Particularites de l’epilepsie au cours des maladies inflammatoires du systeme nerveux central

Introduction : Les crises épileptiques (CE) font partie des manifestations neurologiques des maladies inflammatoires (MI). Elles constituent un tournant évolutif grave de la maladie. Objectifs : Nous avons évalué les particularités sémiologiques, électriques, radiologiques, thérapeutiques et évolutives de l’épilepsie au cours des MI du système nerveux central (SNC). Nous avons également discuté les mécanismes physiopathologiques de l’épilepsie ainsi que les facteurs prédictifs de survenue de CE chez ces patients. Méthodes : C’est une étude rétrospective incluant les patients suivis pour épilepsie dans le cadre d’une MI du SNC. Tous nos patients ont bénéficié d’une imagerie cérébrale. Résultat : Nous avons colligé 32 patients (11 avec sclérose en plaque, 6 avec maladie de Behcet et 15 avec lupus érythémateux disséminé). Le délai des CE au cours des MI était de 3,2 ans. Elles étaient généralisées dans 62,5 % des cas. L’IRM a montré des lésions sous corticales et des lésions du tronc cérébral respectivement dans 71,8 % et 25% des cas. Une thrombose veineuse cérébrale était diagnostiquée chez 3 malades. L’EEG a objectivé des ondes lentes dans 34% des cas, et des anomalies paroxystiques chez 3 patients. Le phénobarbital était le traitement le plus prescrit. Le contrôle des CE était obtenu dans la majorité des cas. Conclusion : La survenue des CE au cours des MI pose un problème de prise en charge. Un diagnostic précoce et un traitement de l’épilepsie permettent de contrôler ces crises afin d’éviter les états de mal épileptiques qui mettent en jeu le pronostic vital des patients. Mots clés: Epilepsie, Facteurs de risque, Maladies inflammatoires  Particularities of epilepsy associated with inflammatory diseases of the central nervous systemIntroduction: The frequency of the central nervous system involvement in autoimmune disorders is very variable. Seizures are among the most common neurological manifestations, and can be occasionally the presenting symptom.Methods: All files of 32 patients with autoimmune disorder diagnosed with epilepsy were evaluated retrospectively (11 with multiple sclerosis, 6 with Behcet disease, and 15 systemic lupus erythematosus). The demographic data, clinical findings including seizures, EEG and neuroimaging findings were reviewed. Results: The sex ratio was 0.45 (10H / 22F). Seizures started 3.2 years after the onset of the inflammatory diseases. They were during either the first or following neurological attacks in 68.7% of cases. 20 patients (62,5%) had only generalized tonic-clonic seizures. Brain magnetic resonance imaging (MRI) was performed to all patients. Sub-cortical and brainstem lesions were identified respectively in 71,8 % and 25%. MRI revealed cerebral sinus thrombosis in three patients. The EEG revealed focal epileptiform discharges in three patients. In 12 patients (34%) slow waves were seen. Antiepileptic drugs were prescribed in all cases (phenobarbital :53%, valproic acid: 31%, Carbamazepine: 15%). A sufficient control of seizures was obtained in most cases. Conclusion: Seizures often complicate systemic autoimmune disorders through a variety of mechanisms. A better understanding of the mechanisms of epileptogenesis in those patients could lead to targeted treatments and better outcomes. Key words: Epilepsy, inflammatory disease, risk factor

Neurological Characteristics of Allgrove Syndrome: A Case Series

Purpose Allgrove syndrome, also known as “triple A” syndrome, is characterized by adrenal insufficiency, achalasia, and alacrimia. When neurological signs are also present, the condition is referred to as “4 A” syndrome. Methods We conducted a retrospective analysis of three patients with 4 A syndrome confirmed genetically. A complete neurological exam was carried out by an experimented neurologist. Results Herein, we describe the neurological characteristics often associated with this condition, through the clinical and electrophysiological analysis of three patients. All patients exhibited a mutation in AAAS, the gene coding for ALADIN. While these individuals presented with the classic features of triple-A syndrome, neurological symptoms were not prominent. Conclusion The neurological manifestations of Allgrove syndrome have historically been overlooked and inadequately explored. Due to the condition’s rarity and substantial phenotypic heterogeneity, only recently have a variety of symptoms been recognized and described

PTPA variants and impaired PP2A activity in early-onset Parkinsonism with intellectual disability

APPENDIX 1 : French and Mediterranean clinicians’ network for Parkinson’s disease genetics (the PDG group) collaborators French PDG collaborators Yves Agid, Mathieu Anheim, Michel Borg, Alexis Brice, Emmanuel Broussolle, Jean-Christophe Corvol, Philippe Damier, Luc Defebvre, Alexandra Dürr, Franck Durif, Jean Luc Houeto, Paul Krack, Stephan Klebe, Suzanne Lesage, Ebba Lohmann, Maria Martinez, Graziella Mangone, Louise-Laure Mariani, Pierre Pollak, Olivier Rascol, François Tison, Christine Tranchant, Marc Vérin, François Viallet, and Marie Vidailhet. Collaborators from Mediterranean countries Ebba Lohmann, Murat Emre, Hasmet Hanagasi, Basar Bilgic, Bedia Marangozoğlu, Mustapha Benmahdjoub, Mohammed Arezki, Sofiane A. Bouchetara, Traki Benhassine, Meriem Tazir, Mouna Ben Djebara, Riadh Gouider, Sawssan Ben Romdhan, Chokri Mhiri, Ahmed Bouhouche.APPENDIX 2 : Collaborators of the International Parkinsonism Genetics Network. Vincenzo Bonifati, Wim Mandemakers, Anneke J. A. Kievit, Agnita J. W. Boon, Joaquim J. Ferreira, Leonor Correia Guedes, Murat Emre, Hasmet A. Hanagasi, Basar Bilgic, Zeynep Tufekcioglu, Bülent Elibol, Okan Doğu, Murat Gultekin, Hsin F. Chien, Egberto Barbosa, Laura Bannach Jardim, Carlos R. M. Rieder, Hsiu-Chen Chang, Chin-Song Lu, Yah-Huei Wu-Chou, Tu-Hsueh Yeh, Leonardo Lopiano, Cristina Tassorelli, Claudio Pacchetti, Cristoforo Comi, Francesco Raudino, Laura Bertolasi, Michele Tinazzi, Alberto Bonizzato, Carlo Ferracci, Roberto Marconi, Marco Guidi, Marco Onofrj, Astrid Thomas, Nicola Vanacore, Giuseppe Meco, Edito Fabrizio, Giovanni Fabbrini, Alfredo Berardelli, Fabrizio Stocchi, Laura Vacca, Paolo Barone, Marina Picillo, Giuseppe De Michele, Chiara Criscuolo, Michele De Mari, Claudia Dell’Aquila, Giovanni Iliceto, Vincenzo Toni, Giorgio Trianni, Valeria Saddi, Gianni Cossu, Maurizio Melis.The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alphasynuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C>A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.The Stichting ParkinsonFonds (The Netherlands); the Fondation pour la Recherche Médicale; PTC Therapeutics, the Fondation de France, France-Parkinson Association, la Fédération pour la Recherche sur le Cerveau (FRC) and the French program ‘Investissements d’avenir’ (ANR-10-IAIHU-06) to AB; and grants from the South African Medical Research Council (Self-Initiated Research Grant) and the National Research Foundation of South Africa.https://academic.oup.com/brainNeurologySDG-03:Good heatlh and well-bein

PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.</p

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely