Literatur-Dauerrecherche – 1 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Literatur-Dauerrecherche Multiple Sklerose Ausgabe Februar 2018
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Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de Ungefiltert, unredigiert und nach Journals sortierthttp://www.ms -gateway.de Quelle: Public Medline; 288 Abstracts (=Neuaufnahmen in der Literaturdatenbank) Längste Therapieerfahrung 1,2,3,4 EDSS – Berufstätigkeit – Kognition BETAPLUS® Persönliche Patienten-Betreuung BETACONNECT® Innovative Injektionshilfe
MEHR ALS 25 JAHRE KLINISCHE ERFAHRUNG
1 Goodin D et al., Neurology 2012;78:1315–1322, 2 Ebers G et al., JNNP 2010;81:907-912, 3 Kappos L et al.,Poster M1715WIP, ANA 2014, 4 Edan G et al., Poster P7.012,AAN 2015 Betaferon® 250 Mikrogramm/ml, Pulver und Lösungsmittel zur Herstellung einer Injektionslösung. Wirkstoff: Interferon beta-1b (Vor Verschreibung bitte die Fachinformation beachten.) Zusammensetzung: Arzneilich wirksamer Bestandteil: 1 ml der gebrauchsfertigen Injektionslösung enthält 250 Mikrogramm (8,0 Mio. I.E.) rekombinantes Interferon beta-1b. 1 Durchstechfl asche enthält 300 Mikrogramm (9,6 Mio. I.E.) rekombinantes Interferon beta-1b. Sonstige Bestandteile: Pulver für Injektionslösung: Albumin vom Menschen, Mannitol, Lösungsmittel: Natriumchloridlösung 0,54 % G/V. Anwendungsgebiete: Betaferon® ist indiziert zur Behandlung von Patienten mit erstmaligem demyelinisierendem Ereignis mit aktivem entzündlichem Prozess, wenn dieses Ereignis schwer genug ist, um eine intravenöse Kortikosteroidtherapie zu rechtfertigen, wenn mögliche Differentialdiagnosen ausgeschlossen wurden und wenn bei diesen Patienten der Beurteilung zufolge ein hohes Risiko für das Auftreten einer klinisch gesicherten Multiplen Sklerose besteht, von Patienten mit schubweise verlaufender Multipler Sklerose, die in den letzten zwei Jahren zwei oder mehr Schübe durchgemacht haben und von Patienten mit sekundär progredient verlaufender Multipler Sklerose, die sich in einem akuten Krankheitsstadium befi nden, d. h. klinische Schübe erfahren. Gegenanzeigen: Beginn der Behandlung während der Schwangerschaft, Überempfi ndlichkeit gegen natürliches oder rekombinantes Interferon beta, Humanalbumin oder einen der sonstigen Bestandteile in der Anamnese, bestehende schwere Depressionen und/oder Suizidneigungen, dekompensierte Leberinsuffi zienz. Warnhinweise: Zytokin-Gabe bei vorbestehender monoklonaler Gammopathie in Zusammenhang mit Entwicklung eines Capillary-Leak-Syndroms mit schockähnlichen Symptomen und tödlichem Ausgang. In seltenen Fällen Pankreatitis, oft mit Hypertriglyzeridämie. Vorsicht bei vorbestehenden oder aktuellen depressiven Störungen, insbesondere Suizidneigung. Depression und Suizidneigung können bei Multipler Sklerose und Interferonbehandlung vermehrt auftreten. Depression oder Suizidneigung unmittelbar an behandelnden Arzt berichten und engmaschig beobachten und behandeln. Gegebenenfalls Abbruch der Betaferon-Behandlung. Vorsicht bei Krampfanfällen in der Anamnese, Antiepileptikabehandlung und Epilepsie, die nicht adäquat mit Antiepileptika kontrolliert ist. Das Präparat enthält Humanalbumin und birgt daher ein Risiko der Übertragung viraler Erkrankungen. Das Risiko für die Übertragung der Creutzfeld-Jacob-Krankheit (CJK) kann nicht ausgeschlossen werden. Regelmäßige Schilddrüsenfunktionstests empfohlen bei Funktionsstörung der Schilddrüse oder medizinischer Indikation. Vor Behandlungsbeginn und regelmäßig während Betaferon-Behandlung großes Blutbild mit differentiellen Leukozyten- und Thrombozytenzahlen sowie Labor einschließlich Leberwerte (z. B. AST [SGOT], ALT [SGPT] und γ-GT) auch ohne klinische Symptome. Patienten mit Anämie, Thrombozytopenie und/oder Leukopenie bedürfen möglicherweise eines intensiveren Monitorings. Selten Berichte über schwere Leberschädigung einschließlich Fälle von Leberversagen. Schwerwiegendste Fälle häufi g in Kombination mit Lebertoxizität assoziierten Substanzen oder bei gleichzeitigen Erkrankungen. Überwachung auf Anzeichen von Leberversagen. Erhöhte Transaminasenwerte engmaschig kontrollieren. Bei signifi kanter Erhöhung oder Symptomen wie Gelbsucht, Absetzen in Erwägung ziehen. Vorsicht bei schwerer Niereninsuffi zienz und engmaschige Überwachung. Fälle von nephrotischem Syndrom mit unterschiedlichen zugrundeliegenden Nephropathien, einschließlich der kollabierenden Form der fokal segmentalen Glomerulosklerose (FSGS), Minimal-Change-Glomerulonephritis (MCG), membranoproliferativen Glomerulonephritis (MPGN) und membranösen Glomerulopathie (MGN) wurden während der Behandlung mit Interferon-beta Produkten berichtet. Ereignisse wurden zu verschiedenen Zeitpunkten der Behandlung berichtet und können nach mehreren Jahren der Behandlung mit Interferon-beta auftreten. Eine regelmäßige Überprüfung auf frühe Anzeichen oder Symptome, besonders bei Patienten mit einem erhöhten Risiko von Nierenerkrankungen, wird empfohlen. Eine sofortige Behandlung des nephrotischen Syndroms ist erforderlich und ein Abbruch der Behandlung mit Betaferon sollte in Erwägung gezogen werden. Vorsicht bei vorbestehenden Herzerkrankungen wie Herzinsuffi zienz, koronarer Herzkrankheit oder Herzrhythmusstörungen. Dann insbesondere zu Beginn der Behandlung auf Verschlechterung des kardialen Zustands überwachen. Betaferon besitzt zwar keine bekannte direkte kardiotoxische Wirkung, Grippe-ähnliche Symptome, die unter Beta-Interferonen auftreten können, können sich für Patienten mit vorbestehender relevanter Herzerkrankung jedoch als belastend erweisen. Seltene Fälle von Kardiomyopathie wurden berichtet. Behandlungsabbruch bei Kardiomyopathie und Verdacht eines Zusammenhangs mit Betaferon. Berichtete Fälle von thrombotischer Mikroangiopathie (TMA), die sich als thrombotisch-thrombozytopenische Purpura (TTP) oder hämolytisch-urämisches Syndrom (HUS) manifestierte. Die Ereignisse wurden zu unterschiedlichen Zeitpunkten während der Behandlung gemeldet und können mehrere Wochen bis mehrere Jahre nach Beginn der Behandlung mit Interferon beta auftreten. Bei Diagnose einer TMA ist eine umgehende Behandlung erforderlich und ein sofortiges Absetzen von Betaferon wird empfohlen. Schwere Überempfi ndlichkeitsreaktionen möglich. Bei schweren Reaktionen Behandlungsabbruch und geeignete ärztliche Maßnahmen. Berichtete Nekrosen an den Injektionsstellen können ausgedehnt sein und zur Narbenbildung führen. Bei Hautläsion aus der Injektionsstelle ärztliche Konsultation vor weiterer Behandlung. Bei mehreren Läsionen Unterbrechung bis Abheilung der Läsion. Nebenwirkungen: Zu Beginn der Behandlung sind unerwünschte Wirkungen häufi g, diese klingen aber im Allgemeinen bei weiterer Behandlung ab. Die am häufi gsten beobachteten unerwünschten Wirkungen waren ein grippeähnlicher Symptomenkomplex und Reaktionen an der Injektionsstelle. Zu Beginn der Behandlung wird eine Auftitrierung der Dosis empfohlen, um die Verträglichkeit von Betaferon zu verbessern. Grippeähnliche Symptome lassen sich außerdem durch Verabreichung eines nicht-steroidalen Entzündungshemmers verringern. Die Häufi gkeit von Reaktionen an der Injektionsstelle lässt sich durch Anwendung eines Autoinjektors vermindern. Liste der unerwünschten Ereignisse: Infektion, Abszess, Lymphopenie, Anämie, Thrombozytopenie, Thrombotische Mikroangiopathie, einschließlich thrombotischer thrombozytopenischer Purpura/hämolytisch- urämisches Syndrom, Neutropenie, Leukopenie, Lymphadenopathie, Palpitationen, Kardiomyopathie, Tachykardie, Hypothyreose, Hyperthyreose, Schilddrüsenerkrankungen, Diarrhoe, Verstopfung, Übelkeit, Erbrechen, abdominelle Schmerzen, Pankreatitis, Anstieg der Glutamatpyruvat-, Glutamatoxalacetattransaminase, des Bilirubin-Spiegels und der Gammaglutamyltransferase, Hepatitis, Leberschaden (inkl. Hepatitis), Leberinsuffi zienz, anaphylaktische Reaktion, Kapillarlecksyndrom bei vorbestehender monoklonaler Gammopathie, Gewichtsverlust, Gewichtszunahme, Anstieg der Triglyzeride im Blut, Anorexie, Hypoglykämie, Arthralgie, arzneimittelinduzierter Lupus erythematodes, Hypertonie (Skelettmuskulatur), Muskelschmerzen, Myasthenie, Rückenschmerzen, Schmerzen in einer Extremität, Krampfanfälle, Kopfschmerzen, Schwindel, Schlafl osigkeit, Migräne, Parästhesie, Verwirrtheit, Suizidversuch, emotionale Instabilität, Depression, Angst, Menorrhagie, Dysmenorrhoe, Menstruationsstörungen, Metrorrhagie, Impotenz, Bronchospasmus, pulmonale arterielle Hypertonie, Infektionen der oberen Atemwege, Sinusitis, vermehrtes Husten, Dyspnoe, Urtikaria, Pruritus, Alopezie, Hautverfärbung, Hauterkrankungen, Hautausschlag, Konjunktivitis, Sehstörungen, Ohrenschmerzen, Vasodilatation, Hypertonie, Harnverhaltung, pos. Harnprotein, häufi ge Blasenentleerung, Harninkontinenz, starker Harndrang, nephrotisches Syndrom, Glomerulosklerose, Reaktionen und Nekrose an der Injektionsstelle, grippeähnliche Symptome, Fieber, Schmerzen, Thoraxschmerzen, periphere Ödeme, Asthenie, Schüttelfrost, Schwitzen, Unwohlsein. Verschreibungspfl ichtig. Bayer AG, 51368 Leverkusen, Deutschland. Version: FI/4, 03/2017 L.DE.MKT.SM.04.2017.5532 Literatur-Dauerrecherche – 2 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Inhaltsverzeichnis MRI features of primary hepatic lymphoma...... 19 Correlated Heterospectral Lipidomics for Biomolecular Profiling of Remyelination in Multiple Sclerosis...... 20 Conflict of interest statement: The authors declare no competing financial interest...... 20 Potential Therapeutic Applications for Inhibitors of Autotaxin, a Bioactive Lipid-Producing Lysophospholipase D, in Disorders Affecting the Nervous System...... 21 The First Hospital-Based Registry of Patients with Multiple Sclerosis in Croatia...... 22 Efficacy of group cognitive rehabilitation therapy in multiple sclerosis...... 23 Functional morphology of the blood-brain barrier in health and disease. .... 24 Activin receptors regulate the oligodendrocyte lineage in health and disease...... 25 Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis...... 26 Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945...... 27 Oscillations of Subarachnoid Space Width as a Potential Marker of Cerebrospinal Fluid Pulsatility...... 28 Robot-Assisted Body-Weight-Supported Treadmill Training in Gait Impairment in Multiple Sclerosis Patients: A Pilot Study...... 29 Riboflavin in Human Health: A Review of Current Evidences...... 30 Evaluation of Leptomeningeal Contrast Enhancement Using Pre-and Postcontrast Subtraction 3D-FLAIR Imaging in Multiple Sclerosis...... 31 Iron-Insensitive Quantitative Assessment of Subcortical Gray Matter Demyelination in Multiple Sclerosis Using the Macromolecular Proton Fraction...... 32 Improved Visualization of Cortical Lesions in Multiple Sclerosis Using 7T MP2RAGE...... 33 An Automated Statistical Technique for Counting Distinct Multiple Sclerosis Lesions...... 34 Evaluation of the Sensitivity of Inhomogeneous Magnetization Transfer (ihMT) MRI for Multiple Sclerosis...... 35 Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis...... 36 Retrograde interferon-gamma signaling induces major histocompatibility class I expression in human-induced pluripotent stem cell-derived neurons...... 37
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 3 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Cognitive assessment in patients with multiple sclerosis: from neuropsychological batteries to ecological tools...... 38 Dynamic changes and molecular analysis of cell death in the spinal cord of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus...... 39 Predictive Models of Cognitive Fatigue in Multiple Sclerosis...... 40 Predictors for employment status in people with multiple sclerosis: a 10-year longitudinal observational study...... 41 Self-regulatory strategies as correlates of physical activity behavior in persons with multiple sclerosis...... 42 Validation of the Brief Fear of Negative Evaluation Scale-II in patients with systemic sclerosis: A Scleroderma Patient-centered Intervention Network Cohort study...... 43 Efficacy of a Computer-Assisted Cognitive Rehabilitation Intervention in Relapsing-Remitting Multiple Sclerosis Patients: A Multicenter Randomized Controlled Trial...... 44 Pediatric Multiple Sclerosis and Cognition: A Review of Clinical, Neuropsychologic, and Neuroradiologic Features...... 44 Face-to-Face or Telematic Cognitive Stimulation in Patients with Multiple Sclerosis and Cognitive Impairment: Why Not Both? ...... 45 Butylphthalide ameliorates experimental autoimmune encephalomyelitis by suppressing PGAM5-induced necroptosis and inflammation in microglia. .... 46 Regulatory-Accepted Drug Development Tools Are Needed to Accelerate Innovative CNS Disease Treatments...... 47 Chemiluminescent detection of oligoclonal immunoglobulins after isoelectric focusing and affinity-mediated immunoblotting...... 48 MicroRNA signature of regulatory T cells in health and autoimmunity...... 49 Neuroprotective effects of selegiline on rat neural stem cells treated with hydrogen peroxide...... 50 The MRZ reaction helps to distinguish rheumatologic disorders with central nervous involvement from multiple sclerosis...... 51 Increasing prevalence of familial recurrence of multiple sclerosis in Iran: a population based study of Tehran registry 1999-2015...... 52 Predictors of activity and participation across neurodegenerative conditions: a comparison of people with motor neurone disease, multiple sclerosis and Parkinson's disease...... 52 NMDAR (N-methyl-D-aspartate receptor) encephalitis in a patient with MS (multiple sclerosis): a rare and challenging case...... 53 Biopsy-proven multiple sclerosis in an adult patient with atypical craniometaphyseal dysplasia...... 54 Transforming growth factor-β in stem cells and tissue homeostasis...... 55 GSH-PEGylated liposomal methylprednisolone in comparison to free methylprednisolone: slow release characteristics and prolonged lymphocyte depression in a first-in-human study...... 56 Multiple sclerosis: dealing with complex treatment decisions...... 56
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 4 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Spectrum of MRI brain lesion patterns in neuromyelitis optica spectrum disorder: a pictorial review...... 57 The value of oligoclonal bands in the multiple sclerosis diagnostic criteria. . 58 Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome...... 59 Cardiac repolarization during fingolimod treatment in patients with relapsing- remitting multiple sclerosis...... 60 Progressive multiple sclerosis, cognitive function, and quality of life...... 61 Efficacy and safety of everolimus in patients younger than 12 months with congenital subependymal giant cell astrocytoma...... 62 Structural disconnection is responsible for increased functional connectivity in multiple sclerosis...... 63 Movement-Related Somatosensory Activity Is Altered in Patients with Multiple Sclerosis...... 64 Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms...... 65 Simplified guideline for prescribing medical cannabinoids in primary care. . 66 Sensory processing, cognitive fatigue, and quality of life in multiple sclerosis: Traitement de l'information sensorielle, fatigue cognitive et qualité de vie des personnes atteintes de sclérose en plaques...... 67 Gentamicin bladder instillations decrease symptomatic urinary tract infections in neurogenic bladder patients on intermittent catheterization. .. 68 Association of Limb-Girdle muscular dystrophy with multiple sclerosis: A case report...... 69 Exploring the genetics and non-cell autonomous mechanisms underlying ALS/FTLD...... 70 Knockout of zebrafish interleukin 7 receptor (IL7R) by the CRISPR/Cas9 system delays retinal neurodevelopment...... 71 MYCN drives glutaminolysis in neuroblastoma and confers sensitivity to an ROS augmenting agent...... 72 Lenalidomide regulates CNS autoimmunity by promoting M2 macrophages polarization...... 73 De novo vs. inherited copy number variations in multiple sclerosis susceptibility...... 73 TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms...... 74 Cuprizone Administration Alters the Iron Metabolism in the Mouse Model of Multiple Sclerosis...... 75 Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation...... 76 Time Is Cerebellum...... 77 Diagnostic potential of tears in ophthalmology...... 77 Transient neurologic syndromes: A diagnostic approach...... 78 Search for new biomarkers of pediatric multiple sclerosis: application of immunoglobulin free light chain analysis...... 78
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 5 – Multiple Sklerose: Veröffentlichungen Oktober 2013
CSF free light chain identification of demyelinating disease: comparison with oligoclonal banding and other CSF indexes...... 79 Dysfunction of CD3-CD16+CD56dim and CD3-CD16-CD56bright NK cell subsets in RR-MS patients...... 80 A Rare Presentation of Neuromyelitis Optica Spectrum Disorders...... 81 Multiple sclerosis or "inflammatory CADASIL?": Case Report and review of the literature...... 82 Effect of comorbidities on the course of multiple sclerosis...... 83 Safety and Efficacy of Rituximab: Experience of a Single Multiple Sclerosis Center...... 84 Dextromethorphan/Quinidine in Migraine Prophylaxis: An Open-label Observational Clinical Study...... 84 The utility of motor unit number estimation methods versus quantitative motor unit potential analysis in diagnosis of ALS...... 85 The Immunologic Paradoxes of IgG4-Related Disease...... 86 Depression in Multiple Sclerosis: Epidemiology, Aetiology, Diagnosis and Treatment...... 87 Effects of repeated long-term psychosocial stress and acute cannabinoid exposure on mouse corticostriatal circuitries: Implications for neuropsychiatric disorders...... 88 Genetics of Multiple Sclerosis: An Overview and New Directions...... 89 The Evolving Mechanisms of Action of Glatiramer Acetate...... 89 Neurodegeneration in Progressive Multiple Sclerosis...... 90 Microglial Phenotypes and Functions in Multiple Sclerosis...... 90 Counting of peripheral extracellular vesicles in Multiple Sclerosis patients by an improved nanoplasmonic assay and dynamic light scattering...... 91 Management of IFN-beta-induced flu-like symptoms with Chinese herbal medicine in a patient with multiple sclerosis: A case report...... 92 Use of complementary and alternative medicine in patients with multiple sclerosis in Germany...... 93 Neurocutaneous Disorders...... 93 Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer's disease and Less Well-Known Diseases...... 94 New life to an old treatment: pegylated Interferon beta 1a in the management of multiple sclerosis...... 95 The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews...... 96 The autoimmune ecology: an update...... 97 Chemokines beyond chemo-attraction: CXCL10 and its significant role in cancer and autoimmunity...... 97 Children with myelin oligodendrocyte glycoprotein antibodies-associated disease: relation of phenotypes to central nervous system myelin maturation...... 97 Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach...... 98 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 6 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Computer-assisted cognitive rehabilitation in persons with multiple sclerosis: Results of a multi-site randomized controlled trial with six month follow-up...... 100 Cladribine for multiple sclerosis...... 100 Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural Progenitors in Progressive Multiple Sclerosis...... 101 Tau protein liquid-liquid phase separation can initiate tau aggregation. ....102 The evaluation of depression in multiple sclerosis using the newly proposed Multiple Sclerosis Depression Rating Scale...... 103 Ozone, NO2 and PM10 are associated with the occurrence of multiple sclerosis relapses. Evidence from seasonal multi-pollutant analyses...... 104 Italian Wikipedia and epilepsy: An infodemiological study of online information-seeking behavior...... 105 Smoking is not associated with higher prevalence of JC virus in MS patients...... 106 The changing multiple sclerosis treatment landscape: impact of new drugs and treatment recommendations...... 107 Real Life Long-Term Effectiveness of Fingolimod in Swiss Patients with Relapsing-Remitting Multiple Sclerosis (REALITE)...... 108 Is diffusion MRI the future biomarker to measure therapeutic efficacy in multiple sclerosis? ...... 109 Four-pulse transcranial magnetic stimulation using multiple conditioning inputs. Normative MEP responses...... 109 Amelioration of progressive autoimmune encephalomyelitis by epigenetic regulation involves selective repression of mature neutrophils during the preclinical phase...... 110 A comparison of human natural monoclonal antibodies and aptamer conjugates for promotion of CNS remyelination: where are we now and what comes next?...... 111 The development of biological therapies for neurological diseases: moving on from previous failures...... 112 Merits and complexities of modeling multiple sclerosis in non-human primates: implications for drug discovery...... 113 Improving multiple sclerosis management and collecting safety information in the real world: the MSDS3D software approach...... 114 Investigational immunosuppressants in early-stage clinical trials for the treatment of multiple sclerosis...... 115 Potential neuroprotective effect of Fingolimod in multiple sclerosis and its association with clinical variables...... 116 Preservation of neuronal function as measured by clinical and MRI endpoints in relapsing-remitting multiple sclerosis: how effective are current treatment strategies? ...... 117 Optical coherence tomography in multiple sclerosis...... 117 Mitochondrial dysfunction and axon degeneration in progressive multiple sclerosis...... 118
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 7 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Dual-Tasking in Multiple Sclerosis - Implications for a Cognitive Screening Instrument...... 118 Prolactin and Autoimmunity...... 119 Cytokines Stimulate the Release of Microvesicles from Myeloid Cells Independently from the P2X7 Receptor/Acid Sphingomyelinase Pathway. .120 Understanding Progressive Multifocal Leukoencephalopathy Risk in Multiple Sclerosis Patients Treated with Immunomodulatory Therapies: A Bird's Eye View...... 120 Challenges and Opportunities for Biomarkers of Clinical Response to AHSCT in Autoimmunity...... 121 Bioactive Lipids and Chronic Inflammation: Managing the Fire Within...... 122 NLR-Dependent Regulation of Inflammation in Multiple Sclerosis- Dependent Regulation of Inflammation in Multiple Sclerosis...... 123 Shuttling Tolerogenic Dendritic Cells across the Blood-Brain Barrier In Vitro via the Introduction of De Novo C-C Chemokine Receptor 5 Expression Using Messenger RNA Electroporation...... 124 Lactobacillus helveticus SBT2171 Attenuates Experimental Autoimmune Encephalomyelitis in Mice...... 125 Biomarkers of Amyotrophic Lateral Sclerosis: Current Status and Interest of Oxysterols and Phytosterols...... 126 Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease...... 127 Hypothalamic Alterations in Neurodegenerative Diseases and Their Relation to Abnormal Energy Metabolism...... 128 Eye Movement Abnormalities in Multiple Sclerosis: Pathogenesis, Modeling, and Treatment...... 129 Sun Exposure across the Life Course Significantly Modulates Early Multiple Sclerosis Clinical Course...... 130 Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis...... 131 Technologies for Advanced Gait and Balance Assessments in People with Multiple Sclerosis...... 132 A Fully Automated Pipeline for Normative Atrophy in Patients with Neurodegenerative Disease...... 133 Alemtuzumab Improves Cognitive Processing Speed in Active Multiple Sclerosis-A Longitudinal Observational Study...... 134 Psychological Shift in Partners of People with Multiple Sclerosis Who Undertake Lifestyle Modification: An Interpretive Phenomenological Study...... 135 Walking speed measurement with an Ambient Measurement System (AMS) in patients with multiple sclerosis and walking impairment...... 136 Postural control deficits in people with Multiple Sclerosis: A systematic review and meta-analysis...... 137 Differential local tissue permissiveness influences the final fate of GPR17- expressing oligodendrocyte precursors in two distinct models of demyelination...... 138
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 8 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Astrocyte disruption of neurovascular communication is linked to cortical damage in an animal model of multiple sclerosis...... 139 Vitamin C promotes oligodendrocytes generation and remyelination...... 140 Semaphorin4A and H-ferritin utilize Tim-1 on human oligodendrocytes: A novel neuro-immune axis...... 141 Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune-mediated demyelinating diseases. ..142 Multiple sclerosis...... 143 Changes in the axo-glial junctions of the optic nerves of cuprizone-treated mice...... 143 Changes in structural network are associated with cortical demyelination in early multiple sclerosis...... 144 Explaining the heterogeneity of functional connectivity findings in multiple sclerosis: An empirically informed modeling study...... 145 High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease...... 146 Absence of the tag polymorphism for the risk haplotype HLA-DR2 for multiple sclerosis in Wixárika subjects from Mexico...... 147 The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders. ...148 Immune modulatory effects of statins...... 148 Cathepsin H deficiency in mice induces excess Th1 cell activation and early- onset of EAE though impairment of toll-like receptor 3 cascade...... 149 Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome...... 149 Reparative bone-like tissue formation in the tooth of a systemic sclerosis patient...... 150 Relation of serum levels of homocysteine, vitamin B12 and folate to cognitive functions in multiple sclerosis patients...... 150 The role of robotic gait training coupled with virtual reality in boosting the rehabilitative outcomes in patients with multiple sclerosis...... 151 Multiple sclerosis and HIV: a case of multiple sclerosis-immune reconstitution inflammatory syndrome associated with antiretroviral therapy initiation. ..151 Impairment of acquired color vision in multiple sclerosis: an early diagnostic sign linked to the greatness of disease...... 152 Effect of Multiple Intraperitoneal Injections of Human Bone Marrow Mesenchymal Stem Cells on Cuprizone Model of Multiple Sclerosis ...... 153 Seroepidemiological Study of Epstein-Barr Virus in Different Population Groups in Croatia...... 154 Using the International Classification of Functioning, Disability, and Health Model to Gain Perspective of the Benefits of Yoga in Stroke, Multiple Sclerosis, and Children to Inform Practice for Children with Cerebral Palsy: A Meta-Analysis...... 155 The First Historically Reported Italian Family with FTD/ALS Teaches a Lesson on C9orf72 RE: Clinical Heterogeneity and Oligogenic Inheritance...... 156 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 9 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Th17 cells, γδ T cells and their interplay in EAE and multiple sclerosis...... 157 Do we have enough evidence for recommending therapeutic apheresis for natalizumab-related progressive multifocal leukoencephalopathy patients? Comment on "Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for apheresis: The seventh special issue." ...... 157 Blood Mononuclear Cell Mitochondrial Respiratory Chain Complex IV Activity Is Decreased in Multiple Sclerosis Patients: Effects of β-Interferon Treatment...... 158 Symptom-associated change of motor-related neuromagnetic fields in a patient with multiple sclerosis: A case report...... 159 Evaluation of Vitamin B12 Deficiency and Associated Factors in Patients With Systemic Sclerosis...... 160 Tuberous Sclerosis Complex with Gingival Enlargement in an Adolescent. .161 Bu Shen Yi Sui capsule promotes remyelination correlating with Sema3A/NRP-1, LIF/LIFR and Nkx6.2 in mice with experimental autoimmune encephalomyelitis...... 162 Altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery...... 163 Guided Imagery Improves Mood, Fatigue, and Quality of Life in Individuals With Multiple Sclerosis: An Exploratory Efficacy Trial of Healing Light Guided Imagery...... 164 Neurological, physical and sociodemographic correlates of employment in multiple sclerosis: A meta-analysis...... 164 Pattern of TSC1 and TSC2 germline mutations in Russian patients with tuberous sclerosis...... 165 A sensitive and selective ELISA methodology quantifies a demyelination marker in experimental and clinical samples...... 166 The Role of Microglia and Macrophages in CNS Homeostasis, Autoimmunity, and Cancer...... 167 Repeated Attacks of Dizziness Caused by a Rare Mitochondrial Encephalomyopathy...... 168 Discovery of 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine Derivatives as Potent, Orally Available, and Brain-penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors; Analysis of Structure-Kinetic Relationships...... 168 A Multidimensional Tool Based on the eHealth Literacy Framework: Development and Initial Validity Testing of the eHealth Literacy Questionnaire (eHLQ)...... 169 Neuroprotective Effects of Melatonin on Experimental Allergic Encephalomyelitis Mice Via Anti-Oxidative Stress Activity...... 170 Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis...... 171 Classic Block Design "Pseudo"-Resting-State fMRI Changes After a Neurorehabilitation Program in Patients with Multiple Sclerosis...... 172
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 10 – Multiple Sklerose: Veröffentlichungen Oktober 2013
The Role of High-Frequency MRI Monitoring in the Detection of Brain Atrophy in Multiple Sclerosis...... 173 Cholinergic imbalance in lumbar spinal cord of a rat model of multiple sclerosis...... 174 Differentiation of remitting neuromyelitis optica spectrum disorders from multiple sclerosis by integrating parameters from serum proteins and lymphocyte subsets...... 174 Laquinimod attenuates inflammation by modulating macrophage functions in traumatic brain injury mouse model...... 175 18F-VC701-PET and MRI in the in vivo neuroinflammation assessment of a mouse model of multiple sclerosis...... 176 [18F]FSPG-PET reveals increased cystine/glutamate antiporter (xc-) activity in a mouse model of multiple sclerosis...... 177 Cerebrospinal fluid level of Nogo receptor 1 antagonist lateral olfactory tract usher substance (LOTUS) correlates inversely with the extent of neuroinflammation...... 178 Defining spasticity: a new approach considering current movement disorders terminology and botulinum toxin therapy...... 179 MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein...... 180 Up-to-date knowledge about the association between multiple sclerosis and the reactivation of human endogenous retrovirus infections...... 181 Identifying neuropathic pain in patients with multiple sclerosis: a cross- sectional multicenter study using highly specific criteria...... 182 Positive effects of fampridine on cognition, fatigue and depression in patients with multiple sclerosis over 2 years...... 183 Smoking at time of CIS increases the risk of clinically definite multiple sclerosis...... 184 Cerebellum and cognition in multiple sclerosis: the fall status matters...... 185 Treatment of neuromyelitis optica with rituximab: a 2-year prospective multicenter study...... 186 The cortical blood-brain barrier in multiple sclerosis: a gateway to progression? ...... 187 Effectiveness and baseline factors associated to fingolimod response in a real-world study on multiple sclerosis patients...... 187 Insular multiple sclerosis lesions are associated with erectile dysfunction. .188 The long-term impact of early treatment of multiple sclerosis on the risk of disability pension...... 189 Worldwide prevalence of neuromyelitis optica spectrum disorders...... 189 Cognition in multiple sclerosis: Between cognitive reserve and brain volume...... 190 Anti-cholinergic medications for bladder dysfunction worsen cognition in persons with multiple sclerosis...... 191 Neuroinflammation following disease modifying therapy in multiple sclerosis: A pilot positron emission tomography study...... 192
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 11 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Argentinean recommendations on the identification of treatment failure in relapsing remitting multiple sclerosis patients...... 193 Autoimmunity in multiple sclerosis: role of sphingolipids, invariant NKT cells and other immune elements in control of inflammation and neurodegeneration...... 194 Demyelination with preferential MAG loss: A complex message from MS paraffin blocks...... 195 Preliminary evidence of the cerebellar role on cognitive performances in clinically isolated syndrome...... 196 Corrigendum to "Argentinean recommendations on the identification of treatment failure in relapsing remitting multiple sclerosis patients" [J. Neurol. Sci. 385C (2018) 217-224]...... 197 New Ways of "Seeing" the Mechanistic Heterogeneity of Multiple Sclerosis Plaque Pathogenesis...... 198 Keep Your Eyes Wide Open: On Visual- and Vision-Related Measurements to Better Understand Multiple Sclerosis Pathophysiology...... 199 Multiple Sclerosis: Eyes on the Future...... 199 Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis...... 200 Early Nodal and Paranodal Disruption in Autoimmune Optic Neuritis...... 201 Animal models of multiple sclerosis: Focus on experimental autoimmune encephalomyelitis...... 201 Stereotactic radiosurgery for tremor: systematic review...... 202 LPA5 signaling is involved in multiple sclerosis-mediated neuropathic pain in the cuprizone mouse model...... 203 Cognitive behavioural therapy for MS-related fatigue explained: A longitudinal mediation analysis...... 204 Estrogen serum concentration affects blood immune cell composition and polarization in human females under controlled ovarian stimulation...... 205 Association Between Pemphigus and Neurologic Diseases...... 206 Differences in the Reponses to Apheresis Therapy of Patients With 3 Histopathologically Classified Immunopathological Patterns of Multiple Sclerosis...... 207 Tissue Markers for Acute Multiple Sclerosis Treatment Response-A Step Toward Personalized Medicine...... 208 Prevalence of Myelin Oligodendrocyte Glycoprotein and Aquaporin-4-IgG in Patients in the Optic Neuritis Treatment Trial...... 208 Exploring the Specific Needs of Persons with Multiple Sclerosis for mHealth Solutions for Physical Activity: Mixed-Methods Study...... 209 Efficacy of Natalizumab in Intermediate Uveitis Related to Multiple Sclerosis: A Case Report...... 210 Differential anxiety-like responses in NOD/ShiLtJ and C57BL/6J mice following experimental autoimmune encephalomyelitis induction and oral gavage...... 210 Evolving diagnostic criteria for multiple sclerosis...... 210 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 12 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Role of proteoglycans in neuro-inflammation and central nervous system fibrosis...... 211 Analysis of Vitamin D Receptor Polymorphisms in Patients with Familial Multiple Sclerosis...... 212 Editorial: Multiple Sclerosis: Pathogenesis and Therapeutics...... 212 Catastrophic health expenditure among households with members with special diseases: A case study in Kurdistan...... 213 Characteristics of headache in relation to the manifestation of Susac syndrome...... 214 Efficacy of alemtuzumab and natalizumab in the treatment of different stages of multiple sclerosis patients...... 215 Copper Complexes in Cancer Therapy...... 216 Fractional anisotropy of white matter, disability and blood iron parameters in multiple sclerosis...... 217 Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model...... 218 A Cyclic Altered Peptide Analogue Based on Myelin Basic Protein 87-99 Provides Lasting Prophylactic and Therapeutic Protection Against Acute Experimental Autoimmune Encephalomyelitis...... 219 Relationship between cerebrospinal fluid biomarkers and structural brain network properties in Parkinson's disease...... 220 The contribution of secondhand tobacco smoke exposure to pediatric multiple sclerosis risk...... 221 Convergent effects of a functional C3 variant on brain atrophy, demyelination, and cognitive impairment in multiple sclerosis...... 222 Online meditation training for people with multiple sclerosis: A randomized controlled trial...... 223 Severe hypertriglyceridemia associated with teriflunomide in a patient with multiple sclerosis: A case report...... 224 Clinical commentary on 'Severe hypertriglyceridemia associated with teriflunomide in a patient with multiple sclerosis'...... 224 Rituximab is an acceptable alternative to ocrelizumab for treating multiple sclerosis - Yes...... 224 Rituximab is an acceptable alternative to ocrelizumab for treating multiple sclerosis - Commentary...... 224 Rituximab is an acceptable alternative to ocrelizumab for treating multiple sclerosis - No...... 225 Multiple sclerosis-related fatigue: Altered resting-state functional connectivity of the ventral striatum and dorsolateral prefrontal cortex...... 226 Measurement of soluble CD59 in CSF in demyelinating disease: Evidence for an intrathecal source of soluble CD59...... 227 Radiologically isolated syndrome or subclinical multiple sclerosis: MAGNIMS consensus recommendations...... 228 A randomized study to evaluate the effect of exercise on fatigue in people with relapsing-remitting multiple sclerosis treated with fingolimod...... 228
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 13 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Movement measurements at home for multiple sclerosis: walking speed measured by a novel ambient measurement system...... 229 LIF and multiple sclerosis: One protein with two healing properties...... 229 Multiple sclerosis in pediatric patients in Slovenia...... 230 Investigating the dynamic plantar pressure distribution and loading pattern in subjects with multiple sclerosis...... 231 Uncovering the link between reproductive factors and multiple sclerosis: A case-control study on Iranian females...... 232 Correlation between the corpus callosum index and brain atrophy, lesion load, and cognitive dysfunction in multiple sclerosis...... 233 Symbol Digit Modalities Test adaptation for Magnetic Resonance Imaging environment: A systematic review and meta-analysis...... 234 A longitudinal study of JC virus serostatus stability among multiple sclerosis patients...... 235 Digital epidemiology confirms a latitude gradient of MS in France...... 236 Relationship between Social Cognition and traditional cognitive impairment in Progressive Multiple Sclerosis and possible implicated neuroanatomical regions...... 237 Response to the commentary of Yates RL and DeLuca GC on the study: HLA- DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis...... 238 Comment: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis...... 239 The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and adults...... 240 Humoral response to John Cunningham virus during pregnancy in multiple sclerosis...... 241 Dimethyl fumarate in a patient with multiple sclerosis and type 1 diabetes mellitus: The importance of ketonuria...... 242 The use of satellite data to measure ultraviolet-B penetrance and its potential association with age of multiple sclerosis onset...... 243 Structural MRI correlates of cognitive function in multiple sclerosis...... 244 Early relapse after RTX initiation in a patient with NMO/MS overlap syndrome: How long to conclude to a failure treatment? ...... 245 Fingolimod reduces the clinical expression of active demyelinating lesions in MS...... 246 Why do people search Wikipedia for information on multiple sclerosis? .....247 The interplay of multiple sclerosis and menstrual cycle: Which one affects the other one? ...... 248 Predicting falls in multiple sclerosis: Do electrophysiological measures have a better predictive accuracy compared to clinical measures? ...... 249 Knee flexor strength and balance control impairment may explain declines during prolonged walking in women with mild multiple sclerosis...... 250 A case of dextrocardia following maternal exposure to generic Fingolimod during the first trimester of pregnancy...... 251
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 14 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Prevalence of multiple sclerosis in Poland...... 252 The influence of biogenic amines on Th17-mediated immune response in multiple sclerosis...... 253 Predictors of retinal atrophy in multiple sclerosis: A longitudinal study using spectral domain optical coherence tomography with segmentation analysis...... 254 Muscle carnosine in experimental autoimmune encephalomyelitis and multiple sclerosis...... 255 Factors associated with excessive sitting time in multiple sclerosis...... 256 The value of tests evaluating visual functions in detecting overt or subclinical optic neuritis in multiple sclerosis...... 256 Cardiac repolarization evolves differently during the course of benign and disabling multiple sclerosis...... 257 Letter to the Editors - Multiple sclerosis and related disorders - Birnbaum et al., 2017...... 258 Multiple sclerosis onset after granulocyte macrophage colony-stimulating factor withdrawal...... 258 Physical activity and disability outcomes in multiple sclerosis: A systematic review (2011-2016)...... 259 Correlating serum microRNAs and clinical parameters in Amyotrophic lateral sclerosis...... 260 A transcriptomic atlas of aged human microglia...... 261 EGFL7 reduces CNS inflammation in mouse...... 262 Multiple sclerosis in 2017: Progress in multiple sclerosis - from diagnosis to therapy...... 262 [Multiple sclerosis and hepatitis B vaccination : What does the verdict of the European Court of Justice on liability after vaccination mean?] ...... 263 [Coagulation factors and multiple sclerosis : Key factors in the pathogenesis?] ...... 263 Estimates of age-dependent cutoffs for pathological brain volume loss using SIENA/FSL-a longitudinal brain volumetry study in healthy adults...... 264 The small heat shock proteins, especially HspB4 and HspB5 are promising protectants in neurodegenerative diseases...... 265 PDGF Modulates Synaptic Excitability and Short-Latency Afferent Inhibition in Multiple Sclerosis...... 266 The exciting field of neuro-repair in multiple sclerosis: an interview with Sarah I Sheikh...... 266 Deciphering the microstructure of hippocampal subfields with in vivo DTI and NODDI: Applications to experimental multiple sclerosis...... 267 Preserved canonicality of the BOLD hemodynamic response reflects healthy cognition: Insights into the healthy brain through the window of multiple sclerosis...... 268 Diagnostic accuracy of semiautomatic lesion detection plus quantitative susceptibility mapping in the identification of new and enhancing multiple sclerosis lesions...... 269
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 15 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Evidence of progressive tissue loss in the core of chronic MS lesions: A longitudinal DTI study...... 270 Familial monophasic acute transverse myelitis due to the pathogenic variant in VPS37A...... 271 Optical coherence tomography in diagnosis and monitoring multiple sclerosis...... 271 Cervical spinal cord atrophy: An early marker of progressive MS onset. ....272 Disability progression in multiple sclerosis: a Tunisian prospective cohort study...... 273 An electroglottographical analysis-based discriminant function model differentiating multiple sclerosis patients from healthy controls...... 274 Natalizumab reduces serum pro-angiogenic activity in MS patients...... 275 Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology...... 276 Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks...... 277 Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks...... 278 An intervention to improve balance in persons with multiple sclerosis...... 280 Efficacy of Balance and Eye-Movement Exercises for Persons With Multiple Sclerosis (BEEMS)...... 280 Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis...... 281 Journal Club: MRI reveals acute inflammation in cortical lesions during early MS...... 282 Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era...... 283 Cardiovascular Autonomic Dysfunction: Link Between Multiple Sclerosis Osteoporosis and Neurodegeneration...... 283 Multiple Sclerosis: Mechanisms and Immunotherapy...... 284 Imaging Pediatric Multiple Sclerosis-Challenges and Recent Advances...... 284 Mildly disabled persons with multiple sclerosis use similar net joint power strategies as healthy controls when walking speed increases...... 285 What is the opinion of patients with multiple sclerosis and their healthcare professionals about lower limb orthoses? A qualitative study using focus group discussions...... 286 Male and female opinions about orthotic devices of the lower limb: A multicentre, observational study in patients with central neurological movement disorders...... 287 Beneficial effect of atorvastatin-modified dendritic cells pulsed with myelin oligodendrocyte glycoprotein autoantigen on experimental autoimmune encephalomyelitis...... 288 Subcortical grey matter structures in multiple sclerosis: what is their role in cognition? ...... 288 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 16 – Multiple Sklerose: Veröffentlichungen Oktober 2013
Examining the effectiveness of acetylcholinesterase inhibitors and stimulant- based medications for cognitive dysfunction in multiple sclerosis: A systematic review and meta-analysis...... 289 The Role of the Cerebellum in Multiple Sclerosis - 150 years after Charcot...... 290 Stroke and seizure continue to be the major brunt of in patient neurology care. An observation from teaching hospital...... 291 Preliminary experience with a transcranial magnetic resonance-guided focused ultrasound surgery system integrated with a 1.5-T MRI unit in a series of patients with essential tremor and Parkinson's disease...... 292 Value of urodynamic findings in predicting upper urinary tract damage in neuro-urological patients: A systematic review...... 293 Multi-compartmental diffusion characterization of the human cervical spinal cord in vivo using the spherical mean technique...... 294 Vitamin D down-regulates the expression of some Th17 cell-related cytokines, key inflammatory chemokines, and chemokine receptors in experimental autoimmune encephalomyelitis...... 295 Vitamin D-Binding Protein Polymorphisms, 25-Hydroxyvitamin D, Sunshine and Multiple Sclerosis...... 296 Identifying characteristic miRNAs-genes and risk pathways of multiple sclerosis based on bioinformatics analysis...... 297 Case report of a patient with 'one-and-a-half plus syndrome: nine syndrome'...... 297 Support needs of caregivers of patients with amyotrophic lateral sclerosis: A qualitative study...... 298 Syncytial variant of nodular sclerosing Hodgkin lymphoma in children: A prognostic factor? ...... 299 Comparison of Disease-Modifying Therapies for the Management of Multiple Sclerosis: Analysis of Healthcare Resource Utilization and Relapse Rates from US Insurance Claims Data...... 300 A protocol for a randomised double-blind placebo-controlled feasibility study to determine whether the daily consumption of flavonoid-rich pure cocoa has the potential to reduce fatigue in people with relapsing and remitting multiple sclerosis (RRMS)...... 301 The cellular uptake of angiogenin, an angiogenic and neurotrophic factor is through multiple pathways and largely dynamin independent...... 302 Sexual dysfunctions in MS in relation to neuropsychiatric aspects and its psychological treatment: A scoping review...... 303 Support service utilization and out-of-pocket payments for health services in a population-based sample of adults with neurological conditions...... 304 Highly conserved extended haplotypes of the major histocompatibility complex and their relationship to multiple sclerosis susceptibility...... 305 Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls. ..306 Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells...... 307
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Socio-economic status influences access to second-line disease modifying treatment in Relapsing Remitting Multiple Sclerosis patients...... 308 Safety, Tolerability, and Effectiveness of Dextromethorphan/Quinidine for Pseudobulbar Affect Among Study Participants With Traumatic Brain Injury: Results From the PRISM-II Open Label Study...... 309 Neuropsychological testing...... 310 Bryostatin-1 alleviates experimental multiple sclerosis...... 311 Sex bias in MHC I-associated shaping of the adaptive immune system. ....312 Management of multiple sclerosis: the role of coping self-efficacy and self- esteem...... 313 The Experience of Persons With Multiple Sclerosis Using MS INFoRm: An Interactive Fatigue Management Resource...... 313 Re: Effects of serial macrocyclic-based contrast materials gadoterate meglumine and gadobutrol administrations on gadolinium-related dentate nuclei signal increases in unenhanced T1-weighted brain: a retrospective study in 158 multiple sclerosis (MS) patients...... 314 Novel Patents Targeting Interleukin-17A; Implications in Cancer and Inflammation...... 314 Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-κB pathway...... 315 Whole genome diversity of inherited chromosomally integrated HHV-6 derived from healthy individuals of diverse geographic origin...... 316 Impaired Cardiac Function in Patients with Multiple Sclerosis by Comparison with Normal Subjects...... 317 Enhanced release of acid sphingomyelinase-enriched exosomes generates a lipidomics signature in CSF of Multiple Sclerosis patients...... 318 Human subarachnoid space width oscillations in the resting state...... 319 Expression, Purification and Characterization of the Human Cannabinoid 1 Receptor...... 320 Expression and replication of virus-like circular DNA in human cells...... 321 Evaluating upper limb impairments in multiple sclerosis by exposure to different mechanical environments...... 322 Grey matter OPCs are less mature and less sensitive to IFNγ than white matter OPCs: consequences for remyelination...... 323 Judgment hurts: The psychological consequences of experiencing stigma in multiple sclerosis...... 324 Temporal evolution of a patient with a spinal dural arteriovenous fistula on serial MRI...... 325 A review on stem cell therapy for multiple sclerosis: special focus on human embryonic stem cells...... 325 Stemness Characteristics of Periodontal Ligament Stem Cells from Donors and Multiple Sclerosis Patients: A Comparative Study...... 326 Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY Extension study. .327
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 18 – Multiple Sklerose: Veröffentlichungen Oktober 2013
An epidemiological study on the course of disease and therapeutic considerations in relapsing-remitting multiple sclerosis patients receiving injectable first-line disease-modifying therapies in Germany (EPIDEM). ....328 Patient satisfaction and healthcare services in specialized multiple sclerosis centres in Germany...... 329 Decreased platelet number in multiple sclerosis during alemtuzumab infusion: a common, transient and clinically silent phenomenon...... 330 Endothelial cell functions impaired by interferon in vitro: Insights into the molecular mechanism of thrombotic microangiopathy associated with interferon therapy...... 331 Low, but not high, dose triptolide controls neuroinflammation and improves behavioral deficits in toxic model of multiple sclerosis by dampening of NF-κB activation and acceleration of intrinsic myelin repair...... 332 Protection by dimethyl fumarate against diabetic cardiomyopathy in type 1 diabetic mice likely via activation of nuclear factor erythroid-2 related factor 2...... 333 Mitochondrial dysfunction induced by leflunomide and its active metabolite...... 334 Botulinum Toxin A for Sialorrhoea Associated with Neurological Disorders: Evaluation of the Relationship between Effect of Treatment and the Number of Glands Treated...... 335 Hepatitis B vaccination and the putative risk of central demyelinating diseases - A systematic review and meta-analysis...... 336 The impact of visible and invisible symptoms on employment status, work and social functioning in Multiple Sclerosis...... 337
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Mehr als 25 Jahre 1 klinische Erfahrung Mehr als 1,5 Millionen Patientenjahre Erfahrung 2 Für Kinder ab 12 Jahren einsetzbar 3
1 The IFNB MS Study Group, Neurology 1993; 43: 655-661. 2 Bayer Pharma AG, Data on fi le. 3 Fachinformation Betaferon®, Stand September 2015. Betaferon® 250 Mikrogramm/ml, Pulver und Lösungsmittel zur Herstellung einer Injektionslösung. Wirkstoff: Interferon beta-1b (Vor Verschreibung bitte die Fachinformation beachten.) Zusammensetzung: Arzneilich wirksamer Bestandteil: 1 ml der gebrauchsfertigen Injektionslösung enthält 250 Mikrogramm (8,0 Mio. I.E.) rekombinantes Interferon beta-1b. 1 Durchstechfl asche enthält 300 Mikrogramm (9,6 Mio. I.E.) rekombinantes Interferon beta-1b. Sonstige Bestandteile: Pulver für Injektionslösung: Albumin vom Menschen, Mannitol, Lösungsmittel: Natriumchloridlösung 0,54 % G/V. Anwendungsgebiete: Betaferon® ist indiziert zur Behandlung von Patienten mit erstmaligem demyelinisierendem Ereignis mit aktivem entzündlichem Prozess, wenn dieses Ereignis schwer genug ist, um eine intravenöse Kortikosteroidtherapie zu rechtfertigen, wenn mögliche Differentialdiagnosen ausgeschlossen wurden und wenn bei diesen Patienten der Beurteilung zufolge ein hohes Risiko für das Auftreten einer klinisch gesicherten Multiplen Sklerose besteht, von Patienten mit schubweise verlaufender Multipler Sklerose, die in den letzten zwei Jahren zwei oder mehr Schübe durchgemacht haben und von Patienten mit sekundär progredient verlaufender Multipler Sklerose, die sich in einem akuten Krankheitsstadium befi nden, d. h. klinische Schübe erfahren. Gegenanzeigen: Beginn der Behandlung während der Schwangerschaft, Überempfi ndlichkeit gegen natürliches oder rekombinantes Interferon beta, Humanalbumin oder einen der sonstigen Bestandteile in der Anamnese, bestehende schwere Depressionen und/oder Suizidneigungen, dekompensierte Leberinsuffi zienz. Warnhinweise: Zytokin-Gabe bei vorbestehender monoklonaler Gammopathie in Zusammenhang mit Entwicklung eines Capillary-Leak-Syndroms mit schockähnlichen Symptomen und tödlichem Ausgang. In seltenen Fällen Pankreatitis, oft mit Hypertriglyzeridämie. Vorsicht bei vorbestehenden oder aktuellen depressiven Störungen, insbesondere Suizidneigung. Depression und Suizidneigung können bei Multipler Sklerose und Interferonbehandlung vermehrt auftreten. Depression oder Suizidneigung unmittelbar an behandelnden Arzt berichten und engmaschig beobachten und behandeln. Gegebenenfalls Abbruch der Betaferon-Behandlung. Vorsicht bei Krampfanfällen in der Anamnese, Antiepileptikabehandlung und Epilepsie, die nicht adäquat mit Antiepileptika kontrolliert ist. Das Präparat enthält Humanalbumin und birgt daher ein Risiko der Übertragung viraler Erkrankungen. Das Risiko für die Übertragung der Creutzfeld-Jacob-Krankheit (CJK) kann nicht ausgeschlossen werden. Regelmäßige Schilddrüsenfunktionstests empfohlen bei Funktionsstörung der Schilddrüse oder medizinischer Indikation. Vor Behandlungsbeginn und regelmäßig während Betaferon-Behandlung großes Blutbild mit differentiellen Leukozyten- und Thrombozytenzahlen sowie Labor einschließlich Leberwerte (z. B. AST [SGOT], ALT [SGPT] und γ-GT) auch ohne klinische Symptome. Patienten mit Anämie, Thrombozytopenie und/oder Leukopenie bedürfen möglicherweise eines intensiveren Monitorings. Selten Berichte über schwere Leberschädigung einschließlich Fälle von Leberversagen. Schwerwiegendste Fälle häufi g in Kombination mit Lebertoxizität assoziierten Substanzen oder bei gleichzeitigen Erkrankungen. Überwachung auf Anzeichen von Leberversagen. Erhöhte Transaminasenwerte engmaschig kontrollieren. Bei signifi kanter Erhöhung oder Symptomen wie Gelbsucht, Absetzen in Erwägung ziehen. Vorsicht bei schwerer Niereninsuffi zienz und engmaschige Überwachung. Fälle von nephrotischem Syndrom mit unterschiedlichen zugrundeliegenden Nephropathien, einschließlich der kollabierenden Form der fokal segmentalen Glomerulosklerose (FSGS), Minimal-Change-Glomerulonephritis (MCG), membranoproliferativen Glomerulonephritis (MPGN) und membranösen Glomerulopathie (MGN) wurden während der Behandlung mit Interferon-beta Produkten berichtet. Ereignisse wurden zu verschiedenen Zeitpunkten der Behandlung berichtet und können nach mehreren Jahren der Behandlung mit Interferon-beta auftreten. Eine regelmäßige Überprüfung auf frühe Anzeichen oder Symptome, besonders bei Patienten mit einem erhöhten Risiko von Nierenerkrankungen, wird empfohlen. Eine sofortige Behandlung des nephrotischen Syndroms ist erforderlich und ein Abbruch der Behandlung mit Betaferon sollte in Erwägung gezogen werden. Vorsicht bei vorbestehenden Herzerkrankungen wie Herzinsuffi zienz, koronarer Herzkrankheit oder Herzrhythmusstörungen. Dann insbesondere zu Beginn der Behandlung auf Verschlechterung des kardialen Zustands überwachen. Betaferon besitzt zwar keine bekannte direkte kardiotoxische Wirkung, Grippe-ähnliche Symptome, die unter Beta-Interferonen auftreten können, können sich für Patienten mit vorbestehender relevanter Herzerkrankung jedoch als belastend erweisen. Seltene Fälle von Kardiomyopathie wurden berichtet. Behandlungsabbruch bei Kardiomyopathie und Verdacht eines Zusammenhangs mit Betaferon. Berichtete Fälle von thrombotischer Mikroangiopathie (TMA), die sich als thrombotisch-thrombozytopenische Purpura (TTP) oder hämolytisch-urämisches Syndrom (HUS) manifestierte. Die Ereignisse wurden zu unterschiedlichen Zeitpunkten während der Behandlung gemeldet und können mehrere Wochen bis mehrere Jahre nach Beginn der Behandlung mit Interferon beta auftreten. Bei Diagnose einer TMA ist eine umgehende Behandlung erforderlich und ein sofortiges Absetzen von Betaferon wird empfohlen. Schwere Überempfi ndlichkeitsreaktionen möglich. Bei schweren Reaktionen Behandlungsabbruch und geeignete ärztliche Maßnahmen. Berichtete Nekrosen an den Injektionsstellen können ausgedehnt sein und zur Narbenbildung führen. Bei Hautläsion aus der Injektionsstelle ärztliche Konsultation vor weiterer Behandlung. Bei mehreren Läsionen Unterbrechung bis Abheilung der Läsion. Nebenwirkungen: Zu Beginn der Behandlung sind unerwünschte Wirkungen häufi g, diese klingen aber im Allgemeinen bei weiterer Behandlung ab. Die am häufi gsten beobachteten unerwünschten Wirkungen waren ein grippeähnlicher Symptomenkomplex und Reaktionen an der Injektionsstelle. Zu Beginn der Behandlung wird eine Auftitrierung der Dosis empfohlen, um die Verträglichkeit von Betaferon zu verbessern. Grippeähnliche Symptome lassen sich außerdem durch Verabreichung eines nicht-steroidalen Entzündungshemmers verringern. Die Häufi gkeit von Reaktionen an der Injektionsstelle lässt sich durch Anwendung eines Autoinjektors vermindern. Liste der unerwünschten Ereignisse: Infektion, Abszess, Lymphopenie, Anämie, Thrombozytopenie, Thrombotische Mikroangiopathie, einschließlich thrombotischer thrombozytopenischer Purpura/hämolytisch- urämisches Syndrom, Neutropenie, Leukopenie, Lymphadenopathie, Palpitationen, Kardiomyopathie, Tachykardie, Hypothyreose, Hyperthyreose, Schilddrüsenerkrankungen, Diarrhoe, Verstopfung, Übelkeit, Erbrechen, abdominelle Schmerzen, Pankreatitis, Anstieg der Glutamatpyruvat-, Glutamatoxalacetattransaminase, des Bilirubin-Spiegels und der Gammaglutamyltransferase, Hepatitis, Leberschaden (inkl. Hepatitis), Leberinsuffi zienz, anaphylaktische Reaktion, Kapillarlecksyndrom bei vorbestehender monoklonaler Gammopathie, Gewichtsverlust, Gewichtszunahme, Anstieg der Triglyzeride im Blut, Anorexie, Hypoglykämie, Arthralgie, arzneimittelinduzierter Lupus erythematodes, Hypertonie (Skelettmuskulatur), Muskelschmerzen, Myasthenie, Rückenschmerzen, Schmerzen in einer Extremität, Krampfanfälle, Kopfschmerzen, Schwindel, Schlafl osigkeit, Migräne, Parästhesie, Verwirrtheit, Suizidversuch, emotionale Instabilität, Depression, Angst, Menorrhagie, Dysmenorrhoe, Menstruationsstörungen, Metrorrhagie, Impotenz, Bronchospasmus, pulmonale arterielle Hypertonie, Infektionen der oberen Atemwege, Sinusitis, vermehrtes Husten, Dyspnoe, Urtikaria, Pruritus, Alopezie, Hautverfärbung, Hauterkrankungen, Hautausschlag, Konjunktivitis, Sehstörungen, Ohrenschmerzen, Vasodilatation, Hypertonie, Harnverhaltung, pos. Harnprotein, häufi ge Blasenentleerung, Harninkontinenz, starker Harndrang, nephrotisches Syndrom, Glomerulosklerose, Reaktionen und Nekrose an der Injektionsstelle, grippeähnliche Symptome, Fieber, Schmerzen, Thoraxschmerzen, periphere Ödeme, Asthenie, Schüttelfrost, Schwitzen, Unwohlsein. Verschreibungspfl ichtig. Bayer AG, 51368 Leverkusen, Deutschland. Version: FI/4, 03/2017 L.DE.MKT.SM.04.2017.5532 Literatur-Dauerrecherche – 19 – Multiple Sklerose: Veröffentlichungen Oktober 2013
1. Abdom Radiol (NY). 2018 Feb 19. doi: 10.1007/s00261-018-1476-5. [Epub ahead of print] MRI features of primary hepatic lymphoma. Colagrande S(1), Calistri L(2), Grazzini G(1), Nardi C(1), Busoni S(3), Morana G(4), Grazioli L(5). Author information: (1)Department of Experimental and Clinical Biomedical Sciences, Radiodiagnostic Unit n. 2, University of Florence - Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy. (2)Department of Experimental and Clinical Biomedical Sciences, Radiodiagnostic Unit n. 2, University of Florence - Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy. [email protected]. (3)Medical Physics Department, University of Florence - Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy. (4)Department of Radiology, General Hospital Ca' Foncello, Piazza Ospedale 1, 31100, Treviso, Italy. (5)Department of Radiology, University of Brescia "Spedali Civili", P.le Spedali Civili 1, 25123, Brescia, Italy. PURPOSE: Our retrospective study sought to describe the spectrum of magnetic resonance imaging (MRI) features of primary hepatic lymphoma (PHL) by analyzing its morphological aspects, signal intensity before and after contrast agent (CA) administration, and diffusion-weighted imaging (DwI) with the apparent diffusion coefficient (ADC) values. METHODS: A retrospective analysis was conducted on 25 patients with pathologically proven PHL who underwent MRI between January 2011 and December 2016. For the evaluation of the ADC, we used a control group of 87 patients (22 with hepatocellular carcinoma, 15 with cholangiocellular carcinoma, 23 with liver metastasis, 22 with focal nodular hyperplasia, and 5 with adenoma). Two radiologists evaluated the morphological features, the signal intensity before and after CA administration, and the DwI. The sensitivity and specificity of the ADC values in distinguishing the PHL lesions from other hepatic lesions were calculated by analyzing the receiver operating characteristic (ROC) curves. RESULTS: Twenty-one patients had non- Hodgkin's lymphoma (18 had diffuse large B-cell lymphoma and three had mucosa-associated lymphoid tissue) and four had Hodgkin's lymphoma (nodular sclerosis). The PHL had a variable morphologic distribution (17 focal mass and eight multiple nodules) and mainly an insinuative growth (24/25). Usually, PHL was usually hypointense on the T1-weighted images (23/25) and hyperintense on the T2-weighted images (21/25); non-specific dynamic enhancement was found after CA administration, but in the hepatobiliary phase, PHL is mainly hypointense (92%). All PHLs showed a signal restriction in the DwI. The sensitivity and specificity in the differential diagnosis between PHL and the other malignant lesions were respectively 81.7% and 100%, with applying an ADC cut-off value of 0.918 × 10-3 mm2/s. CONCLUSION: Although PHL is a rare disease and biopsy is still required, an MRI could be indicative. In our series, PHL showed an insinuative growth, hypointense signal in the hepatobiliary phase, signal restriction in the DwI, and an ADC value lower than that of the other hepatic lesions analyzed. DOI: 10.1007/s00261-018-1476-5 PMID: 29460044
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 20 – Multiple Sklerose: Veröffentlichungen Oktober 2013
2. ACS Cent Sci. 2018 Jan 24;4(1):39-51. doi: 10.1021/acscentsci.7b00367. Epub 2017 Dec 27. Correlated Heterospectral Lipidomics for Biomolecular Profiling of Remyelination in Multiple Sclerosis. Bergholt MS(1)(2)(3), Serio A(1)(2)(3), McKenzie JS(4), Boyd A(5), Soares RF(4), Tillner J(4), Chiappini C(1)(2)(3), Wu V(4), Dannhorn A(4), Takats Z(4), Williams A(5), Stevens MM(1)(2)(3). Author information: (1)Department of Materials, Imperial College London, London SW7 2AZ, United Kingdom. (2)Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom. (3)Institute of Biomedical Engineering, Imperial College London, London SW7 2AZ, United Kingdom. (4)Computational and Systems Medicine, Imperial College London, London SW7 2AZ, United Kingdom. (5)MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom. Analyzing lipid composition and distribution within the brain is important to study white matter pathologies that present focal demyelination lesions, such as multiple sclerosis. Some lesions can endogenously re-form myelin sheaths. Therapies aim to enhance this repair process in order to reduce neurodegeneration and disability progression in patients. In this context, a lipidomic analysis providing both precise molecular classification and well-defined localization is crucial to detect changes in myelin lipid content. Here we develop a correlated heterospectral lipidomic (HSL) approach based on coregistered Raman spectroscopy, desorption electrospray ionization mass spectrometry (DESI-MS), and immunofluorescence imaging. We employ HSL to study the structural and compositional lipid profile of demyelination and remyelination in an induced focal demyelination mouse model and in multiple sclerosis lesions from patients ex vivo. Pixelwise coregistration of Raman spectroscopy and DESI-MS imaging generated a heterospectral map used to interrelate biomolecular structure and composition of myelin. Multivariate regression analysis enabled Raman-based assessment of highly specific lipid subtypes in complex tissue for the first time. This method revealed the temporal dynamics of remyelination and provided the first indication that newly formed myelin has a different lipid composition compared to normal myelin. HSL enables detailed molecular myelin characterization that can substantially improve upon the current understanding of remyelination in multiple sclerosis and provides a strategy to assess remyelination treatments in animal models. DOI: 10.1021/acscentsci.7b00367 PMCID: PMC5785772 PMID: 29392175
Conflict of interest statement: The authors declare no competing financial interest.
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 21 – Multiple Sklerose: Veröffentlichungen Oktober 2013
3. ACS Chem Neurosci. 2018 Feb 19. doi: 10.1021/acschemneuro.8b00057. [Epub ahead of print] Potential Therapeutic Applications for Inhibitors of Autotaxin, a Bioactive Lipid-Producing Lysophospholipase D, in Disorders Affecting the Nervous System. Herr DR(1)(2), Ong JH(3), Ong WY(3)(4). Author information: (1)Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 117600. (2)Department of Biology, San Diego State University , San Diego, California 92182, United States. (3)Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 119260. (4)Neurobiology and Ageing Research Programme, Life Sciences Institute, National University of Singapore , Singapore 119260. Autotaxin is a dual-function ecto-enzyme, encoded by the gene ENPP2, which is the primary source of the bioactive signaling lipid, lysophosphatidic acid. Aberrations in autotaxin/lysophosphatidic acid signaling have been associated with a number of neurological, psychiatric, neoplastic, and neurodevelopmental conditions, such as pain, pruritus, glioblastoma multiforme, multiple sclerosis, Alzheimer's disease, hydrocephalus, and schizophrenia. This Viewpoint offers a brief overview of the likely indications for therapeutic targeting of autotaxin, in disorders affecting the nervous system. DOI: 10.1021/acschemneuro.8b00057 PMID: 29457888
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 22 – Multiple Sklerose: Veröffentlichungen Oktober 2013
4. Acta Clin Croat. 2017 Sep;56(3):487-493. doi: 10.20471/acc.2017.56.03.16. The First Hospital-Based Registry of Patients with Multiple Sclerosis in Croatia. Bašić Kes V(1), Lisak M(1), Jurašić M(1), Zavoreo I(1), Dimitrović A(1), Kobasić I(1), Zadro Matovina L(1). Author information: (1)Clinical Department of Neurology, Sestre milosrdnice University Hospital Centre, Reference Center for Neuroimmunology and Neurogenetics, Reference Center for Neurovascular Disorders, Reference Center for Headaches, Reference Center for Diagnosis and Treatment of Acute and Chronic Pain, Ministry of Health of the Republic of Croatia, Zagreb, Croatia. The first hospital-based registry of patients with multiple sclerosis (MS) was established at the University Department of Neurology, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia, in 2014. The aim of the registry was to continuously provide data on the number of hospital-managed MS patients, patterns of disease progression, predictors of disability progression, changes in lifespan and long-term outcomes. Relevant medical data included age and gender of MS patients, family history of MS, data on previous immunization, disease course, Expanded Disability Status Scale (EDSS) score, cerebral magnetic resonance imaging (MRI) lesion load quantification, and cerebrospinal fluid analysis. Lifestyle habits in MS patients including smoking and alcohol consumption were also analyzed. All data were obtained from primary medical records between January 1, 2014 and January 1, 2015, and entered into the database. Data were evaluated retrospectively according to age and gender differences. Results showed that the majority of patients enrolled in the registry had the remitting relapsing course of disease, with low EDSS score indicating no disability or minimal disability. Cerebrospinal fluid analysis showed that oligoclonal bands were present in the majority of MS patients, with affected blood-brain-barrier permeability. According to the remitting relapsing course of the disease, cerebral MRI quantitative analysis demonstrated a significant lesion load in the majority of patients. When stratified by lifestyle habits, smokers and alcohol consumers were more prevalent among male patients. Our hospital-based registry might be considered as a prototype for the national MS registry and should be improved for reliable statistical analysis. DOI: 10.20471/acc.2017.56.03.16 PMID: 29479915
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 23 – Multiple Sklerose: Veröffentlichungen Oktober 2013
5. Acta Neurol Scand. 2018 Feb 7. doi: 10.1111/ane.12904. [Epub ahead of print] Efficacy of group cognitive rehabilitation therapy in multiple sclerosis. Mani A(1), Chohedri E(1), Ravanfar P(1), Mowla A(2), Nikseresht A(3). Author information: (1)Research Center for Psychiatry and Behavioral Sciences, Shiraz University of Medical Sciences, Shiraz, Iran. (2)Substance Abuse and Mental Health Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. (3)Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. OBJECTIVE: Cognitive impairment occurs in 40%-65% of patients with multiple sclerosis (MS). Several techniques for cognitive rehabilitation (CR) in these patients have been evaluated; however, the results have been controversial. In this study, we investigated the efficacy of group compensatory CR in patients with MS-related cognitive impairment. MATERIALS AND METHODS: Thirty-four female patients with diagnosed relapsing-remitting MS and evidence of impaired cognitive function were included and randomized to intervention (n = 17) and control (n = 17) groups. CR intervention consisted of eight 2-hour sessions of comprehensive group CR over a 4-week period that focused on improvement of memory, attention, and executive function. As placebo, the control group received the same number of non-therapeutic group sessions. Assessment of cognitive function was performed before intervention (pretest), at the end of intervention (post-test), and 3 months later (follow-up). RESULTS: The study population included 34 patients with a mean age of 35.5 years. Statistical comparison of memory assessments at 3-month follow-up showed significantly higher scores in the CR group than in the control group (93.33 vs 86.40 for Addenbrooke's Cognitive Examination test and 16.58 vs 12.00 for visual memory, 19.32 vs 14.05 for verbal memory, and 51.28 vs 44.41 for general scores on the Memory Functioning Questionnaire test, respectively). Wisconsin card sorting test score comparison showed significantly lower total time consumption in the CR group than in the control group (308.1 vs 340.8 seconds, respectively). Behavior rating inventory of executive function- adult scores in all four subtests were significantly higher in the CR group than in the control group (40.25 vs 55.4 for behavioral regulation index, 51.16 vs 68.6 for metacognition index, and 97.41 vs 124.00 for global executive composite, respectively). Attention was the only domain in which we did not observe any significant variation between groups in terms of post-test and follow-up scores. CONCLUSION: This study supports the efficacy of group CR in the improvement of cognitive function in patients with MS. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. DOI: 10.1111/ane.12904 PMID: 29411360
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 24 – Multiple Sklerose: Veröffentlichungen Oktober 2013
6. Acta Neuropathol. 2018 Mar;135(3):311-336. doi: 10.1007/s00401-018-1815-1. Epub 2018 Feb 6. Functional morphology of the blood-brain barrier in health and disease. Liebner S(1)(2)(3), Dijkhuizen RM(4), Reiss Y(5)(6)(7)(8)(9), Plate KH(5)(6)(7)(8)(9), Agalliu D(10)(11)(12)(13), Constantin G(14). Author information: (1)Institute of Neurology, Goethe University Clinic, Frankfurt am Main, Germany. [email protected]. (2)Excellence Cluster Cardio-Pulmonary Systems (ECCPS), Partner site Frankfurt, Frankfurt am Main, Germany. [email protected]. (3)German Center for Cardiovascular Research (DZHK), Partner site Frankfurt/Mainz, Frankfurt am Main, Germany. [email protected]. (4)Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands. (5)Institute of Neurology, Goethe University Clinic, Frankfurt am Main, Germany. (6)Excellence Cluster Cardio-Pulmonary Systems (ECCPS), Partner site Frankfurt, Frankfurt am Main, Germany. (7)German Center for Cardiovascular Research (DZHK), Partner site Frankfurt/Mainz, Frankfurt am Main, Germany. (8)German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany. (9)German Cancer Research Center (DKFZ), Heidelberg, Germany. (10)Departments of Neurology, Columbia University Medical Center, New York, NY, 10032, USA. (11)Departments of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA. (12)Departments of Pharmacology, Columbia University Medical Center, New York, NY, 10032, USA. (13)Departments of Columbia Translational Neuroscience Initiative, Columbia University Medical Center, New York, NY, 10032, USA. (14)Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy. The adult quiescent blood-brain barrier (BBB), a structure organised by endothelial cells through interactions with pericytes, astrocytes, neurons and microglia in the neurovascular unit, is highly regulated but fragile at the same time. In the past decade, there has been considerable progress in understanding not only the molecular pathways involved in BBB development, but also BBB breakdown in neurological diseases. Specifically, the Wnt/β-catenin, retinoic acid and sonic hedgehog pathways moved into the focus of BBB research. Moreover, angiopoietin/Tie2 signalling that is linked to angiogenic processes has gained attention in the BBB field. Blood vessels play an essential role in initiation and progression of many diseases, including inflammation outside the central nervous system (CNS). Therefore, the potential influence of CNS blood vessels in neurological diseases associated with BBB alterations or neuroinflammation has become a major focus of current research to understand their contribution to pathogenesis. Moreover, the BBB remains a major obstacle to pharmaceutical intervention in the CNS. The complications may either be expressed by inadequate therapeutic delivery like in brain tumours, or by poor delivery of the drug across the BBB and ineffective bioavailability. In this review, we initially describe the cellular and molecular components that contribute to the steady state of the healthy BBB. We then discuss BBB alterations in ischaemic stroke, primary and metastatic brain tumour, chronic inflammation and Alzheimer's disease. Throughout the review, we highlight common mechanisms of BBB abnormalities among these diseases, in particular the contribution of neuroinflammation to BBB dysfunction and disease progression, and emphasise unique aspects of BBB alteration in certain diseases such as brain tumours. Moreover, this review highlights novel strategies to monitor BBB function by non-invasive imaging techniques focussing on ischaemic stroke, as well as novel ways to modulate BBB permeability and function to promote treatment of brain tumours, inflammation and Alzheimer's disease. In conclusion, a deep understanding of signals that maintain the healthy BBB and promote fluctuations in BBB permeability in disease states will be key to elucidate disease mechanisms and to identify potential targets for diagnostics and therapeutic modulation of the BBB. DOI: 10.1007/s00401-018-1815-1 PMID: 29411111
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 25 – Multiple Sklerose: Veröffentlichungen Oktober 2013
7. Acta Neuropathol. 2018 Feb 3. doi: 10.1007/s00401-018-1813-3. [Epub ahead of print] Activin receptors regulate the oligodendrocyte lineage in health and disease. Dillenburg A(1), Ireland G(1), Holloway RK(1), Davies CL(1), Evans FL(1), Swire M(2), Bechler ME(2), Soong D(1), Yuen TJ(3)(4), Su GH(5), Becher JC(6), Smith C(7), Williams A(2), Miron VE(8). Author information: (1)Medical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. (2)Medical Research Council Centre for Regenerative Medicine, The University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 5UU, UK. (3)Department of Veterinary Medicine, Wellcome Trust MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB3 0E5, UK. (4)Department of Neuroscience, Genentech Inc., South San Francisco, CA, 94080, USA. (5)Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Centre, New York, 10032, USA. (6)Simpson's Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SA, UK. (7)Centre for Clinical Brain Sciences, Centre for Comparative Pathology, The University of Edinburgh, Chancellor's Building, Edinburgh, EH16 4TJ, UK. (8)Medical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. [email protected]. The most prevalent neurological disorders of myelin include perinatal brain injury leading to cerebral palsy in infants and multiple sclerosis in adults. Although these disorders have distinct etiologies, they share a common neuropathological feature of failed progenitor differentiation into myelin-producing oligodendrocytes and lack of myelin, for which there is an unmet clinical need. Here, we reveal that a molecular pathology common to both disorders is dysregulation of activin receptors and that activin receptor signaling is required for the majority of myelin generation in development and following injury. Using a constitutive conditional knockout of all activin receptor signaling in oligodendrocyte lineage cells, we discovered this signaling to be required for myelination via regulation of oligodendrocyte differentiation and myelin compaction. These processes were found to be dependent on the activin receptor subtype Acvr2a, which is expressed during oligodendrocyte differentiation and axonal ensheathment in development and following myelin injury. During efficient myelin regeneration, Acvr2a upregulation was seen to coincide with downregulation of Acvr2b, a receptor subtype with relatively higher ligand affinity; Acvr2b was shown to be dispensable for activin receptor-driven oligodendrocyte differentiation and its overexpression was sufficient to impair the abovementioned ligand-driven responses. In actively myelinating or remyelinating areas of human perinatal brain injury and multiple sclerosis tissue, respectively, oligodendrocyte lineage cells expressing Acvr2a outnumbered those expressing Acvr2b, whereas in non-repairing lesions Acvr2b+ cells were increased. Thus, we propose that following human white matter injury, this increase in Acvr2b expression would sequester ligand and consequently impair Acvr2a-driven oligodendrocyte differentiation and myelin formation. Our results demonstrate dysregulated activin receptor signaling in common myelin disorders and reveal Acvr2a as a novel therapeutic target for myelin generation following injury across the lifespan. DOI: 10.1007/s00401-018-1813-3 PMID: 29397421
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 26 – Multiple Sklerose: Veröffentlichungen Oktober 2013
8. Acta Neuropathol. 2018 Feb 13. doi: 10.1007/s00401-018-1818-y. [Epub ahead of print] Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Luchetti S(1), Fransen NL(1), van Eden CG(1), Ramaglia V(1)(2), Mason M(1), Huitinga I(3). Author information: (1)Laboratory of Neuroimmunology, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA, Amsterdam, The Netherlands. (2)Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. (3)Laboratory of Neuroimmunology, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA, Amsterdam, The Netherlands. [email protected]. Multiple sclerosis (MS) is a highly heterogeneous disease with large inter-individual differences in disease course. MS lesion pathology shows considerable heterogeneity in localization, cellular content and degree of demyelination between patients. In this study, we investigated pathological correlates of disease course in MS using the autopsy cohort of the Netherlands Brain Bank (NBB), containing 182 MS brain donors. Using a standardized autopsy procedure including systematic dissection from standard locations, 3188 tissue blocks containing 7562 MS lesions were dissected. Unbiased measurements of lesion load were made using the tissue from standard locations. Lesion demyelinating and innate inflammatory activity were visualized by immunohistochemistry for proteolipid protein and human leukocyte antigen. Lesions were classified into active, mixed active/inactive (also known as chronic active), inactive or remyelinated, while microglia/macrophage morphology was classified as ramified, amoeboid or foamy. The severity score was calculated from the time from first symptoms to EDSS-6. Lesion type prevalence and microglia/macrophage morphology were analyzed in relation to clinical course, disease severity, lesion load and sex, and in relation to each other. This analysis shows for the first time that (1) in progressive MS, with a mean disease duration of 28.6 ± 13.3 years (mean ± SD), there is substantial inflammatory lesion activity at time to death. 57% of all lesions were either active or mixed active/inactive and 78% of all patients had a mixed active/inactive lesion present; (2) patients that had a more severe disease course show a higher proportion of mixed active/inactive lesions (p = 6e-06) and a higher lesion load (p = 2e-04) at the time of death, (3) patients with a progressive disease course show a higher lesion load (p = 0.001), and a lower proportion of remyelinated lesions (p = 0.03) compared to patients with a relapsing disease course, (4) males have a higher incidence of cortical grey matter lesions (p = 0.027) and a higher proportion of mixed active/inactive lesions compared to females across the whole cohort (p = 0.007). We confirm that there is a higher proportion of mixed active/inactive lesions (p = 0.006) in progressive MS compared to relapsing disease. Identification of mixed active/inactive lesions on MRI is necessary to determine whether they can be used as a prognostic tool in living MS patients. DOI: 10.1007/s00401-018-1818-y PMID: 29441412
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 27 – Multiple Sklerose: Veröffentlichungen Oktober 2013
9. Acta Neuropathol Commun. 2018 Feb 15;6(1):9. doi: 10.1186/s40478-018-0510-8. Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945. Beckmann N(1), Giorgetti E(1), Neuhaus A(2), Zurbruegg S(2), Accart N(1), Smith P(3)(4), Perdoux J(3), Perrot L(5), Nash M(1), Desrayaud S(6), Wipfli P(6), Frieauff W(7), Shimshek DR(8). Author information: (1)Musculoskeletal Diseases Area, Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland. (2)Neuroscience, Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland. (3)Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland. (4)Present address: Incyte, 1801 Augustine Cut-off, Wilmington, DE, 19803, USA. (5)Global Scientific Operations, Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland. (6)PK Sciences, Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland. (7)Preclinical Safety, Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland. (8)Neuroscience, Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland. [email protected]. Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system (CNS). While multiple effective immunomodulatory therapies for MS exist today, they lack the scope of promoting CNS repair, in particular remyelination. Microglia play a pivotal role in regulating myelination processes, and the colony-stimulating factor 1 (CSF-1) pathway is a key regulator for microglia differentiation and survival. Here, we investigated the effects of the CSF-1 receptor kinase inhibitor, BLZ945, on central myelination processes in the 5-week murine cuprizone model by non-invasive and longitudinal magnetic resonance imaging (MRI) and histology. Therapeutic 2-week BLZ945 treatment caused a brain region-specific enhancement of remyelination in the striatum/cortex, which was absent in the corpus callosum/external capsule. This beneficial effect correlated positively with microglia reduction, increased oligodendrocytes and astrogliosis. Prophylactic BLZ945 treatment prevented excessive demyelination in the corpus callosum by reducing microglia and increasing oligondendrocytes. In the external capsule oligodendrocytes were depleted but not microglia and a buildup of myelin debris and axonal damage was observed. A similar microglial dysfunction in the external capsule with an increase of myelin debris was obvious in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice treated with cuprizone. Finally, therapeutic BLZ945 treatment did not change the disease course in experimental autoimmune encephalomyelitis mice, a peripherally driven neuroinflammation model. Taken together, our data suggest that a short-term therapeutic inhibition of the CSF-1 receptor pathway by BLZ945 in the murine cuprizone model enhances central remyelination by modulating neuroinflammation. Thus, microglia-modulating therapies could be considered clinically for promoting myelination in combination with standard-of-care treatments in MS patients. DOI: 10.1186/s40478-018-0510-8 PMCID: PMC5815182 PMID: 29448957
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 28 – Multiple Sklerose: Veröffentlichungen Oktober 2013
10. Adv Exp Med Biol. 2018 Feb 13. doi: 10.1007/5584_2018_155. [Epub ahead of print] Oscillations of Subarachnoid Space Width as a Potential Marker of Cerebrospinal Fluid Pulsatility. Gruszecki M(1), Nuckowska MK(2), Szarmach A(3), Radkowski M(4), Szalewska D(5), Waskow M(6), Szurowska E(3), Frydrychowski AF(2), Demkow U(7), Winklewski PJ(8)(9)(10). Author information: (1)Department of Radiology Informatics and Statistics, Medical University of Gdansk, Gdansk, Poland. (2)Department of Human Physiology, Medical University of Gdansk, Gdansk, Poland. (3)Second Department of Radiology, Medical University of Gdansk, Gdansk, Poland. (4)Department of Immunopathology of Infectious and Parasitic Diseases, Warsaw Medical University, Warsaw, Poland. (5)Chair of Rehabilitation Medicine, Medical University of Gdansk, Gdansk, Poland. (6)Faculty of Health Sciences, Slupsk Pomeranian University, Slupsk, Poland. (7)Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Warsaw Medical University, Warsaw, Poland. (8)Department of Human Physiology, Medical University of Gdansk, Gdansk, Poland. [email protected]. (9)Second Department of Radiology, Medical University of Gdansk, Gdansk, Poland. [email protected]. (10)Faculty of Health Sciences, Slupsk Pomeranian University, Slupsk, Poland. [email protected]. In the cerebrospinal fluid (CSF) circulation, two components can be distinguished: bulk flow (circulation) and pulsatile flow (back and forth motion). CSF pulsatile flow is generated by both cardiac and respiratory cycles. Recent years have seen increased interest in cardiac and respiratory-driven CSF pulsatility as an important component of cerebral homeostasis. CSF pulsatility is affected by cerebral arterial inflow and jugular outflow and potentially linked to white matter abnormalities in various diseases, such as multiple sclerosis or hypertension. In this review, we discuss the physiological mechanisms associated with CSF pulsation and its clinical significance. Finally, we explain the concept of using the oscillations of subarachnoid space width as a surrogate for CSF pulsatility. DOI: 10.1007/5584_2018_155 PMID: 29435957
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 29 – Multiple Sklerose: Veröffentlichungen Oktober 2013
11. Adv Exp Med Biol. 2018 Feb 13. doi: 10.1007/5584_2018_158. [Epub ahead of print] Robot-Assisted Body-Weight-Supported Treadmill Training in Gait Impairment in Multiple Sclerosis Patients: A Pilot Study. Łyp M(1), Stanisławska I(2), Witek B(3), Olszewska-Żaczek E(1), Czarny-Działak M(4), Kaczor R(1). Author information: (1)Department of Physiotherapy, College of Rehabilitation, Warsaw, Poland. (2)Department of Physiotherapy, College of Rehabilitation, Warsaw, Poland. [email protected]. (3)Department of Animal Physiology, Institute of Biology, The Jan Kochanowski University in Kielce, Kielce, Poland. (4)Faculty of Medicine and Health Sciences, The Jan Kochanowski University in Kielce, Kielce, Poland. This study deals with the use of a robot-assisted body-weight-supported treadmill training in multiple sclerosis (MS) patients with gait dysfunction. Twenty MS patients (10 men and 10 women) of the mean of 46.3 ± 8.5 years were assigned to a six-week-long training period with the use of robot- assisted treadmill training of increasing intensity of the Lokomat type. The outcome measure consisted of the difference in motion-dependent torque of lower extremity joint muscles after training compared with baseline before training. We found that the training uniformly and significantly augmented the torque of both extensors and flexors of the hip and knee joints. The muscle power in the lower limbs of SM patients was improved, leading to corrective changes of disordered walking movements, which enabled the patients to walk with less effort and less assistance of care givers. The torque augmentation could have its role in affecting the function of the lower extremity muscle groups during walking. The results of this pilot study suggest that the robot-assisted body-weight-supported treadmill training may be a potential adjunct measure in the rehabilitation paradigm of 'gait reeducation' in peripheral neuropathies. DOI: 10.1007/5584_2018_158 PMID: 29435956
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 30 – Multiple Sklerose: Veröffentlichungen Oktober 2013
12. Adv Food Nutr Res. 2018;83:57-81. doi: 10.1016/bs.afnr.2017.11.002. Epub 2018 Feb 2. Riboflavin in Human Health: A Review of Current Evidences. Saedisomeolia A(1), Ashoori M(2). Author information: (1)School of Nutrition Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran; School of Medicine, Western Sydney University, Sydney, NSW, Australia. Electronic address: [email protected]. (2)School of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Riboflavin is a water-soluble vitamin, which was initially isolated from milk. There are two coenzyme forms of riboflavin, flavin mononucleotide and flavin adenine dinucleotide, in which riboflavin plays important roles in the enzymatic reactions. Riboflavin is found in a wide variety of animal and plant foods. Meat and dairy products are the major contributors of riboflavin dietary intake. In this chapter, the latest evidence on the relationship between riboflavin status and specific health risks will be reviewed. Also, some of the mechanisms by which riboflavin exerts its roles will be discussed. The evidence accrued suggests that riboflavin is an antioxidant nutrient which may prevent lipid peroxidation and reperfusion oxidative injury. Moreover, riboflavin deficiency may increase the risk of some cancers. Riboflavin may also exert a neuroprotective effects in some neurological disorders (e.g., Parkinson disease, migraine, and multiple sclerosis) through its role in some pathways that are hypothesized to be impaired in neurological disorders such as antioxidation, myelin formation, mitochondrial function, and iron metabolism. © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/bs.afnr.2017.11.002 PMID: 29477226
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 31 – Multiple Sklerose: Veröffentlichungen Oktober 2013
13. AJNR Am J Neuroradiol. 2018 Feb 8. doi: 10.3174/ajnr.A5541. [Epub ahead of print] Evaluation of Leptomeningeal Contrast Enhancement Using Pre-and Postcontrast Subtraction 3D- FLAIR Imaging in Multiple Sclerosis. Zivadinov R(1)(2), Ramasamy DP(3), Hagemeier J(3), Kolb C(2), Bergsland N(3), Schweser F(3), Dwyer MG(3), Weinstock-Guttman B(4), Hojnacki D(2). Author information: (1)From the Department of Neurology (R.Z., D.P.R., J.H., N.B., F.S., M.G.D.), Buffalo Neuroimaging Analysis Center, Jacobs School of Medicine and Biomedical Sciences [email protected]. (2)Department of Neurology (R.Z., C.K., D.H.), Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, State University of New York, Buffalo, New York. (3)From the Department of Neurology (R.Z., D.P.R., J.H., N.B., F.S., M.G.D.), Buffalo Neuroimaging Analysis Center, Jacobs School of Medicine and Biomedical Sciences. (4)Translational Imaging Center at Clinical Translational Science Institute (B.W.-G.). BACKGROUND AND PURPOSE: Leptomeningeal contrast enhancement is found in patients with multiple sclerosis, though reported rates have varied. The use of 3D-fluid-attenuated inversion recovery pre- and postcontrast subtraction imaging may more accurately determine the frequency of leptomeningeal contrast enhancement. The purpose of this study was to investigate the frequency of leptomeningeal contrast enhancement using the pre- and postcontrast subtraction approach and to evaluate 3 different methods of assessing the presence of leptomeningeal contrast enhancement. MATERIALS AND METHODS: We enrolled 258 consecutive patients with MS (212 with relapsing- remitting MS, 32 with secondary-progressive MS, and 14 with clinically isolated syndrome) who underwent both pre- and 10-minute postcontrast 3D-FLAIR sequences after a single dose of gadolinium injection on 3T MR imaging. The analysis included leptomeningeal contrast-enhancement evaluation on 3D-FLAIR postcontrast images in native space (method A), on pre- and postcontrast 3D- FLAIR images in native space (method B), and on pre-/postcontrast 3D-FLAIR coregistered and subtracted images (method C, used as the criterion standard). RESULTS: In total, 51 (19.7%) patients with MS showed the presence of leptomeningeal contrast enhancement using method A; 39 (15.1%), using method B; and 39 (15.1%), using method C (P = .002). Compared with method C as the criterion standard, method A showed 89.8% sensitivity and 92.7% specificity, while method B showed 84.6% sensitivity and 97.3% specificity (P < .001) at the patient level. Reproducibility was the highest using method C (κ agreement, r = 088, P < .001). The mean time to analyze the 3D-FLAIR images was significantly lower with method C compared with methods A and B (P < .001). CONCLUSIONS: 3D- FLAIR postcontrast imaging offers a sensitive method for detecting leptomeningeal contrast enhancement in patients with MS. However, the use of subtraction imaging helped avoid false-positive cases, decreased reading time, and increased the accuracy of leptomeningeal contrast-enhancement foci detection in a clinical routine. © 2018 by American Journal of Neuroradiology. DOI: 10.3174/ajnr.A5541 PMID: 29439125
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 32 – Multiple Sklerose: Veröffentlichungen Oktober 2013
14. AJNR Am J Neuroradiol. 2018 Feb 8. doi: 10.3174/ajnr.A5542. [Epub ahead of print] Iron-Insensitive Quantitative Assessment of Subcortical Gray Matter Demyelination in Multiple Sclerosis Using the Macromolecular Proton Fraction. Yarnykh VL(1)(2), Krutenkova EP(2), Aitmagambetova G(2), Repovic P(3), Mayadev A(3), Qian P(3), Jung Henson LK(3)(4), Gangadharan B(3), Bowen JD(3). Author information: (1)From the Department of Radiology (V.L.Y.), University of Washington, Seattle, Washington [email protected]. (2)Research Institute of Biology and Biophysics (E.P.K., G.A., V.L.Y.), Tomsk State University, Tomsk, Russian Federation. (3)Multiple Sclerosis Center (P.R., A.M., P.Q., L.K.J.H., B.G., J.D.B.), Swedish Neuroscience Institute, Seattle, Washington. (4)Piedmont Henry Hospital (L.K.J.H.), Stockbridge, Georgia. BACKGROUND AND PURPOSE: Fast macromolecular proton fraction mapping is a recent quantitative MR imaging method for myelin assessment. The objectives of this study were to evaluate the macromolecular proton fraction as a measure of demyelination in subcortical GM structures in multiple sclerosis and assess a potential relationship between demyelination and excess iron deposition using the macromolecular proton fraction and T2* mapping. MATERIALS AND METHODS: Macromolecular proton fraction and T2* maps were obtained from 12 healthy controls, 18 patients with relapsing-remitting MS, and 12 patients with secondary-progressive MS using 3T MR imaging. Parameter values in the caudate nucleus, globus pallidus, putamen, substantia nigra, and thalamus were compared between groups and correlated to clinical data. RESULTS: The macromolecular proton fraction in all subcortical structures and T2* in the globus pallidus, putamen, and caudate nucleus demonstrated a significant monotonic decrease from controls to patients with relapsing- remitting MS and from those with relapsing-remitting MS to patients with secondary-progressive MS. The macromolecular proton fraction in all subcortical structures significantly correlated with the Expanded Disability Status Scale and MS Functional Composite scores with absolute Pearson correlation coefficient (r) values in a range of 0.4-0.6. Significant correlations (r = -0.4 to -0.6) were also identified between the macromolecular proton fraction and the 9-Hole Peg Test, indicating a potential relationship with nigrostriatal pathway damage. Among T2* values, weak significant correlations with clinical variables were found only in the putamen. The macromolecular proton fraction did not correlate with T2* in any of the studied anatomic structures. CONCLUSIONS: The macromolecular proton fraction provides an iron-insensitive measure of demyelination. Myelin loss in subcortical GM structures in MS is unrelated to excess iron deposition. Subcortical GM demyelination is more closely associated with the disease phenotype and disability than iron overload. © 2018 by American Journal of Neuroradiology. DOI: 10.3174/ajnr.A5542 PMID: 29439122
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 33 – Multiple Sklerose: Veröffentlichungen Oktober 2013
15. AJNR Am J Neuroradiol. 2018 Feb 8. doi: 10.3174/ajnr.A5534. [Epub ahead of print] Improved Visualization of Cortical Lesions in Multiple Sclerosis Using 7T MP2RAGE. Beck ES(1), Sati P(1), Sethi V(1), Kober T(2)(3)(4), Dewey B(1), Bhargava P(5), Nair G(1), Cortese IC(6), Reich DS(7). Author information: (1)From the Translational Neuroradiology Section (E.S.B., P.S., V.S., B.D., G.N., D.S.R.). (2)Advanced Clinical Imaging Technology Group (T.K.), Siemens Healthcare Switzerland, Lausanne, Switzerland. (3)Department of Radiology (T.K.), Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. (4)LTS5, Ecole Polytechnique Fédérale de Lausanne (T.K.), Lausanne, Switzerland. (5)Department of Neurology (P.B.), Johns Hopkins University, Baltimore, Maryland. (6)Neuroimmunology Clinic (I.C.C.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. (7)From the Translational Neuroradiology Section (E.S.B., P.S., V.S., B.D., G.N., D.S.R.) [email protected]. BACKGROUND AND PURPOSE: Cortical lesions are common and often extensive in multiple sclerosis but are difficult to visualize by MRI, leaving important questions about their clinical implications and response to therapy unanswered. Our aim was to determine whether cortical lesions are better visualized using magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) than T2*-weighted imaging on 7T MR imaging. MATERIALS AND METHODS: Brain MR imaging using T1-weighted MP2RAGE at 500-μm isotropic resolution, T2*-weighted gradient-echo, and T2*- weighted segmented echo-planar imaging sequences were collected for 13 patients with MS and 5 age-matched neurologically healthy controls on a 7T research system. One MS case underwent postmortem MR imaging including gradient-echo and MP2RAGE sequences, after which cortical lesions seen on MR imaging were assessed with immunohistochemistry. RESULTS: MP2RAGE detected 203 cortical lesions (median, 16 lesions/case; interquartile range, 15), compared to 92 with T2*gradient-echo (median, 7; interquartile range, 8; P < .001) and 81 with T2*EPI (median, 7; interquartile range, 5; P < .001). This increase in lesion number detected on MP2RAGE versus T2* was observed for juxtacortical, leukocortical, and intracortical lesions. Forty-three percent of all cortical lesions were identified only on MP2RAGE. White matter lesion volume correlated with total juxtacortical (r = 0.86, P < .001) and leukocortical lesion volume (r = 0.70, P < .01) but not intracortical lesion volume, suggesting that pathophysiology may differ by lesion type. Of 4 suspected lesions seen on postmortem imaging, 3 were found to be true cortical lesions while 1 represented postmortem tissue damage. CONCLUSIONS: A combination of MP2RAGE and T2*-weighted imaging at 7T improved detection of cortical lesions and should enable longitudinal studies to elucidate their spatiotemporal dynamics and clinical implications. © 2018 by American Journal of Neuroradiology. DOI: 10.3174/ajnr.A5534 PMID: 29439120
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 34 – Multiple Sklerose: Veröffentlichungen Oktober 2013
16. AJNR Am J Neuroradiol. 2018 Feb 22. doi: 10.3174/ajnr.A5556. [Epub ahead of print] An Automated Statistical Technique for Counting Distinct Multiple Sclerosis Lesions. Dworkin JD(1), Linn KA(2), Oguz I(3), Fleishman GM(3), Bakshi R(4)(5)(6), Nair G(7), Calabresi PA(8), Henry RG(9), Oh J(10), Papinutto N(9), Pelletier D(11), Rooney W(12), Stern W(9), Sicotte NL(13), Reich DS(7)(8), Shinohara RT(2); North American Imaging in Multiple Sclerosis Cooperative. Author information: (1)From the Departments of Biostatistics, Epidemiology, and Informatics (J.D.D., K.A.L., R.T.S.) [email protected]. (2)From the Departments of Biostatistics, Epidemiology, and Informatics (J.D.D., K.A.L., R.T.S.). (3)Radiology (I.O., G.M.F.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. (4)Laboratory for Neuroimaging Research (R.B.), Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases. (5)Departments of Neurology (R.B.). (6)Radiology (R.B.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. (7)Translational Neuroradiology Section (G.N., D.S.R.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. (8)Department of Neurology (P.A.C., J.O., D.S.R.), the Johns Hopkins University School of Medicine, Baltimore, Maryland. (9)Department of Neurology (R.G.H., N.P., W.S.), University of California, San Francisco, San Francisco, California. (10)Keenan Research Centre for Biomedical Science (J.O.), St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. (11)Department of Neurology (D.P.), Keck School of Medicine, University of Southern California, Los Angeles, California. (12)Advanced Imaging Research Center (W.R.), Oregon Health & Science University, Portland, Oregon. (13)Department of Neurology (N.L.S.), Cedars-Sinai Medical Center, Los Angeles, California. BACKGROUND AND PURPOSE: Lesion load is a common biomarker in multiple sclerosis, yet it has historically shown modest association with clinical outcome. Lesion count, which encapsulates the natural history of lesion formation and is thought to provide complementary information, is difficult to assess in patients with confluent (ie, spatially overlapping) lesions. We introduce a statistical technique for cross-sectionally counting pathologically distinct lesions. MATERIALS AND METHODS: MR imaging was used to assess the probability of a lesion at each location. The texture of this map was quantified using a novel technique, and clusters resembling the center of a lesion were counted. Validity compared with a criterion standard count was demonstrated in 60 subjects observed longitudinally, and reliability was determined using 14 scans of a clinically stable subject acquired at 7 sites. RESULTS: The proposed count and the criterion standard count were highly correlated (r = 0.97, P < .001) and not significantly different (t59 = -.83, P = .41), and the variability of the proposed count across repeat scans was equivalent to that of lesion load. After accounting for lesion load and age, lesion count was negatively associated (t58 = -2.73, P < .01) with the Expanded Disability Status Scale. Average lesion size had a higher association with the Expanded Disability Status Scale (r = 0.35, P < .01) than lesion load (r = 0.10, P = .44) or lesion count (r = -.12, P = .36) alone. CONCLUSIONS: This study introduces a novel technique for counting pathologically distinct lesions using cross-sectional data and demonstrates its ability to recover obscured longitudinal information. The proposed count allows more accurate estimation of lesion size, which correlated more closely with disability scores than either lesion load or lesion count alone. © 2018 by American Journal of Neuroradiology. DOI: 10.3174/ajnr.A5556 PMID: 29472300
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 35 – Multiple Sklerose: Veröffentlichungen Oktober 2013
17. AJNR Am J Neuroradiol. 2018 Feb 22. doi: 10.3174/ajnr.A5563. [Epub ahead of print] Evaluation of the Sensitivity of Inhomogeneous Magnetization Transfer (ihMT) MRI for Multiple Sclerosis. Van Obberghen E(1), Mchinda S(1), le Troter A(1), Prevost VH(1), Viout P(1), Guye M(1), Varma G(2), Alsop DC(2), Ranjeva JP(1), Pelletier J(1)(3), Girard O(1), Duhamel G(4). Author information: (1)From Aix-Marseille Université (E.V.O., S.M., A.l.T., V.H.P., P.V., M.G., J.-P.R., J.P., O.G., G.D.), Centre de Résonance Magnétique Biologique et Médicale (CRMBM), UMR 7339 Centre National de Recherche Scientifique (CNRS), Marseille, France. (2)Department of Radiology (G.V., D.C.A.), Division of MR Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. (3)Aix-Marseille University (J.P.), Assistance Publique des Hôpitaux de Marseille (APHM), Hôpital de La Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, Marseille, France. (4)From Aix-Marseille Université (E.V.O., S.M., A.l.T., V.H.P., P.V., M.G., J.-P.R., J.P., O.G., G.D.), Centre de Résonance Magnétique Biologique et Médicale (CRMBM), UMR 7339 Centre National de Recherche Scientifique (CNRS), Marseille, France guillaume.duhamel@univ- amu.fr. BACKGROUND AND PURPOSE: Inhomogeneous magnetization transfer is a new endogenous MR imaging contrast mechanism that has demonstrated high specificity for myelin. Here, we tested the hypothesis that inhomogeneous magnetization transfer is sensitive to pathology in a population of patients with relapsing-remitting MS in a way that both differs from and complements conventional magnetization transfer. MATERIALS AND METHODS: Twenty-five patients with relapsing-remitting MS and 20 healthy volunteers were enrolled in a prospective MR imaging research study, whose protocol included anatomic imaging, standard magnetization transfer, and inhomogeneous magnetization transfer imaging. Magnetization transfer and inhomogeneous magnetization transfer ratios measured in normal-appearing brain tissue and in MS lesions of patients were compared with values measured in control subjects. The potential association of inhomogeneous magnetization transfer ratio variations with the clinical scores (Expanded Disability Status Scale) of patients was further evaluated. RESULTS: The magnetization transfer ratio and inhomogeneous magnetization transfer ratio measured in the thalami and frontal, occipital, and temporal WM of patients with MS were lower compared with those of controls (P < .05). The mean inhomogeneous magnetization transfer ratio measured in lesions was lower than that in normal-appearing WM (P < .05). Significant (P < .05) negative correlations were found between the clinical scores and inhomogeneous magnetization transfer ratio measured in normal-appearing WM structures. Weaker nonsignificant correlation trends were found for the magnetization transfer ratio. CONCLUSIONS: The sensitivity of the inhomogeneous magnetization transfer technique for MS was highlighted by the reduction in the inhomogeneous magnetization transfer ratio in MS lesions and in normal-appearing WM of patients compared with controls. Stronger correlations with the Expanded Disability Status Scale score were obtained with the inhomogeneous magnetization transfer ratio compared with the standard magnetization transfer ratio, which may be explained by the higher specificity of inhomogeneous magnetization transfer for myelin. © 2018 by American Journal of Neuroradiology. DOI: 10.3174/ajnr.A5563 PMID: 29472299
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 36 – Multiple Sklerose: Veröffentlichungen Oktober 2013
18. Am J Transl Res. 2018 Jan 15;10(1):212-223. eCollection 2018. Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis. Meng M(1)(2), Liu Y(2), Wang W(2), Wei C(2), Liu F(2), Du Z(2), Xie Y(2), Tang W(2), Hou Z(2), Li Q(1). Author information: (1)Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeKunming 650118, China. (2)Yan'an Affiliated Hospital of Kunming Medical University, Yunnan Cell Biology and Clinical Translation Research Center, Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan ProvinceKunming 650051, Yunnan, People's Republic of China. To investigate the clinical efficacy and safety of umbilical cord mesenchymal stem cell (UCMSC) transplantation for treating multiple sclerosis (MS), the patients with MS were recruited and treated with UCMSC. The procedure of preparing UCMSC was in accordance with the standards formulated by the International Society for Cell Biology. Cell surface markers, multiple differentiation potential and safety of UCMSC for transplantation were detected. The number of cells in each infusion was 1 to 2×106 cells/kg. Patients were recruited in accordance with the standards of the International Mesenchymal Stem Cells Transplantation Study Group. After treatment, the clinical therapeutic effects including symptoms, vital signs, clinical attacks, magnetic resonance imaging (MRI), neurological function scores and adverse reactions such as fever, dizziness, and vascular irritation were monitored and evaluated. In addition, the regulatory effects of UCMSC on immune system of patients were also assessed. The results showed that the patients' symptoms were improved after UCMSC transplantation. No clinical attacks occurred during transplantation. MRI revealed a reduced number of foci and Expanded Disability Status Scale scores were decreased. Some of patients had adverse reactions after transplantation. These adverse effects were not serious and lasted short duration, thus no intervention was conducted and let it be eliminated by itself. The mRNA expression of CD86, IL-2, CTLA-4, and HLADRB1 in peripheral blood was significantly decreased after UCMSC transplantation (P < 0.05). Based on our present studies, UCMSCs would be considered as a safe and alternative option for treatment of MS. PMCID: PMC5801359 PMID: 29423006
Conflict of interest statement: None.
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 37 – Multiple Sklerose: Veröffentlichungen Oktober 2013
19. Ann Clin Transl Neurol. 2017 Dec 21;5(2):172-185. doi: 10.1002/acn3.516. eCollection 2018 Feb. Retrograde interferon-gamma signaling induces major histocompatibility class I expression in human- induced pluripotent stem cell-derived neurons. Clarkson BDS(1), Patel MS(1), LaFrance-Corey RG(1), Howe CL(1)(2)(3)(4). Author information: (1)Department of NeurologyMayo ClinicRochesterMinnesota. (2)Department of NeuroscienceMayo ClinicRochesterMinnesota. (3)Department of ImmunologyMayo ClinicRochesterMinnesota. (4)Center for Multiple Sclerosis and Autoimmune NeurologyMayo ClinicRochesterMinnesota. Objective: Injury-associated axon-intrinsic signals are thought to underlie pathogenesis and progression in many neuroinflammatory and neurodegenerative diseases, including multiple sclerosis (MS). Retrograde interferon gamma (IFN γ) signals are known to induce expression of major histocompatibility class I (MHC I) genes in murine axons, thereby increasing the susceptibility of these axons to attack by antigen-specific CD8+ T cells. We sought to determine whether the same is true in human neurons. Methods: A novel microisolation chamber design was used to physically isolate and manipulate axons from human skin fibroblast-derived induced pluripotent stem cell (iPSC)-derived neuron-enriched neural aggregates. Fluorescent retrobeads were used to assess the fraction of neurons with projections to the distal chamber. Axons were treated with IFN γ for 72 h and expression of MHC class I and antigen presentation genes were evaluated by RT-PCR and immunofluorescence. Results: Human iPSC-derived neural stem cells maintained as 3D aggregate cultures in the cell body chamber of polymer microisolation chambers extended dense axonal projections into the fluidically isolated distal chamber. Treatment of these axons with IFN γ resulted in upregulation of MHC class I and antigen processing genes in the neuron cell bodies. IFN γ-induced MHC class I molecules were also anterogradely transported into the distal axon. Interpretation: These results provide conclusive evidence that human axons are competent to express MHC class I molecules, suggesting that inflammatory factors enriched in demyelinated lesions may render axons vulnerable to attack by autoreactive CD8+ T cells in patients with MS. Future work will be aimed at identifying pathogenic anti- axonal T cells in these patients. DOI: 10.1002/acn3.516 PMCID: PMC5817842 PMID: 29468178
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 38 – Multiple Sklerose: Veröffentlichungen Oktober 2013
20. Ann Phys Rehabil Med. 2018 Feb 17. pii: S1877-0657(18)30012-5. doi: 10.1016/j.rehab.2018.01.006. [Epub ahead of print] Cognitive assessment in patients with multiple sclerosis: from neuropsychological batteries to ecological tools. Ruet A(1), Brochet B(2). Author information: (1)Université de Bordeaux, F-33076 Bordeaux, France; Inserm U1215- Neurocentre Magendie, F-33000 Bordeaux, France. Electronic address: [email protected]. (2)CHU de Bordeaux, F-33076 Bordeaux, France; Inserm U1215- Neurocentre Magendie, F-33000 Bordeaux, France. BACKGROUND: Cognitive impairment (CI) is frequent in patients with multiple sclerosis (PwMS) and could negatively affect family social and vocational activities. Detecting CI is clinically relevant, so the emerging question is the strategy for assessing cognition in MS. OBJECTIVE: An update on cognitive assessment in PwMS with use of standard neuropsychological (NP) tests and ecological tools. RESULTS: The minimal cognitive assessment in MS should include at least NP tests assessing information processing speed (IPS) and verbal and visuospatial episodic memory. The IPS could be easily and quickly evaluated with symbol digit substitution tests by using paper for the oral version of the Symbol Digit Modalities Test or a laptop for the Computerised Speed Cognitive Test. The comprehensive NP battery must be performed by a qualified neuropsychologist to adequately characterize the extent and severity of CI in PwMS. The quiet and controlled environment used for this standardized assessment could be a limitation for generalizing the results because it does not reflect real daily life conditions. Thus, this context could decrease the ability to detect some cognitive deficits that could occur only in more complex situations. Thus, ecological evaluation seems a complementary and promising approach for detecting cognitive abnormalities in daily activities. CONCLUSION: Recent efforts have been made to detect and characterize cognitive deficits in PwMS. Some IPS and episodic memory NP tests have been validated in MS and should be proposed to patients in the clinical setting. Besides NP tests, ecological tools are becoming important for detecting cognitive dysfunction in everyday-like conditions. Further research is needed to validate relevant tools for monitoring cognition in MS and the ability to detect clinically meaningful change in longitudinal studies. Copyright © 2018. Published by Elsevier Masson SAS. DOI: 10.1016/j.rehab.2018.01.006 PMID: 29462665
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 39 – Multiple Sklerose: Veröffentlichungen Oktober 2013
21. Apoptosis. 2018 Feb;23(2):170-186. doi: 10.1007/s10495-018-1448-9. Dynamic changes and molecular analysis of cell death in the spinal cord of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus. Gerhauser I(1), Li L(1), Li D(1), Klein S(1), Elmarabet SA(1), Deschl U(2), Kalkuhl A(2), Baumgärtner W(1)(3), Ulrich R(1)(3)(4), Beineke A(5)(6). Author information: (1)Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany. (2)Department of Non-Clinical Drug Safety, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach (Riss), Germany. (3)Center for Systems Neuroscience Hannover, Bünteweg 17, 30559, Hannover, Germany. (4)Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Greifswald, Insel Riems, Germany. (5)Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany. [email protected]. (6)Center for Systems Neuroscience Hannover, Bünteweg 17, 30559, Hannover, Germany. [email protected]. Theiler's murine encephalomyelitis (TME) is caused by the TME virus (TMEV) and represents an important animal model for multiple sclerosis (MS). Oligodendroglial apoptosis and reduced apoptotic elimination of encephalitogenic leukocytes seem to participate in autoimmune demyelination in MS. The present study quantified apoptotic cells in BeAn-TMEV-induced spinal cord white matter lesions at 14, 42, 98, and 196 days post infection (dpi) using immunostaining. Apoptotic cells were identified by transmission electron microscopy and double-immunofluorescence. The mRNA expression of apoptosis-related genes was investigated using microarray analysis. Oligodendroglial apoptosis was already detected in the predemyelinating phase at 14 dpi. Apoptotic cell numbers peaked at 42 dpi and decreased until 196 dpi partly due to reduced T cell apoptosis. In addition to genes involved in the classical pathways of apoptosis induction, microarray analysis detected the expression of genes related to alternative mechanisms of cell death such as pyroptosis, necroptosis, and endoplasmic reticulum stress. Consequently, oligodendroglial apoptosis is involved in the initiation of the TME demyelination process, whereas the development of apoptosis resistance of T cells potentially favors the maintenance of inflammation and myelin loss. DOI: 10.1007/s10495-018-1448-9 PMID: 29435686
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 40 – Multiple Sklerose: Veröffentlichungen Oktober 2013
22. Arch Clin Neuropsychol. 2018 Feb 17. doi: 10.1093/arclin/acy014. [Epub ahead of print] Predictive Models of Cognitive Fatigue in Multiple Sclerosis. Berard JA(1)(2), Smith AM(1)(2)(3), Walker LAS(1)(2)(3)(4). Author information: (1)University of Ottawa, School of Psychology, Ottawa, Canada. (2)The Ottawa Hospital Research Institute, Ottawa, Canada. (3)University of Ottawa Brain and Mind Research Institute, Ottawa, Canada. (4)Carleton University, School of Psychology and Institute of Cognitive Science, Ottawa, Canada. Objective: Cognitive fatigue (CF) can be defined as decreased performance with sustained cognitive effort. The present study examined the interrelatedness of disease severity, fatigue, depression, and sleep quality in order to evaluate their predictive roles of CF in MS. Four theoretical models examining these variables were assessed. Methods: Fifty-eight individuals with a diagnosis of MS were recruited. CF was measured by examining last third versus first third performance on the Paced Auditory Serial Addition Test (PASAT). The PASAT and self-report measures of fatigue, depression, and sleep quality were administered. Path analysis was used to evaluate each of the models. Results: CF was correlated only with depression (r = .362, p = .006) and sleep quality (r = .433, p = .001). Sleep quality was the greatest significant independent predictor of CF (β = .433, t(1,55) = 3.53, p < .001), accounting for 17.3% of the total variance. The best fitting model showed sleep quality as the largest contributor to CF; however, depression played a smaller predictive role. Furthermore, depression emerged as the strongest predictor of sleep quality and fatigue. Disease severity weakly predicted depression. Conclusions: Sleep quality is the most significant predictor of CF in MS. As such, sleep quality may be a treatable cause of CF. Sleep quality itself, however, accounted for only 17.3% of the variance in CF suggesting that other variables which were not formally assessed in this sample (e.g., anxiety, etc.) may also play a predictive role. Follow-up studies should evaluate how results may differ with a larger sample size. DOI: 10.1093/arclin/acy014 PMID: 29471423
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 41 – Multiple Sklerose: Veröffentlichungen Oktober 2013
23. Arch Phys Med Rehabil. 2018 Jan 30. pii: S0003-9993(18)30046-7. doi: 10.1016/j.apmr.2017.12.028. [Epub ahead of print] Predictors for employment status in people with multiple sclerosis: a 10-year longitudinal observational study. Forslin M(1), Fink K(2), Hammar U(3), von Koch L(4), Johansson S(5). Author information: (1)Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Stockholm, Sweden; Rehab Station Stockholm, Solna, Sweden; Karolinska University Hospital, Function Area Occupational Therapy and Physiotherapy, Stockholm, Sweden. (2)Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden; Karolinska University Hospital, Department of Neurology, Stockholm, Sweden. (3)Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden. (4)Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Stockholm, Sweden; Karolinska University Hospital, Department of Neurology, Stockholm, Sweden. (5)Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Stockholm, Sweden; Karolinska University Hospital, Function Area Occupational Therapy and Physiotherapy, Stockholm, Sweden. Electronic address: [email protected]. OBJECTIVE: To identify predictors for employment status after 10 years in a cohort of people with multiple sclerosis (MS), with the aim to increase knowledge concerning factors present at an early stage important for working life and work-life balance. DESIGN: A 10-year longitudinal observational cohort study. SETTING: People with a definite MS diagnosis, who at inclusion were outpatients at an MS Centre at a university hospital in Stockholm, Sweden. PARTICIPANTS: A consecutive sample of 154 people with MS of working age were included at baseline of which a total of 116 people participated in the 10-year follow-up - 27 people declined participation and 11 were deceased. METHODS: Baseline data on personal factors and functioning were used as independent variables. Employment status 10 years after baseline, categorized as full-time work, part-time work and no work, was used as the dependent variable. A generalized ordinal logistic regression was used to analyse the predictive value of the independent variables. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Employment status. RESULTS: Predictors for full- or part-time work after 10 years were young age (p=0.002), low perceived physical impact of MS (p=0.02), fatigue (p=0.03), full-time work (p=0.001) and high frequency of social/lifestyle activities (p=0.001) at baseline. Low perceived physical impact of MS (p=0.02) at baseline also predicted full-time work after 10 years. CONCLUSIONS: This study underlines the complexity of working life for people with MS, and indicates that it may be valuable to give more attention to the balance between working and private life, both in clinical practice and future research, in order to achieve a sustainable working life over time. Copyright © 2018. Published by Elsevier Inc. DOI: 10.1016/j.apmr.2017.12.028 PMID: 29407519
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 42 – Multiple Sklerose: Veröffentlichungen Oktober 2013
24. Arch Phys Med Rehabil. 2018 Feb 8. pii: S0003-9993(18)30088-1. doi: 10.1016/j.apmr.2017.12.037. [Epub ahead of print] Self-regulatory strategies as correlates of physical activity behavior in persons with multiple sclerosis. Cederberg KL(1), Balto JM(2), Motl RW(3). Author information: (1)Departments of Physical and Occupational Therapy; University of Alabama at Birmingham, 1720 2(nd) Avenue South, Birmingham, Alabama USA. Electronic address: [email protected]. (2)Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, 906 S Goodwin Ave, Urbana, Illinois USA. (3)Department of Physical Therapy; University of Alabama at Birmingham, 1720 2nd, Avenue South, Birmingham, Alabama USA. Electronic address: [email protected]. OBJECTIVE: To examine self-regulation strategies as correlates of physical activity in persons with multiple sclerosis (MS). DESIGN: Cross-sectional, or survey, study. SETTING: University-based research laboratory. PARTICIPANTS: Convenience sample of 68 persons with MS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Exercise Self-Efficacy Scale (EXSE), Physical Activity Self-Regulation Scale (PASR-12), and Godin Leisure-Time Exercise Questionnaire (GLTEQ). RESULTS: Correlation analyses indicated that GLTEQ scores were positively and significantly associated with overall self-regulation (r=0.43), self-monitoring (r=0.45), goal-setting (r=0.27), reinforcement (r=0.30), time management (r=0.41), and relapse prevention (r=0.53) PASR-12 scores. Regression analyses indicated that relapse prevention (B=5.01; SE B=1.74; β=0.51) and self- monitoring (B=3.65; SE B=1.71; β=0.33) were unique predictors of physical activity behavior, and relapse prevention demonstrated a significant association with physical activity behavior that was accounted for by EXSE. CONCLUSIONS: Our results indicate that self-regulatory strategies, particularly relapse prevention, may be important correlates of physical activity behavior that can inform the design of future behavioral interventions in MS. Copyright © 2018. Published by Elsevier Inc. DOI: 10.1016/j.apmr.2017.12.037 PMID: 29428345
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25. Arthritis Care Res (Hoboken). 2018 Feb 6. doi: 10.1002/acr.23532. [Epub ahead of print] Validation of the Brief Fear of Negative Evaluation Scale-II in patients with systemic sclerosis: A Scleroderma Patient-centered Intervention Network Cohort study. Fox RS(1)(2), Kwakkenbos L(3)(4)(5), Carrier ME(3), Mills SD(2), Gholizadeh S(2), Jewett LR(3)(6), Roesch SC(2)(7), Merz EL(8), Assassi S(9), Furst DE(10), Gottesman K(11), Mayes MD(9), Thombs BD(3)(4)(12)(13)(14), Malcarne VL(2)(7); SPIN Investigators. Collaborators: Baron M, Bartlet SJ, van den Hooge F, Moutho L, Nielso WR, Riggs R, Sauve M, Wigley F, Boutron I, Maia AC, El-Baalbaki G, Ells C, van den Ende C, Fligelstone K, Fortune C, Frech T, Godard D, Harel D, Hudson M, Impens A, Jang Y, Johnson SR, Kennedy AT, Körner A, Larche M, Leite C, Marra C, Nielsen K, Pope J, Portales A, Reyna TSR, Schouffoer AA, Steele RJ, Suarez- Almazor ME, Welling J, Wong-Rieger D, Agard C, Albert A, André M, Arsenault G, Benmostefa N, Benzida I, Berthier S, Bissonnette L, Boire G, Bruns A, Carreira P, Casadevall M, Chaigne B, Chung L, Cohen P, Dagenais P, Denton C, Domsic R, Dunne JV, Fare R, Farge-Bancel D, Fortin PR, Gill A, Gordon J, Granel-Rey B, Grange C, Gyger G, Hachulla E, Hatron PY, Herrick AL, Hij A, Hinchcliff M, Ikic A, Jones N, de Fernandes AJB, Kafaja S, Khalidi N, Korman B, Launay D, Liang P, London J, Luna D, Manning J, Martin M, Martin T, Masetto A, Maurier F, Mekinian A, Melchor S, Paule R, Régent A, Rivière S, Robinson D, Rodriguez E, Roux S, Smets P, Smith D, Sobanski V, Spiera R, Steen V, Sutton E, Terrier B, Thorne C, Varga J, Wilcox P, Cumin J, Levis B, Pepin MR, Turner K. Author information: (1)Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States. (2)San Diego State University/University of California, San Diego Joint Doctoral Program in Clinical Psychology, San Diego, California, United States. (3)Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada. (4)Department of Psychiatry, McGill University, Montreal, Quebec, Canada. (5)Behavioural Science Institute, Clinical Psychology, Radboud University, Nijmegen, The Netherlands. (6)Department of Educational and Counselling Psychology, McGill University, Montreal, Quebec, Canada. (7)Department of Psychology, San Diego State University, San Diego, California, United States. (8)Department of Psychology, California State University Dominguez Hills, Carson, California, United States. (9)Department of Internal Medicine, Division of Rheumatology, University of Texas McGovern Medical School, Houston, Texas, United States. (10)Division of Rheumatology, Geffen School of Medicine, at the University of California, Los Angeles, California, United States. (11)Scleroderma Foundation, United States. (12)Departments of Medicine, Biostatistics and Occupational Health, McGill University, Montreal, Canada, Quebec. (13)Departments of Psychology, Biostatistics and Occupational Health, McGill University, Montreal, Canada, Quebec. (14)Departments of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada. OBJECTIVE: Fear of negative evaluation is a common concern among individuals with visible differences but has received limited attention in systemic sclerosis (SSc), which can involve substantial changes to appearance. The Brief Fear of Negative Evaluation Scale (BFNE) was specifically designed to evaluate fear of negative evaluation. There are currently three versions of the BFNE with strong demonstrated measurement properties: two eight-item versions (BFNE-S, BFNE-8) and one 12-item version (BFNE-II). The present study evaluated these versions in SSc, and identified the most appropriate version for use among SSc patients. METHODS: Participants were 1010 patients with SSc enrolled in the Scleroderma Patient-centered Intervention Network (SPIN) Cohort. Multiple group confirmatory factor analysis, Cronbach's alpha, and Pearson product-moment correlations were used to evaluate structural validity, internal consistency reliability, and convergent and divergent validity, respectively. RESULTS: Confirmatory factor analysis demonstrated that one-factor models fit acceptably well for the 12-item BFNE-II, the eight-item BFNE-S, and the eight-item BFNE-8. All Cronbach's alphas were excellent (BFNE-II: 0.98; BFNE-S: 0.97; BFNE-8: 0.96), and all versions had comparable associations with measures of social anxiety, body-related attitudes, depression, age, and education. CONCLUSION: Psychometric support was found for all three versions of the BFNE, though the longer 12-item BFNE-II did not improve measurement compared to the shorter eight-item versions. Of these two, the BFNE-S has been more widely studied with strong validity data in a greater number of populations. Therefore, the BFNE-S is recommended to assess fear of negative evaluation among patients with SSc. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1002/acr.23532 PMID: 29409146
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 44 – Multiple Sklerose: Veröffentlichungen Oktober 2013
26. Behav Neurol. 2017;2017:5919841. doi: 10.1155/2017/5919841. Epub 2017 Dec 31. Efficacy of a Computer-Assisted Cognitive Rehabilitation Intervention in Relapsing-Remitting Multiple Sclerosis Patients: A Multicenter Randomized Controlled Trial. Messinis L(1)(2), Nasios G(3), Kosmidis MH(4), Zampakis P(5), Malefaki S(6), Ntoskou K(7), Nousia A(3), Bakirtzis C(8), Grigoriadis N(8), Gourzis P(2), Papathanasopoulos P(9). Author information: (1)Neuropsychology Section, Department of Neurology, University of Patras Medical School, 26504 Patras, Greece. (2)Department of Psychiatry, University Hospital of Patras and University of Patras Medical School, 26504 Patras, Greece. (3)Department of Speech and Language Therapy, Higher Educational Institute of Epirus, Ioannina, Ioannina, Greece. (4)Lab of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, Thessaloniki, Greece. (5)Department of Radiology, University of Patras Medical School, 26504 Patras, Greece. (6)Department of Mechanical Engineering & Aeronautics, University of Patras, 26504 Patras, Greece. (7)Rehabilitation Unit for Patients with Spinal Cord Injury, "Demetrios and Vera Sfikas", Department of Medicine, University of Patras, 26504 Patras, Greece. (8)B'Department of Neurology and the MS Center, AHEPA University Hospital of Thessaloniki, Thessaloniki, Greece. (9)University of Patras Medical School, 26504 Patras, Greece. Cognitive impairment is frequently encountered in multiple sclerosis (MS) affecting between 40-65% of individuals, irrespective of disease duration and severity of physical disability. In the present multicenter randomized controlled trial, fifty-eight clinically stable RRMS patients with mild to moderate cognitive impairment and relatively low disability status were randomized to receive either computer- assisted (RehaCom) functional cognitive training with an emphasis on episodic memory, information processing speed/attention, and executive functions for 10 weeks (IG; n = 32) or standard clinical care (CG; n = 26). Outcome measures included a flexible comprehensive neuropsychological battery of tests sensitive to MS patient deficits and feedback regarding personal benefit gained from the intervention on four verbal questions. Only the IG group showed significant improvements in verbal and visuospatial episodic memory, processing speed/attention, and executive functioning from pre - to postassessment. Moreover, the improvement obtained on attention was retained over 6 months providing evidence on the long-term benefits of this intervention. Group by time interactions revealed significant improvements in composite cognitive domain scores in the IG relative to the demographically and clinically matched CG for verbal episodic memory, processing speed, verbal fluency, and attention. Treated patients rated the intervention positively and were more confident about their cognitive abilities following treatment. DOI: 10.1155/2017/5919841 PMCID: PMC5804109 PMID: 29463950
27. Behav Neurol. 2017;2017:1463570. doi: 10.1155/2017/1463570. Epub 2017 Dec 25. Pediatric Multiple Sclerosis and Cognition: A Review of Clinical, Neuropsychologic, and Neuroradiologic Features. Ekmekci O(1). Author information: (1)Department of Neurology, Faculty of Medicine, Ege University, Izmir, Turkey. Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease. Although cognitive impairment has been well established in adult patients with MS, its occurrence in patients with pediatric-onset MS has recently been reported. In this review, I discuss the main features of cognitive impairment in pediatric MS as determined by long-term follow-up studies, neuropsychiatric test batteries, and the results of neuroradiological imaging studies that investigated the pathogenesis of pediatric MS. The most commonly affected cognitive domains in adults are attention, processing speed, and visuomotor skills; language and intelligence are also affected in pediatric MS. A young age at disease onset is the strongest risk factor for these impairments, which may be due to the effect of inflammatory demyelination and neurodegeneration on the developing central nervous system and neural networks in children. Cognitive impairment has long-term effects on patients' academic life and the quality of their social life. Therefore, all patients with pediatric MS should be screened and monitored for cognitive impairment. This review also highlights the need for neuropsychological test batteries that assess different cognitive domains in children and adolescents with multiple sclerosis and for cognitive rehabilitation programs to improve the quality of their academic and social life. DOI: 10.1155/2017/1463570 PMCID: PMC5757108 PMID: 29434433
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28. Behav Neurol. 2017;2017:5713934. doi: 10.1155/2017/5713934. Epub 2017 Dec 13. Face-to-Face or Telematic Cognitive Stimulation in Patients with Multiple Sclerosis and Cognitive Impairment: Why Not Both? Guijarro-Castro C(1), Aladro-Benito Y(2), Sánchez-Musulim A(3), Belen-Caminero A(4), Pérez Molina I(5), Gómez-Moreno I(1), Gómez-Romero L(1), Millán-Pascual J(6), Laredo MJ(2), Cerezo-García M(2). Author information: (1)Sección de Neurología, Hospital Virgen de la Luz, Cuenca, Spain. (2)Sección de Neurología, Hospital Universitario de Getafe de Madrid, Madrid, Spain. (3)Hospital Santa Bárbara de Puertollano, Ciudad Real, Spain. (4)Sección de Neurología, Hospital Ntra. Sra. de Sonsoles de Ávila, Ávila, Spain. (5)Hospital Universitario Virgen de la Salud de Toledo, Toledo, Spain. (6)Sección de Neurología, Hospital La Mancha Centro de Alcazar de San Juan, Ciudad Real, Spain. Introduction: Cognitive impairment (CI) affects 40-65% of patients with multiple sclerosis (MS). Few studies address telematic cognitive stimulation (TCS) in MS. The objective of this study is to evaluate the efficacy and impact of telestimulation or distance cognitive stimulation (TCS), with and without the support of face-to-face cognitive stimulation (FCS) in cognitive impairment in MS. Methods: Multicentre, prospective, randomised, controlled study. We will include 98 MS patients with EDSS ≤ 6, symbol digit modality test (SDMT) ≤ Pc 25, and Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) > 26 points. Patients will be randomised into 3 groups, a TCS group, a mixed TCS/FCS group, and a control group. CS is performed 3 days a week for 3 months. Processing speed, memory, attention, and executive functions will be rehabilitated. FCS will include ecological exercises and strategies. EDSS and a cognitive evaluation (SDMT, CTMT, PASAT, and TAVEC), MSNQ, psychological impact scales (MSIS), and depression (BDI) will be carried out, baseline, postrehabilitation, and also 6 and 12 months later, to evaluate the effect of CS in the longer term. Conclusion: This study could help to establish the usefulness of TCS or, in its absence, TCS with face- to-face help for CI in MS. The interest lies in the clear benefits of remote rehabilitation in the daily life of patients. DOI: 10.1155/2017/5713934 PMCID: PMC5745745 PMID: 29386749
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 46 – Multiple Sklerose: Veröffentlichungen Oktober 2013
29. Biochem Biophys Res Commun. 2018 Feb 3. pii: S0006-291X(18)30247-X. doi: 10.1016/j.bbrc.2018.02.024. [Epub ahead of print] Butylphthalide ameliorates experimental autoimmune encephalomyelitis by suppressing PGAM5- induced necroptosis and inflammation in microglia. Wang Y(1), Bi Y(2), Xia Z(1), Shi W(1), Li B(3), Li B(1), Chen L(1), Guo L(4). Author information: (1)Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, China. (2)Laboratory of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, China. (3)Department of Neurology, The Bethune International Peace Hospital, Shijiazhuang 050000, Hebei, China. (4)Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, China. Electronic address: [email protected]. Multiple sclerosis (MS) is a long-lasting autoimmune disease of the central nervous system. Currently, the etiology of MS is not known. Experimental autoimmune encephalomyelitis (EAE), has been recognized as the most widely used animal models to study the molecular mechanisms underlying MS and the efficacy of potential drugs for treatment of MS. In the present study, we found that Dl-3-n- butylphthalide (NBP), a neuroprotective drug in ischemic brain injury, prevented development of disease in experimental autoimmune encephalomyelitis (EAE) and significantly reduced inflammatory factors and necroptosis-associated genes, including PGAM5 in the spinal cord tissues. Similarly, silence of PGAM5 in spinal cord also ameliorated the disease severity in the mice with EAE. Moreover, re-expression of PGAM5 counteracted the protective effect of NBP on the pathogenesis of EAE. Importantly, we found that both NBP and silence of PGAM5 inhibited cellular necroptosis and inflammation in microglia induced by TNFα plus zVAD-fmk. Meanwhile, overexpression of PGAM5 reactivated cellular necroptosis and inflammation suppressed by NBP in vitro. Taken together, our findings provide evidence that NBP can attenuate the progression of EAE by suppressing PGAM5- induced necroptosis and inflammation in microglia and represents a new therapeutic strategy for treating autoimmune diseases. Copyright © 2018. Published by Elsevier Inc. DOI: 10.1016/j.bbrc.2018.02.024 PMID: 29407174
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30. Biochem Pharmacol. 2018 Jan 30. pii: S0006-2952(18)30049-2. doi: 10.1016/j.bcp.2018.01.043. [Epub ahead of print] Regulatory-Accepted Drug Development Tools Are Needed to Accelerate Innovative CNS Disease Treatments. Arnerić SP(1), Kern VD(2), Stephenson DT(3). Author information: (1)Critical Path for Alzheimer's Disease, Crititcal Path Institute, United States. Electronic address: [email protected]. (2)Critical Path for Alzheimer's Disease, Crititcal Path Institute, United States. (3)Critical Path for Parkinson's, Crititcal Path Institute, United States. Central Nervous System (CNS) diseases represent one of the most challenging therapeutic areas for successful drug approvals. Developing quantitative biomarkers as Drug Development Tools (DDTs) can catalyze the path to innovative treatments, and improve the chances of drug approvals. Drug development and healthcare management requires sensitive, reliable, validated, and regulatory accepted biomarkers and endpoints. This review highlights the regulatory paths and considerations for developing DDTs required to advance biomarker and endpoint use in clinical development (e.g., consensus CDISC [Clinical Data Interchange Standards Consortium] data standards, precompetitive sharing of anonymized patient-level data, and continual alignment with regulators). Summarized is the current landscape of biomarkers in a range of CNS diseases including Alzheimer disease, Parkinson Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorders, Depression, Huntington's disease, Multiple Sclerosis and Traumatic Brain Injury. Advancing DDTs for these devastating diseases that are both validated and qualified will require an integrated, cross-consortium approach to accelerate the delivery of innovative CNS therapeutics. Copyright © 2018. Published by Elsevier Inc. DOI: 10.1016/j.bcp.2018.01.043 PMID: 29410157
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31. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2018 Feb 21. doi: 10.5507/bp.2018.003. [Epub ahead of print] Chemiluminescent detection of oligoclonal immunoglobulins after isoelectric focusing and affinity- mediated immunoblotting. Dlouhy O(1), Kusnierova P(2)(3), Kurasova I(1), Cisarikova M(2), Zeman D(2)(3). Author information: (1)Department of Physics, Faculty of Natural Sciences, University of Ostrava, Ostrava, Czech Republic. (2)Department of Biomedical Sciences, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic. (3)Institute of Laboratory Diagnostics, University Hospital Ostrava, Ostrava, Czech Republic. BACKGROUND AND AIMS: Detection of oligoclonal IgG (o-IgG) in the cerebrospinal fluid (CSF) not found in serum is the principal laboratory test to support a diagnosis of multiple sclerosis. The aim of this study was to compare chemiluminescent and chromogenic detection of oligoclonal immunoglobulins in the cerebrospinal fluid and serum after their separation by means of isoelectric focusing followed by immunoblotting. METHODS: A set of experiments was designed to detect oligoclonal immunoglobulins by means of alkaline phosphatase BCIP/NBT substrate and chemiluminescent peroxidase substrate. RESULTS: Based on visual evaluation of signals, chemiluminescent detection requires about a 4 times lower amount of applied protein than very sensitive BCIP/NBT chromogenic detection. Very good correlation between methods has been shown for oligoclonal IgG. Antigen-specific oligoclonal IgG could be demonstrated by both methods although the pattern was clearer using chemiluminescence. In one patient, oligoclonal IgD bands barely visible by BCIP/NBT were convincingly demonstrated by chemiluminescence. CONCLUSION: Chemiluminescent detection is a feasible option for oligoclonal immunoglobulin detection and could be used in cases when the sensitivity needs to be improved. Further studies and method optimisation are warranted. DOI: 10.5507/bp.2018.003 PMID: 29467546
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32. Biomed Pharmacother. 2018 Feb 13;100:316-323. doi: 10.1016/j.biopha.2018.02.030. [Epub ahead of print] MicroRNA signature of regulatory T cells in health and autoimmunity. Soltanzadeh-Yamchi M(1), Shahbazi M(1), Aslani S(2), Mohammadnia-Afrouzi M(3). Author information: (1)Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran. (2)Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran. (3)Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran. Electronic address: [email protected]. MicroRNAs (miRNAs) are small RNA molecules with regulatory functions on the expression of genes through binding directly to target messenger RNA (mRNA) transcripts, eventuating in gene expression suppression via translational hindrance and/or target mRNA cleavage. These molecules have been established to participate in numerous critical cellular settings, including differentiation, development, and function of immune cells. As an important suppressor cell of immune system, regulatory T cells (Tregs) are important in modulating the immune homeostasis as well as tolerance to self-antigens. Despite identification of numerous transcription factors, cytokines, and other mediators regulate the biology of Tregs, investigations have demonstrated that noncoding RNAs are involved in several mechanisms of the regulation of Treg cells. On the other side, dysregulation of expression of several miRNAs has been reported in Tregs, implicating to the impaired function of these regulatory cells, resulting in autoimmune and other immune-based disorders. In this review, we aim to go through the overall microRNA network and specific miRNAs that are involved in the development, differentiation, and function of Tregs. Moreover, an overview was provided with respect to the role of aberrant expression of miRNAs in Tregs of autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, diabetes, and psoriasis. Copyright © 2018 Elsevier Masson SAS. All rights reserved. DOI: 10.1016/j.biopha.2018.02.030 PMID: 29453041
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33. Biomed Rep. 2018 Jan;8(1):41-46. doi: 10.3892/br.2017.1023. Epub 2017 Nov 22. Neuroprotective effects of selegiline on rat neural stem cells treated with hydrogen peroxide. Abdanipour A(1), Jafari Anarkooli I(1), Shokri S(1), Ghorbanlou M(1), Bayati V(2), Nejatbakhsh R(1). Author information: (1)Department of Anatomical Sciences, School of Medicine, Zanjan University of Medical Sciences, Zanjan 45139-56184, Iran. (2)Cellular and Molecular Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan 6135715794, Iran. Oxidative stress and reactive oxygen species generation have been implicated in the pathogenesis of several neurological disorders including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. In the present study, the neuroprotective effects of selegiline against hydrogen peroxide-induced oxidative stress in hippocampus-derived neural stem cells (NSCs) were evaluated. NSCs isolated from neonatal Wistar rats were pretreated with different doses of selegiline for 48 h and then exposed to 125 µM H2O2 for 30 min. Using MTT and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assays, acridine orange/ethidium bromide staining and reverse transcription-quantitative polymerase chain reaction, the effects of selegiline on cell survival, apoptosis and the expression of B-cell lymphoma 2 (Bcl-2) and heat shock protein 4 (Hspa4) in pretreated stem cells were assessed compared with a control group lacking pretreatment. The results indicated that the viability of cells pretreated with 20 µM selegiline was significantly increased compared with the control group (P<0.05). Additionally, 20 µM selegiline increased the mRNA expression of Bcl-2 and Hspa4 (P<0.05 vs. control) and suppressed oxidative stress-induced cell death (apoptosis and necrosis; P<0.05 vs. control and 10 µM groups). From these findings, it was concluded that selegiline may be a therapeutic candidate for the treatment of neurological diseases mediated by oxidative stress. DOI: 10.3892/br.2017.1023 PMCID: PMC5772055 PMID: 29399337
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34. BMC Neurol. 2018 Jan 31;18(1):14. doi: 10.1186/s12883-018-1018-3. The MRZ reaction helps to distinguish rheumatologic disorders with central nervous involvement from multiple sclerosis. Hottenrott T(1), Dersch R(2), Berger B(2), Endres D(3), Huzly D(4), Thiel J(5), Rauer S(2), Stich O(2), Salzer U(5), Venhoff N(5). Author information: (1)Department of Neurology and Neurophysiology, Faculty of Medicine, Medical Center - University of Freiburg, Breisacher Strasse 64, D-79106, Freiburg, Germany. [email protected]. (2)Department of Neurology and Neurophysiology, Faculty of Medicine, Medical Center - University of Freiburg, Breisacher Strasse 64, D-79106, Freiburg, Germany. (3)Department of Psychiatry and Psychotherapy, Faculty of Medicine, Medical Center - University of Freiburg, Hauptstraße 5, D-79104, Freiburg, Germany. (4)Institute of Virology, University Medical Center Freiburg, Hermann-Herder-Strasse 11, D-79104, Freiburg, Germany. (5)Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center - University of Freiburg, Hugstetter Strasse 55, D-79106, Freiburg, Germany. BACKGROUND: Some rheumatologic disorders may initially manifest with central nervous system (CNS) affection, mimicking the clinical, magnetic resonance imaging, and cerebrospinal fluid findings of multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, has been found positive frequently in MS patients. However, it is unclear whether the MRZR is helpful to distinguish rheumatologic disorders with CNS involvement (RDwCNS) from MS. METHODS: The MRZR was evaluated in patients with RDwCNS (n = 23), MS (n = 46; age and sex matched to patients with RDwCNS), and other inflammatory autoimmune neurological diseases affecting the CNS (OIND; n = 48). Both the stringency levels that have been used in previous MRZR studies, MRZR-1 (≥ 1 of 3 AIs positive) and MRZR-2 (≥ 2 of 3 AIs positive), were applied. RESULTS: There was no statistically significant difference in the prevalence of positive MRZR between patients with RDwCNS (MRZR-1: 13.0% and MRZR-2: 8.7%, respectively) and OIND (MRZR-1: 22.9% and MRZR-2: 8.3%, respectively). Compared to these two study cohorts, the MS group exhibited significantly higher prevalences of positive MRZR (MRZR-1: 82.6%, MRZR-2: 63.0%; p < 0.005 each). CONCLUSIONS: Considering the high specificity of MRZR-2 for MS found in this study, MRZR-2 can be a useful diagnostic tool for distinguishing MS from RDwCNS or OIND. DOI: 10.1186/s12883-018-1018-3 PMCID: PMC5793342 PMID: 29386006
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35. BMC Neurol. 2018 Feb 7;18(1):15. doi: 10.1186/s12883-018-1019-2. Increasing prevalence of familial recurrence of multiple sclerosis in Iran: a population based study of Tehran registry 1999-2015. Eskandarieh S(1)(2), Allahabadi NS(2), Sadeghi M(2), Sahraian MA(3)(4). Author information: (1)Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. (2)MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. (3)MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. [email protected]. (4)MS Research Center, Sina Hospital, Hassan Abad square, Tehran, Iran. [email protected]. BACKGROUND: Tehran is the capital of Iran with an increasing multiple sclerosis (MS) prevalence. A retrospective population-based study was conducted to evaluate the trends of MS prevalence in Tehran. METHODS: A population-based survey was conducted for the period 1999 to 2015, based on Iranian MS Society (IMSS) registry system of Tehran, the capital city of Iran. Point regression analysis was applied on MS trend data to find annual percent change (APC). The logistic regression analysis was used to estimate the odds ratio (OR) for individual variables in order to assess factors associating with familial recurrence of MS. P values < 0.05 were considered significant. RESULTS: MS prevalence has significantly increased during the study period from 1999 to 2015 (56.22 per 100,000). Total point prevalence of MS was 115.94 per 100,000 persons in 2015 compared to general population. Positive family history of MS was observed among 12.4% of patients. The strongest association amongst first- degree relatives was found in siblings, p value ≤ 0.001. CONCLUSION: MS prevalence is rising in Tehran and this city is one of the regions with highest MS prevalence in Asia. In this sample, the largest proportion of relatives with MS were found among first-degree relatives, particularly siblings. Familial recurrence correlated with relative type. DOI: 10.1186/s12883-018-1019-2 PMCID: PMC5804012 PMID: 29415659
36. BMC Neurol. 2018 Feb 17;18(1):19. doi: 10.1186/s12883-018-1024-5. Predictors of activity and participation across neurodegenerative conditions: a comparison of people with motor neurone disease, multiple sclerosis and Parkinson's disease. Morley D(1)(2), Dummett S(3), Kelly L(3), Fitzpatrick R(3), Jenkinson C(3). Author information: (1)Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK. david[email protected]. (2)Health Services Research Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK. [email protected]. (3)Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK. BACKGROUND: Comparisons between neurological conditions have the potential to inform service providers by identifying particular areas of difficulty experienced by affected individuals. This study aimed to identify predictors of activity and participation in people with motor neurone disease (MND), people with multiple sclerosis (MS) and people with Parkinson's Disease (PD). METHODS: The Oxford Participation and Activities Questionnaire (Ox-PAQ) and Medical Outcomes Study 36-Item Short Form Survey (MOS SF-36) were administered by postal survey to 386 people with a confirmed diagnosis of MND, MS or PD. Data analyses focused on stepwise regression analyses in order to identify predictors of activity and participation in the three conditions assessed. RESULTS: Three hundred and thirty four participants completed the survey, a response rate of 86.5%. Regression analyses identified multiple predictors of activity and participation dependent on Ox-PAQ domain and disease group, the most prominent being social and physical functioning as measured by the MOS SF-36. CONCLUSIONS: Results indicate that the physical and social consequences of neurological illness are of greatest relevance to people experiencing the conditions assessed. Whilst the largely inevitable physical implications of disease take hold, emphasis should be placed on the avoidance of social withdrawal and isolation, and the maintenance of social engagement should become a significant priority. DOI: 10.1186/s12883-018-1024-5 PMCID: PMC5816512 PMID: 29454326
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37. BMJ Case Rep. 2018 Feb 17;2018. pii: bcr-2017-222086. doi: 10.1136/bcr-2017-222086. NMDAR (N-methyl-D-aspartate receptor) encephalitis in a patient with MS (multiple sclerosis): a rare and challenging case. Suleman S(1), Javed Q(2). Author information: (1)General Adult Psychiatry, Mersey Care NHS Foundation Trust, Liverpool. (2)Liaison Psychiatry, Aintree University Hospitals NHS Foundation Trust, Liverpool, UK. We present a rare case of N-methyl-D-aspartate receptor (NMDAR) encephalitis in a 41-year-old Caucasian woman, who initially presented with prominent neuropsychiatric symptoms on the background of pre-existing multiple sclerosis. Here, the authors navigate the muddy water between neurology and psychiatry, describing the caveats of antibody testing with a misdiagnosed case of acute and transient psychotic episode. NMDAR encephalitis in MS is a rare condition, which can be easily confused with a new onset psychotic episode. This case report can be helpful in recognition and diagnosis of this rare condition. Making the right diagnosis is important since it can prevent an unnecessary radical treatment and long-term neuropsychiatric complications. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. DOI: 10.1136/bcr-2017-222086 PMID: 29455177
Conflict of interest statement: Competing interests: None declared.
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38. BMJ Case Rep. 2018 Feb 14;2018. pii: bcr-2017-223390. doi: 10.1136/bcr-2017-223390. Biopsy-proven multiple sclerosis in an adult patient with atypical craniometaphyseal dysplasia. DiFrancesco JC(1), Isimbaldi G(2), Bedeschi MF(3), Castellotti B(4). Author information: (1)Department of Neurology and Laboratory of Neurobiology, SanGerardo Hospital, University of Milano-Bicocca, Monza, Italy. (2)Department of Pathology, San Gerardo Hospital, Monza, Italy. (3)Clinical Genetics Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy. (4)Unit of Genetics of Neurodegenerative and Metabolic Diseases, IRCCS Fondazione "Istituto Neurologico C Besta", Milano, Italy. Craniometaphyseal dysplasia (CMD) is a rare condition characterised by progressive, diffuse hyperostosis of cranial and long bones, with compression of cranial nerves, linked to mutations in ANKH or GJA1 genes. Here we describe an adult case with clinical features of CMD, who developed cerebral expansive lesion of undetermined nature. Brain biopsy revealed active demyelinating lesions, consistent with multiple sclerosis. The genetic screening of target genes for CMD (ANKH and GJA1) resulted negative in this patient. The peculiar clinical association and the negativity of genetic analyses allow to hypothesise that other genetic causes, not already known, are responsible for the combination of these pathological conditions. Future studies aim to identify the genetic causes of CMD, which will be important to further understand the pathogenetic mechanism of this rare and invalidating disease. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. DOI: 10.1136/bcr-2017-223390 PMID: 29444796
Conflict of interest statement: Competing interests: None declared.
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39. Bone Res. 2018 Jan 31;6:2. doi: 10.1038/s41413-017-0005-4. eCollection 2018. Transforming growth factor-β in stem cells and tissue homeostasis. Xu X(1), Zheng L(2), Yuan Q(3), Zhen G(4), Crane JL(4)(5), Zhou X(1), Cao X(4). Author information: (1)1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China. (2)2State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China. (3)3State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China. (4)4Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD USA. (5)5Department of Pediatrics, Johns Hopkins University, Baltimore, MD USA. TGF-β 1-3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix (ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well- documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context- dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β. DOI: 10.1038/s41413-017-0005-4 PMCID: PMC5802812 PMID: 29423331
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40. Br J Clin Pharmacol. 2018 Jan 31. doi: 10.1111/bcp.13525. [Epub ahead of print] GSH-PEGylated liposomal methylprednisolone in comparison to free methylprednisolone: slow release characteristics and prolonged lymphocyte depression in a first-in-human study. Kanhai KMS(1), Zuiker RGJA(1), Stavrakaki I(2), Gladdines W(2), Gaillard PJ(2)(3), Klaassen ES(1), Groeneveld GJ(1). Author information: (1)Centre for Human Drug Research, Leiden, the Netherlands. (2)Former to-BBB technologies BV, Leiden, the Netherlands. (3)2-BBB Medicines BV, Leiden, the Netherlands. AIM: Intravenous high-dose free methylprednisolone hemisuccinate (MP) is the primary treatment for an acute relapse in relapsing-remitting (RR) multiple sclerosis (MS). However, it is inconvenient and its side effects are undesirable. Both dose and dosing frequency can be reduced by incorporating free MP in glutathione (GSH) PEGylated liposomes, creating a slow-release formulation with reduced toxicity and prolonged peripheral efficacy. This first-in-human study was designed to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of GSH-PEGylated liposomes containing MP (2B3-201). METHODS: The first part was a double-blind, 3-way cross over study in 18 healthy male subjects, receiving ascending doses of 2B3-201, active comparator (free MP) or placebo. Part 2 of the study was an open-label infusion of 2B3-201 (different doses), exploring pre-treatment with antihistamines and different infusion schedules in another 18 healthy male subjects, and a cross-over study in 6 healthy female subjects. MP plasma concentrations, lymphocyte counts, ACTH, osteocalcin and fasting glucose were determined. Safety and tolerability profiles were assessed based on adverse events, safety measurements and CNS tests. RESULTS: The most frequent recorded AE related to 2B3-201 was an infusion related reaction (89%). 2B3-201 was shown to have a plasma half-life between 24 and 37 hours and caused a prolonged decrease in the lymphocyte count, ACTH and osteocalcin, and a rise in fasting glucose. CONCLUSION: 2B3-201 is considered safe, with no clinically relevant changes in (CNS) safety parameters and no serious adverse events. In addition, 2B3-201 shows a long plasma half-life and prolonged immunosuppressive effects. This article is protected by copyright. All rights reserved. DOI: 10.1111/bcp.13525 PMID: 29385232
41. Br J Nurs. 2018 Feb 8;27(3):132-136. doi: 10.12968/bjon.2018.27.3.132. Multiple sclerosis: dealing with complex treatment decisions. Abel N(1), Embrey N(2). Author information: (1)Lecturer Practitioner in MS, Birmingham City University and Queen Elizabeth Hospital, Birmingham. (2)Clinical Nurse Specialist (MS), Royal Stoke MS Centre of Excellence, Stoke- on-Trent. DOI: 10.12968/bjon.2018.27.3.132 PMID: 29412032
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42. Br J Radiol. 2018 Feb 5:20170690. doi: 10.1259/bjr.20170690. [Epub ahead of print] Spectrum of MRI brain lesion patterns in neuromyelitis optica spectrum disorder: a pictorial review. Wang KY(1), Chetta J(1), Bains P(2), Balzer A(1), Lincoln J(3), Uribe T(1), Lincoln CM(1). Author information: (1)1 Department of Radiology, Baylor College of Medicine , Houston, TX , USA. (2)2 Radiology Associates of North Texas , Fort Worth, TX , USA. (3)3 Department of Neurology, The University of Texas Health Science Center at Houston , Houston, TX , USA. Neuromyelitis optica is a neurotropic autoimmune inflammatory disease of the central nervous system traditionally thought to exclusively involve the optic nerves and spinal cord. With the discovery of the disease-specific aquaporin-4 antibody and the increasing recognition of clinical and characteristic imaging patterns of brain involvement in what is now termed neuromyelitis optica spectrum disorder (NMOSD), MRI now plays a greater role in diagnosis of NMOSD based on the 2015 consensus criteria and in distinguishing it from other inflammatory disorders, particularly multiple sclerosis (MS). Several brain lesion patterns are highly suggestive of NMOSD, whereas others may serve as red flags. Specifically, long corticospinal lesions, hemispheric cerebral white matter lesions and periependymal lesions in the diencephalon, dorsal brainstem and white matter adjacent to lateral ventricles are typical of NMOSD. In contrast, juxtacortical, cortical, or lesions perpendicularly oriented to the surface of the lateral ventricle suggests MS as the diagnosis. Ultimately, a strong recognition of the spectrum of MRI brain findings in NMOSD is essential for accurate diagnosis, and particularly in differentiating from MS. This pictorial review highlights the spectrum of characteristic brain lesion patterns that may be seen in NMOSD and further delineates findings that may help distinguish it from MS. DOI: 10.1259/bjr.20170690 PMID: 29388807
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43. Brain. 2018 Feb 16. doi: 10.1093/brain/awy006. [Epub ahead of print] The value of oligoclonal bands in the multiple sclerosis diagnostic criteria. Arrambide G(1), Tintore M(1), Espejo C(1), Auger C(2), Castillo M(1), Río J(1), Castilló J(1), Vidal- Jordana A(1), Galán I(1), Nos C(1), Mitjana R(2), Mulero P(1), de Barros A(2), Rodríguez-Acevedo B(1), Midaglia L(1), Sastre-Garriga J(1), Rovira A(2), Comabella M(1), Montalban X(1)(3). Author information: (1)Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. (2)Section of Neuroradiology and Magnetic Resonance Unit, Department of Radiology (IDI), Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. (3)Division of Neurology, University of Toronto, St. Michael's Hospital, Toronto, Canada. The presence of oligoclonal bands in clinically isolated syndromes is an independent risk factor for developing multiple sclerosis and has been largely excluded from the more recent multiple sclerosis diagnostic criteria. Therefore, our objective was to explore the value of oligoclonal bands in the context of the 2010 McDonald criteria, especially in patients fulfilling exclusively dissemination in space at baseline. For this purpose, we selected 566 patients from a clinically isolated syndrome inception cohort who had IgG oligoclonal bands determination and sufficient data on baseline brain MRI to assess dissemination in space and time. We excluded the cases already fulfilling both dissemination in space and time and divided the remaining 398 into 'no dissemination in space and time' (n = 218), 'dissemination in space' (n = 164) and 'dissemination in time' (n = 16). We assessed Cox proportional hazards regression models with 2010 McDonald as the outcome, using 'no dissemination in space and time' with 0 lesions and negative oligoclonal bands as the reference for different subgroups according to oligoclonal bands status (positive/negative). To assess the diagnostic properties, we selected cases with a follow-up ≥3 years or fulfilling 2010 McDonald within 3 years of the clinically isolated syndrome (n = 314), and compared the performance of all 'dissemination in space' cases (n = 137) versus patients with 'dissemination in space' and positive oligoclonal bands (n = 101). The remaining patients classified as fulfilling 'dissemination in time' or 'no dissemination in space and time' were taken into account to calculate the diagnostic properties. The respective adjusted hazard ratios (95% confidence interval) were 1.5 (0.4-5.7) for 'no dissemination in space and time' with 0 lesions and positive oligoclonal bands, 3.1 (1.4-7.2) for 'no dissemination in space and time' with ≥1 lesions and negative oligoclonal bands, 7.4 (3.5-15.7) for 'no dissemination in space and time' with ≥1 lesions and positive oligoclonal bands, 10.4 (4.8-22.6) for 'dissemination in space' with negative oligoclonal bands, 15.3 (7.5-31.3) for 'dissemination in space' with positive oligoclonal bands, and 9.1 (3.5-23.4) for 'dissemination in time' (not subdivided due to the sample size). The specificity for all cases with 'dissemination in space' was 80.6 and increased to 88.1 after selecting those with positive oligoclonal bands. According to these results, we propose radiological dissemination in space at any time plus positive oligoclonal bands as an additional criterion for diagnosing multiple sclerosis. DOI: 10.1093/brain/awy006 PMID: 29462277
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44. Brain. 2018 Feb 14. doi: 10.1093/brain/awy021. [Epub ahead of print] Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome. Matute-Blanch C(1), Villar LM(2), Álvarez-Cermeño JC(2), Rejdak K(3), Evdoshenko E(4)(5), Makshakov G(4)(5), Nazarov V(5), Lapin S(5), Midaglia L(1), Vidal-Jordana A(1), Drulovic J(6), García-Merino A(7), Sánchez-López AJ(7), Havrdova E(8), Saiz A(9), Llufriu S(9), Alvarez-Lafuente R(10), Schroeder I(11), Zettl UK(11), Galimberti D(12), Ramió-Torrentà L(13), Robles R(13), Quintana E(13), Hegen H(14), Deisenhammer F(14), Río J(1), Tintoré M(1), Sánchez A(15)(16), Montalban X(1), Comabella M(1). Author information: (1)Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. (2)Departments of Neurology and Immunology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigacion Sanitaria, Madrid, Spain. (3)Department of Neurology, Medical University of Lublin, Lublin, Poland. (4)MS Center (City Clinical Hospital 31), Saint Petersburg, Russia. (5)First Pavlov Saint-Petersburg State Medical University, Saint-Petersburg, Russia. (6)Neurology Clinic, Clinical Centre of Serbia, Belgrade, Serbia. (7)Neuroimmunology Unit, Hospital Universitario Puerta de Hierro, Madrid, Spain. (8)Department of Neurology, Charles University in Prague, First Faculty of Medicine, Prague, Czech Republic. (9)Center of Neuroimmunology, Service of Neurology, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain. (10)Hospital Clínico San Carlos, Servicio de Neurología, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. (11)Department of Neurology, Neuroimmunological Section, University of Rostock, Rostock, Germany. (12)University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy. (13)Unitat de Neuroimmunologia i Esclerosi Múltiple, Servei de Neurologia, Hospital Universitari Dr. Josep Trueta, Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain. (14)Medical University of Innsbruck, Department of Neurology, Innsbruck, Austria. (15)Unitat d'Estadística i Bioinformàtica, VHIR, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. (16)Genetics, Microbiology and Statistics Department, Universitat de Barcelona, Barcelona, Spain. The prognostic role of cerebrospinal fluid molecular biomarkers determined in early pathogenic stages of multiple sclerosis has yet to be defined. In the present study, we aimed to investigate the prognostic value of chitinase 3 like 1 (CHI3L1), neurofilament light chain, and oligoclonal bands for conversion to clinically isolated syndrome and to multiple sclerosis in 75 patients with radiologically isolated syndrome. Cerebrospinal fluid levels of CHI3L1 and neurofilament light chain were measured by enzyme-linked immunosorbent assay. Uni- and multivariable Cox regression models including as covariates age at diagnosis of radiologically isolated syndrome, number of brain lesions, sex and treatment were used to investigate associations between cerebrospinal fluid CHI3L1 and neurofilament light chain levels and time to conversion to clinically isolated syndrome and multiple sclerosis. Neurofilament light chain levels and oligoclonal bands were independent risk factors for the development of clinically isolated syndrome (hazard ratio = 1.02, P = 0.019, and hazard ratio = 14.7, P = 0.012, respectively) and multiple sclerosis (hazard ratio = 1.03, P = 0.003, and hazard ratio = 8.9, P = 0.046, respectively). The best cut-off to classify cerebrospinal fluid neurofilament light chain levels into high and low was 619 ng/l, and high neurofilament light chain levels were associated with a trend to shorter time to clinically isolated syndrome (P = 0.079) and significant shorter time to multiple sclerosis (P = 0.017). Similarly, patients with radiologically isolated syndrome presenting positive oligoclonal bands converted faster to clinically isolated syndrome and multiple sclerosis (P = 0.005 and P = 0.008, respectively). The effects of high neurofilament light chain levels shortening time to clinically isolated syndrome and multiple sclerosis were more pronounced in radiologically isolated syndrome patients with ≥37 years compared to younger patients. Cerebrospinal fluid CHI3L1 levels did not influence conversion to clinically isolated syndrome and multiple sclerosis in radiologically isolated syndrome patients. Overall, these findings suggest that cerebrospinal neurofilament light chain levels and oligoclonal bands are independent predictors of clinical conversion in patients with radiologically isolated syndrome. The association with a faster development of multiple sclerosis reinforces the importance of cerebrospinal fluid analysis in patients with radiologically isolated syndrome. © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]. DOI: 10.1093/brain/awy021 PMID: 29452342
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 60 – Multiple Sklerose: Veröffentlichungen Oktober 2013
45. Brain Behav. 2018 Jan 30;8(2):e00925. doi: 10.1002/brb3.925. eCollection 2018 Feb. Cardiac repolarization during fingolimod treatment in patients with relapsing-remitting multiple sclerosis. Laiho A(1), Laitinen TM(1), Hartikainen P(2), Hartikainen JEK(3), Laitinen TP(1), Simula S(4). Author information: (1)Department of Clinical Physiology and Nuclear MedicineKuopio University HospitalUniversity of Eastern FinlandKuopioFinland. (2)Neuro CenterDepartment of NeurologyKuopio University HospitalUniversity of Eastern FinlandKuopioFinland. (3)Heart CenterKuopio University HospitalUniversity of Eastern FinlandKuopioFinland. (4)Department of NeurologyMikkeli Central HospitalMikkeliFinland. Background: Fingolimod is a sphingosine-1-phosphate receptor modulator for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite an established effect on heart rate, the effect of fingolimod on cardiac repolarization is not completely known. Methods: Twenty-seven patients with RRMS underwent 24-hr ambulatory ECG before fingolimod (baseline), at the day of fingolimod initiation (1D) and after three-month treatment (3M). The mean values of RR-interval as well as QT- interval corrected by Bazzet's (QTcBaz) and Fridericia's (QTcFri) formula were compared between baseline, 1D, and 3M over 24-hr period as well as at daytime and nighttime. Results: QTcBaz over 24- hr was shorter at 1D (414 ± 20 ms, p < .001) and at 3M (414 ± 20 ms, p < .001) than at baseline (418 ± 20 ms). In contrast, QTcFri over 24-hr was longer at 1D (410 ± 19 ms, p < .001) but similar at 3M (406 ± 19 ms, p = .355) compared to baseline (407 ± 19 ms). Daytime QTcBaz was shorter at 1D (p < .001) and at 3M (p = .007), whereas daytime QTcFri was longer at 1D (p < .05) but similar at 3M (p = ns) compared to baseline. During the night, changes were observed neither in QTcBaz nor in QTcFri between baseline, 1D, and 3M. Conclusions: Changes in cardiac repolarization after fingolimod initiation were mild and occurred at daytime. Ambiguously, QTcBaz demonstrated shortening, whereas QTcFri showed prolongation in cardiac repolarization after fingolimod initiation. The formula applied for QT-interval correction needs to be taken carefully into account as evaluating pharmacovigilance issues related to fingolimod. DOI: 10.1002/brb3.925 PMCID: PMC5822581 PMID: 29484274
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46. Brain Behav. 2018 Jan 5;8(2):e00875. doi: 10.1002/brb3.875. eCollection 2018 Feb. Progressive multiple sclerosis, cognitive function, and quality of life. Højsgaard Chow H(1), Schreiber K(1), Magyari M(1), Ammitzbøll C(1), Börnsen L(1), Romme Christensen J(1), Ratzer R(1), Soelberg Sørensen P(1), Sellebjerg F(1). Author information: (1)Department of NeurologyDanish Multiple Sclerosis CenterRigshospitaletUniversity of CopenhagenCopenhagenDenmark. Background: Patients with progressive multiple sclerosis (MS) often have cognitive impairment in addition to physical impairment. The burden of cognitive and physical impairment progresses over time, and may be major determinants of quality of life. The aim of this study was to assess to which degree quality of life correlates with physical and cognitive function in progressive MS. Methods: This is a retrospective study of 52 patients with primary progressive (N = 18) and secondary progressive MS (N = 34). Physical disability was assessed using the Expanded Disability Status Scale, Timed 25 Foot Walk (T25FW) test and 9-Hole Peg Test (9HPT). Cognitive function was assessed using Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test, and Trail Making Test B (TRAIL-B). In addition, quality of life was assessed by the Short Form 36 (SF-36) questionnaire. Results: Only measures of cognitive function correlated with the overall SF-36 quality of life score and the Mental Component Summary score from the SF-36. The only physical measure that correlated with a measure of quality of life was T25FW test, which correlated with the Physical Component Summary from the SF-36. We found no other significant correlations between the measures of cognitive function and the overall physical measures but interestingly, we found a possible relationship between the 9HPT score for the nondominant hand and the SDMT and TRAIL-B. Conclusion: Our findings support inclusion of measures of cognitive function in the assessment of patients with progressive MS as these correlated closer with quality of life than measures of physical impairment. DOI: 10.1002/brb3.875 PMCID: PMC5822575 PMID: 29484253
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 62 – Multiple Sklerose: Veröffentlichungen Oktober 2013
47. Brain Dev. 2018 Jan 30. pii: S0387-7604(18)30005-6. doi: 10.1016/j.braindev.2018.01.001. [Epub ahead of print] Efficacy and safety of everolimus in patients younger than 12 months with congenital subependymal giant cell astrocytoma. Kuki I(1), Kawawaki H(2), Okazaki S(2), Ehara E(3), Yoshida Y(4), Kunihiro N(5), Matsusaka Y(5). Author information: (1)Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan. Electronic address: [email protected]. (2)Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan. (3)Department of Pediatric Cardiology, Osaka City General Hospital, Osaka, Japan. (4)Department of Pediatric Electrophysiology, Osaka City General Hospital, Osaka, Japan. (5)Department of Pediatric Neurosurgery, Osaka City General Hospital, Osaka, Japan. Tuberous sclerosis complex (TSC) is a multisystem genetic disorder that activates mammalian target of rapamycin and produces tumor growth in several organs. We present five patients younger than 12 months who were diagnosed with TSC and treated with everolimus (EVL), after which congenital subependymal giant astrocytoma (cSEGA) promptly regressed in all patients. All patients achieved at least 50% reduction in the volume of cSEGA within 6 months. The most rapid reduction of cSEGA volume (79.1%) was found during the initial 3 months of EVL treatment. Patients underwent EVL treatment for an average of 27 months (range: 4-55 months). Mean EVL maintenance dose was 1.35 mg per day. EVL blood trough concentrations ranged from 2.0 to 11.7 ng/ml. The cSEGA became larger after discontinuing EVL in two patients. In all four patients who had multiple cardiac rhabdomyomas (CRMs), the CRMs showed accelerated regression after receiving EVL. Adverse events were noted in four patients: infection, stomatitis, and increased triglycerides. Four patients had febrile status epilepticus, which occurred during acute encephalopathy in a patient, and after discontinuing EVL in another. Three patients were still receiving EVL at their latest evaluations. Maintenance therapy with EVL is an effective therapeutic option for patients with cSEGA, and moreover may have additional favorable effects on other complications, even in early infancy; however, adverse effects should be carefully monitored. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.braindev.2018.01.001 PMID: 29395661
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 63 – Multiple Sklerose: Veröffentlichungen Oktober 2013
48. Brain Struct Funct. 2018 Feb 16. doi: 10.1007/s00429-018-1619-z. [Epub ahead of print] Structural disconnection is responsible for increased functional connectivity in multiple sclerosis. Patel KR(1), Tobyne S(2), Porter D(2), Bireley JD(2), Smith V(2), Klawiter E(2). Author information: (1)Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. [email protected]. (2)Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. Increased synchrony within neuroanatomical networks is often observed in neurophysiologic studies of human brain disease. Most often, this phenomenon is ascribed to a compensatory process in the face of injury, though evidence supporting such accounts is limited. Given the known dependence of resting-state functional connectivity (rsFC) on underlying structural connectivity (SC), we examine an alternative hypothesis: that topographical changes in SC, specifically particular patterns of disconnection, contribute to increased network rsFC. We obtain measures of rsFC using fMRI and SC using probabilistic tractography in 50 healthy and 28 multiple sclerosis subjects. Using a computational model of neuronal dynamics, we simulate BOLD using healthy subject SC to couple regions. We find that altering the model by introducing structural disconnection patterns observed in those multiple sclerosis subjects with high network rsFC generates simulations with high rsFC as well, suggesting that disconnection itself plays a role in producing high network functional connectivity. We then examine SC data in individuals. In multiple sclerosis subjects with high network rsFC, we find a preferential disconnection between the relevant network and wider system. We examine the significance of such network isolation by introducing random disconnection into the model. As observed empirically, simulated network rsFC increases with removal of connections bridging a community with the remainder of the brain. We thus show that structural disconnection known to occur in multiple sclerosis contributes to network rsFC changes in multiple sclerosis and further that community isolation is responsible for elevated network functional connectivity. DOI: 10.1007/s00429-018-1619-z PMID: 29453522
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 64 – Multiple Sklerose: Veröffentlichungen Oktober 2013
49. Brain Topogr. 2018 Feb 9. doi: 10.1007/s10548-018-0632-0. [Epub ahead of print] Movement-Related Somatosensory Activity Is Altered in Patients with Multiple Sclerosis. Arpin DJ(1)(2), Gehringer JE(1)(2), Wilson TW(2)(3), Kurz MJ(4)(5). Author information: (1)Department of Physical Therapy, Munroe-Meyer Institute for Genetics, and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, 68198-5450, USA. (2)Center for Magnetoencephalography, University of Nebraska Medical Center, Omaha, NE, USA. (3)Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA. (4)Department of Physical Therapy, Munroe-Meyer Institute for Genetics, and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, 68198-5450, USA. [email protected]. (5)Center for Magnetoencephalography, University of Nebraska Medical Center, Omaha, NE, USA. [email protected]. During active movement the somatosensory cortical responses are often attenuated. This attenuation is referred to as movement-related sensory gating. It is well known that patients with multiple sclerosis (MS) have sensory processing deficits, and recent work has also suggested that these patients display impaired motor control of the ankle musculature. The primary goal of the current study was to: (1) examine the movement-related somatosensory gating in patients with MS and demographically- matched controls, and (2) identify the relationship between the sensory gating and motor control of the ankle musculature. To this end, we used magnetoencephalography brain imaging to assess the neural responses to a tibial nerve electrical stimulation that was applied at rest (passive) and during an ankle plantarflexion motor task (active condition). All participants also completed an ankle isometric motor control task that was performed outside the scanner. Our results indicated that the controls, but not patients with MS, exhibited significantly reduced somatosensory responses during the active relative to passive conditions, and that patients with MS had stronger responses compared with controls during the active condition. Additionally, control of the ankle musculature was related to the extent of movement-related sensory attenuation, with poor motor control being associated with reduced gating. Overall, these results show that patients with MS do not attenuate the somatosensory cortical activity during motor actions, and that the inability to modulate somatosensory cortical activity is partially related to the poor ankle motor control seen in these patients. DOI: 10.1007/s10548-018-0632-0 PMID: 29427250
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50. Can Fam Physician. 2018 Feb;64(2):e78-e94. Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms. Allan GM(1), Finley CR(2), Ton J(2), Perry D(2), Ramji J(2), Crawford K(3), Lindblad AJ(4), Korownyk C(5), Kolber MR(5). Author information: (1)Professor of Evidence-Based Medicine in the Department of Family Medicine at the University of Alberta in Edmonton. [email protected]. (2)Knowledge Translation Expert in the Physician Learning Program with the Alberta Medical Association and in Lifelong Learning and the Department of Family Medicine at the University of Alberta. (3)Coordinator of the Integrated Knowledge Translation Network of the Physician Learning Program with the Alberta Medical Association and in Lifelong Learning and the Department of Family Medicine at the University of Alberta. (4)Knowledge Translation and Evidence Coordinator for the Alberta College of Family Physicians and Associate Clinical Professor in the Department of Family Medicine at the University of Alberta. (5)Associate Professor of Evidence-Based Medicine in the Department of Family Medicine at the University of Alberta. OBJECTIVE: To determine the effects of medical cannabinoids on pain, spasticity, and nausea and vomiting, and to identify adverse events. DATA SOURCES: MEDLINE, the Cochrane Database, and the references of included studies were searched. STUDY SELECTION: Systematic reviews with 2 or more randomized controlled trials (RCTs) that focused on medical cannabinoids for pain, spasticity, or nausea and vomiting were included. For adverse events, any meta-analysis for the conditions listed or of adverse events of cannabinoids was included. SYNTHESIS: From 1085 articles, 31 relevant systematic reviews were identified including 23 for pain, 5 for spasticity, 6 for nausea and vomiting, and 12 for adverse events. Meta-analysis of 15 RCTs found more patients taking cannabinoids attained at least a 30% pain reduction: risk ratio (RR) of 1.37 (95% CI 1.14 to 1.64), number needed to treat (NNT) of 11. Sensitivity analysis found study size and duration affected findings (subgroup differences, P ≤ .03), with larger and longer RCTs finding no benefit. Meta-analysis of 4 RCTs found a positive global impression of change in spasticity (RR = 1.45, 95% CI 1.08 to 1.95, NNT = 7). Other results were not consistently statistically significant, but when positive, a 30% or more improvement in spasticity had an NNT of 10. Meta-analysis of 7 RCTs for control of nausea and vomiting after chemotherapy found an RR of 3.60 (95% CI 2.55 to 5.09) with an NNT of 3. Adverse effects caused more patients to stop treatment (number needed to harm [NNH] of 8 to 22). Individual adverse events were very common, including dizziness (NNH = 5), sedation (NNH = 5), confusion (NNH = 15), and dissociation (NNH = 20). "Feeling high" was reported in 35% to 70% of users. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) evaluation reduced evidence ratings of benefit to low or very low. CONCLUSION: There is reasonable evidence that cannabinoids improve nausea and vomiting after chemotherapy. They might improve spasticity (primarily in multiple sclerosis). There is some uncertainty about whether cannabinoids improve pain, but if they do, it is neuropathic pain and the benefit is likely small. Adverse effects are very common, meaning benefits would need to be considerable to warrant trials of therapy. Copyright© the College of Family Physicians of Canada. PMID: 29449262
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51. Can Fam Physician. 2018 Feb;64(2):111-120. Simplified guideline for prescribing medical cannabinoids in primary care. Allan GM(1), Ramji J(2), Perry D(2), Ton J(2), Beahm NP(3), Crisp N(4), Dockrill B(5), Dubin RE(6), Findlay T(7), Kirkwood J(8), Fleming M(9), Makus K(10), Zhu X(11), Korownyk C(12), Kolber MR(13), McCormack J(14), Nickel S(15), Noël G(16), Lindblad AJ(17). Author information: (1)Professor of Evidence-Based Medicine in the Department of Family Medicine at the University of Alberta in Edmonton. [email protected]. (2)Knowledge Translation Expert in the Physician Learning Program with the Alberta Medical Association and in Lifelong Learning and the Department of Family Medicine at the University of Alberta. (3)Research Fellow in the EPICORE Centre at the University of Alberta. (4)Nurse practitioner in the Division of Hematology at the University of Alberta Hospital in Edmonton. (5)Retired registered nurse and patient representative from Edmonton. (6)Associate Professor at Queen's University and the Northern Ontario School of Medicine in Kingston, Ont. (7)Consultant for Alberta Health Services Chronic Pain Centre and Clinical Assistant Professor at the University of Calgary in Alberta. (8)Family physician at the Boyle McCauley Health Centre in Edmonton. (9)Director of Family Physician Programs in Continuing Professional Development in the Faculty of Medicine at Dalhousie University in Halifax, NS. (10)Director of the Adult Compulsive Disorder Clinic and Clinical Assistant Professor at the University of Alberta. (11)Medical oncologist at Cross Cancer Institute in Edmonton. (12)Associate Professor of Evidence- Based Medicine in the Department of Family Medicine at the University of Alberta. (13)Associate Professor of Evidence-Based Medicine in the Department of Family Medicine at the University of Alberta in Peace River. (14)Professor in the Faculty of Pharmaceutical Sciences at the University of British Columbia in Vancouver. (15)Coordinator of Evidence-Based Medicine in the Department of Family Medicine at the University of Alberta and the Alberta College of Family Physicians. (16)Health Innovation Studio Lead and Human-centred Knowledge Designer for Lifelong Learning in the Faculty of Medicine and Dentistry at the University of Alberta. (17)Knowledge Translation and Evidence Coordinator for the Alberta College of Family Physicians and Associate Clinical Professor in the Department of Family Medicine at the University of Alberta. OBJECTIVE: To develop a clinical practice guideline for a simplified approach to medical cannabinoid use in primary care; the focus was on primary care application, with a strong emphasis on best available evidence and a promotion of shared, informed decision making. METHODS: The Evidence Review Group performed a detailed systematic review of 4 clinical areas with the best evidence around cannabinoids: pain, nausea and vomiting, spasticity, and adverse events. Nine health professionals (2 generalist family physicians, 2 pain management-focused family physicians, 1 inner- city family physician, 1 neurologist, 1 oncologist, 1 nurse practitioner, and 1 pharmacist) and a patient representative comprised the Prescribing Guideline Committee (PGC), along with 2 nonvoting members (pharmacist project managers). Member selection was based on profession, practice setting, location, and lack of financial conflicts of interest. The guideline process was iterative through content distribution, evidence review, and telephone and online meetings. The PGC directed the Evidence Review Group to address and provide evidence for additional questions as needed. The key recommendations were derived through consensus of the PGC. The guideline was drafted, refined, and distributed to a group of clinicians and patients for feedback, then refined again and finalized by the PGC. RECOMMENDATIONS: Recommendations include limiting medical cannabinoid use in general, but also outline potential restricted use in a small subset of medical conditions for which there is some evidence (neuropathic pain, palliative and end-of-life pain, chemotherapy-induced nausea and vomiting, and spasticity due to multiple sclerosis or spinal cord injury). Other important considerations regarding prescribing are reviewed in detail, and content is offered to support shared, informed decision making. CONCLUSION: This simplified medical cannabinoid prescribing guideline provides practical recommendations for the use of medical cannabinoids in primary care. All recommendations are intended to assist with, not dictate, decision making in conjunction with patients. Copyright© the College of Family Physicians of Canada. PMID: 29449241
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52. Can J Occup Ther. 2018 Jan 1:8417417727298. doi: 10.1177/0008417417727298. [Epub ahead of print] Sensory processing, cognitive fatigue, and quality of life in multiple sclerosis: Traitement de l'information sensorielle, fatigue cognitive et qualité de vie des personnes atteintes de sclérose en plaques. Colbeck M. BACKGROUND: Quality of life for persons living with multiple sclerosis (MS) is significantly lower than population norms. Fatigue, both physical and cognitive, is one of the most prevalent and debilitating symptoms of MS that decrease quality of life. Cognitive fatigue presents similarly to sensory overresponsiveness, but the connection has not been explored. PURPOSE: This study aims to describe how sensory-processing preferences and cognitive fatigue relate to variances in quality of life for people with MS. METHOD: A cross-sectional design was used with 30 people living with MS to complete the Adolescent/Adult Sensory Profile (AASP), Modified Fatigue Impact Scale, and RAND-36. Spearman's coefficient measured nonparametric correlations between variables. FINDINGS: People with MS who have high scores in low registration, sensory sensitivity, and sensation avoidant quadrants of the AASP also have higher levels of cognitive fatigue and poorer quality of life. Those with high scores in sensory seeking experience greater quality of life and less cognitive fatigue. IMPLICATIONS: The findings shape clinical practice by supporting the assessment of sensory processing alongside fatigue, offering individualized intervention planning to shape fatigue management, and fostering hope and quality of life for persons living with MS. DOI: 10.1177/0008417417727298 PMID: 29482340
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 68 – Multiple Sklerose: Veröffentlichungen Oktober 2013
53. Can Urol Assoc J. 2017 Sep;11(9):E350-E354. doi: 10.5489/cuaj.4434. Gentamicin bladder instillations decrease symptomatic urinary tract infections in neurogenic bladder patients on intermittent catheterization. Cox L(1), He C(1), Bevins J(2), Clemens JQ(1), Stoffel JT(1), Cameron AP(1). Author information: (1)Department of Urology; University of Michigan, Ann Arbor, MI, United States. (2)College of Medicine; University of Michigan, Ann Arbor, MI, United States. INTRODUCTION: This study aimed to determine if gentamicin bladder instillations reduce the rate of symptomatic urinary tract infection (UTI) in neurogenic bladder (NGB) patients on intermittent self- catheterization (ISC) who have recurrent UTIs. Secondary aims were to examine the effects of intravesical gentamicin on the organism resistance patterns. METHODS: We retrospectively reviewed our prospective NGB database. Inclusion criteria were NGB patients performing ISC exclusively for bladder drainage with clinical data available for six months before and six months after initiating prophylactic intravesical gentamicin instillations. Symptomatic UTIs were defined as symptoms consistent with UTI plus the need for antibiotic treatment. RESULTS: Twenty-two patients met inclusion criteria; etiology of NGB was 63.6% spinal cord injury, 13.6% multiple sclerosis. Median time since injury/diagnosis was 14 years and 6/22 (27.3%) had undergone urological reconstruction. Patients had fewer symptomatic UTI's (median 4 vs. 1 episodes; p<0.004) and underwent fewer courses of oral antibiotics after initiating gentamicin (median 3.5 vs. 1; p<0.01). Days of oral antibiotic therapy decreased from 15 before to five after gentamicin, but this did not reach significance. There were fewer telephone encounters for UTI concerns per patient (median 3 vs. 0; p=0.03). The proportion of multi-drug-resistant organisms in urine cultures decreased from 58.3% to 47.1% (p=0.04) and the rate of gentamicin resistance did not increase. Adverse events were mild and rare. CONCLUSIONS: Gentamicin bladder instillations decrease symptomatic UTI episodes and reduce oral antibiotics in patients with NGB on ISC who were suffering from recurrent UTIs. Antibiotic resistance decreased while on gentamicin instillations. DOI: 10.5489/cuaj.4434 PMCID: PMC5798439 PMID: 29382457
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 69 – Multiple Sklerose: Veröffentlichungen Oktober 2013
54. Caspian J Intern Med. 2018 Winter;9(1):96-99. doi: 10.22088/cjim.9.1.96. Association of Limb-Girdle muscular dystrophy with multiple sclerosis: A case report. Arzani M(1), Rezaei H(2), Moghadasi AN(1)(3). Author information: (1)Department of Neurology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. (2)Department of Urology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. (3)Sina MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Background: The association of limb-girdle muscular dystrophy (LGMD) with other neurological disorders is uncommon. Case presentation: We report a 25-year-old female with LGMD who suffered from slowly progressive proximal muscular weakness and atrophy since she was 12 years of age. The patient recently presented with acute loss of left side visual acuity. After evaluation, findings were suggestive of multiple sclerosis. Conclusions: This is the first report of LGMD in association with MS. The simultaneous occurrence of MS with myopathies may be incidental but there may be a genetic susceptibility for both diseases. This comorbidity may influence the treatment of MS. DOI: 10.22088/cjim.9.1.96 PMCID: PMC5771368 PMID: 29387327
Conflict of interest statement: The authors declare no conflict of interest.
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 70 – Multiple Sklerose: Veröffentlichungen Oktober 2013
55. Cell Death Differ. 2018 Feb 19. doi: 10.1038/s41418-018-0060-4. [Epub ahead of print] Exploring the genetics and non-cell autonomous mechanisms underlying ALS/FTLD. Chen H(1)(2), Kankel MW(3), Su SC(3), Han SWS(3)(4)(5), Ofengeim D(6)(7). Author information: (1)Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. (2)Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA, 02115, USA. (3)Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA. (4)Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. (5)GSK, Upper Providence, PA, 19426, USA. (6)Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA. [email protected]. (7)Sanofi Neuroscience, Framingham, MA, USA. [email protected]. Although amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, was first described in 1874, a flurry of genetic discoveries in the last 10 years has markedly increased our understanding of this disease. These findings have not only enhanced our knowledge of mechanisms leading to ALS, but also have revealed that ALS shares many genetic causes with another neurodegenerative disease, frontotemporal lobar dementia (FTLD). In this review, we survey how recent genetic studies have bridged our mechanistic understanding of these two related diseases and how the genetics behind ALS and FTLD point to complex disorders, implicating non-neuronal cell types in disease pathophysiology. The involvement of non-neuronal cell types is consistent with a non-cell autonomous component in these diseases. This is further supported by studies that identified a critical role of immune-associated genes within ALS/FTLD and other neurodegenerative disorders. The molecular functions of these genes support an emerging concept that various non-autonomous functions are involved in neurodegeneration. Further insights into such a mechanism(s) will ultimately lead to a better understanding of potential routes of therapeutic intervention. Facts ALS and FTLD are severe neurodegenerative disorders on the same disease spectrum. Multiple cellular processes including dysregulation of RNA homeostasis, imbalance of proteostasis, contribute to ALS/FTLD pathogenesis. Aberrant function in non-neuronal cell types, including microglia, contributes to ALS/FTLD. Strong neuroimmune and neuroinflammatory components are associated with ALS/FTLD patients. Open Questions Why can patients with similar mutations have different disease manifestations, i.e., why do C9ORF72 mutations lead to motor neuron loss in some patients while others exhibit loss of neurons in the frontotemporal lobe? Do ALS causal mutations result in microglial dysfunction and contribute to ALS/FTLD pathology? How do microglia normally act to mitigate neurodegeneration in ALS/FTLD? To what extent do cellular signaling pathways mediate non-cell autonomous communications between distinct central nervous system (CNS) cell types during disease? Is it possible to therapeutically target specific cell types in the CNS? DOI: 10.1038/s41418-018-0060-4 PMID: 29459769
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 71 – Multiple Sklerose: Veröffentlichungen Oktober 2013
56. Cell Death Dis. 2018 Feb 15;9(3):273. doi: 10.1038/s41419-018-0337-z. Knockout of zebrafish interleukin 7 receptor (IL7R) by the CRISPR/Cas9 system delays retinal neurodevelopment. Cai S(1)(2), Chen Y(1), Shang Y(1), Cui J(1)(3), Li Z(1), Li Y(4)(5). Author information: (1)Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University School of Medicine, Tianjin, 300071, China. (2)State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, China. (3)Medical International Collaborative Innovation Center, Nankai University, Tianjin, 300071, China. (4)Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University School of Medicine, Tianjin, 300071, China. [email protected]. (5)Medical International Collaborative Innovation Center, Nankai University, Tianjin, 300071, China. [email protected]. Interleukin 7 receptor (il7r), a transmembrane receptor, belongs to the type I cytokine receptor family. Il7r is involved in the pathogenesis of neurodegenerative disorders, such as multiple sclerosis. Targeted knockdown of il7r leads to delayed myelination, highlighting the potential role of il7r in the development of the nervous system. Zebrafish is an ideal model for the study of neurogenesis; moreover, the il7r gene is highly conserved between zebrafish and human. The aim of the present study was to investigate the novel function of il7r in neurogenesis. First, an il7r -/- homozygous mutant line was generated by clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) technology. Second, the gross development of il7r-/- mutants revealed remarkably smaller eyes and delayed retinal neurodifferentiation. Third, microarray analysis revealed that genes associated with the phototransduction signalling pathway were strongly down-regulated in il7r -/- mutants. Finally, the results from behavioural tests indicated that visual function was impaired in il7r -/- mutant larvae. Overall, our data demonstrate that a lack of il7r retards the development of the retina. Thus, il7r is an essential molecule for maintaining normal retinal development in zebrafish. DOI: 10.1038/s41419-018-0337-z PMID: 29449560
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 72 – Multiple Sklerose: Veröffentlichungen Oktober 2013
57. Cell Death Dis. 2018 Feb 14;9(2):220. doi: 10.1038/s41419-018-0295-5. MYCN drives glutaminolysis in neuroblastoma and confers sensitivity to an ROS augmenting agent. Wang T(1), Liu L(1), Chen X(1), Shen Y(1), Lian G(1), Shah N(1), Davidoff AM(2), Yang J(3), Wang R(4). Author information: (1)Center for Childhood Cancer and Blood Diseases, Hematology/Oncology and BMT, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA. (2)Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. (3)Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. [email protected]. (4)Center for Childhood Cancer and Blood Diseases, Hematology/Oncology and BMT, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA. [email protected]. Heightened aerobic glycolysis and glutaminolysis are characteristic metabolic phenotypes in cancer cells. Neuroblastoma (NBL), a devastating pediatric cancer, is featured by frequent genomic amplification of MYCN, a member of the Myc oncogene family that is primarily expressed in the early stage of embryonic development and required for neural crest development. Here we report that an enriched glutaminolysis gene signature is associated with MYCN amplification in children with NBL. The partial knockdown of MYCN suppresses glutaminolysis in NBL cells. Conversely, forced overexpression of MYCN in neural crest progenitor cells enhances glutaminolysis. Importantly, glutaminolysis induces oxidative stress by producing reactive oxygen species (ROS), rendering NBL cells sensitive to ROS augmentation. Through a small-scale metabolic-modulator screening, we have found that dimethyl fumarate (DMF), a Food and Drug Administration-approved drug for multiple sclerosis, suppresses NBL cell proliferation in vitro and tumor growth in vivo. DMF suppresses NBL cell proliferation through inducing ROS and subsequently suppressing MYCN expression, which is rescued by an ROS scavenger. Our findings suggest that the metabolic modulation and ROS augmentation could be used as novel strategies in treating NBL and other MYC-driven cancers. DOI: 10.1038/s41419-018-0295-5 PMID: 29445162
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 73 – Multiple Sklerose: Veröffentlichungen Oktober 2013
58. Cell Death Dis. 2018 Feb 14;9(2):251. doi: 10.1038/s41419-018-0290-x. Lenalidomide regulates CNS autoimmunity by promoting M2 macrophages polarization. Weng Q(1)(2), Wang J(1), Wang J(1), Wang J(1), Sattar F(1), Zhang Z(1), Zheng J(1), Xu Z(1), Zhao M(1), Liu X(1), Yang L(1), Hao G(3), Fang L(4), Lu QR(5), Yang B(6), He Q(7)(8). Author information: (1)Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. (2)Center for Drug Safety Evaluation and Research, Zhejiang University, Hangzhou, China. (3)Department of Rheumatology, Zhejiang Provincial People's Hospital, Hangzhou, China. (4)Cancer Research Program, Max Delbrueck Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany. (5)Department of Pediatrics, Brain Tumor Center, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. (6)Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected]. (7)Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected]. (8)Center for Drug Safety Evaluation and Research, Zhejiang University, Hangzhou, China. [email protected]. Multiple sclerosis (MS) is a chronic and debilitating neurological disorder of the central nervous system (CNS), characterized by infiltration of leukocytes into CNS and subsequent demyelination. Emerging evidences have revealed the beneficial roles of M2 macrophages in ameliorating experimental autoimmune encephalomyelitis (EAE), a model for MS. Here, we identify that lenalidomide alone could promote macrophages M2 polarization to prevent the progression of EAE, which is associated with subsequent inhibition of proinflammatory Th1 and Th17 cells both in peripheral lymph system and CNS. Depletion of macrophages by pharmacology treatment of clodronate liposomes or transferring lenalidomide-induced BMDMs in EAE mice completely abolished the therapeutic effect of lenalidomide or prevented EAE development, respectively. The macrophages-derived IL10 was upregulated both in vivo and in vitro after lenalidomide treatment. Moreover, lenalidomide-treated IL10-dificient EAE mice had higher clinical scores and more severe CNS damage, and intravenous injection of lenalidomide- treated IL10-/- BMDMs into mice with EAE at disease onset did not reverse disease severity, implying IL10 may be essential in lenalidomide-ameliorated EAE. Mechanistically, lenalidomide significantly increased expression and autocrine secretion of IL10, subsequently activated STAT3-mediated expression of Ym1. These studies facilitate the development of potential novel therapeutic application of lenalidomide for the treatment of MS. DOI: 10.1038/s41419-018-0290-x PMID: 29445144
59. Cell Mol Immunol. 2018 Feb 12. doi: 10.1038/cmi.2017.166. [Epub ahead of print] De novo vs. inherited copy number variations in multiple sclerosis susceptibility. Tizaoui K(1). Author information: (1)Department of Basic Sciences, Medicine Faculty of Tunis, Tunis El Manar University, 15 Rue Djebel Lakdar, Tunis 1007, Tunisia. DOI: 10.1038/cmi.2017.166 PMID: 29429997
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 74 – Multiple Sklerose: Veröffentlichungen Oktober 2013
60. Cell Mol Life Sci. 2018 Feb 2. doi: 10.1007/s00018-018-2761-8. [Epub ahead of print] TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms. Rosengren T(1), Larsen LJ(1), Pedersen LB(2), Christensen ST(2), Møller LB(3). Author information: (1)Applied Human Molecular Genetics, Clinical Genetic Clinic, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, 2600, Glostrup, Denmark. (2)Department of Biology, The August Krogh Building, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, Denmark. (3)Applied Human Molecular Genetics, Clinical Genetic Clinic, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, 2600, Glostrup, Denmark. [email protected]. Primary cilia are sensory organelles that coordinate multiple cellular signaling pathways, including Hedgehog (HH), Wingless/Int (WNT) and Transforming Growth Factor-β (TGF-β) signaling. Similarly, primary cilia have been implicated in regulation of mTOR signaling, in which Tuberous Sclerosis Complex proteins 1 and 2 (TSC1/2) negatively regulate protein synthesis by inactivating the mTOR complex 1 (mTORC1) at energy limiting states. Here we report that TSC1 and TSC2 regulate Smoothened (SMO)-dependent HH signaling in mouse embryonic fibroblasts (MEFs). Reduced SMO- dependent expression of Gli1 was demonstrated in both Tsc1-/- and Tsc2-/- cells, and we found that Tsc1 is required for TGF-β induced phosphorylation of SMAD2/3 and subsequent expression of the HH signaling effector and transcription factor GLI2. Hedgehog signaling was restored in Tsc1-/- cells after exogenous expression of Gli2, whereas rapamycin restored HH signaling in Tsc2-/- cells. Furthermore, we observed that Tsc1-/- MEFs display significantly elongated cilia, whereas cilia in Tsc2-/- MEFs were shorter than normal. The elongated cilium phenotype of Tsc1-/- MEFs is likely due to increased mTORC1-dependent autophagic flux observed in these cells, as both the autophagic flux and the cilia length phenotype was restored by rapamycin. In addition, ciliary length control in Tsc1-/- MEFs was also influenced by reduced expression of Gli2, which compromised expression of Wnt5a that normally promotes cilia disassembly. In summary, our results support distinct functions of Tsc1 and Tsc2 in cellular signaling as the two genes affect ciliary length control and HH signaling via different mechanisms. DOI: 10.1007/s00018-018-2761-8 PMID: 29396625
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 75 – Multiple Sklerose: Veröffentlichungen Oktober 2013
61. Cell Mol Neurobiol. 2018 Feb 20. doi: 10.1007/s10571-018-0578-5. [Epub ahead of print] Cuprizone Administration Alters the Iron Metabolism in the Mouse Model of Multiple Sclerosis. Varga E(1), Pandur E(1), Abrahám H(2), Horváth A(3), Ács P(4), Komoly S(4), Miseta A(5), Sipos K(6)(7). Author information: (1)Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Pécs, Rókus str. 2., Pécs, 7624, Hungary. (2)Department of Medical Biology and Central Electron Microscope Laboratory, Medical School, University of Pécs, Szigeti str. 12., Pécs, 7624, Hungary. (3)Department of Neurosurgery, Medical School, University of Pécs, Rét str. 2., Pécs, 7623, Hungary. (4)Department of Neurology, Medical School, University of Pécs, Rét str. 2., Pécs, 7623, Hungary. (5)Department of Laboratory Medicine, Medical School, University of Pécs, Ifjúság str. 13., Pécs, 7624, Hungary. (6)Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Pécs, Rókus str. 2., Pécs, 7624, Hungary. [email protected]. (7), Szigeti str. 12., Pécs, 7624, Hungary. [email protected]. Cuprizone (CZ) is a widely used copper chelating agent to develop non-autoimmune animal model of multiple sclerosis, characterized by demyelination of the corpus callosum (CC) and other brain regions. The exact mechanisms of CZ action are still arguable, but it seems that the only affected cells are the mature oligodendrocytes, possibly via metabolic disturbances caused by copper deficiency. During the pathogenesis of multiple sclerosis, high amount of deposited iron can be found throughout the demyelinated areas of the brain in the form of extracellular iron deposits and intracellularly accumulated iron in microglia. In the present study, we used the accepted experimental model of 0.2% CZ-containing diet with standard iron concentration to induce demyelination in the brain of C57BL/6 mice. Our aim was to examine the changes of iron homeostasis in the CC and as a part of the systemic iron regulation, in the liver. Our data showed that CZ treatment changed the iron metabolism of both tissues; however, it had more impact on the liver. Besides the alterations in the expressions of iron storage and import proteins, we detected reduced serum iron concentration and iron stores in the liver, together with elevated hepcidin levels and feasible disturbances in the Fe-S cluster biosynthesis. Our results revealed that the CZ-containing diet influences the systemic iron metabolism in mice, particularly the iron homeostasis of the liver. This inadequate systemic iron regulation may affect the iron homeostasis of the brain, eventually indicating a relationship among CZ treatment, iron metabolism, and neurodegeneration. DOI: 10.1007/s10571-018-0578-5 PMID: 29464444
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 76 – Multiple Sklerose: Veröffentlichungen Oktober 2013
62. Cell Stem Cell. 2018 Feb 14. pii: S1934-5909(18)30061-4. doi: 10.1016/j.stem.2018.01.020. [Epub ahead of print] Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation. Peruzzotti-Jametti L(1), Bernstock JD(2), Vicario N(3), Costa ASH(4), Kwok CK(5), Leonardi T(3), Booty LM(6), Bicci I(3), Balzarotti B(3), Volpe G(3), Mallucci G(3), Manferrari G(3), Donegà M(3), Iraci N(7), Braga A(3), Hallenbeck JM(8), Murphy MP(6), Edenhofer F(9), Frezza C(10), Pluchino S(11). Author information: (1)Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK. Electronic address: [email protected]. (2)Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK; Stroke Branch, National Institute of Neurological Disorders and Stroke, NIH (NINDS/NIH), Bethesda, MD, USA. (3)Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK. (4)MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK. (5)Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany. (6)MRC Mitochondrial Biology Unit, Hills Road, University of Cambridge, Cambridge, UK. (7)Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK; Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, Via S. Sofia 97, Catania 95125, Italy. (8)Stroke Branch, National Institute of Neurological Disorders and Stroke, NIH (NINDS/NIH), Bethesda, MD, USA. (9)Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany; Institute of Molecular Biology and CMBI, Genomics, Stem Cell Biology and Regenerative Medicine, Leopold- Franzens-University Innsbruck, Innsbruck, Austria. Electronic address: [email protected]. (10)MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK. Electronic address: [email protected]. (11)Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK. Electronic address: [email protected]. Neural stem cell (NSC) transplantation can influence immune responses and suppress inflammation in the CNS. Metabolites, such as succinate, modulate the phenotype and function of immune cells, but whether and how NSCs are also activated by such immunometabolites to control immunoreactivity and inflammatory responses is unclear. Here, we show that transplanted somatic and directly induced NSCs ameliorate chronic CNS inflammation by reducing succinate levels in the cerebrospinal fluid, thereby decreasing mononuclear phagocyte (MP) infiltration and secondary CNS damage. Inflammatory MPs release succinate, which activates succinate receptor 1 (SUCNR1)/GPR91 on NSCs, leading them to secrete prostaglandin E2 and scavenge extracellular succinate with consequential anti-inflammatory effects. Thus, our work reveals an unexpected role for the succinate- SUCNR1 axis in somatic and directly induced NSCs, which controls the response of stem cells to inflammatory metabolic signals released by type 1 MPs in the chronically inflamed brain. Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.stem.2018.01.020 PMID: 29478844
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63. Cerebellum. 2018 Feb 19. doi: 10.1007/s12311-018-0925-6. [Epub ahead of print] Time Is Cerebellum. Mitoma H(1), Manto M(2)(3)(4), Hampe CS(5). Author information: (1)Medical Education Promotion Center, Tokyo Medical University, Tokyo, Japan. [email protected]. (2)Unité d'Etude du Mouvement (UEM), FNRS, ULB-Erasme, 1070, Bruxelles, Belgium. (3)Service des Neurosciences, University of Mons, 7000, Mons, Belgium. (4)Department of Neurology, Centre Hospitalier Universitaire (CHU) de Charleroi, 6000, Charleroi, Belgium. (5)School of Medicine, University of Washington, Seattle, WA, 98109, USA. The cerebellum characteristically has the capacity to compensate for and restore lost functions. These compensatory/restorative properties are explained by an abundant synaptic plasticity and the convergence of multimodal central and peripheral signals. In addition, extra-cerebellar structures contribute also to the recovery after a cerebellar injury. Clinically, some patients show remarkable improvement of severe ataxic symptoms associated with trauma, stroke, metabolism, or immune- mediated cerebellar ataxia (IMCA, e.g., multiple sclerosis, paraneoplastic cerebellar degeneration, gluten ataxia, anti-GAD65 antibody-associated cerebellar ataxia). However, extension of a cerebellar lesion can impact upon the fourth ventricle or the brainstem, either by direct or indirect mechanisms, leading to serious complications. Moreover, cerebellar reserve itself is affected by advanced cell loss and, at some point of disease progression, deficits become irreversible. Such phase transition from a treatable/restorable state (the reserve is still sufficient) to an untreatable state (the reserve is severely affected) is a loss of therapeutic opportunity, highlighting the need for early treatment during the restorable stage. Based on the motto of "Time is Brain," a warning that stresses the importance of early therapeutic intervention in ischemic diseases, we propose "Time is Cerebellum" as a principle in the management of patients with cerebellar diseases, especially immune ataxias whose complexity often delay the therapeutic intervention. Indeed, this concept should not be restricted to ischemic cerebellar diseases. We argue that every effort should be made to reduce the diagnostic delay and to initiate early therapy to avoid the risk of transition from a treatable state to an irreversible condition and an associated accumulation of disability. The myriad of disorders affecting the cerebellum is a challenging factor that may contribute to irreversible disability if the window of therapeutic opportunity is missed. DOI: 10.1007/s12311-018-0925-6 PMID: 29460203
64. Cesk Slov Oftalmol. 2017 Fall;73(3):101-108. Diagnostic potential of tears in ophthalmology. Glinská G, Krajčíková K, Tomečková V. In research circles, there is an increasing need to seek and identify new methods in the diagnosis of pathologies, monitoring the progression of the disease and response to treatment. The sensitivity of detection technologies has improved markedly, and enables the quantification of analyses in very small quantities. Tears represent a biological material with ever increasingly developing possibilities in the diagnosis of various pathologies. Our objective was to compile a basic overview of the diagnostic potential of tears via a summary of the potential lachrymal biomarkers of various pathologies. The article contains descriptions of protein biomarkers studied particularly in recent years, which correlate with a certain ocular pathology (dry eye, allergy, glaucoma etc.). It also summarises the results published to date in the field of systemic pathologies in patients with scleroderma, cystic fibrosis, diabetes mellitus, multiple sclerosis, cancers and Parkinson's disease. It concentrates on proteomic analyses, with the aim of improving the effectiveness of markers which could be used in future also in the timely diagnosis of ocular pathologies in clinical practice.Key words: Tears, proteins, biomarker, ocular pathologies, systemic pathologies. PMID: 29394076
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65. Cleve Clin J Med. 2018 Feb;85(2):155-163. doi: 10.3949/ccjm.85a.17022. Transient neurologic syndromes: A diagnostic approach. Abbatemarco JR(1), Rae-Grant AD(2)(3). Author information: (1)Department of Neurology, Cleveland Clinic, Cleveland, OH, USA. [email protected]. (2)Mellen Center for Multiple Sclerosis, Department of Neurology, Cleveland Clinic, Cleveland, OH, USA. (3)Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA. Clinicians are often confronted with patients who have transient neurologic symptoms lasting seconds to hours. In many of these patients, their symptoms have gone away or returned to baseline by the time of evaluation, making the diagnosis even more challenging. Elements such as correlation of symptoms with vascular territory, prodromes, triggers, motor symptoms, confusion, and sleep behavior can guide the diagnostic workup. Copyright © 2018 Cleveland Clinic. DOI: 10.3949/ccjm.85a.17022 PMID: 29425086
66. Clin Chem Lab Med. 2018 Feb 6. pii: /j/cclm.ahead-of-print/cclm-2017-0911/cclm-2017-0911.xml. doi: 10.1515/cclm-2017-0911. [Epub ahead of print] Search for new biomarkers of pediatric multiple sclerosis: application of immunoglobulin free light chain analysis. Ganelin-Cohen E(1), Golderman S(2), Yeskaraev R(3), Rozenberg A(4), Livneh A(5), Kaplan B(2). Author information: (1)Institute of Pediatric Neurology, Schneider Children's Medical Center, Petach Tikva 49202, Israel. (2)Heller Institute of Medical Research, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. (3)Department of Clinical Biochemistry, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. (4)Department of Neuroimmunology, Rambam Health Care Campus, Haifa, Israel. (5)Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. BACKGROUND: Identifying new biomarkers is needed to overcome the diagnostic difficulties of pediatric multiple sclerosis (MS). Recently, we developed a new technique including CSF analysis of free light chain (FLC) monomers and dimers, which can improve diagnosis of adult MS. The present study has been designed to evaluate the utility of our technique for MS diagnosis in children. METHODS: Patients with MS (n=21) and non-MS demyelinating or inflammatory neurological disorders (n=35) participated in the study. MS diagnosis was based on clinical and magnetic resonance imaging (MRI) findings. Western blot analysis was applied to examine FLC in the patients' CSF and serum. FLC indices for FLC monomer and dimer levels and κ/λ ratios were estimated. The samples were also analyzed by oligoclonality test. RESULTS: The study revealed abnormally elevated levels of κ-FLC monomers and dimers in the CSF of 10 MS patients ("κ-type MS"). Increased amounts of λ dimers were found in six MS cases ("λ-type MS"), while high levels of both κ and λ FLC ("mixed type MS") were documented in three MS cases. MRI and clinical assessment showed a more aggressive disease form for the "mixed" and "λ-type" cases. Our method demonstrated higher sensitivity (90.5%) and specificity (91.4%) for discrimination between MS and non-MS patients, as compared to oligoclonality test (81% and 65.7%, respectively). CONCLUSIONS: The proposed method may significantly contribute to diagnosis and prognosis of pediatric MS. DOI: 10.1515/cclm-2017-0911 PMID: 29408796
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67. Clin Chem Lab Med. 2018 Feb 19. pii: /j/cclm.ahead-of-print/cclm-2017-0901/cclm-2017- 0901.xml. doi: 10.1515/cclm-2017-0901. [Epub ahead of print] CSF free light chain identification of demyelinating disease: comparison with oligoclonal banding and other CSF indexes. Gurtner KM(1), Shosha E(2), Bryant SC(3), Andreguetto BD(4), Murray DL(1), Pittock SJ(2), Willrich MAV(1). Author information: (1)Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. (2)Department of Neurology, Mayo Clinic, Rochester, MN, USA. (3)Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. (4)University of Campinas, Sao Paulo, Brazil. BACKGROUND: Cerebrospinal fluid (CSF) used in immunoglobulin gamma (IgG) index testing and oligoclonal bands (OCBs) are common laboratory tests used in the diagnosis of multiple sclerosis. The measurement of CSF free light chains (FLC) could pose as an alternative to the labor-intensive isoelectric-focusing (IEF) gels used for OCBs. METHODS: A total of 325 residual paired CSF and serum specimens were obtained after physician-ordered OCB IEF testing. CSF kappa (cKFLC) and lambda FLC (cLFLC), albumin and total IgG were measured. Calculations were performed based on combinations of analytes: CSF sum of kappa and lambda ([cKFLC+cLFLC]), kappa-index (K-index) ([cKFLC/sKFLC]/[CSF albumin/serum albumin]), kappa intrathecal fraction (KFLCIF) {([cKFLC/sKFLC]-[0.9358×CSF albumin/serum albumin]^[0.6687×sKFLC]/cKFLC)} and IgG-index ([CSF IgG/CSF albumin]/[serum IgG/serum albumin]). RESULTS: Patients were categorized as: demyelination (n=67), autoimmunity (n=53), non-inflammatory (n=50), inflammation (n=38), degeneration (n=28), peripheral neuropathy (n=24), infection (n=13), cancer (n=11), neuromyelitis optica (n=10) and others (n=31). cKFLC measurement used alone at a cutoff of 0.0611 mg/dL showed >90% agreement to OCBs, similar or better performance than all other calculations, reducing the number of analytes and variables. When cases of demyelinating disease were reviewed, cKFLC measurements showed 86% clinical sensitivity/77% specificity. CONCLUSIONS: cKFLC alone demonstrates comparable performance to OCBs along with increased sensitivity for demyelinating diseases. Replacing OCB with cKFLC would alleviate the need for serum and CSF IgG and albumin and calculated conversions. cKFLC can overcome challenges associated with performance, interpretation, and cost of traditional OCBs, reducing costs and maintaining sensitivity and specificity supporting MS diagnosis. DOI: 10.1515/cclm-2017-0901 PMID: 29455184
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68. Clin Immunol. 2018 Feb 12. pii: S1521-6616(17)30674-5. doi: 10.1016/j.clim.2018.02.005. [Epub ahead of print] Dysfunction of CD3-CD16+CD56dim and CD3-CD16-CD56bright NK cell subsets in RR-MS patients. Tahrali I(1), Kucuksezer UC(1), Altintas A(2), Uygunoglu U(2), Akdeniz N(1), Cetin EA(1), Deniz G(3). Author information: (1)Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Istanbul, Turkey. (2)Istanbul University, Cerrahpasa Faculty of Medicine, Department of Neurology, Istanbul, Turkey. (3)Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Istanbul, Turkey. Electronic address: [email protected]. Multiple sclerosis (MS), is a chronic inflammatory disease of central nervous system with unclear etiology. Relapsing-remitting (RR)-MS is the most frequent subtype of disease. Natural Killer (NK) cells have roles in cytotoxicity and immune regulation by cytokine secretions, with uncertain contribution to MS pathogenesis. This study aimed to explore contribution of NK cells to MS pathogenesis. Percentages of CD3-CD16+CD56+ total NK cells, CD3-CD16+CD56dim and CD3- CD16-CD56bright NK cell subsets, NK cytotoxicity and intracellular IFN-γ, IL-10 and IL-22 levels were investigated in patients with RR-MS and clinically isolated syndrome (CIS) as well as healthy subjects. Findings support the possible contribution of NK cells to RR-MS immunopathogenesis. Decreased IFN-γ and increased IL-22 production might have detrimental effects on the clinical course of RR-MS. Impaired cytotoxicity is correlated with disease duration in RR-MS. Moreover, NK cell ratios and EDSS values are negatively correlated in CIS revealing a possible protective role in converting to RR-MS. Copyright © 2017. Published by Elsevier Inc. DOI: 10.1016/j.clim.2018.02.005 PMID: 29448007
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69. Clin Med Insights Case Rep. 2018 Feb 5;11:1179547617752685. doi: 10.1177/1179547617752685. eCollection 2018. A Rare Presentation of Neuromyelitis Optica Spectrum Disorders. Singh NK(1), Sweidan AJ(1), Strube S(1), Carrillo-Nunez I(1). Author information: (1)Internal Medicine Residency Program, St. Mary Medical Center and UCLA, Long Beach, CA, USA. Neuromyelitis optica spectrum disorders (NMOSDs) are a set of demyelinating disorders that primarily target the optic nerves and the spinal cord. Previously thought to be a subset of multiple sclerosis (MS), now is recognized as a distinct entity. We present a 59-year-old female patient who was admitted for acute upper and lower extremity weakness. The patient had woken up from sleep with sudden onset of weakness. Patient was initially diagnosed with a right hemispheric stroke; however, magnetic resonance imaging of the cervical spine later performed showed abnormal enhancement from C2-C4, representing transverse myelitis. Cerebrospinal fluid was negative for organisms and inflammatory biomarkers. An anti-aquaporin-4 receptor antibody titer was found to be elevated with titers >80 units/mL. The patient was treated with high-dose steroids and plasmapheresis. The NMOSD is a rare entity and, here, we present a rare presentation of the disease. Since its description in 1870, it was confused with MS for years. The advent of anti-aquaporin-4 antibody has been instrumental in differentiating the disease process from MS. This distinction is important, in terms of agents used for treatment and prognostication. The NMOSD is a set of debilitating disease, which requires prompt recognition and appropriate treatment, to avoid the disabling sequelae. Future prospects of the disease include development of novel biological treatment modalities which focus on restoring the loss of immune tolerance which is key to the pathogenesis of the disease. DOI: 10.1177/1179547617752685 PMCID: PMC5802599 PMID: 29434480
Conflict of interest statement: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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70. Clin Neurol Neurosurg. 2018 Feb 8. pii: S0303-8467(18)30041-6. doi: 10.1016/j.clineuro.2018.01.035. [Epub ahead of print] Multiple sclerosis or "inflammatory CADASIL?": Case Report and review of the literature. Schiess N(1), Huether K(2), Szolics M(3), Agarwal G(4), El-Hattab AW(5), Sathe S(6). Author information: (1)Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, United States; Department of Neurology, Tawam Hospital, Al Ain, United Arab Emirates. Electronic address: [email protected]. (2)Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, United States. (3)Department of Neurology, Tawam Hospital, Al Ain, United Arab Emirates. (4)Department of Neuroradiology, Johns Hopkins Hospital, Baltimore, MD, United States; Unit of Radiology, Hospital "S.Maria del Carmine" (APSS), Rovereto, Italy. (5)Division of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates. (6)Department of Neurology, Rutgers University, NJ, United States. BACKGROUND: Multiple sclerosis (MS) and CADASIL presenting together is exceedingly rare. As more cases of "inflammatory" CADASIL emerge, diagnostic challenges for clinicians increase. We report an individual with MS and CADASIL presenting with cognitive decline at age 25. She presented with gadolinium enhancing lesions on MRI and inflammatory cerebrospinal fluid raising the question of whether these patients should be given a diagnosis of "inflammatory CADASIL" or both MS and CADASIL. METHODS: A literature review was conducted on reports of inflammatory CADASIL or MS and CADASIL, clinical presentations including spinal cord lesions and CSF inflammatory markers. RESULTS: Nine cases in the literature of individuals with CADASIL and inflammatory presentations were found with treatment varying from intravenous steroids to MS immunomodulatory therapy. CONCLUSIONS: If individuals with CADASIL present with immune mediated inflammatory components they may benefit from immunomodulatory therapy. This is discussed with a review of the inflammatory CADASIL/MS cases in the literature and report of a case. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.clineuro.2018.01.035 PMID: 29449082
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71. Clin Neurol Neurosurg. 2018 Feb 11;167:76-81. doi: 10.1016/j.clineuro.2018.02.014. [Epub ahead of print] Effect of comorbidities on the course of multiple sclerosis. Puz P(1), Lasek-Bal A(2), Steposz A(2), Bartoszek K(3), Radecka P(3). Author information: (1)Department of Neurology, Medical University of Silesia, Professor Leszek Giec Upper Silesian Medical Centre, Katowice, Poland; School of Health Sciences in Katowice, Medical University of Silesia, Katowice, Poland. Electronic address: [email protected]. (2)Department of Neurology, Medical University of Silesia, Professor Leszek Giec Upper Silesian Medical Centre, Katowice, Poland; School of Health Sciences in Katowice, Medical University of Silesia, Katowice, Poland. (3)Department of Neurology, Medical University of Silesia, Professor Leszek Giec Upper Silesian Medical Centre, Katowice, Poland. OBJECTIVE: The clinical condition of multiple sclerosis (MS) patients depends not only on the course of MS but also on their lifestyle and comorbidities. This study aimed to assess the effect of selected comorbidities, lifestyle-related factors and clinical data available at the time of MS diagnosis, on the disease activity and the disability progression in patients with relapsing-remitting multiple sclerosis (RRMS). PATIENTS AND METHODS: Based on clinical relapses over a period of 12 months of observation and the results of MRI scans, 138 patients with RRMS were qualified into two groups: 'active' or 'stable' course of the disease. Patients from both groups were compared regarding the clinical data determined at diagnosis, comorbidities and lifestyle-related factors. Similar comparisons were carried out between patients with EDSS < 3 vs, patients with EDSS ≥ 3. RESULTS: No significant differences in comorbidities and lifestyle-related data between the stable and active group were detected. Arterial hypertension, hyperlipidemia, higher BMI values, older age and a lower education level, were found more frequently in patients with EDSS ≥ 3. Oligoclonal bands, multifocal clinical manifestation as the first relapse, higher EDSS score and many T2 MRI lesions at the diagnosis were detected significantly more often in the active group. Motor or brainstem/cerebellum damage symptoms as the first relapse were observed more frequently in patients with EDSS ≥ 3. CONCLUSIONS: Cardiovascular diseases may exacerbate disability progression in MS patients. Relapses and radiological activity do not depend on chronic comorbidities. Clinical data available at the diagnosis may be useful in forecasting a distant course of MS. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.clineuro.2018.02.014 PMID: 29459257
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72. Clin Neuropharmacol. 2018 Jan 31. doi: 10.1097/WNF.0000000000000268. [Epub ahead of print] Safety and Efficacy of Rituximab: Experience of a Single Multiple Sclerosis Center. Alldredge B(1), Jordan A, Imitola J, Racke MK. Author information: (1)The Ohio State University Wexner Medical Center, Columbus, OH. OBJECTIVES: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. B cells play an important pathogenic role in MS. Rituximab (RTX), a B-cell depleting drug, has been used to treat MS and neuromyelitis optica (NMO). Patient characteristics, safety, and efficacy measures are reviewed to ascertain the therapeutic benefit and safety of RTX in a real-world setting with long-term follow-up. METHODS: This is a retrospective chart review of patients who received RTX at The Ohio State University's MS clinic from January 2005 to October 2016. RESULTS: Of the 64 patient charts reviewed, 23 had a relapsing remitting MS, 17 had primary progressive MS (PPMS), and 24 had NMO. In the relapsing remitting MS cohort, there was an annual relapse rate of 0.005 and 87% were reported as clinically stable at the end of the chart review period. In the primary progressive MS cohort, 47% were reported as clinically stable at the end of the chart review period. In the NMO cohort, there was an annual relapse rate of 0.0074 and 79% were reported as clinically stable at the end of the chart review period. A total of 29 infusion reactions were reported in 21 patients. None were serious and only 1 patient elected to stop RTX due to an adverse event. CONCLUSIONS: Rituximab demonstrated good tolerability and efficacy in cases of both relapsing and progressive forms of MS and NMO. DOI: 10.1097/WNF.0000000000000268 PMID: 29389745
73. Clin Neuropharmacol. 2018 Feb 22. doi: 10.1097/WNF.0000000000000272. [Epub ahead of print] Dextromethorphan/Quinidine in Migraine Prophylaxis: An Open-label Observational Clinical Study. Berkovich RR, Sokolov AY, Togasaki DM, Yakupova AA, Cesar PH, Sahai-Srivastava S. OBJECTIVE: This study aimed to assess potential efficacy and safety of dextromethorphan/quinidine (DMQ) in prophylactic treatment of migraine in patients with multiple sclerosis (MS) with superimposed pseudobulbar affect (PBA). METHODS: Multiple sclerosis patients with superimposed PBA and comorbid migraine were enrolled into this open-label observational study at the University of Southern California Comprehensive MS Center. The baseline characteristics included, among other data, frequency and severity of acute migraine attacks and use of migraine relievers. The DMQ was used exclusively per its primary indication - PBA symptoms control - 20/10 mg orally, twice a day for the mean of 4.5 months (the shortest exposure registered was 3 months and the longest, 6 months). To determine whether treatment caused an effect on migraine frequency and severity, the baseline and posttreatment values were compared using nonparametric sign test. RESULTS: Thirty-three MS subjects with PBA, who also suffered from migraines, were identified. Twenty-nine subjects had improvement in headache frequency, 4 had no change, and none had worsening (P < 0.001 as compared with the baseline). Twenty-eight subjects had improvement in headache severity, 5 had no change, and none had worsening (P < 0.001). CONCLUSIONS: Our pilot study results provide evidence that DMQ shows promise as a candidate for larger clinical studies evaluating its efficacy for the prevention of migraine headaches. DOI: 10.1097/WNF.0000000000000272 PMID: 29474194
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74. Clin Neurophysiol. 2018 Mar;129(3):646-653. doi: 10.1016/j.clinph.2018.01.002. Epub 2018 Jan 17. The utility of motor unit number estimation methods versus quantitative motor unit potential analysis in diagnosis of ALS. Jacobsen AB(1), Kristensen RS(1), Witt A(1), Kristensen AG(2), Duez L(1), Beniczky S(1), Fuglsang- Frederiksen A(1), Tankisi H(3). Author information: (1)Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark. (2)Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark; Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. (3)Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: [email protected]. OBJECTIVE: To compare the diagnostic utility of motor unit number estimation (MUNE) methods to motor unit potential (MUP) analysis in amyotrophic lateral sclerosis (ALS). METHODS: Twenty-five patients (1 definite, 11 probable, 9 possible ALS and 4 progressive muscular atrophy) and 22 healthy controls were prospectively included. Quantitative MUP analysis and three MUNE methods; Multiple Point Stimulation MUNE (MPS), Motor Unit Number Index (MUNIX) and MScanFit MUNE (MScan) were done in abductor pollicis brevis muscle. The sensitivities were compared by McNemar chi- square test. MUNE, MUP and revised ALS Functional Rating Scale (ALSFRS-R) parameters were correlated by regression analysis. RESULTS: The sensitivities of MPS (76%) and MScan (68%) were higher than MUP duration (36%) and amplitude (40%) in detecting motor unit loss (p < 0.05). MUNE methods increased the categorical probability from possible to probable ALS in 4 patients (16%). There was only significant correlation between ALSFRS-R and MScan (r = 0.443, p = 0.027) among the electrophysiological tests. MUNE methods did not correlate to MUP parameters. CONCLUSIONS: MUNE methods are more sensitive in showing abnormality than MUP analysis. SIGNIFICANCE: MUNE methods, in particular MScan, may have the potential to be implemented in the clinical practice for diagnosis and follow-up of neuromuscular disorders particularly ALS. Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.clinph.2018.01.002 PMID: 29414408
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75. Clin Rev Allergy Immunol. 2018 Feb 19. doi: 10.1007/s12016-018-8679-y. [Epub ahead of print] The Immunologic Paradoxes of IgG4-Related Disease. Xiao X(1)(2)(3)(4), Lian M(1)(2)(3)(4), Zhang W(5), Eric Gershwin M(6), Ma X(7)(8)(9)(10). Author information: (1)Division of Gastroenterology and Hepatology, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China. (2)Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai JiaoTong University; Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China. (3)State Key Laboratory for Oncogenes and Related Genes, Shanghai JiaoTong University; Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China. (4)Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China. (5)Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA. (6)Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA. [email protected]. (7)Division of Gastroenterology and Hepatology, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China. [email protected]. (8)Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai JiaoTong University; Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China. [email protected]. (9)State Key Laboratory for Oncogenes and Related Genes, Shanghai JiaoTong University; Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China. [email protected]. (10)Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China. [email protected]. IgG4-related disease (IgG4-RD), which usually occurs in middle-aged and elderly men, is a newly recognized fibroinflammatory condition characterized by swelling and sclerosis of involved organs, increased IgG4-positive plasma cell infiltration in lesions, and elevated IgG4 concentration in serum. Despite growing interest in the research, the pathophysiological mechanism remains elusive. Most IgG4-RD patients respond well to steroid therapy initially, but recurrent and refractory cases are common, especially in advanced fibrotic stage. Recent studies have documented the heterogeneity of the B cell lineages, which suggests their multiple functions in IgG4-RD beyond IgG4 production, such as cytokine secretion, antigen presentation, autoantibody production, and modulation of T and B cell interactions. Thus, a critical balance exists between pathogenic and regulatory B subsets to prevent immunopathology. A prompt response to B cell depletion therapy reported in recent cases strongly suggests the imbalance within B cell lineages in IgG4-RD. A more precise understanding of the pathogenesis of IgG4-RD will open up new perspectives for therapeutic strategy. With a particular emphasis on the novel B cell-targeted therapeutic strategies, this review highlights the immunologic features of IgG4-RD and the possible roles of B cell lineages in the pathogenesis of IgG4-RD. DOI: 10.1007/s12016-018-8679-y PMID: 29460058
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 87 – Multiple Sklerose: Veröffentlichungen Oktober 2013
76. CNS Drugs. 2018 Feb 7. doi: 10.1007/s40263-018-0489-5. [Epub ahead of print] Depression in Multiple Sclerosis: Epidemiology, Aetiology, Diagnosis and Treatment. Solaro C(1), Gamberini G(2), Masuccio FG(2). Author information: (1)Department of Rehabilitation, C.R.R.F. "Mons. L. Novarese", Trompone Street, Moncrivello, VC, Italy. [email protected]. (2)Department of Rehabilitation, C.R.R.F. "Mons. L. Novarese", Trompone Street, Moncrivello, VC, Italy. Depressive disorders are common in patients with multiple sclerosis, influencing their quality of life and adherence to treatments, as well as becoming more frequent with the progression of the disease and in the secondary progressive form of multiple sclerosis. Patients with multiple sclerosis often experience a typical cluster of symptoms in association with depression, such as fatigue, pain and cognitive impairment. However, the pathogenesis of multiple sclerosis-related depression remains partially unclear, even though genetic, immune-inflammatory and psychosocial factors might be seen to play a role, in addition to the brain structural alterations documented by magnetic resonance imaging studies. The high incidence and burden of depression in people affected with multiple sclerosis are matters of crucial importance. Despite such importance, the efficacy of pharmacologic treatments has been poorly studied and, for the most part, the access to non-pharmacological treatments is partially dependent on the local health system availability. It has been determined that interferon-beta and glatiramer acetate do not cause depressive symptoms; however, no definitive data in this regard are avaible for the newer disease-modifyng medications. In this review, we discuss the diagnosis, prevalence, pathogenesis, clinical aspects, magnetic resonance imaging findings and treatments available in patients experiencing multiple sclerosis-related depression. DOI: 10.1007/s40263-018-0489-5 PMID: 29417493
