"Flamand-Roze","given":"Constance"},{"family":"Adanyeguh","given":"Isaac"},{"family":"Charbonnier-Beaupel","given":"Fanny"},{"family":"Retail","given":"Maryvonne"},{"family":"Le Toullec","given":"Benjamin"},{"family":"Atencio","given":"Mariana"},{"family":"Rivaud-Péchoux","given":"Sophie"},{"family":"Brochard","given":"Vanessa"},{"family":"Habarou","given":"Florence"},{"family":"Ottolenghi","given":"Chris"},{"family":"Cormier","given":"Florence"},{"family":"Méneret","given":"Aurélie"},{"family":"Ruiz","given":"Marta"},{"family":"Doulazmi","given":"Mohamed"},{"family":"Roubergue","given":"Anne"},{"family":"Corvol","given":"Jean-Christophe"},{"family":"Vidailhet","given":"Marie"},{"family":"Mochel","given":"Fanny"},{"family":"Roze","given":"Emmanuel"}],"issued":{"date-parts":[["2017",12]]}}}],"schema":""} 7. La stimulation cérébrale profonde (SCP) du pallidum interne (GPi) n’a pas amélioré la dystonie chez plusieurs patients RDP rapportés dans la littérature ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8sjooVk1","properties":{"formattedCitation":"\\super 8\\uc0\\u8211{}13\\nosupersub{}","plainCitation":"8–13","noteIndex":0},"citationItems":[{"id":5488,"uris":[""],"uri":[""],"itemData":{"id":5488,"type":"article-journal","container-title":"Movement Disorders","DOI":"10.1002/mds.20296","ISSN":"08853185","issue":"2","language":"en","page":"254-257","source":"Crossref","title":"Sporadic rapid-onset dystonia-parkinsonism syndrome: Failure of bilateral pallidal stimulation: Clinical/Scientific Notes","title-short":"Sporadic rapid-onset dystonia-parkinsonism syndrome","volume":"20","author":[{"family":"Deutschl?nder","given":"Angela"},{"family":"Asmus","given":"Friedrich"},{"family":"Gasser","given":"Thomas"},{"family":"Steude","given":"Ulrich"},{"family":"B?tzel","given":"Kai"}],"issued":{"date-parts":[["2005",2]]}}},{"id":5491,"uris":[""],"uri":[""],"itemData":{"id":5491,"type":"article-journal","container-title":"Neurology","DOI":"10.1212/01.wnl.0000310431.41036.e0","ISSN":"0028-3878, 1526-632X","issue":"Issue 16, Part 2","language":"en","page":"1501-1503","source":"Crossref","title":"Novel ATP1A3 mutation in a sporadic RDP patient with minimal benefit from Deep brain stimulation","volume":"70","author":[{"family":"Kamm","given":"C."},{"family":"Fogel","given":"W."},{"family":"Wachter","given":"T."},{"family":"Schweitzer","given":"K."},{"family":"Berg","given":"D."},{"family":"Kruger","given":"R."},{"family":"Freudenstein","given":"D."},{"family":"Gasser","given":"T."}],"issued":{"date-parts":[["2008",4,15]]}}},{"id":5489,"uris":[""],"uri":[""],"itemData":{"id":5489,"type":"article-journal","container-title":"Movement Disorders Clinical Practice","DOI":"10.1002/mdc3.12124","ISSN":"23301619","issue":"1","language":"en","page":"76-78","source":"Crossref","title":"Failure of Pallidal Deep Brain Stimulation in a Case of Rapid-Onset Dystonia Parkinsonism (DYT12)","volume":"2","author":[{"family":"Brücke","given":"Christof"},{"family":"Horn","given":"Andreas"},{"family":"Huppke","given":"Peter"},{"family":"Kupsch","given":"Andreas"},{"family":"Schneider","given":"Gerd-Helge"},{"family":"Kühn","given":"Andrea A."}],"issued":{"date-parts":[["2015",3]]}}},{"id":5490,"uris":[""],"uri":[""],"itemData":{"id":5490,"type":"article-journal","container-title":"Parkinsonism & Related Disorders","DOI":"10.1016/j.parkreldis.2017.09.008","ISSN":"13538020","language":"en","page":"99-100","source":"Crossref","title":"Failure of pallidal deep brain stimulation in DYT12-ATP1A3 dystonia","volume":"45","author":[{"family":"Albanese","given":"Alberto"},{"family":"Di Giovanni","given":"Mario"},{"family":"Amami","given":"Paolo"},{"family":"Lalli","given":"Stefania"}],"issued":{"date-parts":[["2017",12]]}}},{"id":5493,"uris":[""],"uri":[""],"itemData":{"id":5493,"type":"article-journal","container-title":"Movement Disorders Clinical Practice","DOI":"10.1002/mdc3.12605","ISSN":"23301619","issue":"4","language":"en","page":"427-429","source":"Crossref","title":"Atypical Presentation of Rapid-onset Dystonia-parkinsonism (DYT12) Unresponsive to Deep Brain Stimulation of the Subthalamic Nucleus: STN-DBS in DYT12 patient","title-short":"Atypical Presentation of Rapid-onset Dystonia-parkinsonism (DYT12) Unresponsive to Deep Brain Stimulation of the Subthalamic Nucleus","volume":"5","author":[{"family":"Weber","given":"Juliane"},{"family":"Piroth","given":"Tobias"},{"family":"Rijntjes","given":"Michel"},{"family":"Jung","given":"Bernhard"},{"family":"Reinacher","given":"Peter C."},{"family":"Weiller","given":"Cornelius"},{"family":"Coenen","given":"Volker A."},{"family":"Klebe","given":"Stephan"}],"issued":{"date-parts":[["2018",7]]}}},{"id":5492,"uris":[""],"uri":[""],"itemData":{"id":5492,"type":"article-journal","container-title":"Movement Disorders Clinical Practice","DOI":"10.1002/mdc3.12559","ISSN":"23301619","issue":"4","language":"en","page":"444-445","source":"Crossref","title":"Failure of Sequential Pallidal and Motor Thalamus DBS for Rapid-Onset Dystonia-Parkinsonism (DYT12)","volume":"5","author":[{"family":"Fearon","given":"Conor"},{"family":"McKinley","given":"John"},{"family":"McCarthy","given":"Allan"},{"family":"Rebelo","given":"Pedro"},{"family":"Goggin","given":"Carole"},{"family":"Magennis","given":"Brian"},{"family":"Aziz","given":"Tipu"},{"family":"Green","given":"Alexander L."},{"family":"Lynch","given":"Timothy"}],"issued":{"date-parts":[["2018",7]]}}}],"schema":""} 8–13, alors qu’elle est efficace dans de nombreux cadres de dystonie génétique sans lésions visibles sur l’IRM cérébrale ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"CU3vnk75","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":4492,"uris":[""],"uri":[""],"itemData":{"id":4492,"type":"article-journal","container-title":"Movement Disorders Clinical Practice","DOI":"10.1002/mdc3.12519","ISSN":"23301619","issue":"4","language":"en","page":"486-494","source":"CrossRef","title":"Deep Brain Stimulation for the Dystonias: Evidence, Knowledge Gaps, and Practical Considerations","title-short":"Deep Brain Stimulation for the Dystonias","volume":"4","author":[{"family":"Reese","given":"René"},{"family":"Volkmann","given":"Jens"}],"issued":{"date-parts":[["2017",7]]}}}],"schema":""} 14. Une seule étude récente a suggéré l’efficacité de la SCP du GPi dans la réduction des accès dystoniques chez un patient ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lFRWqOyA","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":13803,"uris":[""],"uri":[""],"itemData":{"id":13803,"type":"article-journal","abstract":"Background: Paroxysmal movement disorders are a heterogeneous group of neurological diseases, better understood in recent years thanks to widely available genetic testing. Case report: A pair of monozygotic twins with dystonia and paroxysmal attacks, resembling paroxysmal non-kinesigenic dyskinesias, due to a novel ATP1A3 variant are reported. The complete resolution of their paroxysms was achieved using levodopa and deep brain stimulation of the internal globus pallidus. Improvement of interictal dystonia was also achieved with this therapy.","language":"en","page":"5","source":"Zotero","title":"Generalized Dystonia and Paroxysmal Dystonic Attacks due to a Novel ATP1A3 Variant","author":[{"family":"Zú?iga-Ramírez","given":"Carlos"},{"family":"Kramis-Hollands","given":"Mirelle"},{"family":"Mercado-Pimentel","given":"Rodrigo"},{"family":"González-Usigli","given":"Héctor Alberto"},{"family":"Soto-Escageda","given":"Alberto"},{"family":"Fasano","given":"Alfonso"}]}}],"schema":""} 15. La stimulation du noyau ventral-oral postérieur (VoP) du thalamus réalisé chez un patient n’a pas non plus démontré son efficacité sur la dystonie ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kEFfgawB","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":5492,"uris":[""],"uri":[""],"itemData":{"id":5492,"type":"article-journal","container-title":"Movement Disorders Clinical Practice","DOI":"10.1002/mdc3.12559","ISSN":"23301619","issue":"4","language":"en","page":"444-445","source":"Crossref","title":"Failure of Sequential Pallidal and Motor Thalamus DBS for Rapid-Onset Dystonia-Parkinsonism (DYT12)","volume":"5","author":[{"family":"Fearon","given":"Conor"},{"family":"McKinley","given":"John"},{"family":"McCarthy","given":"Allan"},{"family":"Rebelo","given":"Pedro"},{"family":"Goggin","given":"Carole"},{"family":"Magennis","given":"Brian"},{"family":"Aziz","given":"Tipu"},{"family":"Green","given":"Alexander L."},{"family":"Lynch","given":"Timothy"}],"issued":{"date-parts":[["2018",7]]}}}],"schema":""} 13. La dystonie liée aux mutations du gène ATP1A3 occupe ainsi une place particulière au sein des dystonies génétiques?: il s’agit de la seule pathologie dystonique d’apparition aigue ou subaigue, pouvant se manifester par des accès paroxystiques, qui semble par ailleurs être réfractaire à la la SCP du GPi, en l’absence de lésion visible sur l’IRM cérébrale. Ces différents éléments font poser la question de la physiopathologie de la dystonie dans ces maladies et des alternatives thérapeutiques. Le gène ATP1A3 code pour l’isoforme α3 de la sous-unité α de la pompe Sodium-Potassium Adenosine Triphosphatase (Na+/K+ ATPase). Au sein du système nerveux central, cette isoforme est spécifique des neurones et est particulièrement exprimée dans les cellules GABAergiques du cervelet (cellule de Purkinje du cortex cérébelleux ou des noyaux profonds du cervelet), du cortex, des ganglions de la base ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rYy0ppl5","properties":{"formattedCitation":"\\super 16,17\\nosupersub{}","plainCitation":"16,17","noteIndex":0},"citationItems":[{"id":234,"uris":[""],"uri":[""],"itemData":{"id":234,"type":"article-journal","abstract":"In the CNS, there are multiple isozymes of the sodium and potassium ion-stimulated adenosine triphosphatase (Na,K-ATPase) that have differences in affinity for Na+, ATP, and cardiac glycosides. Three forms of the catalytic subunit (designated alpha 1, alpha 2, and alpha 3) are known to be derived from different genes, but little is known of the cellular distributions of the proteins or their physiological roles. Isozyme-specific monoclonal antibodies permitted the immunofluorescent localization of the 3 Na,K-ATPases in the rat CNS, and markedly different patterns of staining were seen. All 3 isozymes were detected, singly or in combination, in 1 or more neuronal structures, while both alpha 1 and alpha 2 were detected in glia. Many different neuroanatomic structures or cell types stained for more than 1 isozyme. Even when a structure or region stained for more than 1 isozyme, the pattern of staining was frequently dissimilar, suggesting complex differences in gene expression and cellular localization.","container-title":"The Journal of Neuroscience: The Official Journal of the Society for Neuroscience","ISSN":"0270-6474","issue":"2","journalAbbreviation":"J. Neurosci.","language":"eng","note":"PMID: 1846906","page":"381-391","source":"PubMed","title":"Immunofluorescent localization of three Na,K-ATPase isozymes in the rat central nervous system: both neurons and glia can express more than one Na,K-ATPase","title-short":"Immunofluorescent localization of three Na,K-ATPase isozymes in the rat central nervous system","volume":"11","author":[{"family":"McGrail","given":"K. M."},{"family":"Phillips","given":"J. M."},{"family":"Sweadner","given":"K. J."}],"issued":{"date-parts":[["1991",2]]}}},{"id":12956,"uris":[""],"uri":[""],"itemData":{"id":12956,"type":"article-journal","container-title":"Neuroscience","DOI":"10.1016/j.neuroscience.2018.07.018","ISSN":"03064522","journalAbbreviation":"Neuroscience","language":"en","page":"274-294","source":" (Crossref)","title":"A Transgenic Mouse Model to Selectively Identify α3 Na,K-ATPase Expressing Cells in the Nervous System","volume":"398","author":[{"family":"Dobretsov","given":"Maxim"},{"family":"Hayar","given":"Abdallah"},{"family":"Kockara","given":"Neriman T."},{"family":"Kozhemyakin","given":"Maxim"},{"family":"Light","given":"Kim E."},{"family":"Patyal","given":"Pankaj"},{"family":"Pierce","given":"Dwight R."},{"family":"Wight","given":"Patricia A."}],"issued":{"date-parts":[["2019",2]]}}}],"schema":""} 16,17. La pompe Na+/K+ ATPase maintient un gradient électrochimique au niveau de la membrane plasmatique des neurones, essentiel pour le maintien du potentiel de repos et la génération des potentiels d’action. La pompe Na+/K+ ATPase exprimant l’isoforme α3 semble particulièrement mise en jeu dans des situations d’élévation du sodium et permet d’en restaurer les concentrations après une activité neuronale soutenue ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qHFvNEpR","properties":{"formattedCitation":"\\super 18,19\\nosupersub{}","plainCitation":"18,19","noteIndex":0},"citationItems":[{"id":13687,"uris":[""],"uri":[""],"itemData":{"id":13687,"type":"article-journal","abstract":"The Na/K-ATPase is a complex of integral membrane proteins that carries out active transport of sodium and potassium across the cell plasma membrane, and maintains chemical gradients of these ions. The alpha subunit of the Na/K-ATPase has several isoforms that are expressed in a cell type- and tissue-dependent manner. In adult vertebrates, while kidney cells express mostly alpha1, muscle and glial cells -- alpha1 and alpha2, and sperm cells -- alpha1 and alpha4 isoforms of Na/K-ATPase, neurons may express alpha1, alpha2, alpha3 or any combination of these isoforms, and evidence suggests that neuronal type is the determining factor. The functional significance of multiple isoforms of the Na/K-ATPase and their non-uniform expression, and the link between neuron function and expression of a given isoform of the Na/K-ATPase in particular, remains unknown. Several hypotheses on this account were introduced, and in this work we will review the present status of these hypotheses, and their standing in application to recent data on the expression of isoforms of the Na/K-ATPase in the peripheral nervous system of vertebrate animals.","container-title":"Frontiers in Bioscience: A Journal and Virtual Library","DOI":"10.2741/1704","ISSN":"1093-9946","journalAbbreviation":"Front. Biosci.","language":"eng","note":"PMID: 15970502","page":"2373-2396","source":"PubMed","title":"Neuronal function and alpha3 isoform of the Na/K-ATPase","volume":"10","author":[{"family":"Dobretsov","given":"Maxim"},{"family":"Stimers","given":"Joseph R."}],"issued":{"date-parts":[["2005",9,1]]}}},{"id":13139,"uris":[""],"uri":[""],"itemData":{"id":13139,"type":"article-journal","abstract":"Background: Neurons express two Na,K-ATPase isoforms, the ubiquitous ?1 and neuron-specific ?3.\nResults: ?3 is important for control of membrane potential and is fully responsible for restoration of large [Na?]i increases.\nConclusion: ?1 and ?3 are required for basal neuronal function, but ?3 controls restoration of [Na?]i following sustained discharge. Significance: Conditions associated with defect ?3 function are likely aggravated by suprathreshold neuronal activity.","container-title":"Journal of Biological Chemistry","DOI":"10.1074/jbc.M112.425785","ISSN":"0021-9258, 1083-351X","issue":"4","journalAbbreviation":"J. Biol. Chem.","language":"en","page":"2734-2743","source":" (Crossref)","title":"A Specific and Essential Role for Na,K-ATPase α3 in Neurons Co-expressing α1 and α3","volume":"288","author":[{"family":"Azarias","given":"Guillaume"},{"family":"Kruusm?gi","given":"Markus"},{"family":"Connor","given":"Siobhan"},{"family":"Akkuratov","given":"Evgeny E."},{"family":"Liu","given":"Xiao-Li"},{"family":"Lyons","given":"David"},{"family":"Brismar","given":"Hjalmar"},{"family":"Broberger","given":"Christian"},{"family":"Aperia","given":"Anita"}],"issued":{"date-parts":[["2013",1,25]]}}}],"schema":""} 18,19. Ainsi, dans le RDP, le début brutal des sympt?mes après un stress pourrait être lié à l’incapacité de cette pompe de restaurer les concentrations de sodium après une période de décharge accrue au-delà d’un certain seuil. On comprend également que l’effet d’un dysfonctionnement de l’isoforme α3 liée à une mutation du gène ATP1A3 va être particulièrement marqué dans des neurones exprimant de fa?on préférentielle ou exclusive l’isoforme α3, et ayant un taux de décharge rapide, comme c’est le cas des cellules de Purkinje du cervelet. Chez la souris, l’association d’un stress physique à une inhibition partielle des pompes Na+/K+ ATPase du cervelet et des ganglions de la base induit un phénotype clinique reproduisant le RDP ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"JFeg4Bi3","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":242,"uris":[""],"uri":[""],"itemData":{"id":242,"type":"article-journal","container-title":"Nature Neuroscience","DOI":"10.1038/nn.2753","ISSN":"1097-6256, 1546-1726","issue":"3","page":"357-365","source":"CrossRef","title":"The neural substrates of rapid-onset Dystonia-Parkinsonism","volume":"14","author":[{"family":"Calderon","given":"D Paola"},{"family":"Fremont","given":"Rachel"},{"family":"Kraenzlin","given":"Franca"},{"family":"Khodakhah","given":"Kamran"}],"issued":{"date-parts":[["2011",3]]}}}],"schema":""} 20. L’enregistrement électrophysiologique des neurones des cellules des souris RDP retrouve une activité neuronale irrégulière avec bursts à haute fréquence dans les cellules de Purkinje ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5mdmWAZS","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":13172,"uris":[""],"uri":[""],"itemData":{"id":13172,"type":"article-journal","container-title":"Journal of Neuroscience","DOI":"10.1523/JNEUROSCI.1409-14.2014","ISSN":"0270-6474, 1529-2401","issue":"35","journalAbbreviation":"Journal of Neuroscience","language":"en","page":"11723-11732","source":" (Crossref)","title":"Abnormal High-Frequency Burst Firing of Cerebellar Neurons in Rapid-Onset Dystonia-Parkinsonism","volume":"34","author":[{"family":"Fremont","given":"R."},{"family":"Calderon","given":"D. P."},{"family":"Maleki","given":"S."},{"family":"Khodakhah","given":"K."}],"issued":{"date-parts":[["2014",8,27]]}}}],"schema":""} 21, dans les neurones des noyaux profonds du cervelet ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"J4cofBNG","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":13172,"uris":[""],"uri":[""],"itemData":{"id":13172,"type":"article-journal","container-title":"Journal of Neuroscience","DOI":"10.1523/JNEUROSCI.1409-14.2014","ISSN":"0270-6474, 1529-2401","issue":"35","journalAbbreviation":"Journal of Neuroscience","language":"en","page":"11723-11732","source":" (Crossref)","title":"Abnormal High-Frequency Burst Firing of Cerebellar Neurons in Rapid-Onset Dystonia-Parkinsonism","volume":"34","author":[{"family":"Fremont","given":"R."},{"family":"Calderon","given":"D. P."},{"family":"Maleki","given":"S."},{"family":"Khodakhah","given":"K."}],"issued":{"date-parts":[["2014",8,27]]}}}],"schema":""} 21 et dans le striatum ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Hd2vxyoT","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":13186,"uris":[""],"uri":[""],"itemData":{"id":13186,"type":"article-journal","container-title":"nature NEUROSCIENCE","language":"en","page":"12","source":"Zotero","title":"Short latency cerebellar modulation of the basal ganglia","author":[{"family":"Chen","given":"Christopher H"},{"family":"Fremont","given":"Rachel"},{"family":"Arteaga-Bracho","given":"Eduardo E"},{"family":"Khodakhah","given":"Kamran"}],"issued":{"date-parts":[["2014"]]}}}],"schema":""} 22. L’activité neuronale anormale des cellules de Purkinje serait la source de l’activité neuronale anormale des neurones des noyaux profonds du cervelet et du striatum ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ZOlS2p2d","properties":{"formattedCitation":"\\super 23\\nosupersub{}","plainCitation":"23","noteIndex":0},"citationItems":[{"id":13165,"uris":[""],"uri":[""],"itemData":{"id":13165,"type":"article-journal","abstract":"Loss-of-function mutations in the α3 isoform of the sodium pump are responsible for Rapid Onset Dystonia-Parkinsonism (RDP). A pharmacologic model of RDP replicates the most salient features of RDP, and implicates both the cerebellum and basal ganglia in the disorder; dystonia is associated with aberrant cerebellar output, and the parkinsonism-like features are attributable to the basal ganglia. The pharmacologic agent used to generate the model, ouabain, is selective for sodium pumps. However, close to the infusion sites in vivo it likely affects all sodium pump isoforms. Therefore, it remains to be established whether selective loss of α3-containing sodium pumps replicates the pharmacologic model. Moreover, while the pharmacologic model suggested that aberrant firing of Purkinje cells was the main cause of abnormal cerebellar output, it did not allow the scrutiny of this hypothesis. To address these questions RNA interference using small hairpin RNAs (shRNAs) delivered via adeno-associated viruses (AAV) was used to specifically knockdown α3-containing sodium pumps in different regions of the adult mouse brain. Knockdown of the α3-containing sodium pumps mimicked both the behavioral and electrophysiological changes seen in the pharmacologic model of RDP, recapitulating key aspects of the human disorder. Further, we found that knockdown of the α3 isoform altered the intrinsic pacemaking of Purkinje cells, but not the neurons of the deep cerebellar nuclei. Therefore, acute knockdown of proteins associated with inherited dystonias may be a good strategy for developing phenotypic genetic mouse models where traditional transgenic models have failed to produce symptomatic mice.","container-title":"Neurobiology of Disease","DOI":"10.1016/j.nbd.2015.06.004","ISSN":"09699961","journalAbbreviation":"Neurobiology