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77. CNS Neurosci Ther. 2018 Jan 31. doi: 10.1111/cns.12810. [Epub ahead of print] Effects of repeated long-term psychosocial stress and acute cannabinoid exposure on mouse corticostriatal circuitries: Implications for neuropsychiatric disorders. Tomas-Roig J(1)(2)(3), Piscitelli F(4), Gil V(5)(6), Quintana E(3), Ramió-Torrentà LL(3), Del Río JA(5)(6), Moore TP(1)(2)(7), Agbemenyah H(8), Salinas G(9), Pommerenke C(9), Lorenzen S(10)(11), Beißbarth T(10), Hoyer-Fender S(12), Di Marzo V(4), Havemann-Reinecke U(1)(2). Author information: (1)Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany. (2)Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. (3)Girona Neuroimmunology and Multiple Sclerosis Unit (UNIEMTG), Dr. Josep Trueta University Hospital and Neurodegeneration and Neuroinflammation Research Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain. (4)Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy. (5)Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. (6)Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain. (7)Department of Child and Adolescent Psychiatry, University Hospital Münster, Münster, Germany. (8)Laboratory for Aging and Cognitive Diseases, European Neuroscience Institute, Goettingen, Germany. (9)Department of Developmental Biochemistry, Georg-August- Universität Göttingen, Göttingen, Germany. (10)Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany. (11)Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. (12)Johann-Friedrich-Blumenbach Institute for Zoology and Anthropology, Developmental Biology, Göttingen, Germany. INTRODUCTION: Vulnerability to psychiatric manifestations is achieved by the influence of genetic and environment including stress and cannabis consumption. Here, we used a psychosocial stress model based on resident-intruder confrontations to study the brain corticostriatal-function, since deregulation of corticostriatal circuitries has been reported in many psychiatric disorders. CB1 receptors are widely expressed in the central nervous system and particularly, in both cortex and striatum brain structures. AIMS AND METHODS: The investigation presented here is addressed to assess the impact of repeated stress following acute cannabinoid exposure on behavior and corticostriatal brain physiology by assessing mice behavior, the concentration of endocannabinoid and endocannabinoid-like molecules and changes in the transcriptome. RESULTS: Stressed animals urinated frequently; showed exacerbated scratching activity, lower striatal N-arachidonylethanolamine (AEA) levels and higher cortical expression of cholinergic receptor nicotinic alpha 6. The cannabinoid agonist WIN55212.2 diminished locomotor activity while the inverse agonist increased the distance travelled in the center of the open field. Upon CB1 activation, N-oleoylethanolamide and N- palmitoylethanolamide, two AEA congeners that do not interact directly with cannabinoid receptors, were enhanced in the striatum. The co-administration with both cannabinoids induced an up-regulation of striatal FK506 binding protein 5. The inverse agonist in controls reversed the effects of WIN55212.2 on motor activity. When Rimonabant was injected under stress, the cortical levels of 2- arachidonoylglycerol were maximum. The agonist and the antagonist influenced the cortical expression of cholinergic receptor nicotinic alpha 6 and serotonin transporter neurotransmitter type 4 in opposite directions, while their co-administration tended to produce a null effect under stress. CONCLUSIONS: The endocannabinoid system had a direct effect on serotoninergic neurotransmission and glucocorticoid signaling. Cholinergic receptor nicotinic alpha-6 was shown to be deregulated in response to stress and following synthetic cannabinoid drugs thus could confer vulnerability to cannabis addiction and psychosis. Targeting the receptors of endocannabinoids and endocannabinoid-like mediators might be a valuable option for treating stress-related neuropsychiatric symptoms. © 2018 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd. DOI: 10.1111/cns.12810 PMID: 29388323
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78. Cold Spring Harb Perspect Med. 2018 Feb 12. pii: a028951. doi: 10.1101/cshperspect.a028951. [Epub ahead of print] Genetics of Multiple Sclerosis: An Overview and New Directions. Patsopoulos NA(1)(2). Author information: (1)Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115. (2)Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142. The contribution of genetic inheritance in multiple sclerosis was established early on. Although multiple sclerosis is not a Mendelian disease, its incidence and prevalence is higher in family members of affected individuals compared with the general population. Throughout the last decade, several small studies failed to identify any robust genetic associations besides the classic associations in the major histocompatibility complex region. During the past few years, genome-wide association studies (GWAS) have revolutionized the genetics of multiple sclerosis, uncovering more than 200 implicated genetic loci. Here, we describe these main findings and discuss the new avenues that these discoveries lay open. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved. DOI: 10.1101/cshperspect.a028951 PMID: 29440325
79. Cold Spring Harb Perspect Med. 2018 Feb 12. pii: a029249. doi: 10.1101/cshperspect.a029249. [Epub ahead of print] The Evolving Mechanisms of Action of Glatiramer Acetate. Prod'homme T(1), Zamvil SS(2). Author information: (1)Momenta Pharmaceuticals, Cambridge, Massachusetts 02142. (2)Department of Neurology and Program in Immunology, University of California, San Francisco, San Francisco, California 94158. Glatiramer acetate (GA) is a synthetic amino acid copolymer that is approved for treatment of relapsing remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS). GA reduces multiple sclerosis (MS) disease activity and has shown comparable efficacy with high-dose interferon- β. The mechanism of action (MOA) of GA has long been an enigma. Originally, it was recognized that GA treatment promoted expansion of GA-reactive T-helper 2 and regulatory T cells, and induced the release of neurotrophic factors. However, GA treatment influences both innate and adaptive immune compartments, and it is now recognized that antigen-presenting cells (APCs) are the initial cellular targets for GA. The anti-inflammatory (M2) APCs induced following treatment with GA are responsible for the induction of anti-inflammatory T cells that contribute to its therapeutic benefit. Here, we review studies that have shaped our current understanding of the MOA of GA. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved. DOI: 10.1101/cshperspect.a029249 PMID: 29440323
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80. Cold Spring Harb Perspect Med. 2018 Feb 12. pii: a028985. doi: 10.1101/cshperspect.a028985. [Epub ahead of print] Neurodegeneration in Progressive Multiple Sclerosis. Campbell G(1), Mahad D(1). Author information: (1)The Centre for Clinical Brain Science, University of Edinburgh, Chancellor's Building, Edinburgh EH16 4SB, United Kingdom. The neuron is the target of inflammatory demyelinating processes in multiple sclerosis (MS). In progressive MS, however, there is a gathering body of evidence indicating molecular changes within neuronal cell bodies. All of these molecular changes to intrinsic neurons converge on mitochondria, and the most reproduced change relates to mitochondrial respiratory chain complex deficiency. This compromise in the capacity to generate ATP in the neuronal cell body is coupled with an increased demand for energy by the demyelinated axon, which is particularly relevant to the long tracts such as corticospinal tracts with long projection axons. Recent work in our laboratory and that of our collaborators indicate limited reflection of the molecular changes that are intrinsic neurons in the experimental disease models. The mitochondrial changes within neuronal compartments are an under-recognized aspect of progressive MS and likely to offer novel targets for the improvement of neuronal function as well as neuroprotection. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved. DOI: 10.1101/cshperspect.a028985 PMID: 29440322
81. Cold Spring Harb Perspect Med. 2018 Feb 1;8(2). pii: a028993. doi: 10.1101/cshperspect.a028993. Microglial Phenotypes and Functions in Multiple Sclerosis. O'Loughlin E(1), Madore C(1), Lassmann H(2), Butovsky O(1)(3). Author information: (1)Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115. (2)Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria. (3)Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115. Microglia are the resident immune cells that constantly survey the central nervous system. They can adapt to their environment and respond to injury or insult by altering their morphology, phenotype, and functions. It has long been debated whether microglial activation is detrimental or beneficial in multiple sclerosis (MS). Recently, the two opposing yet connected roles of microglial activation have been described with the aid of novel microglial markers, RNA profiling, and in vivo models. In this review, microglial phenotypes and functions in the context of MS will be discussed with evidence from both human pathological studies, in vitro and in vivo models. Microglial functional diversity-phagocytosis, antigen presentation, immunomodulation, support, and repair-will also be examined in detail. In addition, this review discusses the emerging evidence for microglia-related targets as biomarkers and therapeutic targets for MS. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved. DOI: 10.1101/cshperspect.a028993 PMID: 29419406
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82. Colloids Surf B Biointerfaces. 2018 Feb 5. pii: S0927-7765(18)30075-4. doi: 10.1016/j.colsurfb.2018.02.006. [Epub ahead of print] Counting of peripheral extracellular vesicles in Multiple Sclerosis patients by an improved nanoplasmonic assay and dynamic light scattering. Mallardi A(1), Nuzziello N(2), Liguori M(3), Avolio C(4), Palazzo G(5). Author information: (1)CNR-IPCF, National Research Council of Italy, Institute for the Chemical Physics Processes, Division of Bari, Bari, Italy. (2)National Research Council of Italy, Institute of Biomedical Technologies, Section of Bari, Bari, Italy; Department of Basic Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy. (3)National Research Council of Italy, Institute of Biomedical Technologies, Section of Bari, Bari, Italy. (4)Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. (5)Department of Chemistry and Center for colloid and surface science (CSGI), University of Bari, Bari, Italy; CNR-NANOTEC, National Research Council of Italy, Istitute of Nanotechnology, Bari, Italy. Electronic address: [email protected]. Extracellular vesicles (EVs) are vesicles naturally secreted by the majority of human cells. Being composed by a closed phospholipid bilayer secluding proteins and RNAs they are used to transfer molecular information to other cells, thereby influencing the recipient cell functions. Despite the increasingly recognized relevance of EVs, the clarification of their physiological role is hampered by the lack of suitable analytical tools for their quantification and characterization. In this study, we have implemented a nanoplasmonic assay, previously proposed for the purity of the EV fractions, to achieve a robust analytical protocol in order to quantify the total phospholipid concentration (CPL) and the EVs number. We show how the coupling of the nanoplasmonic assay with serial dilutions of the unknown sample allows, by simple visual inspection, to detect deviations from the physiological EVs content. The use of a response that depends on the absorbance values at three wavelengths permits to reduce the limit of detection of CPL to 5 μM (total) and the limit of quantification to 35 μM. We also propose a method that takes into account the spread in EV size when the concentration of phospholipids is turned into a concentration of vesicles. The proposed analytical protocol is successfully applied to a small cohort of Multiple Sclerosis patients examined in different stages of their clinical diseases. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.colsurfb.2018.02.006 PMID: 29428682
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83. Complement Ther Med. 2018 Feb;36:123-128. doi: 10.1016/j.ctim.2017.12.011. Epub 2018 Jan 2. Management of IFN-beta-induced flu-like symptoms with Chinese herbal medicine in a patient with multiple sclerosis: A case report. Lee LW(1), Lin HJ(2), Huang ST(3). Author information: (1)Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan. (2)Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan. (3)Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan; Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan. Electronic address: [email protected]. OBJECTIVE: The purpose of this case report was to elucidate how Chinese herbal medicine (CHM) was used safely in this patient undergoing interferon beta (IFNβ-1a) treatment and was associated with reduction in the side effects the patient had experienced when using IFNβ-1a treatment alone. CLINICAL FEATURES AND OUTCOME: A 30-year-old man was diagnosed with MS in December 2014. For two years, he suffered from severe flu-like symptoms as side effects of IFNβ-1a treatment. He subsequently received treatment with Chinese herbal medicine. During a two-month period of treatment with CHM, the patient responded well, with most of the symptoms induced by IFNβ-1a ameliorated. The fever subsided. Incidence rates of dizziness and headaches were reduced. The health condition compared to the prior year increased by 50%. According to CCMQ and SF-36 assessments, CHM had the beneficial effects of recovering the yin-yang balance, harmonizing the qi, and regulating the blood state; essentially, improving the patient's comfort level and quality of life. CONCLUSIONS: IFNβ-1a injections will damage qi and cause blood stasis in MS patients, thereby causing various side effects and weakening the body's immune system. Bu-Zhong-Yi-Qi-Tang, associated with Salvia miltiorrhiza, Ligusticum chuanxiong, Angelica dahurica and Polygonum multiflorum Thunb., is an effective prescription to ameliorate such symptoms and signs in patients with MS. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ctim.2017.12.011 PMID: 29458918
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 93 – Multiple Sklerose: Veröffentlichungen Oktober 2013
84. Complement Ther Med. 2018 Feb;36:113-117. doi: 10.1016/j.ctim.2017.12.006. Epub 2017 Dec 13. Use of complementary and alternative medicine in patients with multiple sclerosis in Germany. Gotta M(1), Mayer CA(2), Huebner J(3). Author information: (1)Klinik für Innere Medizin II, Hämatologie und Onkologie, Universitätsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany. Electronic address: [email protected]. (2)Klinik für Neurologie, Johann Wolfgang Goethe Universität, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. Electronic address: [email protected]. (3)Klinik für Innere Medizin II, Hämatologie und Onkologie, Universitätsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany. Electronic address: [email protected]. BACKGROUND: The use of complementary and alternative medicine (CAM) for chronic diseases such as multiple sclerosis (MS) is becoming an increasingly important issue for those affected. Especially in Germany there are only a few studies dealing with CAM, as yet. The aim of this study was to assess the prevalence, the methods used, the subjective benefits as well as physician/patient communication. METHODS: A structured questionnaire including demographic and disease-specific data, CAM use, perceived benefits as well as physician/patient communication was sent to real and web-based self-help groups for MS in Germany. RESULTS: 343 answers could be evaluated. 77.3% of the participants were females. The mean age was 45.0 ± 11.9 years and the duration of the disease was 12.0 ± 9.6 years. 81.9% said they were using CAM, nearly half (44.8%) used it alternatively to conventional medicine. The average number of CAM- methods used were 3.6. The most popular methods were vitamin supplements, Yoga/Thai chi/Qi Gong, relaxation techniques and meditation. Approximately half (139/49.5%) of CAM users disclosed this to their treating neurologist. Yet, 37,6% have doubts on the competence of the respective physician. CONCLUSION: Patients with MS have a strong interest in CAM. Usage as alternative therapy is widespread and puts patients at risk of progress of the disease. As patient/physician communication on the topic is increasing, neurologists should be attentive to guiding their patients through safe complementary methods. Copyright © 2017 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ctim.2017.12.006 PMID: 29458916
85. Continuum (Minneap Minn). 2018 Feb;24(1, Child Neurology):96-129. doi: 10.1212/CON.0000000000000562. Neurocutaneous Disorders. Rosser T. PURPOSE OF REVIEW: This article presents an up-to-date summary of the genetic etiology, diagnostic criteria, clinical features, and current management recommendations for the most common neurocutaneous disorders encountered in clinical adult and pediatric neurology practices. RECENT FINDINGS: The phakomatoses are a phenotypically and genetically diverse group of multisystem disorders that primarily affect the skin and central nervous system. A greater understanding of the genetic and biological underpinnings of numerous neurocutaneous disorders has led to better clinical characterization, more refined diagnostic criteria, and improved treatments in neurofibromatosis type 1, Legius syndrome, neurofibromatosis type 2, Noonan syndrome with multiple lentigines, tuberous sclerosis complex, Sturge-Weber syndrome, and incontinentia pigmenti. SUMMARY: Neurologists require a basic knowledge of and familiarity with a wide variety of neurocutaneous disorders because of the frequent involvement of the central and peripheral nervous systems. A simple routine skin examination can often open a broad differential diagnosis and lead to improved patient care. DOI: 10.1212/CON.0000000000000562 PMID: 29432239
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86. Curr Med Chem. 2018 Feb 25. doi: 10.2174/0929867325666180226095132. [Epub ahead of print] Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer's disease and Less Well-Known Diseases. Paez JA(1), Campillo NE(2). Author information: (1)Instituto de Quimica Medica (IQM-CSIC). C/ Juan de la Cierva, 3, 28006, Madrid. Spain. (2)Centro de Investigaciones Biologicas (CIB-CSIC). C/ Ramiro de Maeztu, 9, 28040, Madrid. Spain. The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 being cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2- arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer's disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]. DOI: 10.2174/0929867325666180226095132 PMID: 29484980
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87. Curr Med Chem. 2018 Feb 25. doi: 10.2174/0929867325666180226105612. [Epub ahead of print] New life to an old treatment: pegylated Interferon beta 1a in the management of multiple sclerosis. Ortiz MA(1), Espino-Paisan L(1), Nunez C(2), Alvarez-Lafuente R(3), Urcelay E(1). Author information: (1)Servicio de Inmunologia Clinica, Hospital Clinico San Carlos, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), 28040 Madrid. Spain. (2)Laboratorio de Investigacion en Genetica de Enfermedades Complejas, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), 28040 Madrid. Spain. (3)Servicio de Neurologia, Hospital Clinico San Carlos, Instituto de Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), 28040 Madrid. Spain. In the 1990s, the betainterferons and glatiramer acetate were introduced for treating relapsing- remitting multiple sclerosis. These medications have a demonstrated record of efficacy and safety, although they require frequent administration via injection and are only partially effective. The optimization of treatment in patients who do not respond adequately to this first-line therapy is essential for attaining the best long-term outcomes. Switching to the recently approved emergent therapies is a strategy to consider for treatment of patients with a suboptimal response. This review summarizes the mechanisms of action, clinical benefits, and safety profiles of current multiple sclerosis disease-modifying therapies, including highly efficacious monoclonal antibodies or convenient oral therapies. Although the first-line interferon beta exhibits a favorable benefit-to-risk profile, treatment compliance is compromised potentially due to its known adverse events and frequent injectable administration. Less frequent dosing and improved pharmacological properties have been achieved by reaction of interferon beta with chemically activated polyethylene glycol. Provided that none of the available therapies shows better effectiveness for all outcomes and their safety in clinical practice is a fundamental concern, the pegylated form of interferon beta seems to keep its place as a competitive therapeutic option. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]. DOI: 10.2174/0929867325666180226105612 PMID: 29484976
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88. Curr Neurol Neurosci Rep. 2018 Feb 13;18(2):8. doi: 10.1007/s11910-018-0814-x. The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews. Nielsen S(1), Germanos R(2), Weier M(2)(3), Pollard J(4), Degenhardt L(2), Hall W(3), Buckley N(4), Farrell M(2). Author information: (1)National Drug and Alcohol Research Centre, University of New South Wales Sydney, Sydney, NSW, 2052, Australia. [email protected]. (2)National Drug and Alcohol Research Centre, University of New South Wales Sydney, Sydney, NSW, 2052, Australia. (3)Centre for Youth Substance Abuse Research, The University of Queensland, Royal Brisbane and Women's Hospital Brisbane, Brisbane, QLD, 4006, Australia. (4)School of Medical Sciences, The University of Sydney, Sydney, NSW, 2006, Australia. PURPOSE OF REVIEW: Pharmaceutical cannabinoids such as nabiximols, nabilone and dronabinol, and plant-based cannabinoids have been investigated for their therapeutic potential in treating multiple sclerosis (MS) symptoms. This review of reviews aimed to synthesise findings from high quality systematic reviews that examined the safety and effectiveness of cannabinoids in multiple sclerosis. We examined the outcomes of disability and disability progression, pain, spasticity, bladder function, tremor/ataxia, quality of life and adverse effects. RECENT FINDINGS: We identified 11 eligible systematic reviews providing data from 32 studies, including 10 moderate to high quality RCTs. Five reviews concluded that there was sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Few reviews reported conclusions for other symptoms. Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non-cannabinoid comparators; this is an important gap in the evidence. DOI: 10.1007/s11910-018-0814-x PMID: 29442178
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89. Curr Opin Rheumatol. 2018 Feb 12. doi: 10.1097/BOR.0000000000000498. [Epub ahead of print] The autoimmune ecology: an update. Anaya JM(1), Restrepo-Jiménez P, Ramírez-Santana C. Author information: (1)Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia. PURPOSE OF REVIEW: The autoimmune ecology refers to the interactions between individuals and their environment leading to a breakdown in immune tolerance and, therefore, to the development of one or more autoimmune diseases in such an individual. Herein, an update is offered on four specific factors associated with autoimmune diseases, namely, vitamin D, smoking, alcohol and coffee consumption from the perspective of exposome and metabolomics. RECENT FINDINGS: Smoking is associated with an increased risk for most of the autoimmune diseases. Carbamylation of proteins as well as NETosis have emerged as possible new pathophysiological mechanisms for rheumatoid arthritis. Low-to-moderate alcohol consumption seems to decrease the risk of systemic lupus erythematosus and rheumatoid arthritis, and studies of vitamin have suggested a beneficial effect on these conditions. Coffee intake appears to be a risk factor for type 1 diabetes mellitus and rheumatoid arthritis and a protective factor for multiple sclerosis and primary biliary cholangitis. SUMMARY: Recent studies support the previously established positive associations between environmental factors and most of the autoimmune diseases. Nevertheless, further studies from the perspective of metabolomics, proteomics and genomics will help to clarify the effect of environment on autoimmune diseases. DOI: 10.1097/BOR.0000000000000498 PMID: 29438164
90. Cytokine. 2018 Feb 12. pii: S1043-4666(18)30052-8. doi: 10.1016/j.cyto.2018.02.012. [Epub ahead of print] Chemokines beyond chemo-attraction: CXCL10 and its significant role in cancer and autoimmunity. Karin N(1), Razon H(2). Author information: (1)Faculty of Medicine, Technion-Institute of Technology, P.O.B. 9697, Haifa 31096, Israel. Electronic address: [email protected]. (2)Faculty of Medicine, Technion-Institute of Technology, P.O.B. 9697, Haifa 31096, Israel. Chemokines are mostly known for their chemotactic properties, and less for their ability to direct the biological function of target cells, including T cells. The current review focuses on a key chemokine named CXCL10 and its role in directing the migratory propertied and biological function of CD4+ and CD8+ T cells in the context of cancer and inflammatory autoimmunity. CXCR3 is a chemokine receptor that is abundant on CD4+ T cells, CD8+ T cells and NK cells. It has three known ligands: CXCL9, CXCL10 and CXCL11. Different studies, including those coming form our laboratory, indicated that aside of attracting CD8+ and CD4+ effector T cells to tumor sites and sites of inflammation CXCL10 directs the polarization and potentiates the biological function of these cells. This makes CXCL10 a "key driver chemokine" and a valid target for therapy of autoimmune diseases such as Inflammatory Bowl's Disease, Multiple Sclerosis, Rheumatoid arthritis and others. As for cancer this motivated different groups, including our group to develop CXCL10 based therapies for cancer due to its ability to enhance T-dependent anti cancer immunity. The current review summarizes these findings and their potential translational implication. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.cyto.2018.02.012 PMID: 29449068
91. Dev Med Child Neurol. 2018 Feb 6. doi: 10.1111/dmcn.13691. [Epub ahead of print] Children with myelin oligodendrocyte glycoprotein antibodies-associated disease: relation of phenotypes to central nervous system myelin maturation. Kuroda H(1), Fujihara K(1)(2)(3). Author information: (1)Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan. (2)Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima, Japan. (3)Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience (STRINS), Koriyama, Japan. DOI: 10.1111/dmcn.13691 PMID: 29405285
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92. Dialogues Clin Neurosci. 2017 Dec;19(4):353-371. Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach. Fernandez BA(1), Scherer SW(2). Author information: (1)Disciplines of Genetics and Medicine, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL Canada. (2)The Center for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; McLaughlin Center and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. Autism spectrum disorder (ASD) encompasses a group of neurodevelopmental conditions diagnosed solely on the basis of behavioral assessments that reveal social deficits. Progress has been made in understanding its genetic underpinnings, but most ASD-associated genetic variants, which include copy number variants (CNVs) and mutations in ASD-risk genes, account for no more than 1 % of ASD cases. This high level of genetic heterogeneity leads to challenges obtaining and interpreting genetic testing in clinical settings. The traditional definition of syndromic ASD is a disorder with a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype that may include ASD. Most have a known genetic cause. Examples include fragile X syndrome and tuberous sclerosis complex. We propose dividing syndromic autism into the following two groups: (i) ASD that occurs in the context of a clinically defined syndrome-recognizing these disorders depends on the familiarity of the clinician with the features of the syndrome, and the diagnosis is typically confirmed by targeted genetic testing (eg, mutation screening of FMR1); (ii) ASD that occurs as a feature of a molecularly defined syndrome-for this group of patients, ASD-associated variants are identified by genome-wide testing that is not hypothesis driven (eg, microarray, whole exome sequencing). These ASD groups cannot be easily clinically defined because patients with a given variant have variable somatic abnormalities (dysmorphism and birth defects). In this article, we review common diagnoses from the above categories and suggest a testing strategy for patients, guided by determining whether the individual has essential or complex ASD; patients in the latter group have multiple morphologic anomalies on physical examination. Finally, we recommend that the syndromic versus nonsyndromic designation ultimately be replaced by classification of ASD according to its genetic etiology, which will inform about the associated spectrum and penetrance of neurobehavioral and somatic manifestations. Publisher: El trastorno del espectro autista (TEA) incluye un grupo diverso de cuadros del neurodesarrollo, diagnosticado por los clínicos únicamente en base a evaluaciones conductuales que revelan déficits sociales. Se ha progresado en la comprensión de sus bases genéticas, pero la mayoría de las variantes genéticas asociadas al TEA dan cuenta de no más del 1 % de los casos, y éstas incluyen variabilidad del número de copias (VNC) y mutaciones en los genes de riesgo para el TEA. Este alto nivel de heterogeneidad genética genera un desafío en la obtención e interpretación de las pruebas genéticas en los ambientes clínicos. La definición tradicional de TEA sindromático se refiere a un trastorno con un patrón clínicamente definido de alteraciones somáticas y un fenotipo neuroconductual que incluye el TEA. La mayoría tiene una causa genéticamente conocida y como ejemplos están el síndrome X frágil y el complejo esclerosis tuberosa. Se propone dividir el autismo sindromático en dos grupos: 1) El TEA que ocurre en el contexto de un síndrome definido clínicamente. El reconocimiento de estos trastornos depende de la familiaridad del clínico con las características del síndrome, y el diagnóstico se confirma típicamente por pruebas genéticas específicas (como la evaluación de FMR1) y 2) El TEA que ocurre como una característica del síndrome definido molecularmente. Para este grupo de pacientes, las variantes asociadas con el TEA se identifican mediante pruebas del genoma completo, que no se basan en una hipótesis (como el estudio de microarray o la secuenciación completa de exoma). Estos grupos de TEA no pueden definirse fácil clínicamente porque los pacientes con una variante determinada tienen alteraciones somáticas variables (dimorfismos y defectos del nacimiento). En este artículo se revisan los diagnósticos comunes a partir de las categorías anteriores y se sugiere una estrategia de evaluación de los pacientes dependiendo de si ellos tienen un TEA esencial o complejo; este último grupo tiene múltiples alteraciones morfológicas al examen físico. Por último, se recomienda que la designación de sindromático versus no-sindromático sea reemplazada finalmente por la clasificación de TEA de acuerdo con su etiología genética, la cual dará cuenta del espectro asociado y de la penetrancia de las manifestaciones neuroconductuales y somáticas.Publisher: Le trouble du spectre de l'autisme (TSA) est un groupe de maladies neurodéveloppementales dont le diagnostic est établi uniquement sur la base d'évaluations comportementales qui signent des déficits sociaux. La compréhension des fondements génétiques du TSA progresse, mais la plupart des variantes génétiques associées au TSA, comme la variabilité du nombre de copies (VNC) et les mutations des gènes liés au TSA, ne représentent pas plus de 1 % des cas de TSA. Cette hétérogénéité génétique élevée rend difficiles la
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 99 – Multiple Sklerose: Veröffentlichungen Oktober 2013 réalisation et l'interprétation des dépistages génétiques en milieu clinique. La définition traditionnelle du TSA syndromique est un tableau clinique défini, composé d'anomalies somatiques associées à un phénotype neurocomportemental pouvant comprendre le TSA. La plupart ont une cause génétique connue, comme le syndrome de l'X fragile et la sclérose tubéreuse complexe. Nous proposons de diviser l'autisme syndromique en deux groupes : 1) le TSA survenant dans le contexte d'un syndrome cliniquement défini - la reconnaissance de ces troubles dépend de la connaissance du médecin des caractéristiques du syndrome, et le diagnostic est confirmé généralement par des tests génétiques ciblés (par exemple le dépistage d'une mutation du gène FMR1) ; 2) le TSA survenant en tant que caractéristique d'un syndrome moléculairement défini - pour ce groupe de patients, les variantes associées au TSA sont identifiées par un dépistage au niveau du génome entier sans a priori (par exemple puces à ADN, séquençage de l'exome entier). Ces groupes de TSA ne sont pas faciles à définir cliniquement car les patients ayant une variante donnée ont des anomalies somatiques variables (dysmorphisme et anomalies congénitales). Dans cet article, nous examinons les diagnostics courants issus des catégories susmentionnées et suggérons une stratégie de dépistage pour les patients, pour déterminer si leur TSA est essentiel ou complexe, ce dernier groupe ayant des anomalies morphologiques multiples à l'examen clinique. Enfin, nous recommandons que la classification syndromique versus non syndromique soit finalement remplacée par une classification du TSA selon son étiologie génétique, qui renseignera sur le spectre et la pénétrance des manifestations neuro-comportementales et somatiques. PMCID: PMC5789213 PMID: 29398931
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93. Disabil Health J. 2018 Feb 16. pii: S1936-6574(18)30036-0. doi: 10.1016/j.dhjo.2018.02.001. [Epub ahead of print] Computer-assisted cognitive rehabilitation in persons with multiple sclerosis: Results of a multi-site randomized controlled trial with six month follow-up. Stuifbergen AK(1), Becker H(2), Perez F(2), Morrison J(2), Brown A(2), Kullberg V(2), Zhang W(2). Author information: (1)School of Nursing, The University of Texas at Austin, USA. Electronic address: [email protected]. (2)School of Nursing, The University of Texas at Austin, USA. BACKGROUND: The effects of multiple sclerosis (MS) on cognition have gained increasing recognition as one of the major disabling symptoms of the disease. Despite the prevalence of these symptoms and their impact on quality of life, limited attention has been given to strategies that might help manage the cognitive changes commonly experienced by persons with MS. OBJECTIVE: The primary purpose of this study was to determine the effectiveness of a novel computer-assisted cognitive rehabilitation intervention MAPSS-MS (Memory, Attention, Problem Solving Skills in MS) in a multi-site trial with persons with MS. METHODS: Persons with MS (N = 183) with cognitive concerns were randomly assigned to either the 8-week MAPSS-MS intervention or usual care plus freely available computer games. Participants completed self-report and performance measures of cognitive functioning, compensatory strategies and depression at baseline, immediately after the MAPSS-MS intervention, and three and six months post-intervention. Changes in study outcomes were analyzed using intention to treat methodology, ANOVA with repeated measures, and ANCOVA. RESULTS: Both groups improved significantly on all outcome measures. The intervention group outperformed the comparison group on all measures, and there were statistically significant differences on selected measures. CONCLUSION: Findings suggest that MAPSS-MS is a feasible intervention that could be broadly implemented in community settings. It has been shown to be modestly successful in improving cognitive functioning. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.dhjo.2018.02.001 PMID: 29477372
94. Drug Ther Bull. 2018 Feb;56(2):21-24. doi: 10.1136/dtb.2018.2.0590. Cladribine for multiple sclerosis. [No authors listed] In the UK, there are twelve disease-modifying drugs licensed for various forms of multiple sclerosis (MS), of which three are oral therapies. An oral formulation of cladribine (Mavenclad - Merck Serono Europe Limited) was recently licensed by the European Medicines Agency (EMA) for the treatment of adult patients with highly active relapsing MS.1,2 It is claimed to be "an innovatively simple approach" for treating this form of MS and "the only disease modifying therapy that can deliver and sustain 4 years of disease control with a maximum of 20 days oral treatment in the first 2 years."3 Here, we consider the evidence for its use in the treatment of highly active relapsing MS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/. DOI: 10.1136/dtb.2018.2.0590 PMID: 29449328
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95. EBioMedicine. 2018 Feb 3. pii: S2352-3964(18)30051-3. doi: 10.1016/j.ebiom.2018.02.002. [Epub ahead of print] Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural Progenitors in Progressive Multiple Sclerosis. Harris VK(1), Stark J(1), Vyshkina T(1), Blackshear L(1), Joo G(1), Stefanova V(1), Sara G(2), Sadiq SA(3). Author information: (1)Tisch Multiple Sclerosis Research Center of New York, New York, NY, USA. (2)Department of Hematology and Medical Oncology, Mount Sinai Hospital, New York, NY, USA. (3)Tisch Multiple Sclerosis Research Center of New York, New York, NY, USA. Electronic address: [email protected]. BACKGROUND: Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system and is one of the leading causes of disability in young adults. Cell therapy is emerging as a therapeutic strategy to promote repair and regeneration in patients with disability associated with progressive MS. METHODS: We conducted a phase I open-label clinical trial investigating the safety and tolerability of autologous bone marrow mesenchymal stem cell-derived neural progenitor (MSC- NP) treatment in 20 patients with progressive MS. MSC-NPs were administered intrathecally (IT) in three separate doses of up to 1 × 107 cells per dose, spaced three months apart. The primary endpoint was to assess safety and tolerability of the treatment. Expanded disability status scale (EDSS), timed 25-ft walk (T25FW), muscle strength, and urodynamic testing were used to evaluate treatment response. This trial is registered with ClinicalTrials.gov, number NCT01933802. FINDINGS: IT MSC-NP treatment was safe and well tolerated. The 20 enrolled subjects completed all 60 planned treatments without serious adverse effects. Minor adverse events included transient fever and mild headaches usually resolving in <24 h. Post-treatment disability score analysis demonstrated improved median EDSS suggesting possible efficacy. Positive trends were more frequently observed in the subset of SPMS patients and in ambulatory subjects (EDSS ≤ 6.5). In addition, 70% and 50% of the subjects demonstrated improved muscle strength and bladder function, respectively, following IT MSC-NP treatment. INTERPRETATION: The possible reversal of disability that was observed in a subset of patients warrants a larger phase II placebo-controlled study to establish efficacy of IT MSC- NP treatment in patients with MS. FUNDING SOURCE: The Damial Foundation. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.ebiom.2018.02.002 PMID: 29449193
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96. EMBO J. 2018 Feb 22. pii: e98049. doi: 10.15252/embj.201798049. [Epub ahead of print] Tau protein liquid-liquid phase separation can initiate tau aggregation. Wegmann S(1), Eftekharzadeh B(2), Tepper K(3), Zoltowska KM(2), Bennett RE(2), Dujardin S(2), Laskowski PR(4), MacKenzie D(2), Kamath T(2), Commins C(2), Vanderburg C(2), Roe AD(2), Fan Z(2), Molliex AM(5), Hernandez-Vega A(6), Muller D(4), Hyman AA(4), Mandelkow E(3)(7)(8), Taylor JP(5)(9), Hyman BT(1). Author information: (1)Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA [email protected] [email protected]. (2)Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. (3)German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. (4)Department for Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. (5)Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. (6)Max-Planck Institute for Molecular Cell Biology & Genetics, Dresden, Germany. (7)Max- Planck Institute for Metabolism Research, Hamburg Outstation c/o DESY, Hamburg, Germany. (8)CAESAR Research Center, Bonn, Germany. (9)Howard Hughes Medical Institute, Chevy Chase, MD, USA. The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid-liquid phase separation (LLPS) under cellular conditions and that phase-separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho-tau isolated from human Alzheimer brain. Droplet-like tau can also be observed in neurons and other cells. We found that tau droplets become gel-like in minutes, and over days start to spontaneously form thioflavin-S-positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases. © 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license. DOI: 10.15252/embj.201798049 PMID: 29472250
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97. Encephale. 2018 Feb 17. pii: S0013-7006(18)30001-0. doi: 10.1016/j.encep.2017.11.004. [Epub ahead of print] The evaluation of depression in multiple sclerosis using the newly proposed Multiple Sclerosis Depression Rating Scale. Palm U(1), Chalah MA(2), Créange A(3), Lefaucheur JP(2), Ayache SS(4). Author information: (1)EA 4391, excitabilité nerveuse et thérapeutique, université Paris-Est-Créteil, 61, avenue du Général-de-Gaulle, 94000 Créteil, France; Department of Psychiatry, Psychotherapy and Psychosomatics, Ludwig-Maximilian University, Geschwister-Scholl Platz 1, 80539 Munich, Germany. (2)EA 4391, excitabilité nerveuse et thérapeutique, université Paris-Est-Créteil, 61, avenue du Général-de-Gaulle, 94000 Créteil, France; Service de physiologie-explorations fonctionnelles, hôpital Henri-Mondor, Assistance publique-Hôpitaux de Paris, 31, rue du Parc, 94000 Créteil, France. (3)EA 4391, excitabilité nerveuse et thérapeutique, université Paris-Est-Créteil, 61, avenue du Général-de-Gaulle, 94000 Créteil, France; Service de neurologie, hôpital Henri-Mondor, Assistance publique-Hôpitaux de Paris, 31, rue du Parc, 94000 Créteil, France. (4)EA 4391, excitabilité nerveuse et thérapeutique, université Paris-Est-Créteil, 61, avenue du Général-de-Gaulle, 94000 Créteil, France; Service de physiologie-explorations fonctionnelles, hôpital Henri-Mondor, Assistance publique-Hôpitaux de Paris, 31, rue du Parc, 94000 Créteil, France; Lebanese American University Medical Center, Rizk hospital (LAUMC-RH), Zahar street, Beirut, Lebanon. Electronic address: [email protected]. Fatigue and depression are frequent symptoms in multiple sclerosis (MS). Both are overlapping and shadowing each other and may impair the quality of life. For detection of depression symptoms in MS, the Multiple Sclerosis Depression Rating Scale (MSDRS) has been proposed recently. Here, we compare the performance of MSDRS in MS patients with and without fatigue to that of established rating scales, i.e. Hospital Anxiety and Depression Scale and Beck Depression Inventory. Twenty-nine MS patients were screened for fatigue and depression symptoms. Patients with fatigue showed significantly higher depression scores compared to patients without fatigue, whereas the number of depressed patients did not differ between the two groups. MSDRS seems to have higher sensitivity to detect severe depression than established rating scales. However, one should keep in mind that such a finding might be due to an increase in false positive cases when using MSDRS. Implementing this scale in future studies might be of help to enhance the understanding of its potential utility. Copyright © 2018 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved. DOI: 10.1016/j.encep.2017.11.004 PMID: 29463384
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98. Environ Res. 2018 Feb 6;163:43-52. doi: 10.1016/j.envres.2018.01.040. [Epub ahead of print] Ozone, NO2 and PM10 are associated with the occurrence of multiple sclerosis relapses. Evidence from seasonal multi-pollutant analyses. Jeanjean M(1), Bind MA(2), Roux J(3), Ongagna JC(4), de Sèze J(5), Bard D(6), Leray E(7). Author information: (1)METIS Department, EHESP French School of Public Health, Sorbonne Paris Cité, 15 avenue du Professeur 6 Léon-Bernard - CS 74312, 35043 Rennes, France. Electronic address: [email protected]. (2)Department of Statistics, Harvard University, Faculty of Arts and Sciences, Cambridge, MA, USA. Electronic address: [email protected]. (3)METIS Department, EHESP French School of Public Health, Sorbonne Paris Cité, 15 avenue du Professeur 6 Léon-Bernard - CS 74312, 35043 Rennes, France; INSERM CIC-P 1414, CHU of Rennes, 2 Rue Henri le Guilloux, 35000 Rennes, France; EA 7449 REPERES, EHESP French School of Public Health, Sorbonne Paris Cité - University of Rennes 1, Rennes, France. Electronic address: [email protected]. (4)Department of neurology, Strasbourg University, INSERM CIC 1434, CHU of Strasbourg, 1 Place de l'Hôpital, 11 67091 Strasbourg cedex, France. Electronic address: jean- [email protected]. (5)Department of neurology, Strasbourg University, INSERM CIC 1434, CHU of Strasbourg, 1 Place de l'Hôpital, 11 67091 Strasbourg cedex, France. Electronic address: jerome[email protected]. (6)METIS Department, EHESP French School of Public Health, Sorbonne Paris Cité, 15 avenue du Professeur 6 Léon-Bernard - CS 74312, 35043 Rennes, France. Electronic address: [email protected]. (7)METIS Department, EHESP French School of Public Health, Sorbonne Paris Cité, 15 avenue du Professeur 6 Léon-Bernard - CS 74312, 35043 Rennes, France; INSERM CIC-P 1414, CHU of Rennes, 2 Rue Henri le Guilloux, 35000 Rennes, France; EA 7449 REPERES, EHESP French School of Public Health, Sorbonne Paris Cité - University of Rennes 1, Rennes, France. Electronic address: [email protected]. BACKGROUND: Triggers of multiple sclerosis (MS) relapses are essentially unknown. PM10 exposure has recently been associated with an increased risk of relapses. OBJECTIVES: We further explore the short-term associations between PM10, NO2, benzene (C6H6), O3, and CO exposures, and the odds of MS relapses' occurrence. METHODS: Using a case-crossover design, we studied 424 MS patients living in the Strasbourg area, France between 2000 and 2009 (1783 relapses in total). Control days were chosen to be ± 35 days relative to the case (relapse) day. Exposure was modeled through ADMS-Urban software at the census block scale. We consider single-pollutant and multi- pollutant conditional logistic regression models coupled with a distributed-lag linear structure, stratified by season ("hot" vs. "cold"), and adjusted for meteorological parameters, pollen count, influenza-like epidemics, and holidays. RESULTS: The single-pollutant analyses indicated: 1) significant associations between MS relapse incidence and exposures to NO2, PM10, and O3, and 2) seasonality in these associations. For instance, an interquartile range increase in NO2 (lags 0-3) and PM10 exposure were associated with MS relapse incidence (OR = 1.08; 95%CI: [1.03-1.14] and OR = 1.06; 95%CI: [1.01-1.11], respectively) during the "cold" season (i.e., October-March). We also observed an association with O3 and MS relapse incidence during "hot" season (OR = 1.16; 95%CI: [1.07-1.25]). C6H6 and CO were not significantly related to MS relapse incidence. However, using multi-pollutant models, only O3 remained significantly associated with the odds of relapse triggering during "hot" season. CONCLUSION: We observed significant single-pollution associations between the occurrence of MS relapses and exposures to NO2, O3 and PM10, only O3 remained significantly associated with occurrence of MS relapses in the multi-pollutant model. Copyright © 2018. Published by Elsevier Inc. DOI: 10.1016/j.envres.2018.01.040 PMID: 29426027
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 105 – Multiple Sklerose: Veröffentlichungen Oktober 2013
99. Epilepsy Behav. 2018 Feb 14. pii: S1525-5050(18)30070-2. doi: 10.1016/j.yebeh.2018.01.037. [Epub ahead of print] Italian Wikipedia and epilepsy: An infodemiological study of online information-seeking behavior. Brigo F(1), Lattanzi S(2), Giussani G(3), Tassi L(4), Pietrafusa N(5), Galimberti CA(6), Nardone R(7), Bragazzi NL(8), Mecarelli O(9). Author information: (1)Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Hospital Franz Tappeiner, Department of Neurology, Merano, Italy. Electronic address: [email protected]. (2)Marche Polytechnic University, Neurological Clinic, Department of Experimental and Clinical Medicine, Ancona, Italy. (3)IRCCS- Istituto di Ricerche Farmacologiche 'Mario Negri', Laboratory of Neurological Disorders, Department of Neuroscience, Milan, Italy. (4)Niguarda Hospital, 'Claudio Munari' Epilepsy Surgery Centre, Milan, Italy. (5)Bambino Gesù Children's Hospital, IRCCS, Department of Neuroscience, Rome, Italy. (6)IRCCS C. Mondino National Neurological Institute, Epilepsy Centre, Pavia, Italy. (7)Hospital Franz Tappeiner, Department of Neurology, Merano, Italy; Paracelsus Medical University, Department of Neurology, Christian Doppler Klinik, Salzburg, Austria. (8)School of Public Health, University of Genoa, Department of Health Sciences (DISSAL), Genoa, Italy. (9)'Sapienza' University of Rome, Human Neuroscience Department, Rome, Italy. Wikipedia is the most commonly accessed source of health information by both healthcare professionals and the lay public worldwide. We aimed to evaluate information-seeking behavior of Internet users searching the Italian Wikipedia for articles related to epilepsy and its treatment. Using Pageviews Analysis, we assessed the total and mean monthly views of articles from the Italian Wikipedia devoted to epilepsy, epileptic syndromes, seizure type, and antiepileptic drugs (AEDs) from January 1, 2015 to October 31, 2017. We compared the views of the article on epilepsy with those of articles focusing on Alzheimer's disease, migraine, multiple sclerosis, syncope, and stroke and adjusted all results for crude disease prevalence. With the only exception of the article on multiple sclerosis, the adjusted views for the Italian Wikipedia article on epilepsy were higher than those for the other neurological disorders. The most viewed articles on seizure type were devoted to tonic- clonic seizure, typical absence seizure, tonic convulsive seizures, and clonic convulsive seizures. The most frequently accessed articles on epilepsy syndromes were about temporal lobe epilepsy and Lennox-Gastaut syndrome. The most frequently viewed articles on AEDs were devoted to valproic acid, carbamazepine, and levetiracetam. Wikipedia searches seem to mirror patients' fears and worries about epilepsy more than its actual epidemiology. The ultimate reasons for searching online remain unknown. Epileptologists and epilepsy scientific societies should make greater efforts to work jointly with Wikipedia to convey more accurate and up-to-date information about epilepsy. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.yebeh.2018.01.037 PMID: 29454607
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 106 – Multiple Sklerose: Veröffentlichungen Oktober 2013
100. Eur J Clin Microbiol Infect Dis. 2018 Feb 8. doi: 10.1007/s10096-018-3204-z. [Epub ahead of print] Smoking is not associated with higher prevalence of JC virus in MS patients. Auer M(1), Bsteh G(2), Hegen H(2), Di Pauli F(2), Wurth S(2), Berger T(2), Deisenhammer F(2). Author information: (1)Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. [email protected]. (2)Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. John Cunningham virus (JCV) causes rare, but potentially life-threatening progressive multifocal leukoencephalopathy (PML) in natalizumab-treated multiple sclerosis (MS) patients. Beside JCV index, there is currently no other factor for further risk stratification. Because smoking was reported as potential risk factor for several viral and bacterial infections, we aimed to investigate whether smoking could increase the risk for JCV infection in MS patients. We screened our database of the MS Clinic of the Department of Neurology, Medical University of Innsbruck, Austria, for patients with known smoking status and test result for anti-JCV antibody index as determined by two-step ELISA at Unilabs, Copenhagen, Denmark. In a representative cohort of 200 MS patients with a rate of 36% current smokers plus 6% former smokers, we were not able to detect any association between smoking and JCV status. Furthermore, there was no association between smoking status and anti- JCV antibody index. Smoking does not seem to be a risk factor for JCV infection in MS patients and, therefore, does not represent a suitable marker for PML-risk stratification under treatment with natalizumab. DOI: 10.1007/s10096-018-3204-z PMID: 29423619
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 107 – Multiple Sklerose: Veröffentlichungen Oktober 2013
101. Eur J Clin Pharmacol. 2018 Feb 10. doi: 10.1007/s00228-018-2429-1. [Epub ahead of print] The changing multiple sclerosis treatment landscape: impact of new drugs and treatment recommendations. Eriksson I(1)(2), Komen J(3), Piehl F(4), Malmström RE(5)(6), Wettermark B(5)(7), von Euler M(5)(6)(8). Author information: (1)Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. [email protected]. (2)Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden. [email protected]. (3)Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands. (4)Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. (5)Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. (6)Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden. (7)Department of Healthcare Development, Stockholm County Council, Stockholm, Sweden. (8)Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden. PURPOSE: The purpose of this study is to describe the utilization of disease-modifying treatments (DMTs) in relapsing-remitting multiple sclerosis (MS) and assess the impact of both the introduction of new drugs and treatment recommendations (local recommendation on rituximab use issued at the largest MS clinic in Stockholm and regional Drug and Therapeutics Committee (DTC) recommendation on how dimethyl fumarate should be used). METHODS: Interrupted time series analyses using monthly data on all MS patients treated with DMTs in the Stockholm County, Sweden, from January 2011 to December 2017. RESULTS: There were 4765 individuals diagnosed with MS residing in the Stockholm County from 2011 to 2017. Of these, 2934 (62%) were treated with an MS DMT. Since 2011, fingolimod, alemtuzumab, teriflunomide, dimethyl fumarate, peginterferon beta-1a, and daclizumab were introduced. Only fingolimod and dimethyl fumarate significantly impacted MS DMT utilization. In parallel, the use of rituximab off-label increased steadily, reaching 58% of all DMT- treated MS patients by the end of the study period. The local recommendation on rituximab was associated with an increase in rituximab use. The regional DTC recommendation on dimethyl fumarate was associated with a decrease in dimethyl fumarate use. CONCLUSIONS: Three MS DMTs- fingolimod, dimethyl fumarate, and rituximab off-label-impacted MS DMT utilization in the Stockholm County. The associations between the treatment recommendations and the subsequent changes in MS DMT utilization indicate that such interventions can influence the uptake and utilization of new drugs used in the specialized care setting. DOI: 10.1007/s00228-018-2429-1 PMID: 29429031
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 108 – Multiple Sklerose: Veröffentlichungen Oktober 2013
102. Eur J Neurol. 2018 Feb 12. doi: 10.1111/ene.13594. [Epub ahead of print] Real Life Long-Term Effectiveness of Fingolimod in Swiss Patients with Relapsing-Remitting Multiple Sclerosis (REALITE). Zecca C(1), Roth S(2), Findling O(3), Perriard G(4), Bachmann V(4), Pless ML(5), Baumann A(6), Kamm CP(7), Lalive PH(8), Czaplinski A(9). Author information: (1)Neurocenter of southern Switzerland, Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland. (2)Neurology Practice, Carouge, Geneva, Switzerland. (3)Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland. (4)Novartis Pharma Schweiz AG, Rotkreuz, Switzerland. (5)Departments of Neurology and Ophthalmology, Hospital of the Canton of Luzern, Luzern, Switzerland. (6)Neurozentrum, Oberaargau, Langenthal, Switzerland. (7)Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. (8)Department of Neurosciences, Division of Neurology, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland. (9)Neurozentrum Bellevue, Zürich and Department of Neurology, University of Basel, Switzerland. BACKGROUND AND PURPOSE: In 2011, fingolimod was approved in Switzerland for the treatment of relapsing remitting multiple sclerosis (RRMS). The aim of the present study was to assess the effectiveness and retention of fingolimod in a real life Swiss setting, in which patients can receive fingolimod both as first or second line treatment for RRMS. METHODS: This cross-sectional, observational study with retrospective data collection was performed at 19 sites that comprised both hospitals and office-based physicians across Switzerland. Sites were asked to document eligible patients in a consecutive chronological order to avoid selection bias. Demographic and clinical data from 274 consenting adult RRMS patients who had received treatment with fingolimod were analyzed. RESULTS: Mean treatment duration with fingolimod was 32 months. Under fingolimod, 77.7% of patients remained free from relapses and 90.3% did not experience disability progression. The proportion of patients free from any clinical disease activity, i.e., without relapses and disability progression, was 72.1%. 28.5% of patients had been RRMS treatment-naïve prior to fingolimod therapy. High long-term treatment retention rates ranging between 95.7% at 24 months and 87.8% at 36 months were observed. CONCLUSION: In this Swiss cohort of naïve and pre-treated RRMS subjects, the majority of patients under fingolimod treatment showed freedom from relapses and disability progression. In addition, treatment retention rate over 2 and 3 years was high, irrespective of prior treatment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/ene.13594 PMID: 29431876
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 109 – Multiple Sklerose: Veröffentlichungen Oktober 2013
103. Eur J Neurol. 2018 Feb 10. doi: 10.1111/ene.13591. [Epub ahead of print] Is diffusion MRI the future biomarker to measure therapeutic efficacy in multiple sclerosis? Kincses ZT(1)(2), Vécsei L(1)(3). Author information: (1)Department of Neurology, University of Szeged. (2)Department of Radiology, University of Szeged. (3)MTA-SZTE Neuroscience Research Group, Szeged, Hungary. MRI is the cornerstone of the diagnosis of multiple sclerosis (MS), and in recent years it was advocated for the follow up of the efficacy of the ever-growing number of disease modifying treatments (DMT). While in the clinical practice the most important biomarkers are still the T2 and T1 enhancing lesion burden, clinical studies are already utilising atrophy estimation. These measures cover a vast majority of MS pathology, namely the perivenular inflammation and gliosis in the white matter lesions as well as grey matter pathology. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/ene.13591 PMID: 29427462
104. Exp Brain Res. 2018 Feb 22. doi: 10.1007/s00221-018-5212-8. [Epub ahead of print] Four-pulse transcranial magnetic stimulation using multiple conditioning inputs. Normative MEP responses. Calancie B(1), Wang D(2), Young E(3), Alexeeva N(4). Author information: (1)Department of Neurosurgery, Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13104, USA. [email protected]. (2)Department of Public Health and Preventive Medicine, Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13104, USA. (3)Department of Neurology, Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13104, USA. (4)Department of Neurosurgery, Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13104, USA. A four-pulse pattern of transcranial magnetic stimulation (TMS) was compared to traditional dual-pulse TMS for its ability to modulate motor cortical excitability. This novel pattern consisted of a three-pulse train of subthreshold conditioning pulses followed by a suprathreshold test pulse (i.e., SC-T). The intervals between these superconditioning (SC) pulses (1, 3, or 6 ms) and the follow-on test pulse (1, 3, 10, or 25 ms) were varied, and the resultant MEPs were compared to those elicited by: (1) single- pulse TMS; and (2) dual-pulse conditioning-test (C-T) TMS with either short (3 ms) or long (10 ms) intervals to elicit short-interval intracortical inhibition (SICI) or intracortical facilitation (ICF), respectively. Testing included abductor pollicis brevis (APB) and tibialis anterior (TA) in 15 neurologically normal adults. For superconditioning inputs, 10 ms test intervals caused especially strong facilitation of the test MEP, while 1 ms test intervals were particularly effective at causing inhibition of the test response. For both muscles and across all subjects, the most effective of the 12 SC-T inputs tested for causing either facilitation or inhibition was-with rare exception-superior to the dual-pulse TMS input for causing facilitation (i.e., ICF) or inhibition (i.e., SICI), while the overall magnitude of effect was more pronounced in APB compared to TA. Nevertheless, after normalization, the impact of a superconditioning input train on the test MEP was similar in APB and TA muscles, suggesting similar mechanisms of action. Limited findings from a single subject with amyotrophic lateral sclerosis (ALS) are included to further illustrate the potential advantages of using a train of conditioning pulses preceding a TMS test pulse to selectively investigate abnormal motor cortical excitatory and inhibitory circuitry. DOI: 10.1007/s00221-018-5212-8 PMID: 29473092
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 110 – Multiple Sklerose: Veröffentlichungen Oktober 2013
105. Exp Neurol. 2018 Feb 14;304:14-20. doi: 10.1016/j.expneurol.2018.02.008. [Epub ahead of print] Amelioration of progressive autoimmune encephalomyelitis by epigenetic regulation involves selective repression of mature neutrophils during the preclinical phase. Jayaraman A(1), Sharma M(1), Prabhakar B(1), Holterman M(2), Jayaraman S(3). Author information: (1)Dept. of Microbiology & Immunology, 909 South Wolcott Avenue, University of Illinois at Chicago, Chicago, IL 60612, USA. (2)Dept. of Surgery, University of Illinois College of Medicine at Peoria, 624 NE Glen Oak Ave, Suite 2675, Peoria, IL 61603, USA. (3)Dept. of Microbiology & Immunology, 909 South Wolcott Avenue, University of Illinois at Chicago, Chicago, IL 60612, USA; Dept. of Surgery, University of Illinois College of Medicine at Peoria, 624 NE Glen Oak Ave, Suite 2675, Peoria, IL 61603, USA. Electronic address: [email protected]. We have recently demonstrated that treatment of NOD mice with the epigenetic drug Trichostatin A (TSA) ameliorated myelin peptide induced progressive experimental autoimmune encephalomyelitis (P-EAE). Protection was accompanied by induction of antigen-specific T-cell tolerance in the periphery and reduced influx of T cells into the spinal cord. In this investigation, we examined whether the epigenetic drug could impact the innate immune system as well. Whereas the mature (MHC class II+) CD11b+Ly-6G+ neutrophils expanded substantially in the peripheral lymphoid compartment during the preclinical phase, the MHC class II+, CD11b+Ly-6C+ mature monocytes increased modestly throughout the disease course. Amelioration of the clinical disease by TSA treatment was accompanied by diminished abundance of CD11b+Ly-6Gdim activated neutrophils in secondary lymphoid organs and their influx into the spinal cord without affecting monocytes. Interestingly, the co- inhibitory ligand CD274+ (PD-L1+) but not CD275+ (ICOS-L+), CD39+ or CD11c+ dendritic cells were decreased in the peripheral lymphoid compartment of drug treated mice. Thus, in addition to myelin- specific T cell tolerance induction observed previously, selective repression of mature neutrophils and PD-L1+ cells is critically involved in the epigenetic regulation of P-EAE. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.expneurol.2018.02.008 PMID: 29453977
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 111 – Multiple Sklerose: Veröffentlichungen Oktober 2013
106. Expert Opin Biol Ther. 2018 Feb 25:1-16. doi: 10.1080/14712598.2018.1441284. [Epub ahead of print] A comparison of human natural monoclonal antibodies and aptamer conjugates for promotion of CNS remyelination: where are we now and what comes next? Perwein MK(1), Smestad JA(2)(3), Warrington AE(1), Heider RM(3), Kaczor MW(1), Maher LJ 3rd(3), Wootla B(1), Kunbaz A(1), Rodriguez M(1)(4). Author information: (1)a Department of Neurology , Mayo Clinic College of Medicine and Science , Rochester , MN , USA. (2)b Medical Scientist Training Program , Mayo Clinic College of Medicine and Science , Rochester , MN , USA. (3)c Department of Biochemistry and Molecular Biology , Mayo Clinic College of Medicine and Science , Rochester , MN , USA. (4)d Department of Immunology , Mayo Clinic College of Medicine and Science , Rochester , MN , USA. INTRODUCTION: Multiple sclerosis (MS) is a chronic and progressive inflammatory demyelinating disease of the human central nervous system (CNS) and is the most common disabling neurological condition in young adults, resulting in severe neurological defects. No curative or long-term progression-inhibiting therapy has yet been developed. However, recent investigation has revealed potential strategies that do not merely modulate potentially pathogenic autoimmune responses, but stimulate remyelination within CNS lesions. Areas covered: We discuss the history and development of natural human IgM-isotype immunoglobulins (HIgMs) and recently-identified aptamer-conjugates that have been shown to enhance endogenous myelin repair in animal models of demyelination by acting on myelin-producing oligodendrocytes (OLs) or oligodendrocyte progenitor cells (OPCs) within CNS lesions. We also discuss future development aims and applications for these important novel technologies. Expert opinion: Aptamer conjugate Myaptavin-3064 and recombinant human IgM- isotype antibody rHIgM22 regenerate CNS myelin, thereby reducing axonal degeneration and offering the potential of recovery from MS relapses, reversal of disability and prevention of disease progression. Advancement of these technologies into the clinic for MS treatment is therefore a top priority. It remains unclear to what extent the therapeutic modalities of remyelinating antibodies and aptamers may synergize with other currently-approved therapies to yield enhanced therapeutic effects. DOI: 10.1080/14712598.2018.1441284 PMID: 29460650
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 112 – Multiple Sklerose: Veröffentlichungen Oktober 2013
107. Expert Opin Drug Discov. 2018 Feb 7:1-11. doi: 10.1080/17460441.2018.1437142. [Epub ahead of print] The development of biological therapies for neurological diseases: moving on from previous failures. Qosa H(1), Volpe DA(1). Author information: (1)a Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences , Center for Drug Evaluation and Research, Food and Drug Administration , Silver Spring , MD , USA. INTRODUCTION: Although years of research have expanded the use of biologics for several clinical conditions, such development has not yet occurred in the treatment of neurological diseases. With the advancement of biologic technologies, there is promise for these therapeutics as novel therapeutic approaches for neurological diseases. Areas covered: In this article, the authors review the therapeutic potential of different types of biologics for the treatment of neurological diseases. Preclinical and clinical studies that investigate the efficacy and safety of biologics in the treatment of neurological diseases, namely Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson disease, multiple sclerosis, and stroke, were reviewed. Moreover, the authors describe the key challenges in the development of therapeutically safe and effective biologics for the treatment of neurological diseases. Expert opinion: Several biologics have shown promise in the treatment of neurological diseases. However, the complexity of the CNS, as well as a limited understanding of disease progression, and restricted access of biologics to the CNS has limited successful development. Therefore, more research needs to be conducted to overcome these hurdles before developing effective and safe biologics for neurological diseases. The emergence of new technologies for the design, production and delivery of biologics will accelerate translating biologics to the clinic. DOI: 10.1080/17460441.2018.1437142 PMID: 29394876
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 113 – Multiple Sklerose: Veröffentlichungen Oktober 2013
108. Expert Opin Drug Discov. 2018 Feb 25:1-11. doi: 10.1080/17460441.2018.1443075. [Epub ahead of print] Merits and complexities of modeling multiple sclerosis in non-human primates: implications for drug discovery. 't Hart BA(1)(2), Laman JD(2), Kap YS(1). Author information: (1)a Department of Immunobiology , Biomedical Primate Research Centre , Rijswijk , The Netherlands. (2)b Department of Neuroscience , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands. INTRODUCTION: The translation of scientific discoveries made in animal models into effective treatments for patients often fails, indicating that currently used disease models in preclinical research are insufficiently predictive for clinical success. An often-used model in the preclinical research of autoimmune neurological diseases, multiple sclerosis in particular, is experimental autoimmune encephalomyelitis (EAE). Most EAE models are based on genetically susceptible inbred/SPF mouse strains used at adolescent age (10-12 weeks), which lack exposure to genetic and microbial factors which shape the human immune system. Areas covered: Herein, the authors ask whether an EAE model in adult non-human primates from an outbred conventionally-housed colony could help bridge the translational gap between rodent EAE models and MS patients. Particularly, the authors discuss a novel and translationally relevant EAE model in common marmosets (Callithrix jacchus) that shares remarkable pathological similarity with MS. Expert opinion: The MS-like pathology in this model is caused by the interaction of effector memory T cells with B cells infected with the γ1-herpesvirus (CalHV3), both present in the pathogen-educated marmoset immune repertoire. The authors postulate that depletion of only the small subset (<0.05%) of CalHV3-infected B cells may be sufficient to limit chronic inflammatory demyelination. DOI: 10.1080/17460441.2018.1443075 PMID: 29465302
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 114 – Multiple Sklerose: Veröffentlichungen Oktober 2013
109. Expert Opin Drug Saf. 2018 Feb 13:1-10. doi: 10.1080/14740338.2018.1437144. [Epub ahead of print] Improving multiple sclerosis management and collecting safety information in the real world: the MSDS3D software approach. Haase R(1), Wunderlich M(1), Dillenseger A(1), Kern R(2), Akgün K(1), Ziemssen T(1). Author information: (1)a Center of Clinical Neuroscience, Department of Neurology , University Hospital Carl Gustav Carus, Dresden University of Technology , Dresden , Germany. (2)b MedicalSyn GmbH , Stuttgart , Germany. INTRODUCTION: For safety evaluation, randomized controlled trials (RCTs) are not fully able to identify rare adverse events. The richest source of safety data lies in the post-marketing phase. Real- world evidence (RWE) and observational studies are becoming increasingly popular because they reflect usefulness of drugs in real life and have the ability to discover uncommon or rare adverse drug reactions. Areas covered: Adding the documentation of psychological symptoms and other medical disciplines, the necessity for a complex documentation becomes apparent. The collection of high- quality data sets in clinical practice requires the use of special documentation software as the quality of data in RWE studies can be an issue in contrast to the data obtained from RCTs. The MSDS3D software combines documentation of patient data with patient management of patients with multiple sclerosis. Following a continuous development over several treatment-specific modules, we improved and expanded the realization of safety management in MSDS3D with regard to the characteristics of different treatments and populations. Expert opinion: eHealth-enhanced post-authorisation safety study may complete the fundamental quest of RWE for individually improved treatment decisions and balanced therapeutic risk assessment. MSDS3D is carefully designed to contribute to every single objective in this process. DOI: 10.1080/14740338.2018.1437144 PMID: 29436244
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 115 – Multiple Sklerose: Veröffentlichungen Oktober 2013
110. Expert Opin Investig Drugs. 2018 Feb 23:1-14. doi: 10.1080/13543784.2018.1442437. [Epub ahead of print] Investigational immunosuppressants in early-stage clinical trials for the treatment of multiple sclerosis. Gajofatto A(1), Turatti M(2). Author information: (1)a Department of Neuroscience, Biomedicine and Movement Sciences , University of Verona , Italy. (2)b Neurology B Unit , Azienda Ospedaliera Universitaria Integrata , Verona , Italy. INTRODUCTION: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system with an immune mediated pathogenesis. Several therapies that suppress or modulate diverse immune system functions have been used for decades with the aim of modifying the disease course. However, these treatments have either limited efficacy or potentially serious adverse events that prevent first-line use on large scale. Areas covered: The aim of the present article is to review ongoing or recently completed clinical trials investigating immunosuppressive drugs for MS. The websites clinicaltrials.gov, clinicaltrialsregister.eu, and pubmed.gov were searched for phase 1, phase 2, and phase 3 trials starting from 2012. Twelve drugs were identified, including seven monoclonal antibodies and five small molecules. Expert opinion: Current or recently completed trials of immunosuppressants for MS are mainly proof-of-concept studies enrolling patients with relapsing disease and using efficacy endpoints based on magnetic resonance imaging measures of inflammatory activity. Sphingosine 1-phosphate receptor modulators and B-cell depleting therapies represent the most commonly investigated drugs, suggesting that mechanisms of action that have already shown promise for MS treatment are being exploited to find new therapies with improved safety, tolerability, and convenience of dosing. Clinical trials of immunosuppressants for progressive MS are largely lacking. DOI: 10.1080/13543784.2018.1442437 PMID: 29455558
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 116 – Multiple Sklerose: Veröffentlichungen Oktober 2013
111. Expert Opin Pharmacother. 2018 Feb 3:1-9. doi: 10.1080/14656566.2018.1434143. [Epub ahead of print] Potential neuroprotective effect of Fingolimod in multiple sclerosis and its association with clinical variables. Pitteri M(1), Magliozzi R(1)(2), Bajrami A(1), Camera V(3), Calabrese M(1). Author information: (1)a Neurology Section, Department of Neurosciences, Biomedicine and Movement Sciences , University of Verona , Verona , Italy. (2)b Division of Brain Sciences, Imperial College Faculty of Medicine , Hammersmith Hospital , London , UK. (3)c Department of Biomedical, Metabolic and Neurosciences , University of Modena and Reggio Emilia , Modena , Italy. INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system affecting both white matter and grey matter in the earliest phases of its course. The crucial role of neurodegeneration in disability progression in MS, regardless of white matter damage, has been confirmed by several imaging and neuropathological studies. Fingolimod is an effective immunomodulator of the sphingosine 1-phosphate receptor, approved in relapsing remitting MS and able to cross the blood-brain barrier and to slow disability progression and brain volume loss. However, it remains unclear whether this neuroprotective action is due to a peripheral anti- inflammatory effect and/or to a direct effect on neuronal cells. Areas covered: In this review, the authors summarize the published preclinical and clinical studies on the effect of Fingolimod in limiting the focal and diffuse grey matter damage in MS. Expert opinion: Fingolimod might have a significant neuroprotective effect on relapsing remitting MS based on its modulatory effect on oligodendroglial cells and astrocytes, and on its direct effect on cortical neurons. Future clinical studies including measures of grey matter damage are required to confirm in vivo such neuroprotective effect. DOI: 10.1080/14656566.2018.1434143 PMID: 29397790
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 117 – Multiple Sklerose: Veröffentlichungen Oktober 2013
112. Expert Rev Neurother. 2018 Mar;18(3):203-219. doi: 10.1080/14737175.2018.1438190. Epub 2018 Feb 15. Preservation of neuronal function as measured by clinical and MRI endpoints in relapsing-remitting multiple sclerosis: how effective are current treatment strategies? Graetz C(1), Groppa S(1), Zipp F(1), Siller N(1). Author information: (1)a Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2) , University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany. INTRODUCTION: Approved medications for relapsing-remitting multiple sclerosis have shown to be effective in terms of their anti-inflammatory potential. However, it is also crucial to evaluate what long- term effects a patient can expect from current MS drugs in terms of preventing neurodegeneration. Here we aim to provide an overview of the current treatment strategies in MS with a specific focus on potential neuroprotective effects. Areas covered: Randomized, double-blind and placebo or referral- drug controlled phase 2a/b and phase 3 trials were examined; non-blinded phase 4 studies (extension studies) were included to provide long-term data, if not otherwise available. Endpoints considered were expanded disability status scale, various neuropsychological tests, percent brain volume change and T1-hypointense lesions as well as multiple sclerosis functional composite, confirmed disease progression, and no evidence of disease activity. Expert commentary: Overall, neuroprotective functions of classical MS therapeutics are not sufficiently investigated, but available data show limited effects. Thus, further research and development in neuroprotection are warranted. When counselling patients, potential long-term beneficial effects should be presented more conservatively. DOI: 10.1080/14737175.2018.1438190 PMID: 29411688
113. Eye (Lond). 2018 Feb 2. doi: 10.1038/s41433-017-0010-2. [Epub ahead of print] Optical coherence tomography in multiple sclerosis. Britze J(1), Frederiksen JL(2). Author information: (1)Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark. (2)Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark. [email protected]. To summarize recent findings regarding the utility of optical coherence tomography in multiple sclerosis. We searched PubMed for relevant articles using the keywords 'optical coherence tomography multiple sclerosis'. Additional articles were found via references in these articles. We selected articles based on relevance. Optical coherence tomography has contributed to greater insights into the pathophysiology of multiple sclerosis. Loss of retinal nerve fibre layer and ganglion cell layer thickness correlate with clinical and paraclinical parameters such as visual function, disability and magnetic resonance imaging. Some studies indicate that OCT parameters may be able to predict disability progression and visual function in MS. OCT angiography has recently emerged as a novel technique to study MS. OCT has proven very useful with regards to research, monitoring and predicting disability in multiple sclerosis. It will be interesting to see how OCT angiography will contribute to this field. DOI: 10.1038/s41433-017-0010-2 PMID: 29391574
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 118 – Multiple Sklerose: Veröffentlichungen Oktober 2013
114. FEBS Lett. 2018 Feb 17. doi: 10.1002/1873-3468.13013. [Epub ahead of print] Mitochondrial dysfunction and axon degeneration in progressive multiple sclerosis. Campbell G(1), Mahad D(1). Author information: (1)The Centre for Clinical Brain Science, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK. The neuron is the target of inflammatory demyelinating processes in multiple sclerosis (MS). In progressive MS, however, there is a gathering body of evidence indicating that molecular changes converge on mitochondria within neuronal cell bodies. The most reproducible change relates to mitochondrial respiratory chain complex deficiency, which compromises the capacity of neurons to generate ATP. The resulting energy failure state is coupled with an increase in demand for energy by the demyelinated axon, being particularly relevant to the long tracts such as corticospinal tracts with long projection axons. Recent work in our laboratory and that of our collaborators indicates the limited reflection of the mitochondria changes within neurons in experimental disease models. The mitochondrial changes within neuronal compartments are likely to offer novel targets for the improvement in neuronal function in patients with progressive MS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1002/1873-3468.13013 PMID: 29453889
115. Front Hum Neurosci. 2018 Jan 31;12:24. doi: 10.3389/fnhum.2018.00024. eCollection 2018. Dual-Tasking in Multiple Sclerosis - Implications for a Cognitive Screening Instrument. Beste C(1), Mückschel M(1)(2), Paucke M(2), Ziemssen T(2). Author information: (1)Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany. (2)Multiple Sclerosis Center, Center of Clinical Neuroscience, Department of Neurology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany. The monitoring of cognitive functions is central to the assessment and consecutive management of multiple sclerosis (MS). Though, especially cognitive processes that are central to everyday behavior like dual-tasking are often neglected. We examined dual-task performance using a psychological- refractory period (PRP) task in N = 21 patients and healthy controls and conducted standard neuropsychological tests. In dual-tasking, MS patients committed more erroneous responses when dual-tasking was difficult. In easier conditions, performance of MS patients did not differ to controls. Interestingly, the response times were generally not affected by the difficulty of the dual task, showing that the deficits observed do not reflect simple motor deficits or deficits in information processing speed but point out deficits in executive control functions and response selection in particular. Effect sizes were considerably large with d∼0.80 in mild affected patients and the achieved power was above 99%. There are cognitive control and dual tasking deficits in MS that are not attributable to simple motor speed deficits. Scaling of the difficulty of dual-tasking makes the test applied suitable for a wide variety of MS-patients and may complement neuropsychological assessments in clinical care and research setting. DOI: 10.3389/fnhum.2018.00024 PMCID: PMC5797790 PMID: 29445335
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 119 – Multiple Sklerose: Veröffentlichungen Oktober 2013
116. Front Immunol. 2018 Feb 12;9:73. doi: 10.3389/fimmu.2018.00073. eCollection 2018. Prolactin and Autoimmunity. Borba VV(1)(2)(3), Zandman-Goddard G(3), Shoenfeld Y(3)(4). Author information: (1)Department "A" of Internal Medicine, Coimbra University Hospital Centre, Coimbra, Portugal. (2)Faculty of Medicine, University of Coimbra, Coimbra, Portugal. (3)Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel. (4)Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL) has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood. DOI: 10.3389/fimmu.2018.00073 PMCID: PMC5816039 PMID: 29483903
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 120 – Multiple Sklerose: Veröffentlichungen Oktober 2013
117. Front Immunol. 2018 Feb 7;9:204. doi: 10.3389/fimmu.2018.00204. eCollection 2018. Cytokines Stimulate the Release of Microvesicles from Myeloid Cells Independently from the P2X7 Receptor/Acid Sphingomyelinase Pathway. Colombo F(1), Bastoni M(1), Nigro A(1), Podini P(1), Finardi A(1), Casella G(1), Ramesh M(1), Farina C(1), Verderio C(2), Furlan R(1). Author information: (1)Department of Neuroscience and INSPE, San Raffaele Scientific Institute, Milano, Italy. (2)CNR Institute of Neuroscience, Milan, Italy. Microvesicles (MVs) are membrane particles of 200-500 nm released by all cell types constitutively. MVs of myeloid origin are found increased in the cerebrospinal fluid (CSF) of patients suffering from neuroinflammatory disorders, although the factors triggering their production have never been defined. Here, we report that both pro- and anti-inflammatory cytokines, specifically interferon-γ and interleukin- 4, are equally able to stimulate the production of MVs from microglia cells and monocytes. Additionally, we found this process to be independent from the best characterized molecular pathway so far described for membrane shedding, which is centered on the purinergic receptor P2X7, whose activation by high concentrations of extracellular ATP (exATP) results in membrane blebbing operated by the secreted enzyme acid sphingomyelinase (ASMase). Moreover, a potent inhibitor of ASMase, injected in a mouse model of multiple sclerosis, failed to reduce the number of MVs in their CSF. This suggests that cytokines, rather than exATP, may exert a long-term control of MV production in the context of chronic inflammation, where both pro- and anti-inflammatory factors play coordinated roles. DOI: 10.3389/fimmu.2018.00204 PMCID: PMC5808348 PMID: 29467770
118. Front Immunol. 2018 Feb 2;9:138. doi: 10.3389/fimmu.2018.00138. eCollection 2018. Understanding Progressive Multifocal Leukoencephalopathy Risk in Multiple Sclerosis Patients Treated with Immunomodulatory Therapies: A Bird's Eye View. Mills EA(1), Mao-Draayer Y(1)(2). Author information: (1)Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, United States. (2)Graduate Program in Immunology, Program in Biomedical Sciences, University of Michigan Medical School, Ann Arbor, MI, United States. The increased use of newer potent immunomodulatory therapies for multiple sclerosis (MS), including natalizumab, fingolimod, and dimethyl fumarate, has expanded the patient population at risk for developing progressive multifocal leukoencephalopathy (PML). These MS therapies shift the profile of lymphocytes within the central nervous system (CNS) leading to increased anti-inflammatory subsets and decreased immunosurveillance. Similar to MS, PML is a demyelinating disease of the CNS, but it is caused by the JC virus. The manifestation of PML requires the presence of an active, genetically rearranged form of the JC virus within CNS glial cells, coupled with the loss of appropriate JC virus- specific immune responses. The reliability of metrics used to predict risk for PML could be improved if all three components, i.e., viral genetic strain, localization, and host immune function, were taken into account. Advances in our understanding of the critical lymphocyte subpopulation changes induced by these MS therapies and ability to detect viral mutation and reactivation will facilitate efforts to develop these metrics. DOI: 10.3389/fimmu.2018.00138 PMCID: PMC5801425 PMID: 29456537
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 121 – Multiple Sklerose: Veröffentlichungen Oktober 2013
119. Front Immunol. 2018 Feb 2;9:100. doi: 10.3389/fimmu.2018.00100. eCollection 2018. Challenges and Opportunities for Biomarkers of Clinical Response to AHSCT in Autoimmunity. Harris KM(1), Lu T(1), Lim N(1), Turka LA(1)(2). Author information: (1)Immune Tolerance Network, Bethesda, MD, United States. (2)Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States. Autoimmunity represents a broad category of diseases that involve a variety of organ targets and distinct autoantigens. For patients with autoimmune diseases who fail to respond to approved disease- modifying treatments, autologous hematopoietic stem cell transplantation (AHSCT) after high-dose immunosuppressive therapy provides an alternative strategy. Although more than 100 studies have been published on AHSCT efficacy in autoimmunity, the mechanisms that confer long-term disease remission as opposed to continued deterioration or disease reactivation remain to be determined. In a phase II clinical trial, high-dose immunosuppressive therapy combined with autologous CD34+ hematopoietic stem cell transplant in treatment-resistant, relapsing-remitting multiple sclerosis (RRMS) resulted in 69.2% of participants achieving long-term remission through 60 months follow-up. Flow cytometry data from the 24 transplanted participants in the high-dose immunosuppression and autologous stem cell transplantation for poor prognosis multiple sclerosis (HALT-MS) trial are presented to illustrate immune reconstitution out to 36 months in patients with aggressive RRMS treated with AHSCT and to highlight experimental challenges inherent in identifying biomarkers for relapse and long-term remission through 60 months follow-up. AHSCT induced changes in numbers of CD4 T cells and in the composition of CD4 and CD8 T cells that persisted through 36 months in participants who maintained disease remission through 60 months. However, changes in T cell phenotypes studied were unable to clearly discriminate durable remission from disease reactivation after AHSCT, possibly due to the small sample size, limited phenotypes evaluated in this real-time assay, and other limitations of the HALT-MS study population. Strategies and future opportunities for identifying biomarkers of clinical outcome to AHSCT in autoimmunity are also discussed. DOI: 10.3389/fimmu.2018.00100 PMCID: PMC5801415 PMID: 29456529
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 122 – Multiple Sklerose: Veröffentlichungen Oktober 2013
120. Front Immunol. 2018 Jan 29;9:38. doi: 10.3389/fimmu.2018.00038. eCollection 2018. Bioactive Lipids and Chronic Inflammation: Managing the Fire Within. Chiurchiù V(1)(2), Leuti A(1)(2), Maccarrone M(1)(2). Author information: (1)Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy. (2)European Center for Brain Research (CERC), Santa Lucia Foundation (IRCCS), Rome, Italy. Inflammation is an immune response that works as a contained fire that is pre-emptively sparked as a defensive process during infections or upon any kind of tissue insult, and that is spontaneously extinguished after elimination or termination of the damage. However, persistent and uncontrolled immune reactions act as a wildfire that promote chronic inflammation, unresolved tissue damage and, eventually, chronic diseases. A wide network of soluble mediators, among which endogenous bioactive lipids, governs all immune processes. They are secreted by basically all cells involved in inflammatory processes and constitute the crucial infrastructure that triggers, coordinates and confines inflammatory mechanisms. However, these molecules are also deeply involved in the detrimental transition from acute to chronic inflammation, be it for persistent or excessive action of pro- inflammatory lipids or for the impairment of the functions carried out by resolving ones. As a matter of fact, bioactive lipids have been linked, to date, to several chronic diseases, including rheumatoid arthritis, atherosclerosis, diabetes, cancer, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis. This review summarizes current knowledge on the involvement of the main classes of endogenous bioactive lipids-namely classical eicosanoids, pro-resolving lipid mediators, lysoglycerophospholipids/sphingolipids, and endocannabinoids-in the cellular and molecular mechanisms that lead to the pathogenesis of chronic disorders. DOI: 10.3389/fimmu.2018.00038 PMCID: PMC5797284 PMID: 29434586
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 123 – Multiple Sklerose: Veröffentlichungen Oktober 2013
121. Front Immunol. 2018 Jan 18;8:2012. doi: 10.3389/fimmu.2017.02012. eCollection 2017. NLR-Dependent Regulation of Inflammation in Multiple Sclerosis- Dependent Regulation of Inflammation in Multiple Sclerosis. Gharagozloo M(1), Gris KV(1), Mahvelati T(1), Amrani A(1), Lukens JR(2), Gris D(1). Author information: (1)Program of Immunology, Faculty of Medicine and Health Sciences, Department of Pediatrics, CR-CHUS, University of Sherbrooke, Sherbrooke, QC, Canada. (2)Center for Brain Immunology and Glia, Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, United States. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) associated with inappropriate activation of lymphocytes, hyperinflammatory responses, demyelination, and neuronal damage. In the past decade, a number of biological immunomodulators have been developed that suppress the peripheral immune responses and slow down the progression of the disease. However, once the inflammation of the CNS has commenced, it can cause serious permanent neuronal damage. Therefore, there is a need for developing novel therapeutic approaches that control and regulate inflammatory responses within the CNS. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular regulators of inflammation expressed by many cell types within the CNS. They redirect multiple signaling pathways initiated by pathogens and molecules released by injured tissues. NLR family members include positive regulators of inflammation, such as NLRP3 and NLRC4 and anti-inflammatory NLRs, such as NLRX1 and NLRP12. They exert immunomodulatory effect at the level of peripheral immune responses, including antigen recognition and lymphocyte activation and differentiation. Also, NLRs regulate tissue inflammatory responses. Understanding the molecular mechanisms that are placed at the crossroad of innate and adaptive immune responses, such as NLR-dependent pathways, could lead to the discovery of new therapeutic targets. In this review, we provide a summary of the role of NLRs in the pathogenesis of MS. We also summarize how anti-inflammatory NLRs regulate the immune response within the CNS. Finally, we speculate the therapeutic potential of targeting NLRs in MS. DOI: 10.3389/fimmu.2017.02012 PMCID: PMC5778124 PMID: 29403486
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 124 – Multiple Sklerose: Veröffentlichungen Oktober 2013
122. Front Immunol. 2018 Jan 23;8:1964. doi: 10.3389/fimmu.2017.01964. eCollection 2017. Shuttling Tolerogenic Dendritic Cells across the Blood-Brain Barrier In Vitro via the Introduction of De Novo C-C Chemokine Receptor 5 Expression Using Messenger RNA Electroporation. De Laere M(1), Derdelinckx J(1)(2), Hassi M(1), Kerosalo M(1), Oravamäki H(1), Van den Bergh J(1), Berneman Z(1)(3), Cools N(1). Author information: (1)Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Wilrijk, Belgium. (2)Department of Neurology, Antwerp University Hospital, Edegem, Belgium. (3)Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium. The use of tolerance-inducing dendritic cells (tolDCs) has been proven to be safe and well tolerated in the treatment of autoimmune diseases. Nevertheless, several challenges remain, including finding ways to facilitate the migration of cell therapeutic products to lymph nodes, and the site of inflammation. In the treatment of neuroinflammatory diseases, such as multiple sclerosis (MS), the blood-brain barrier (BBB) represents a major obstacle to the delivery of therapeutic agents to the inflamed central nervous system (CNS). As it was previously demonstrated that C-C chemokine receptor 5 (CCR5) may be involved in inflammatory migration of DCs, the aim of this study was to investigate CCR5-driven migration of tolDCs. Only a minority of in vitro generated vitamin D3 (vitD3)- treated tolDCs expressed the inflammatory chemokine receptor CCR5. Thus, messenger RNA (mRNA) encoding CCR5 was introduced by means of electroporation (EP). After mRNA EP, tolDCs transiently displayed increased levels of CCR5 protein expression. Accordingly, the capacity of mRNA electroporated tolDCs to transmigrate toward a chemokine gradient in an in vitro model of the BBB improved significantly. Neither the tolerogenic phenotype nor the T cell-stimulatory function of tolDCs was affected by mRNA EP. EP of tolDCs with mRNA encoding CCR5 enabled these cells to migrate to inflammatory sites. The approach used herein has important implications for the treatment of MS. Using this approach, tolDCs actively shuttle across the BBB, allowing in situ down-modulation of autoimmune responses in the CNS. DOI: 10.3389/fimmu.2017.01964 PMCID: PMC5778265 PMID: 29403473
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 125 – Multiple Sklerose: Veröffentlichungen Oktober 2013
123. Front Microbiol. 2018 Jan 22;8:2596. doi: 10.3389/fmicb.2017.02596. eCollection 2017. Lactobacillus helveticus SBT2171 Attenuates Experimental Autoimmune Encephalomyelitis in Mice. Yamashita M(1), Ukibe K(1), Matsubara Y(2), Hosoya T(1), Sakai F(1), Kon S(3), Arima Y(4), Murakami M(4), Nakagawa H(2), Miyazaki T(2). Author information: (1)Milk Science Research Institute, Megmilk Snow Brand Co., Ltd., Saitama, Japan. (2)Department of Probiotics Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. (3)Department of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Japan. (4)Department of Molecular Neuroimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. We recently reported that Lactobacillus helveticus SBT2171 (LH2171) inhibited the proliferation and inflammatory cytokine production of primary immune cells in vitro, and alleviated collagen-induced arthritis (CIA) in mice, a model of human rheumatoid arthritis (RA). In this study, we newly investigated whether LH2171 could relieve the severity of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), which is an autoimmune disease, but develop the symptoms by different mechanisms from RA. In MS and EAE, main cause of the disease is the abnormality in CD4+ T cell immunity, whereas in RA and CIA, is that in antibody-mediated immunity. The intraperitoneal administration of LH2171 significantly decreased the incidence and clinical score of EAE in mice. LH2171 also reduced the numbers of pathogenic immune cells, especially Th17 cells, in the spinal cord at the peak stage of disease severity. Interestingly, before the onset of EAE, LH2171 administration remarkably decreased the ratio of Th17 cells to CD4+ T cells in the inguinal lymph nodes (LNs), where pathogenic immune cells are activated to infiltrate the central nervous system, including the spinal cord. Furthermore, the expression of interleukin (IL)-6, an inflammatory cytokine essential for Th17 differentiation, decreased in the LNs of LH2171-administered mice. Moreover, LH2171 significantly inhibited IL-6 production in vitro from both DC2.4 and RAW264.7 cells, model cell lines of antigen-presenting cells. These findings suggest that LH2171 might down-regulate IL-6 production and the subsequent Th17 differentiation and spinal cord infiltration, consequently alleviating EAE symptoms. DOI: 10.3389/fmicb.2017.02596 PMCID: PMC5786557 PMID: 29403442
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 126 – Multiple Sklerose: Veröffentlichungen Oktober 2013
124. Front Mol Neurosci. 2018 Jan 31;11:12. doi: 10.3389/fnmol.2018.00012. eCollection 2018. Biomarkers of Amyotrophic Lateral Sclerosis: Current Status and Interest of Oxysterols and Phytosterols. Vejux A(1), Namsi A(1)(2), Nury T(1), Moreau T(1)(3), Lizard G(1). Author information: (1)Team Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism EA 7270, INSERM, University of Bourgogne Franche-Comté, Dijon, France. (2)Laboratoire de Neurophysiologie Fonctionnelle et Pathologies, UR11ES/09, Faculté des Sciences Mathématiques, Physiques et Naturelles de Tunis, Université de Tunis El Manar - Bienvenue, Tunis, Tunisia. (3)Department of Neurology, University Hospital/University Bourgogne Franche-Comté, Dijon, France. Amyotrophic lateral sclerosis (ALS) is a non-demyelinating neurodegenerative disease in adults with motor disorders. Two forms exist: a sporadic form (90% of cases) and a family form due to mutations in more than 20 genes including the Superoxide dismutase 1, TAR DNA Binding Protein, Fused in Sarcoma, chromosome 9 open reading frame 72 and VAPB genes. The mechanisms associated with this pathology are beginning to be known: oxidative stress, glutamate excitotoxicity, protein aggregation, reticulum endoplasmic stress, neuroinflammation, alteration of RNA metabolism. In various neurodegenerative diseases, such as Alzheimer's disease or multiple sclerosis, the involvement of lipids is increasingly suggested based on lipid metabolism modifications. With regard to ALS, research has also focused on the possible involvement of lipids. Lipid involvement was suggested for clinical arguments where changes in cholesterol and LDL/HDL levels were reported with, however, differences in positivity between studies. Since lipids are involved in the membrane structure and certain signaling pathways, it may be considered to look for oxysterols, mainly 25- hydroxycholesterol and its metabolites involved in immune response, or phytosterols to find suitable biomarkers for this pathology. DOI: 10.3389/fnmol.2018.00012 PMCID: PMC5797798 PMID: 29445325