of Disease","language":"en","page":"200-212","source":" (Crossref)","title":"Aberrant Purkinje cell activity is the cause of dystonia in a shRNA-based mouse model of Rapid Onset Dystonia–Parkinsonism","volume":"82","author":[{"family":"Fremont","given":"Rachel"},{"family":"Tewari","given":"Ambika"},{"family":"Khodakhah","given":"Kamran"}],"issued":{"date-parts":[["2015",10]]}}}],"schema":""} 23. La réalisation d’une lésion des noyaux profonds cérébelleux ou de leurs afférences thalamiques chez les souris RBD fait dispara?tre la dystonie ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"uBIyHGp0","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":242,"uris":[""],"uri":[""],"itemData":{"id":242,"type":"article-journal","container-title":"Nature Neuroscience","DOI":"10.1038/nn.2753","ISSN":"1097-6256, 1546-1726","issue":"3","page":"357-365","source":"CrossRef","title":"The neural substrates of rapid-onset Dystonia-Parkinsonism","volume":"14","author":[{"family":"Calderon","given":"D Paola"},{"family":"Fremont","given":"Rachel"},{"family":"Kraenzlin","given":"Franca"},{"family":"Khodakhah","given":"Kamran"}],"issued":{"date-parts":[["2011",3]]}}}],"schema":""} 20. Ces travaux démontrent le r?le des neurones cérébelleux et de leur structure de sortie (noyaux profonds du cervelet et ganglion de la base) dans la physiopathologie de la dystonie liée aux mutations ATP1A3. Hypothèse de travailNous faisons l’hypothèse que chez l’homme, la dystonie liée aux mutations du gène ATP1A3 est la conséquence d’activités neuronales anormales au niveau des cellules de Purkinke, transmise aux noyaux de sortie du cervelet (noyaux dentelés notamment), puis au noyau ventral intermédiaire (Vim) du thalamus via le faisceau dentato-rubro-thalamique. La neuromodulation par stimulation cérébrale profonde (SCP) des activités neuronales au niveau de cette voie pourrait améliorer la dystonie ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TxQGMV7t","properties":{"formattedCitation":"\\super 24\\nosupersub{}","plainCitation":"24","noteIndex":0},"citationItems":[{"id":13166,"uris":[""],"uri":[""],"itemData":{"id":13166,"type":"article-journal","abstract":"Dystonia is a common movement disorder that devastates the lives of many patients but the etiology of this disorder remains poorly understood. Dystonia has traditionally been considered a disorder of the basal ganglia. However, growing evidence suggests that the cerebellum may be involved in certain types of dystonia raising several questions. Can different types of dystonia be classified as either a basal ganglia disorder or a cerebellar disorder? Is dystonia a network disorder that involves the cerebellum and basal ganglia? If dystonia is a network disorder, how can we target treatments to alleviate symptoms in patients? A recent study by Chen et al., using the pharmacological mouse model of Rapid-onset dystonia Parkinsonism (RDP), has provided some insight into these important questions. They showed that the cerebellum can directly modulate basal ganglia activity through a short latency cerebello-thalamo-basal ganglia pathway. Further, this paper and others have provided evidence that in some cases, aberrant cerebello-basal ganglia communication can be involved in dystonia. In this review we examine the evidence for the involvement of the cerebellum and cerebello-basal ganglia interactions in dystonia. We conclude that there is ample evidence to suggest that the cerebellum plays a role in some dystonias, including the early-onset primary torsion dystonia DYT1 and that further studies examining the role of this brain region and its interaction with the basal ganglia in dystonia are warranted.","container-title":"Movement Disorders","DOI":"10.1002/mds.27123","ISSN":"08853185","issue":"11","journalAbbreviation":"Mov Disord.","language":"en","page":"1537-1545","source":" (Crossref)","title":"It's not just the basal ganglia: Cerebellum as a target for dystonia therapeutics: Cerebellum as Target for Dystonia Therapeutics","title-short":"It's not just the basal ganglia","volume":"32","author":[{"family":"Tewari","given":"Ambika"},{"family":"Fremont","given":"Rachel"},{"family":"Khodakhah","given":"Kamran"}],"issued":{"date-parts":[["2017",11]]}}}],"schema":""} 24. Objectifs de l’étudeLes principaux objectifs de notre projet de recherche sont?: ?valuer l’efficacité de la SCP bilatérale des noyaux Vim du thalamus sur la dystonie de patients ayant une mutation du gène ATP1A3 9 mois après la chirurgie (étude thérapeutique). ?tudier la physiopathologie de la dystonie liée aux mutations du gène ATP1A3 (étude physiopathologique). Méthodologie de la rechercheCadre de la rechercheIl s’agit d’une recherche interventionnelle impliquant la personne humaine (loi Jardé RIPH Catégorie 1). L’étude aura lieu à l’H?pital de la Pitié Salpêtrière, dans le Département de Neurologie, de Neurochirurgie et au Centre d’investigations Cliniques à l’Institut du Cerveau et de la Moelle ?pinière. Sélection des patientsL’étude inclura deux patients souffrant de dystonie secondaire à une mutation du gène ATP1A3?: un patient avec un phénotype RDP et un patient avec une dystonie paroxystique dans le cadre d’une AHC. Les patients signeront un consentement libre et éclairé avant leur participation à l’étude.??tude thérapeutiqueOrganisation générale (Fig 1)Les visites V1 et V2 pré-chirurgicales permettent de recueillir le consentement éclairé et libre des patients (V1), de vérifier l’éligibilité des patients à la neurochirurgie (V1), d’évaluer la sévérité de la dystonie (V1) et d’étudier la physiopathologie de cette dystonie (V2). La visite V3 correspond au temps neurochirurgical. Les patients bénéficient sous anesthésie générale d’une implantation bilatérale d’électrodes de stimulation (électrodes Medtronic 3389) dans le noyau Vim du thalamus au moyen d’une chirurgie stéréotaxique. La cible Vim est définie gr?ce à la réalisation d’un protocole d’IRM cérébrale effectué usuellement (Tenseur de Diffusion et tractographie) permettant de reconstituer le faisceau dentato-rubro-thalamique ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OSeZn9Af","properties":{"formattedCitation":"\\super 25\\nosupersub{}","plainCitation":"25","noteIndex":0},"citationItems":[{"id":11951,"uris":[""],"uri":[""],"itemData":{"id":11951,"type":"article-journal","abstract":"BACKGROUND: We report a patient who received conventional bilateral deep brain stimulation of the ventral intermediate nucleus of thalamus (Vim) for the treatment of medication refractory essential tremor (ET). After initial beneficial effects, therapeutic efficacy was lost due to a loss of control of his proximal trunkal and extremity tremor. The patient received successful diffusion tensor magnetic resonance imaging fiber tractographic (DTI FT)-assisted DBS revision surgery targeting the dentato-rubro-thalamic tract (DRT) in the subthalamic region (STR).\nOBJECTIVE: To report the concept of DTI FT-assisted DRT DBS revision surgery for ET and to show sophisticated postoperative neuroimaging analysis explaining improved symptom control.\nMETHODS: Analysis was based on preoperative DTI sequences and postoperative helical computed tomography (hCT). Leads, stimulation fields, and fibers were reconstructed using commercial software systems (Elements, Brainlab AG, Feldkirchen, Germany; GUIDE XT, Boston Scientific Corp., Boston, MA, USA).\nRESULTS: The patient showed immediate and sustained tremor improvement after DTI FT-assisted revision surgery. Analysis of the two implantations (electrode positions in both instances) revealed a lateral and posterior shift in the pattern of modulation of the cortical fiber pathway projection after revision surgery as compared to initial implantation, explaining a more efficacious stimulation.\nCONCLUSIONS: Our work underpins a possible superiority of direct targeting approaches using advanced neuroimaging technologies to perform personalized DBS surgery. The evaluation of DBS electrode positions with the herein-described neuroimaging simulation technologies will likely improve targeting and revision strategies. Direct targeting with DTI FT-assisted approaches in a variety of indications is the focus of our ongoing research.","container-title":"Acta Neurochirurgica","DOI":"10.1007/s00701-017-3134-z","ISSN":"0942-0940","issue":"5","journalAbbreviation":"Acta Neurochir (Wien)","language":"eng","note":"PMID: 28283867\nPMCID: PMC5385205","page":"779-787","source":"PubMed","title":"Postoperative neuroimaging analysis of DRT deep brain stimulation revision surgery for complicated essential tremor","volume":"159","author":[{"family":"Coenen","given":"Volker Arnd"},{"family":"Varkuti","given":"Balint"},{"family":"Parpaley","given":"Yaroslav"},{"family":"Skodda","given":"Sabine"},{"family":"Prokop","given":"Thomas"},{"family":"Urbach","given":"Horst"},{"family":"Li","given":"Meng"},{"family":"Reinacher","given":"Peter Christoph"}],"issued":{"date-parts":[["2017"]]}}}],"schema":""} 25. Un enregistrement per-opératoire par micro-électrodes permettant la confirmation de la localisation du Vim est réalisé au bloc opératoire selon la procédure habituelle dans notre centre. Un stimulateur Medtronic Percept PC TM est implanté dans un second temps.Les patients sont hospitalisés pour surveillance post-opératoire dans le Département de Neurochirurgie pendant une durée approximative de 2 semaines. La SCP est débutée 3 mois après la chirurgie et adaptée à la réponse clinique des patients. Des consultations neurologiques et neurochirurgicales régulières effectuées dans le cadre du soin courant sont prévues pour poursuite de la surveillance clinique et ajustement de la SCP suivant la sortie de neurochirurgie. La visite V4 post-opératoire réalisée à 9 mois de la chirurgie permet d’étudier l’efficacité de la SCP sur la dystonie, les effets indésirables potentiels et les modifications physiopathologiques.Critères de jugementLes critères de jugement principal sont?:- Evolution du score de la Burke-Fahn-Marsden évalué en aveugle sur vidéos entre la V1 et la V4 pour le patient RDP- Evolution du nombre d’épisodes dystoniques paroxystiques relevés sur une période de 2 mois par un agenda patient récupéré à la V1 et la V4 pour le patient AHC ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4EIOatdS","properties":{"formattedCitation":"\\super 7\\nosupersub{}","plainCitation":"7","noteIndex":0},"citationItems":[{"id":12949,"uris":[""],"uri":[""],"itemData":{"id":12949,"type":"article-journal","abstract":"Background: Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations.\nMethods: We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects.\nResults: In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated.\nConclusions: Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting. Trial registration: The study has been registered with (NCT002408354) the 03/24/2015.","container-title":"Orphanet Journal of Rare Diseases","DOI":"10.1186/s13023-017-0713-2","ISSN":"1750-1172","issue":"1","journalAbbreviation":"Orphanet J Rare Dis","language":"en","page":"160","source":" (Crossref)","title":"A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood","volume":"12","author":[{"family":"Hainque","given":"Elodie"},{"family":"Caillet","given":"Samantha"},{"family":"Leroy","given":"Sandrine"},{"family":"Flamand-Roze","given":"Constance"},{"family":"Adanyeguh","given":"Isaac"},{"family":"Charbonnier-Beaupel","given":"Fanny"},{"family":"Retail","given":"Maryvonne"},{"family":"Le Toullec","given":"Benjamin"},{"family":"Atencio","given":"Mariana"},{"family":"Rivaud-Péchoux","given":"Sophie"},{"family":"Brochard","given":"Vanessa"},{"family":"Habarou","given":"Florence"},{"family":"Ottolenghi","given":"Chris"},{"family":"Cormier","given":"Florence"},{"family":"Méneret","given":"Aurélie"},{"family":"Ruiz","given":"Marta"},{"family":"Doulazmi","given":"Mohamed"},{"family":"Roubergue","given":"Anne"},{"family":"Corvol","given":"Jean-Christophe"},{"family":"Vidailhet","given":"Marie"},{"family":"Mochel","given":"Fanny"},{"family":"Roze","given":"Emmanuel"}],"issued":{"date-parts":[["2017",12]]}}}],"schema":""} 7. Les critères de jugement secondaires sont?: Clinical Global impression improvement (CGI-I) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UeUMym6Y","properties":{"formattedCitation":"\\super 26\\nosupersub{}","plainCitation":"26","noteIndex":0},"citationItems":[{"id":14101,"uris":[""],"uri":[""],"itemData":{"id":14101,"type":"article-journal","abstract":"Objective: This paper reviews the potential value in daily clinical practice of an easily applied research tool, the Clinical Global Impressions (CGI) Scale, for the nonresearcher clinician to quantify and track patient progress and treatment response over time., Method: The instrument is described and sample patient scenarios are provided with scoring rationales and a practical charting system., Conclusion: The CGI severity and improvement scales offer a readily understood, practical measurement tool that can easily be administered by a clinician in a busy clinical practice setting.","container-title":"Psychiatry (Edgmont)","ISSN":"1550-5952","issue":"7","journalAbbreviation":"Psychiatry (Edgmont)","note":"PMID: 20526405\nPMCID: PMC2880930","page":"28-37","source":"PubMed Central","title":"The Clinical Global Impressions Scale","volume":"4","author":[{"family":"Busner","given":"Joan"},{"family":"Targum","given":"Steven D."}],"issued":{"date-parts":[["2007",7]]}}}],"schema":""} 26 médecin et patient entre la V1 et la V4Evolution de la Canadian Occupational Performance Measure ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"IchxCrhk","properties":{"formattedCitation":"\\super 27\\nosupersub{}","plainCitation":"27","noteIndex":0},"citationItems":[{"id":14106,"uris":[""],"uri":[""],"itemData":{"id":14106,"type":"article-journal","abstract":"PURPOSE: To evaluate the functional goal-directed outcomes of Deep Brain Stimulation (DBS) in childhood dystonia according to aetiology and to explore relationship with a traditional impairment-based measure.\nMETHOD: This is a prospective case series study involving thirty children with dystonia with a 1-year follow-up post-DBS. The Canadian Occupational Performance Measure (COPM) and Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) were used as primary outcome measures. Results were analysed based on aetiology in 3 groups: 1. primary/primary plus dystonia; 2. secondary dystonia-cerebral palsy (CP); 3. secondary dystonia-non-CP group. Correlation between functional outcome using COPM and dystonia improvement as captured by BFMDRS was measured.\nRESULTS: All groups demonstrated significant improvement in individualised goal attainment, measured with the COPM, at 1-year post-DBS. The secondary dystonia-CP group also achieved significant improvement at 6 months for performance and satisfaction scores. In the majority of secondary dystonias, the BFMDRS failed to demonstrate significant improvement. A linear correlation between change in BFMDRS and COPM scores was observed when the entire cohort was analysed.\nINTERPRETATION/CONCLUSIONS: DBS improved functional performance, independently of the dystonic phenotype. Improvements in individualized COPM functional goal areas were seen in the absence of significant changes in BFMDRS scores, highlighting the relative insensitivity of impairment scales in this patient group.","container-title":"European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society","DOI":"10.1016/j.ejpn.2013.12.010","ISSN":"1532-2130","issue":"3","journalAbbreviation":"Eur. J. Paediatr. Neurol.","language":"eng","note":"PMID: 24461258","page":"308-316","source":"PubMed","title":"Evaluation of functional goal outcomes using the Canadian Occupational Performance Measure (COPM) following Deep Brain Stimulation (DBS) in childhood dystonia","volume":"18","author":[{"family":"Gimeno","given":"Hortensia"},{"family":"Tustin","given":"Kylee"},{"family":"Lumsden","given":"Daniel"},{"family":"Ashkan","given":"Keyoumars"},{"family":"Selway","given":"Richard"},{"family":"Lin","given":"Jean-Pierre"}],"issued":{"date-parts":[["2014",5]]}}}],"schema":""} 27 entre la V1 et la V4 Evolution du score de l’échelle GABS entre la V1 et la V4 permettant d’évaluer les modifications fonctionnelles sur la marche et l’équilibre 27Evolution du score de l’échelle SwalQol entre la V1 et la V4 permettant d’étudier la tolérance de la SCP sur les troubles de la déglutition 28 Evolution de l’échelle de bien-être mental de Warwick-Edinburgh (WEMWBS) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"e7vY7LxT","properties":{"formattedCitation":"\\super 28\\nosupersub{}","plainCitation":"28","noteIndex":0},"citationItems":[{"id":14200,"uris":[""],"uri":[""],"itemData":{"id":14200,"type":"article-journal","abstract":"The Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) has been validated in general population samples in many countries. Interest in using this measure in clinical populations is growing, particularly for tertiary prevention and mental health promotion. This paper reports validation of the French WEMWBS in healthy and chronic remitted schizophrenia populations. The French WEMWBS was administered to 319 workers, 75 students and 121 patients. For non-patients, self-reported Trait- and State-Anxiety, Mindfulness, Positive and Negative Affect and the General Health Questionnaire were completed. For patients, the Positive and Negative Syndrome Scale, Clinical Global Impression Severity Scale, Birchwood Insight Scale, Social Adjustment Scale, and Global Assessment of Functioning scale were completed. Test-retest reliability and responsiveness to intervention was assessed at 6 months. Whatever the sample, response frequencies showed normal distributions, and internal consistency was good (Cronbach's α). Scree plots of eigenvalues suggested a single factor in the samples. The one-dimensional solution yielded suboptimal fit indices. Construct validity was confirmed. Significant improvement in scores was observed before and after intervention. Test-retest variation was non-significant. Impairment of insight and cognition in the assessed patients implies that attention must be paid before applying WEMWBS to all patients. Nevertheless, WEMWBS proved valid and reliable in a further European population, suggesting transcultural validity for both monitoring and evaluation of interventions in healthy as well as chronic remitted schizophrenia populations.","container-title":"Psychiatry Research","DOI":"10.1016/j.psychres.2016.08.050","ISSN":"1872-7123","journalAbbreviation":"Psychiatry Res","language":"eng","note":"PMID: 27565700","page":"282-290","source":"PubMed","title":"Validation of the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) in French psychiatric and general populations","volume":"245","author":[{"family":"Trousselard","given":"Marion"},{"family":"Steiler","given":"Dominique"},{"family":"Dutheil","given":"Frédéric"},{"family":"Claverie","given":"Damien"},{"family":"Canini","given":"Frédéric"},{"family":"Fenouillet","given":"Fabien"},{"family":"Naughton","given":"Geraldine"},{"family":"Stewart-Brown","given":"Sarah"},{"family":"Franck","given":"Nicolas"}],"issued":{"date-parts":[["2016"]],"season":"30"}}}],"schema":""} 28 entre la V1 et la V4 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bEobdeEy","properties":{"formattedCitation":"\\super 27\\nosupersub{}","plainCitation":"27","dontUpdate":true,"noteIndex":0},"citationItems":[{"id":14108,"uris":[""],"uri":[""],"itemData":{"id":14108,"type":"article-journal","abstract":"Gait and Balance Scale (GABS) consists of historical information and examination of 14 different gait and balance parameters designed to assess the severity of these functional domains. Thirty-five patients with Parkinson's disease (PD), Hoehn and Yahr stages 1-3, were tested during their \"off\" period. GABS items were compared to quantitative data from two computerized gait analysis instruments, GAITRite and Pro Balance Master. Intra-class correlation coefficients were calculated to establish reliability. Intra-rater test-retest reliability was determined using Cohen's Kappa statistic. Concurrent validity was derived using the Spearman's rho test with the items from GABS, GAITRite and Balance Master. Intra-rater reliability was high with k>0.41 (k=kappa statistic) for 17 items, 6 had k>0.61. When performing validity measurements, a number of items on the GABS had a correlation coefficient significant at p<0.01 (2-tailed). Posture, pull test, balance during stance, single limb stance, tandem stance, turning, toe walking and functional reach had significant correlation with Balance Master data (R=0.46-1). Gait, arm swing, gait speed, steps/5 m, 'up-and-go test', modified performance oriented assessment of gait scale and provocative testing had significant correlation with the GAITRite items (R=0.51-0.83). GABS is an easy-to-use comprehensive clinical scale with high intra-rater and internal item reliability. We have shown concurrent validity with two computerized gait analysis instruments. We expect GABS to have a particular utility in clinical trials designed to modify functional impairment associated with abnormalities in gait and balance.","container-title":"Journal of the Neurological Sciences","DOI":"10.1016/j.jns.2003.09.005","ISSN":"0022-510X","issue":"1","journalAbbreviation":"J. Neurol. Sci.","language":"eng","note":"PMID: 14675615","page":"89-99","source":"PubMed","title":"Clinical gait and balance scale (GABS): validation and utilization","title-short":"Clinical gait and balance scale (GABS)","volume":"217","author":[{"family":"Thomas","given":"Madhavi"},{"family":"Jankovic","given":"Joseph"},{"family":"Suteerawattananon","given":"Monthaporn"},{"family":"Wankadia","given":"Sharmin"},{"family":"Caroline","given":"Kavitha Salomi"},{"family":"Vuong","given":"Kevin Dat"},{"family":"Protas","given":"Elizabeth"}],"issued":{"date-parts":[["2004",1,15]]}}}],"schema":""} Evolution de la Montreal Cognitive assessment (MoCA) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9pr5OOyJ","properties":{"formattedCitation":"\\super 30\\nosupersub{}","plainCitation":"30","noteIndex":0},"citationItems":[{"id":30,"uris":[""],"uri":[""],"itemData":{"id":30,"type":"article-journal","abstract":"OBJECTIVES: To develop a 10-minute cognitive screening tool (Montreal Cognitive Assessment, MoCA) to assist first-line physicians in detection of mild cognitive impairment (MCI), a clinical state that often progresses to dementia.\nDESIGN: Validation study.\nSETTING: A community clinic and an academic center.\nPARTICIPANTS: Ninety-four patients meeting MCI clinical criteria supported by psychometric measures, 93 patients with mild Alzheimer's disease (AD) (Mini-Mental State Examination (MMSE) score > or =17), and 90 healthy elderly controls (NC).\nMEASUREMENTS: The MoCA and MMSE were administered to all participants, and sensitivity and specificity of both measures were assessed for detection of MCI and mild AD.\nRESULTS: Using a cutoff score 26, the MMSE had a sensitivity of 18% to detect MCI, whereas the MoCA detected 90% of MCI subjects. In the mild AD group, the MMSE had a sensitivity of 78%, whereas the MoCA detected 100%. Specificity was excellent for both MMSE and MoCA (100% and 87%, respectively).\nCONCLUSION: MCI as an entity is evolving and somewhat controversial. The MoCA is a brief cognitive screening tool with high sensitivity and specificity for detecting MCI as currently conceptualized in patients performing in the normal range on the MMSE.","container-title":"Journal of the American Geriatrics Society","DOI":"10.1111/j.1532-5415.2005.53221.x","ISSN":"0002-8614","issue":"4","journalAbbreviation":"J Am Geriatr Soc","language":"eng","note":"PMID: 15817019","page":"695-699","source":"PubMed","title":"The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment","title-short":"The Montreal Cognitive Assessment, MoCA","volume":"53","author":[{"family":"Nasreddine","given":"Ziad S."},{"family":"Phillips","given":"Natalie A."},{"family":"Bédirian","given":"Valérie"},{"family":"Charbonneau","given":"Simon"},{"family":"Whitehead","given":"Victor"},{"family":"Collin","given":"Isabelle"},{"family":"Cummings","given":"Jeffrey L."},{"family":"Chertkow","given":"Howard"}],"issued":{"date-parts":[["2005",4]]}}}],"schema":""} 30 entre la V1 et la V4Evolution de la Hospital Anxiety and Depression scale (HAD) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oiQvUuwn","properties":{"formattedCitation":"\\super 31\\nosupersub{}","plainCitation":"31","noteIndex":0},"citationItems":[{"id":14205,"uris":[""],"uri":[""],"itemData":{"id":14205,"type":"article-journal","abstract":"A self-assessment scale has been developed and found to be a reliable instrument for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. The anxiety and depressive subscales are also valid measures of severity of the emotional disorder. It is suggested that the introduction of the scales into general hospital practice would facilitate the large task of detection and management of emotional disorder in patients under investigation and treatment in medical and surgical departments.","container-title":"Acta Psychiatrica Scandinavica","DOI":"10.1111/j.1600-0447.1983.tb09716.x","ISSN":"0001-690X","issue":"6","journalAbbreviation":"Acta Psychiatr Scand","language":"eng","note":"PMID: 6880820","page":"361-370","source":"PubMed","title":"The hospital anxiety and depression scale","volume":"67","author":[{"family":"Zigmond","given":"A. S."},{"family":"Snaith","given":"R. P."}],"issued":{"date-parts":[["1983",6]]}}}],"schema":""} 31 entre la V1 et la V4.Etude physiopathologiqueSous-étude évaluant l’implication du cervelet dans la genèse de la dystonie?:Différentes explorations auront pour objectif d’identifier l’implication du cervelet?:une IRM cérébrale avec séquence de Tenseur de Diffusion et tractographie (DTI) permettant d’étudier la connectivité structurelle du cervelet et du thalamus, et de reconstruire le faisceau dentato-rubro-thalamique pour le ciblage du VIM. un PET scanner cérébral avec étude du métabolisme du cervelet et des ganglions de la base. une étude de stimulation magnétique transcr?nienne (TMS) comprenant un protocole de stimulation appariée associative (Paired-associated stimulation, PAS) après stimulation du cervelet et un test de clignement conditionné (Eye-blink conditionning, EBC). Ce protocole de TMS permet d’étudier le fonctionnement du cervelet et son influence sur la plasticité corticale. A la V2 en pré-opératoire, les patients réalisent l’IRM cérébrale, le PET scanner et la TMS.A la V4 en pos-opératoire à 9 mois de la chirurgie, les patients réalisent seulement le PET scanner et la TMS?; ces données seront comparées aux données pré-opératoires. Sous étude électrophysiologique évaluant l’activité neuronale du Vim?:- Etude de l’enregistrement unitaire de l’activité des neurones du Vim lors de la descente progressive de trois micro-électrodes usuellement employées pour cette intervention neurochirurgicale- Etude en post-opératoire de l’enregistrement électrophysiologiques des potentiels de champs locaux (PCL) du VIM à l’aide du neurostimulateur PerceptTM PC par la mesure de la différence de potentiel entre deux contacts de l’électrode définitive afin de ne recueillir que les signaux générés au sein du Vim. L’enregistrement sera débuté à 2 mois de la chirurgie (après disparition de l’effet lésionnel). Un enregistrement des spectres de fréquence des activités neuronales sera réalisé durant un mois avant la mise en route de la SCP. L’enregistrement sera poursuivi après mise en route de la SCP ce qui permettra de suivre l’évolution des activités neuronales en fonction de l’évolution clinique (évolution de la dystonie, accès paroxystiques, etc.) ?valuation de la rechercheUn comité d’évaluation externe constitué de 3 experts (neurologue, neurochirurgien, neurophysiologiste) sera sollicité après la V4 (à 9 mois de la chirurgie). Les résultats d’efficacité et de tolérance de la SCP, ainsi que les résultats de l’étude physiopathologique seront communiqués au comité d’évaluation. En fonction des résultats, le comité décidera soit de la poursuite de l’étude et de l’inclusion de patients supplémentaires (5 patients), soit de l’arrêt de l’étude. Planning de l’étudeRéférences ADDIN ZOTERO_BIBL {"uncited":[],"omitted":[],"custom":[]} CSL_BIBLIOGRAPHY 1.Carecchio, M., Zorzi, G., Ragona, F., Zibordi, F. & Nardocci, N. ATP1A3-related disorders: An update. European Journal of Paediatric Neurology 22, 257–263 (2018).2.Geyer, H. L. & Bressman, S. B. Rapid-onset dystonia-parkinsonism. in Handbook of Clinical Neurology vol. 100 559–562 (Elsevier, 2011).3.Sasaki, M., Ishii, A., Saito, Y. & Hirose, S. Intermediate form between alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism: Letters: New Observation. Mov Disord. 29, 153–154 (2014).4.Termsarasab, P., Yang, A. C. & Frucht, S. J. Intermediate phenotypes of ATP1A3 mutations: phenotype–genotype correlations. Tremor and Other Hyperkinetic Movements 5, (2015).5.Sweney, M. T., Newcomb, T. M. & Swoboda, K. J. The Expanding Spectrum of Neurological Phenotypes in Children With ATP1A3 Mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and Beyond. Pediatric Neurology 52, 56–64 (2015).6.Pisciotta, L. et al. Alternating Hemiplegia of Childhood: Pharmacological treatment of 30 Italian patients. Brain and Development 39, 521–528 (2017).7.Hainque, E. et al. A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood. Orphanet J Rare Dis 12, 160 (2017).8.Deutschl?nder, A., Asmus, F., Gasser, T., Steude, U. & B?tzel, K. Sporadic rapid-onset dystonia-parkinsonism syndrome: Failure of bilateral pallidal stimulation: Clinical/Scientific Notes. Movement Disorders 20, 254–257 (2005).9.Kamm, C. et al. Novel ATP1A3 mutation in a sporadic RDP patient with minimal benefit from Deep brain stimulation. Neurology 70, 1501–1503 (2008).10.Brücke, C. et al. Failure of Pallidal Deep Brain Stimulation in a Case of Rapid-Onset Dystonia Parkinsonism (DYT12). Movement Disorders Clinical Practice 2, 76–78 (2015).11.Albanese, A., Di Giovanni, M., Amami, P. & Lalli, S. Failure of pallidal deep brain stimulation in DYT12-ATP1A3 dystonia. Parkinsonism & Related Disorders 45, 99–100 (2017).12.Weber, J. et al. Atypical Presentation of Rapid-onset Dystonia-parkinsonism (DYT12) Unresponsive to Deep Brain Stimulation of the Subthalamic Nucleus: STN-DBS in DYT12 patient. Movement Disorders Clinical Practice 5, 427–429 (2018).13.Fearon, C. et al. Failure of Sequential Pallidal and Motor Thalamus DBS for Rapid-Onset Dystonia-Parkinsonism (DYT12). Movement Disorders Clinical Practice 5, 444–445 (2018).14.Reese, R. & Volkmann, J. Deep Brain Stimulation for the Dystonias: Evidence, Knowledge Gaps, and Practical Considerations. Movement Disorders Clinical Practice 4, 486–494 (2017).15.Zú?iga-Ramírez, C. et al. Generalized Dystonia and Paroxysmal Dystonic Attacks due to a Novel ATP1A3 Variant. 5.16.McGrail, K. M., Phillips, J. M. & Sweadner, K. J. Immunofluorescent localization of three Na,K-ATPase isozymes in the rat central nervous system: both neurons and glia can express more than one Na,K-ATPase. J. Neurosci. 11, 381–391 (1991).17.Dobretsov, M. et al. A Transgenic Mouse Model to Selectively Identify α3 Na,K-ATPase Expressing Cells in the Nervous System. Neuroscience 398, 274–294 (2019).18.Dobretsov, M. & Stimers, J. R. Neuronal function and alpha3 isoform of the Na/K-ATPase. Front. Biosci. 10, 2373–2396 (2005).19.Azarias, G. et al. A Specific and Essential Role for Na,K-ATPase α3 in Neurons Co-expressing α1 and α3. J. Biol. Chem. 288, 2734–2743 (2013).20.Calderon, D. P., Fremont, R., Kraenzlin, F. & Khodakhah, K. The neural substrates of rapid-onset Dystonia-Parkinsonism. Nature Neuroscience 14, 357–365 (2011).21.Fremont, R., Calderon, D. P., Maleki, S. & Khodakhah, K. Abnormal High-Frequency Burst Firing of Cerebellar Neurons in Rapid-Onset Dystonia-Parkinsonism. Journal of Neuroscience 34, 11723–11732 (2014).22.Chen, C. H., Fremont, R., Arteaga-Bracho, E. E. & Khodakhah, K. Short latency cerebellar modulation of the basal ganglia. nature NEUROSCIENCE 12 (2014).23.Fremont, R., Tewari, A. & Khodakhah, K. Aberrant Purkinje cell activity is the cause of dystonia in a shRNA-based mouse model of Rapid Onset Dystonia–Parkinsonism. Neurobiology of Disease 82, 200–212 (2015).24.Tewari, A., Fremont, R. & Khodakhah, K. It’s not just the basal ganglia: Cerebellum as a target for dystonia therapeutics: Cerebellum as Target for Dystonia Therapeutics. Mov Disord. 32, 1537–1545 (2017).25.Coenen, V. A. et al. Postoperative neuroimaging analysis of DRT deep brain stimulation revision surgery for complicated essential tremor. Acta Neurochir (Wien) 159, 779–787 (2017).26.Busner, J. & Targum, S. D. The Clinical Global Impressions Scale. Psychiatry (Edgmont) 4, 28–37 (2007).27.Gimeno, H. et al. Evaluation of functional goal outcomes using the Canadian Occupational Performance Measure (COPM) following Deep Brain Stimulation (DBS) in childhood dystonia. Eur. J. Paediatr. Neurol. 18, 308–316 (2014).28.Trousselard, M. et al. Validation of the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) in French psychiatric and general populations. Psychiatry Res 245, 282–290 (2016).29.Thomas, M. et al. Clinical gait and balance scale (GABS): validation and utilization. J. Neurol. Sci. 217, 89–99 (2004).30.Nasreddine, Z. S. et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53, 695–699 (2005).31.Zigmond, A. S. & Snaith, R. P. The hospital anxiety and depression scale. Acta Psychiatr Scand 67, 361–370 (1983).Résumé grand publicLes mutations du gène ATP1A3 se manifestent par des tableaux cliniques très variés, notamment l’hémiplégie alternante de l’enfant (alternating hemiplegia of childhood, AHC) et la dystonie d’apparition rapide (rapid-onset dystonia parkinsonism, RDP). La dystonie se définit cliniquement par des contractions musculaires involontaires qui entra?nent des postures et des mouvements anormaux. Les patients avec mutation du gène ATP1A3 peuvent présenter une dystonie permanente, généralisée, touchant les membres, le tronc, la parole et la capacité à avaler, et/ou des épisodes de dystonie survenant par crises, souvent très longues et très douloureuses. La dystonie est donc une source majeure de handicap et d’altération de la qualité chez un grand nombre de patients ayant une mutation du gène ATP1A3 en particulier chez les patients AHC. Les traitements habituels de la dystonie ne sont pas efficaces chez ces patients. Les mécanismes de la dystonie chez les patients ayant une mutation du gène ATP1A3 ne sont pas complètement élucidés. ATP1A3 est une pompe qui régule l’activité électrique des neurones du cervelet, une région cérébrale qui participe au le contr?le du mouvement et qui est impliquée dans la dystonie causée par d’autres maladies. Le blocage de cette pompe dans le cervelet de la souris induit une dystonie, et cette dystonie disparait quand on déconnecte la région motrice du cervelet du reste du cerveau. L’objectif principal de reproduire ce qui a pu être fait de fa?on expérimentale, en déconnectant certaines régions motrices du cervelet du reste du cerveau. L’objectif est d’améliorer la dystonie, en utilisant une procédure parfaitement réversible. Pour cela nous proposons d’utiliser la stimulation cérébrale profonde à haute fréquence gr?ce à des électrodes intracérébrales placée noyau ventral intermédiaire du thalamus (noyau qui re?oit des fibres motrices du cervelet). Cette technique n’a jamais été utilisée dans ce contexte mais il s’agit d’une technique de routine qui a fait la preuve de sa faisabilité et de sa sécurité d’utilisation dans d’autres maladies, comme le tremblement essentiel. Nous inclurons un patient AHC avec une dystonie paroxystique invalidante et un patient RDP avec une dystonie fixée. L’objectif secondaire de notre projet est de mieux comprendre les mécanismes de la dystonie chez les patients AHC et RDP par des approches de neuroimagerie et de neurophysiologie. En fonction des résultats obtenus, nous discuterons de l’opportunité d’étendre cette étude à un plus grand nombre de patients. ................
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