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 127 – Multiple Sklerose: Veröffentlichungen Oktober 2013
125. Front Mol Neurosci. 2018 Jan 23;11:10. doi: 10.3389/fnmol.2018.00010. eCollection 2018. Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease. Tracey TJ(1), Steyn FJ(2), Wolvetang EJ(1), Ngo ST(1)(2)(3). Author information: (1)Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia. (2)Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia. (3)Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia. Lipids are a fundamental class of organic molecules implicated in a wide range of biological processes related to their structural diversity, and based on this can be broadly classified into five categories; fatty acids, triacylglycerols (TAGs), phospholipids, sterol lipids and sphingolipids. Different lipid classes play major roles in neuronal cell populations; they can be used as energy substrates, act as building blocks for cellular structural machinery, serve as bioactive molecules, or a combination of each. In amyotrophic lateral sclerosis (ALS), dysfunctions in lipid metabolism and function have been identified as potential drivers of pathogenesis. In particular, aberrant lipid metabolism is proposed to underlie denervation of neuromuscular junctions, mitochondrial dysfunction, excitotoxicity, impaired neuronal transport, cytoskeletal defects, inflammation and reduced neurotransmitter release. Here we review current knowledge of the roles of lipid metabolism and function in the CNS and discuss how modulating these pathways may offer novel therapeutic options for treating ALS. DOI: 10.3389/fnmol.2018.00010 PMCID: PMC5787076 PMID: 29410613
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 128 – Multiple Sklerose: Veröffentlichungen Oktober 2013
126. Front Mol Neurosci. 2018 Jan 19;11:2. doi: 10.3389/fnmol.2018.00002. eCollection 2018. Hypothalamic Alterations in Neurodegenerative Diseases and Their Relation to Abnormal Energy Metabolism. Vercruysse P(1)(2)(3), Vieau D(4), Blum D(4), Petersén Å(5), Dupuis L(1)(2). Author information: (1)UMR-S 1118, Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale (INSERM), Strasbourg, France. (2)UMR-S1118, Université de Strasbourg, Strasbourg, France. (3)Department of Neurology, Ulm University, Ulm, Germany. (4)UMR-S 1172- JPArc, Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille), Alzheimer and Tauopathies, Lille, France. (5)Translational Neuroendocrine Research Unit (TNU), Lund University, Lund, Sweden. Neurodegenerative diseases (NDDs) are disorders characterized by progressive deterioration of brain structure and function. Selective neuronal populations are affected leading to symptoms which are prominently motor in amyotrophic lateral sclerosis (ALS) or Huntington's disease (HD), or cognitive in Alzheimer's disease (AD) and fronto-temporal dementia (FTD). Besides the common existence of neuronal loss, NDDs are also associated with metabolic changes such as weight gain, weight loss, loss of fat mass, as well as with altered feeding behavior. Importantly, preclinical research as well as clinical studies have demonstrated that altered energy homeostasis influences disease progression in ALS, AD and HD, suggesting that identification of the pathways leading to perturbed energy balance might provide valuable therapeutic targets Signals from both the periphery and central inputs are integrated in the hypothalamus, a major hub for the control of energy balance. Recent research identified major hypothalamic changes in multiple NDDs. Here, we review these hypothalamic alterations and seek to identify commonalities and differences in hypothalamic involvement between the different NDDs. These hypothalamic defects could be key in the development of perturbations in energy homeostasis in NDDs and further understanding of the underlying mechanisms might open up new avenues to not only treat weight loss but also to ameliorate overall neurological symptoms. DOI: 10.3389/fnmol.2018.00002 PMCID: PMC5780436 PMID: 29403354
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 129 – Multiple Sklerose: Veröffentlichungen Oktober 2013
127. Front Neurol. 2018 Feb 5;9:31. doi: 10.3389/fneur.2018.00031. eCollection 2018. Eye Movement Abnormalities in Multiple Sclerosis: Pathogenesis, Modeling, and Treatment. Serra A(1), Chisari CG(2), Matta M(3). Author information: (1)Neurology, Louis Stokes VA Medical Center, University Hospitals and Case Western Reserve School of Medicine, Cleveland, OH, United States. (2)Neurology, University of Catania, Catania, Italy. (3)Neurology, Ospedale San Luigi Gonzaga, Orbassano, Italy. Multiple sclerosis (MS) commonly causes eye movement abnormalities that may have a significant impact on patients' disability. Inflammatory demyelinating lesions, especially occurring in the posterior fossa, result in a wide range of disorders, spanning from acquired pendular nystagmus (APN) to internuclear ophthalmoplegia (INO), among the most common. As the control of eye movements is well understood in terms of anatomical substrate and underlying physiological network, studying ocular motor abnormalities in MS provides a unique opportunity to gain insights into mechanisms of disease. Quantitative measurement and modeling of eye movement disorders, such as INO, may lead to a better understanding of common symptoms encountered in MS, such as Uhthoff's phenomenon and fatigue. In turn, the pathophysiology of a range of eye movement abnormalities, such as APN, has been clarified based on correlation of experimental model with lesion localization by neuroimaging in MS. Eye movement disorders have the potential of being utilized as structural and functional biomarkers of early cognitive deficit, and possibly help in assessing disease status and progression, and to serve as platform and functional outcome to test novel therapeutic agents for MS. Knowledge of neuropharmacology applied to eye movement dysfunction has guided testing and use of a number of pharmacological agents to treat some eye movement disorders found in MS, such as APN and other forms of central nystagmus. DOI: 10.3389/fneur.2018.00031 PMCID: PMC5807658 PMID: 29467711
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 130 – Multiple Sklerose: Veröffentlichungen Oktober 2013
128. Front Neurol. 2018 Feb 1;9:16. doi: 10.3389/fneur.2018.00016. eCollection 2018. Sun Exposure across the Life Course Significantly Modulates Early Multiple Sclerosis Clinical Course. Simpson S Jr.(1)(2), van der Mei I(1), Lucas RM(3)(4), Ponsonby AL(3)(5)(6), Broadley S(7), Blizzard L(1); Ausimmune/AusLong Investigators Group, Taylor B(1). Collaborators: Lucas RM, Dear K, Ponsonby AL, Dwyer T, van der Mei I, Blizzard L, Simpson S Jr., Taylor BV, Broadley S, Kilpatrick T, Williams D, Lechner-Scott J, Shaw C, Chapman C, Coulthard A, Pender MP, Valery P. Author information: (1)Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia. (2)Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia. (3)National Centre for Epidemiology and Population Health, Research School of Population Health, College of Health and Medicine, Australian National University, Canberra, ACT, Australia. (4)Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia. (5)Murdoch Children's Research Institute, Melbourne, VIC, Australia. (6)Royal Melbourne Hospital, School of Medicine, University of Melbourne, Melbourne, VIC, Australia. (7)School of Medicine, Griffith University, Gold Coast, QLD, Australia. Background: Low vitamin D and/or sun exposure have been associated with increased risk of multiple sclerosis (MS) onset. However, comparatively, few studies have prospectively examined associations between these factors and clinical course. Objectives: To evaluate the association of sun exposure parameters and vitamin D levels with conversion to MS and relapse risk in a prospectively monitored cohort of 145 participants followed after a first demyelinating event up to 5-year review (AusLong Study). Methods: Sun exposure prior to and after onset measured by annual questionnaire; ultraviolet radiation (UVR) "load" estimated by location of residence over the life course and ambient UVR levels. Serum 25-hydroxyvitamin D [25(OH)D] concentrations measured at baseline, 2/3-year, and 5-year review. MS conversion and relapse assessed by neurologist assessment and medical record review. Results: Over two-thirds (69%) of those followed to 5-year review (100/145) converted to MS, with a total of 252 relapses. Higher pre-MS onset sun exposure was associated with reduced risk of MS conversion, with internal consistency between measures and dose-response relationships. Analogous associations were also seen with risk of relapse, albeit less strong. No consistent associations were observed between postonset sun exposure and clinical course, however. Notably, those who increased their sun exposure during follow-up had significantly reduced hazards of MS conversion and relapse. Serum 25(OH)D levels and vitamin D supplementation were not associated with conversion to MS or relapse hazard. Conclusion: We found that preonset sun exposure was protective against subsequent conversion to MS and relapses. While consistent associations between postonset sun exposure or serum 25(OH)D level and clinical course were not evident, possibly masked by behavior change, those participants who markedly increased their sun exposure demonstrated a reduced MS conversion and relapse hazard, suggesting beneficial effects of sun exposure on clinical course. DOI: 10.3389/fneur.2018.00016 PMCID: PMC5799286 PMID: 29449827
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 131 – Multiple Sklerose: Veröffentlichungen Oktober 2013
129. Front Neurol. 2018 Jan 23;9:5. doi: 10.3389/fneur.2018.00005. eCollection 2018. Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis. Mills EA(1), Ogrodnik MA(1), Plave A(1), Mao-Draayer Y(1)(2). Author information: (1)Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, United States. (2)Graduate Program in Immunology, Program in Biomedical Sciences, University of Michigan Medical School, Ann Arbor, MI, United States. Dimethyl fumarate (DMF) is an effective treatment option for relapsing-remitting multiple sclerosis (MS), but its therapeutic mechanism of action has not been fully elucidated. A better understanding of its mechanism will allow for the development of assays to monitor its clinical efficacy and safety in patients, as well as guide the development of the next generation of therapies for MS. In order to build the foundation for determining its mechanism, we reviewed the manner in which DMF alters lymphocyte subsets in MS patients, its impact on clinical efficacy and safety, as well as its molecular effects in cellular and animal models. DMF decreases absolute lymphocyte counts, but does not affect all subsets uniformly. CD8+ T-cells are the most profoundly affected, but reduction also occurs in the CD4+ population, particularly within the pro-inflammatory T-helper Th1 and Th17 subsets, creating a bias toward more anti-inflammatory Th2 and regulatory subsets. Similarly, B-lymphocyte, myeloid, and natural killer populations are also shifted toward a more anti-inflammatory state. In vitro and animal models demonstrate a role for DMF within the central nervous system (CNS) in promoting neuronal survival in an Nrf2 pathway-dependent manner. However, the impact of DMF directly within the CNS of MS patients remains largely unknown. DOI: 10.3389/fneur.2018.00005 PMCID: PMC5787128 PMID: 29410647
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 132 – Multiple Sklerose: Veröffentlichungen Oktober 2013
130. Front Neurol. 2018 Feb 2;8:708. doi: 10.3389/fneur.2017.00708. eCollection 2017. Technologies for Advanced Gait and Balance Assessments in People with Multiple Sclerosis. Shanahan CJ(1), Boonstra FMC(1), Cofré Lizama LE(2)(3), Strik M(1)(4), Moffat BA(1), Khan F(2)(3), Kilpatrick TJ(1)(5), van der Walt A(2), Galea MP(2)(3), Kolbe SC(1)(5). Author information: (1)Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, Australia. (2)Department of Medicine, University of Melbourne, Parkville, VIC, Australia. (3)Australian Rehabilitation Research Centre, Royal Melbourne Hospital, Parkville, VIC, Australia. (4)Department of Anatomy and Neuroscience, VU Medical Centre, Amsterdam, Netherlands. (5)Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia. Subtle gait and balance dysfunction is a precursor to loss of mobility in multiple sclerosis (MS). Biomechanical assessments using advanced gait and balance analysis technologies can identify these subtle changes and could be used to predict mobility loss early in the disease. This update critically evaluates advanced gait and balance analysis technologies and their applicability to identifying early lower limb dysfunction in people with MS. Non-wearable (motion capture systems, force platforms, and sensor-embedded walkways) and wearable (pressure and inertial sensors) biomechanical analysis systems have been developed to provide quantitative gait and balance assessments. Non-wearable systems are highly accurate, reliable and provide detailed outcomes, but require cumbersome and expensive equipment. Wearable systems provide less detail but can be used in community settings and can provide real-time feedback to patients and clinicians. Biomechanical analysis using advanced gait and balance analysis technologies can identify changes in gait and balance in early MS and consequently have the potential to significantly improve monitoring of mobility changes in MS. DOI: 10.3389/fneur.2017.00708 PMCID: PMC5799707 PMID: 29449825
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 133 – Multiple Sklerose: Veröffentlichungen Oktober 2013
131. Front Neurol. 2018 Jan 24;8:727. doi: 10.3389/fneur.2017.00727. eCollection 2017. A Fully Automated Pipeline for Normative Atrophy in Patients with Neurodegenerative Disease. Rummel C(1), Aschwanden F(1), McKinley R(1), Wagner F(1), Salmen A(2), Chan A(2), Wiest R(1). Author information: (1)Support Center for Advanced Neuroimaging (SCAN), University Institute for Diagnostic and Interventional Neuroradiology, Inselspital Bern, University of Bern, Bern, Switzerland. (2)Department of Neurology, Inselspital Bern, University of Bern, Bern, Switzerland. Introduction: Volumetric image analysis to detect progressive brain tissue loss in patients with multiple sclerosis (MS) has recently been suggested as a promising marker for "no evidence of disease activity." Software packages for longitudinal whole-brain volume analysis in individual patients are already in clinical use; however, most of these methods have omitted region-based analysis. Here, we suggest a fully automatic analysis pipeline based on the free software packages FSL and FreeSurfer. Materials and methods: Fifty-five T1-weighted magnetic resonance imaging (MRI) datasets of five patients with confirmed relapsing-remitting MS and mild to moderate disability were longitudinally analyzed compared to a morphometric reference database of 323 healthy controls (HCs). After lesion filling, the volumes of brain segmentations and morphometric parameters of cortical parcellations were automatically screened for global and regional abnormalities. Error margins and artifact probabilities of regional morphometric parameters were estimated. Linear models were fitted to the series of follow- up MRIs and checked for consistency with cross-sectional aging in HCs. Results: As compared to leave-one-out cross-validation in a subset of the control dataset, anomaly detection rates were highly elevated in MRIs of two patients. We detected progressive volume changes that were stronger than expected compared to normal aging in 4/5 patients. In individual patients, we also identified stronger than expected regional decreases of subcortical gray matter, of cortical thickness, and areas of reducing gray-white contrast over time. Conclusion: Statistical comparison with a large normative database may provide complementary and rater independent quantitative information about regional morphological changes related to disease progression or drug-related disease modification in individual patients. Regional volume loss may also be detected in clinically stable patients. DOI: 10.3389/fneur.2017.00727 PMCID: PMC5787548 PMID: 29416523
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 134 – Multiple Sklerose: Veröffentlichungen Oktober 2013
132. Front Neurol. 2018 Jan 16;8:730. doi: 10.3389/fneur.2017.00730. eCollection 2017. Alemtuzumab Improves Cognitive Processing Speed in Active Multiple Sclerosis-A Longitudinal Observational Study. Riepl E(1), Pfeuffer S(1), Ruck T(1), Lohmann H(1), Wiendl H(1), Meuth SG(1), Johnen A(1). Author information: (1)Department of Neurology, University Hospital Muenster, Muenster, Germany. Background: Several disease-modifying drugs have shown promising effects on cognitive impairment in multiple sclerosis (MS). Alemtuzumab, a humanized monoclonal antibody, is effective in controlling disease activity, however, has not been evaluated for its effects on cognition in detail so far. Objective: To explore the influence of alemtuzumab on cognitive impairment in active relapsing-remitting MS (RRMS) as well as possible clinical and neuroimaging predictors of cognitive changes during the first year of therapy. Methods: Extensive neuropsychological assessment was administered to 21 patients with active RRMS at baseline and again after the second treatment with alemtuzumab (mean time span: 15.05 months). Clinical and routine structural neuroimaging markers were explored for their capacity to predict individual courses of cognitive change. Results: Overall cognitive functioning remained stable or improved during the observational period of alemtuzumab treatment on average. Scores on two neuropsychological tests of processing speed significantly improved and clinically relevant individual gains of processing speed were seen in the majority of patients. Linear regression models showed that clinical and routine neuroimaging measures of disease activity could not fully account for these cognitive changes. Conclusion: Results suggest that alemtuzumab treatment in active RRMS stabilizes overall cognitive functioning and furthermore positively affects cognitive processing speed. Changes in processing speed were independent from clinical and structural neuroimaging parameters of disease activity and may thus represent an underrated and independent outcome measure to evaluate treatment effects. DOI: 10.3389/fneur.2017.00730 PMCID: PMC5775967 PMID: 29387035
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 135 – Multiple Sklerose: Veröffentlichungen Oktober 2013
133. Front Psychol. 2018 Jan 31;9:15. doi: 10.3389/fpsyg.2018.00015. eCollection 2018. Psychological Shift in Partners of People with Multiple Sclerosis Who Undertake Lifestyle Modification: An Interpretive Phenomenological Study. Neate SL(1), Taylor KL(1), Jelinek GA(1), De Livera AM(1), Brown CR(1), Weiland TJ(1). Author information: (1)Neuroepidemiolgy Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia. Introduction: Being in an intimate relationship with a person with multiple sclerosis (MS) may have a substantial impact on the partner's quality of life. Existing research has largely focused on negative impacts of MS for both people with MS (PwMS) and their partners and has sampled the population of partners of PwMS who have primarily adopted standard medical management only. Modifiable lifestyle factors have become increasingly recognized in the management of MS symptoms and disease progression. For partners of PwMS who have undertaken lifestyle modification as an additional strategy to minimize disease progression, the impacts, both positive and negative remain unexplored. This research is unique as it focuses on partners of PwMS who have attempted to adopt major lifestyle interventions outside of the prevailing paradigm of MS management. Aim: To explore and interpret the lived experiences of partners of PwMS who have adopted lifestyle modification, to understand partners' attitudes to and experiences of the effect of MS and lifestyle modification on their life, relationship and view of the future. Method: Design: a qualitative, interpretive, phenomenological study using semi-structured interviews.PARTICIPANTS: English-speaking; aged 18 years or more; in a spousal relationship for 12 months or more with a person with MS who had attended a residential lifestyle educational intervention and undertaken lifestyle modification. ANALYSIS: Interviews were recorded, transcribed verbatim and thematically analyzed using NVivo™ software. Results: Twenty- one partners were interviewed. This paper reports one of the study's themes, the psychological shift experienced by partners of PwMS. Sub-themes included adaptation; loss and grief; difficult emotions; reframing, re-evaluating and re-prioritizing; hope and optimism; empowerment and taking control; and self-awareness, greater understanding and personal growth. Conclusion: Partners of PwMS who have undertaken lifestyle modification experienced a broad range of psychological adjustments. Whilst reflecting the potential difficulties that partners of PwMS may experience, this group experienced a range of positive psychological changes that add to the literature regarding partners' potential experiences and may provide hope for those in partnerships with people with MS. This study provides themes to potentially inform a quantitative study of a larger population of partners of PwMS. DOI: 10.3389/fpsyg.2018.00015 PMCID: PMC5797767 PMID: 29445346
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 136 – Multiple Sklerose: Veröffentlichungen Oktober 2013
134. Gait Posture. 2018 Feb 8;61:393-397. doi: 10.1016/j.gaitpost.2018.01.033. [Epub ahead of print] Walking speed measurement with an Ambient Measurement System (AMS) in patients with multiple sclerosis and walking impairment. Bethoux F(1), Varsanik JS(2), Chevalier TW(3), Halpern EF(4), Stough D(5), Kimmel ZM(6). Author information: (1)Mellen Center for MS Treatment and Research, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: [email protected]. (2)Atlas5D, Inc. One Broadway, Cambridge, MA 02142, USA. Electronic address: [email protected]. (3)Atlas5D, Inc. One Broadway, Cambridge, MA 02142, USA. Electronic address: [email protected]. (4)Institute for Technology Assessment, 101 Merrimac St., Boston, MA 02114, USA. Electronic address: [email protected]. (5)Mellen Center for MS Treatment and Research, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: [email protected]. (6)Atlas5D, Inc. One Broadway, Cambridge, MA 02142, USA. Electronic address: [email protected]. BACKGROUND: Walking speed is an important measure of gait impairment in multiple sclerosis (MS). The clinical assessment of walking speed requires dedicated time, space, and personnel, and may not accurately gauge real-world performance. The term "Ambient Measurement System" (AMS) refers to a new class of device that passively measures walking speed at home, without the need for dedicated space or specialized setup. This study compared an AMS, Echo5D, versus in-clinic standard measures of walking speed on a straight path. METHODS: Twenty participants with MS and walking impairment were recruited from the Cleveland Clinic Mellen Center for MS. Each participant traversed an electronic GAITRite CIRFace (GC) sensor mat four times (two at comfortable pace, two at fast pace). Each participant then performed the Timed 25-Foot Walk (T25FW) twice, measured by a manual stopwatch (SW). All traversals were simultaneously measured by an array of Echo5D devices. Echo5D speeds were correlated with the Patient-Determined Disease Steps and the MS Walking Scale-12 patient-reported outcomes. RESULTS: Pearson correlations between Echo5D and clinical tests ranged from 0.89 to 0.98 (p < 0.0001). No statistically significant bias was found between Echo5D and GC. A small statistically significant bias was found between Echo5D and SW, with Echo5D reporting approximately 5% faster walking speeds in aggregate. CONCLUSIONS: Among MS patients with walking impairments, the Echo5D AMS acquired walking speeds which were closely correlated with the standard measures of GC and SW. The strong agreement supports the use of Echo5D to assess in-home, real-world walking performance in MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.gaitpost.2018.01.033 PMID: 29454289
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 137 – Multiple Sklerose: Veröffentlichungen Oktober 2013
135. Gait Posture. 2018 Feb 19;61:445-452. doi: 10.1016/j.gaitpost.2018.02.018. [Epub ahead of print] Postural control deficits in people with Multiple Sclerosis: A systematic review and meta-analysis. Comber L(1), Sosnoff JJ(2), Galvin R(3), Coote S(4). Author information: (1)School of Allied Health, Health Research Institute, University of Limerick, Ireland. Electronic address: [email protected]. (2)Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, IL, USA. Electronic address: [email protected]. (3)School of Allied Health, Health Research Institute, University of Limerick, Ireland. Electronic address: [email protected]. (4)School of Allied Health, Health Research Institute, University of Limerick, Ireland. Electronic address: [email protected]. BACKGROUND: Multiple sclerosis (MS) is a neurological condition that can affect the postural stability of the individual and predispose falls in this population. METHODS: A systematic literature search identified case-control studies investigating differences in postural control across a diversity of task conditions, with the exception of gait, between people with MS and healthy controls. Meta-analysis was conducted where a variable was presented by four or more studies. RESULTS: Forty-three studies of people with a mean Expanded Disability Status Scale (EDSS) of 1.0 to 6.0 were included. Seven conditions of assessment and 105 individual measurement variables relating to postural control were included. Quiet stance was the only condition (11 studies) possessing sufficient data to contribute to meta-analysis in terms of centre of pressure path length (SMD = 1.04, 95% CI {0.86- 1.22}, p < 0.001), medio-lateral velocity (SMD = 1.35, 95% CI {0.77-1.92}, p < 0.001) and 95% confidence ellipse (SMD = 0.83 95% CI {0.59-1.08}, p < 0.001). RESULTS: indicate that regardless of task complexity or sensory condition, people with MS display considerable deficits in postural control in comparison to healthy controls. CONCLUSIONS: The large number of variables and lack of standardisation of reporting makes data synthesis challenging, however, people with MS display considerable deficits in postural control compared to healthy controls regardless of task condition or complexity. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.gaitpost.2018.02.018 PMID: 29486362
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 138 – Multiple Sklerose: Veröffentlichungen Oktober 2013
136. Glia. 2018 Feb 9. doi: 10.1002/glia.23305. [Epub ahead of print] Differential local tissue permissiveness influences the final fate of GPR17-expressing oligodendrocyte precursors in two distinct models of demyelination. Coppolino GT(1), Marangon D(1), Negri C(1), Menichetti G(1), Fumagalli M(1), Gelosa P(2), Dimou L(3), Furlan R(4), Lecca D(1), Abbracchio MP(1). Author information: (1)Laboratory of Molecular and Cellular Pharmacology of the Purinergic Transmission, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, Milan, 20133, Italy. (2)Centro Cardiologico Monzino, Via Parea, 4, Milano, 20138, Italy. (3)Molecular and Translational Neuroscience, University of Ulm, Albert-Einstein-Allee 11, Ulm, D - 89081, Germany. (4)Institute of Experimental Neurology, S. Raffaele Scientific Institute, Via Olgettina, 58, Milano, 20132, Italy. Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17-iCreERT2 xCAG-eGFP mice) allowing to follow the final fate of GPR17+ cells by tamoxifen-induced GFP-labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP+ cells at damaged areas. However, only in the cuprizone model reacting GFP+ cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP+ cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor-1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti-inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery. © 2018 The Authors GLIA Published by Wiley Periodicals, Inc. DOI: 10.1002/glia.23305 PMID: 29424466
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 139 – Multiple Sklerose: Veröffentlichungen Oktober 2013
137. Glia. 2018 Feb 9. doi: 10.1002/glia.23304. [Epub ahead of print] Astrocyte disruption of neurovascular communication is linked to cortical damage in an animal model of multiple sclerosis. Eilam R(1), Segal M(2), Malach R(2), Sela M(3), Arnon R(3), Aharoni R(3). Author information: (1)Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot, 761001, Israel. (2)Department of Neurobiology, The Weizmann Institute of Science, Rehovot, 761001, Israel. (3)Department of Immunology, The Weizmann Institute of Science, Rehovot, 761001, Israel. To elucidate mechanisms contributing to cortical pathology in multiple sclerosis (MS), we investigated neurovascular aberrations, in particular the association of astrocytes with cortical neurons and blood vessels, in mice induced with experimental autoimmune encephalomyelitis (EAE). Blood-brain barrier (BBB) dysfunction was evident by leakage of the tracer sodium fluorescein, along with reduced expression of claudin-5 by endothelial cells and desmin by pericytes. Immunohistological and ultrastructural analyses revealed detachment of the astroglial cell bodies from the blood vessels and loss of their connections with both the blood vessels and the neuronal synapses. Furthermore, examination of individual astrocytic processes at cortical layer IV, where well-defined neuronal columns (barrels) are linked to functional properties, revealed loss of astrocytic confinement to the functional neuronal boundaries. Thus, in contrast to the highly modulated patches of astrocyte processes in naïve mice overlapping the barrel cores, in EAE-mice process distribution was uniform ignoring the barrel boundaries. These aberrations are attributed to the surrounding inflammation, indicated by T-cells presence in the cortex as well as in the subcortical white matter and the meninges. Immunomodulatory treatment with glatiramer acetate partially abrogated the neurovascular damage. These combined findings indicate that under inflammatory conditions, activated perivascular astrocytes fail in neuro-hemodynamic coupling, resulting in obstructed cross-talk between the blood vessels and the neurons. We propose that loss of cortical astrocytic regulation and fine-tuning between the blood supply and the neuronal needs contributes to the neurological impairment and cognitive decline occurring in EAE/MS as well as to the disease progression. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/glia.23304 PMID: 29424049
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 140 – Multiple Sklerose: Veröffentlichungen Oktober 2013
138. Glia. 2018 Feb 9. doi: 10.1002/glia.23306. [Epub ahead of print] Vitamin C promotes oligodendrocytes generation and remyelination. Guo YE(1)(2), Suo N(1)(2), Cui X(3), Yuan Q(1), Xie X(1)(3)(4). Author information: (1)CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. (2)University of Chinese Academy of Sciences, Graduate School, No. 19A Yuquan Road, Beijing, 100049, China. (3)Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. (4)State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Oligodendrocyte-formed myelin sheaths play important roles in the neuronal functions in the central nervous system. In demyelinating diseases, such as Multiple Sclerosis, the myelin sheaths are damaged and the remyelinating process is somehow hindered. Restoration of the myelin sheaths requires the differentiation of the oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). To discover small molecule compounds that might promote the OPC to OL differentiation, a high-throughput screening system is established and L-ascorbyl-2-phosphate (As-2P), a stable form of Vitamin C (Vc), is found to greatly enhance the OPC to OL differentiation. As-2P promotes gradual expression of OL lineage markers, including O4, CNPase and MBP, in a dose- and time-dependent manner. It also facilitates the formation of myelin sheaths in OPC-neuron co-culture. As-2P also promotes the repair of the myelin sheaths in vivo and provides significant therapeutic effect in a cuprizone-mediated demyelination animal model. Interestingly, As-2P's function in promoting OPC differentiation is not related to its antioxidant activity. And an intracellular rather than an extracellular mechanism might be involved. Considering the safe use of Vc as a dietary supplement for many years, it might also be used as an alternative medicine for CNS demyelinating diseases. © 2018 The Authors GLIA Published by Wiley Periodicals, Inc. DOI: 10.1002/glia.23306 PMID: 29423921
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 141 – Multiple Sklerose: Veröffentlichungen Oktober 2013
139. Glia. 2018 Feb 19. doi: 10.1002/glia.23313. [Epub ahead of print] Semaphorin4A and H-ferritin utilize Tim-1 on human oligodendrocytes: A novel neuro-immune axis. Chiou B(1), Lucassen E(2), Sather M(1), Kallianpur A(3)(4), Connor J(1). Author information: (1)Department of Neurosurgery, Penn State University College of Medicine, Hershey, Pennsylvania. (2)Department of Neurology, Penn State University College of Medicine, Hershey, Pennsylvania. (3)Department of Genomic Medicine, Cleveland Clinic/Lerner Research Institute, Cleveland, Ohio. (4)Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio. Deficiency of trophic factors relating to the survival of oligodendrocytes, combined with direct interactions with the immune system, are favored paradigms that are increasingly implicated in demyelinating diseases of the central nervous system. We and others have previously shown that Sema4A and H-ferritin interact through the T-cell immunoglobulin and mucin domain (Tim-2) receptor in mice. H-ferritin has been identified as the iron delivery protein for oligodendrocytes, whereas Sema4A causes a direct cytotoxic effect. However, the expression of Tim-2 has not been detected in humans. Here, we demonstrate that, similar to rodents, human oligodendrocytes undergo apoptosis when exposed to Sema4A and take up H-ferritin for meeting iron requirements and that these functions are mediated via the Tim-1 receptor. Moreover, we also demonstrate the ability of H-ferritin to block Sema4A-mediated cytotoxicity. Furthermore, we show in a series of pilot studies that Sema4A is detectable in the CSF of multiple sclerosis patients and HIV-seropositive persons and can induce oligodendrocyte cell death. Together, these results identify a novel iron uptake mechanism for human oligodendrocytes and a connection between oligodendrocytes and the immune system. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/glia.23313 PMID: 29457657
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 142 – Multiple Sklerose: Veröffentlichungen Oktober 2013
140. Glia. 2018 Feb 13. doi: 10.1002/glia.23307. [Epub ahead of print] Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune-mediated demyelinating diseases. Stone S(1)(2), Wu S(1)(2), Jamison S(1)(2), Durose W(1)(2), Pallais JP(1)(2), Lin W(1)(2). Author information: (1)Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota. (2)Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) play a critical role in immune-mediated demyelinating diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), by regulating the viability of oligodendrocytes. Our previous studies show that activation of the PERK branch of the UPR protects myelinating oligodendrocytes against ER stress in young, developing mice that express IFN-γ, a key pro- inflammatory cytokine in MS and EAE, in the CNS. Several studies also demonstrate that PERK activation preserves oligodendrocyte viability and function, protecting mice against EAE. While evidence suggests activation of the ATF6α branch of the UPR in oligodendrocytes under normal and disease conditions, the effects of ATF6α activation on oligodendrocytes in immune-mediated demyelinating diseases remain unknown. Herein, we showed that ATF6α deficiency had no effect on oligodendrocytes under normal conditions. Interestingly, we showed that ATF6α deficiency exacerbated ER stressed-induced myelinating oligodendrocyte death and subsequent myelin loss in the developing CNS of IFN-γ-expressing mice. Moreover, we found that ATF6α deficiency increased EAE severity and aggravated EAE-induced oligodendrocyte loss and demyelination, without affecting inflammation. Thus, these data suggest the protective effects of ATF6α activation on oligodendrocytes in immune-mediated demyelinating diseases. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/glia.23307 PMID: 29436030
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 143 – Multiple Sklerose: Veröffentlichungen Oktober 2013
141. Handb Clin Neurol. 2018;148:723-730. doi: 10.1016/B978-0-444-64076-5.00046-6. Multiple sclerosis. Cotsapas C(1), Mitrovic M(2), Hafler D(2). Author information: (1)Department of Neurology, Yale School of Medicine, New Haven, CT, United States. Electronic address: [email protected]. (2)Department of Neurology, Yale School of Medicine, New Haven, CT, United States. Multiple sclerosis is a potentially progressive, autoimmune neurologic disorder of the central nervous system, resulting from an autoimmune attack on central nervous system white matter. It is a leading cause of neurologic symptoms in young adults, with no known cure. Emerging disease-modifying therapies aim to control symptoms, with increasingly sophisticated immune function modulation. Though several environmental exposures increase the risk of developing the disease, a large fraction of overall risk is heritable and can be attributed to hundreds of common genetic variants influencing gene regulation in specific immune subsets. Here, we review the history of the disease, the realization that risk is heritable, and the recent revelation of hundreds of genetic variants driving this risk by international consortia studying tens of thousands of patients. Finally, we discuss how these results are revealing the specific pathobiology of multiple sclerosis and how this knowledge is transforming drug discovery. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/B978-0-444-64076-5.00046-6 PMID: 29478610
142. Histochem Cell Biol. 2018 Feb 19. doi: 10.1007/s00418-018-1654-0. [Epub ahead of print] Changes in the axo-glial junctions of the optic nerves of cuprizone-treated mice. Kojima W(1), Hayashi K(2). Author information: (1)Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo, Japan. (2)Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo, Japan. [email protected]. Demyelination induced by cuprizone in mice has served a useful model system for the study of demyelinating diseases, such as multiple sclerosis. Severity of demyelination by cuprizone, however, varies across different regions of the central nervous system; the corpus callosum is sensitive, while the optic nerves are resistant. Here, we investigated the effects of cuprizone on optic nerves, focusing on the axo-glial junctions. Immunostaining for sodium channels, contactin-associated protein, neurofascins, and potassium channels revealed that there were no massive changes in the density and morphology of the axo-glial junctions in cuprizone-treated optic nerves. However, when we counted the number of incomplete junctional complexes, we observed increased numbers of isolated paranodes. These isolated paranodes were immunopositive for both axonal and glial membrane proteins, indicating that they were the contact sites between axons and glia. These were not associated with sodium channels or potassium channels, suggesting the absence of physiological functions. When teased axons from cuprizone-treated optic nerves were immunostained, the isolated paranodes were found at the internode region of the myelin. From these observations, we conclude that cuprizone induces new contacts between axons and myelins at the internode region. DOI: 10.1007/s00418-018-1654-0 PMID: 29460173
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 144 – Multiple Sklerose: Veröffentlichungen Oktober 2013
143. Hum Brain Mapp. 2018 Feb 6. doi: 10.1002/hbm.23993. [Epub ahead of print] Changes in structural network are associated with cortical demyelination in early multiple sclerosis. Mangeat G(1)(2), Badji A(1)(3), Ouellette R(2)(4), Treaba CA(2)(5), Herranz E(2)(5), Granberg T(2)(4)(5), Louapre C(2)(5)(6), Stikov N(1)(7), Sloane JA(5)(8), Bellec P(3)(9), Mainero C(2)(5), Cohen-Adad J(1)(3). Author information: (1)Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, Quebec, Canada. (2)Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, MGH, Charlestown, Massachusetts, USA. (3)Functional Neuroimaging Unit, CRIUGM, Université de Montréal, Montreal, Quebec, Canada. (4)Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. (5)Harvard Medical School, Boston, Massachusetts, USA. (6)Neurology Department, hôpital de la Pitié-Salpêtrière, APHP, Institut du cerveau et de la moelle épinière (ICM), Paris, France. (7)Montreal Health Institute, Montreal, Quebec, Canada. (8)Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. (9)Department of computer science and operations research, Université de Montréal, Montreal, Quebec, Canada. The aim of this study was to investigate the interplay between structural connectivity and cortical demyelination in early multiple sclerosis. About 27 multiple sclerosis patients and 18 age-matched controls underwent two MRI scanning sessions. The first was done at 7T and involved acquiring quantitative T1 and T2 * high-resolution maps to estimate cortical myelination. The second was done on a Connectom scanner and consisted of acquiring high angular resolution diffusion-weighted images to compute white matter structural connectivity metrics: strength, clustering and local efficiency. To further investigate the interplay between structural connectivity and cortical demyelination, patients were divided into four groups according to disease-duration: 0-1 year, 1-2 years, 2-3 years, and >3 years. ANOVA and Spearman's correlations were used to highlight relations between metrics. ANOVA detected a significant effect between disease duration and both cortical myelin (p = 2 × 10-8 ) and connectivity metrics (p < 10-4 ). We observed significant cortical myelin loss in the shorter disease- duration cohorts (0-1 year, p = .0015), and an increase in connectivity in the longer disease-duration cohort (2-3 years, strength: p = .01, local efficiency: p = .002, clustering: p = .001). Moreover, significant covariations between myelin estimation and white matter connectivity metrics were observed: Spearman's Rho correlation coefficients of 0.52 (p = .0003), 0.55 (p = .0001), and 0.53 (p = .0001) for strength, local efficiency, and clustering, respectively. An association between cortical myelin loss and changes in white matter connectivity in early multiple sclerosis was detected. These changes in network organization might be the result of compensatory mechanisms in response to the ongoing cortical diffuse damage in the early stages of multiple sclerosis. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/hbm.23993 PMID: 29411457
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 145 – Multiple Sklerose: Veröffentlichungen Oktober 2013
144. Hum Brain Mapp. 2018 Feb 21. doi: 10.1002/hbm.24020. [Epub ahead of print] Explaining the heterogeneity of functional connectivity findings in multiple sclerosis: An empirically informed modeling study. Tewarie P(1), Steenwijk MD(2)(3), Brookes MJ(1), Uitdehaag BMJ(2), Geurts JJG(3), Stam CJ(4), Schoonheim MM(3). Author information: (1)Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom. (2)Department of Neurology, Amsterdam Neuroscience, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands. (3)Department of Anatomy and Neurosciences, Amsterdam Neuroscience, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands. (4)Department of Clinical Neurophysiology and MEG center, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands. To understand the heterogeneity of functional connectivity results reported in the literature, we analyzed the separate effects of grey and white matter damage on functional connectivity and networks in multiple sclerosis. For this, we employed a biophysical thalamo-cortical model consisting of interconnected cortical and thalamic neuronal populations, informed and amended by empirical diffusion MRI tractography data, to simulate functional data that mimic neurophysiological signals. Grey matter degeneration was simulated by decreasing within population connections and white matter degeneration by lowering between population connections, based on lesion predilection sites in multiple sclerosis. For all simulations, functional connectivity and functional network organization are quantified by phase synchronization and network integration, respectively. Modeling results showed that both cortical and thalamic grey matter damage induced a global increase in functional connectivity, whereas white matter damage induced an initially increased connectivity followed by a global decrease. Both white and especially grey matter damage, however, induced a decrease in network integration. These empirically informed simulations show that specific topology and timing of structural damage are nontrivial aspects in explaining functional abnormalities in MS. Insufficient attention to these aspects likely explains contradictory findings in multiple sclerosis functional imaging studies so far. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/hbm.24020 PMID: 29468785
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 146 – Multiple Sklerose: Veröffentlichungen Oktober 2013
145. Immunity. 2018 Feb 20;48(2):380-395.e6. doi: 10.1016/j.immuni.2018.01.011. Epub 2018 Feb 6. High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease. Mrdjen D(1), Pavlovic A(1), Hartmann FJ(1), Schreiner B(1), Utz SG(1), Leung BP(1), Lelios I(1), Heppner FL(2), Kipnis J(3), Merkler D(4), Greter M(1), Becher B(5). Author information: (1)Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (2)Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany. (3)Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. (4)Department of Pathology and Immunology, University of Geneva, and Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland. (5)Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. Electronic address: [email protected]. Individual reports suggest that the central nervous system (CNS) contains multiple immune cell types with diverse roles in tissue homeostasis, immune defense, and neurological diseases. It has been challenging to map leukocytes across the entire brain, and in particular in pathology, where phenotypic changes and influx of blood-derived cells prevent a clear distinction between reactive leukocyte populations. Here, we applied high-dimensional single-cell mass and fluorescence cytometry, in parallel with genetic fate mapping systems, to identify, locate, and characterize multiple distinct immune populations within the mammalian CNS. Using this approach, we revealed that microglia, several subsets of border-associated macrophages and dendritic cells coexist in the CNS at steady state and exhibit disease-specific transformations in the immune microenvironment during aging and in models of Alzheimer's disease and multiple sclerosis. Together, these data and the described framework provide a resource for the study of disease mechanisms, potential biomarkers, and therapeutic targets in CNS disease. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.immuni.2018.01.011 PMID: 29426702
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 147 – Multiple Sklerose: Veröffentlichungen Oktober 2013
146. Immunogenetics. 2018 Feb 3. doi: 10.1007/s00251-018-1052-8. [Epub ahead of print] Absence of the tag polymorphism for the risk haplotype HLA-DR2 for multiple sclerosis in Wixárika subjects from Mexico. González-Enríquez GV(1), Torres-Mendoza BM(1)(2), Márquez-Pedroza J(2)(3), Macías-Islas MA(3)(4), Ortiz GG(5), Cruz-Ramos JA(6)(7). Author information: (1)Departamento de Disciplinas Filosóficas, Metodológicas e Instrumentales, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Sierra Mojada 950, 44340, Guadalajara, Jalisco, Mexico. (2)Laboratorio de Inmunodeficiencias y Retrovirus Humanos, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico. (3)Doctorado en Farmacología, CUCS, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico. (4)Departamento de Neurología, Unidad Médica de Alta Especialidad (UMAE)-Hospital de Especialidades, Centro Médico Nacional de Occidente (CMNO), IMSS, Guadalajara, Jalisco, Mexico. (5)Laboratorio de Desarrollo- Envejecimiento, Enfermedades Neurodegenerativas, División de Neurociencias, CIBO, IMSS, Guadalajara, Jalisco, Mexico. (6)Departamento de Disciplinas Filosóficas, Metodológicas e Instrumentales, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Sierra Mojada 950, 44340, Guadalajara, Jalisco, Mexico. [email protected]. (7)Instituto Jalisciense de Cancerología, Guadalajara, Jalisco, Mexico. [email protected]. The HLA-DRB1*15:01 allele has a demonstrated risk for the development of multiple sclerosis (MS) in most populations around the world. The single nucleotide polymorphism (SNP) rs3129934 is found in linkage disequilibrium with the risk haplotype formed by the HLA-DRB1*15:01 and HLA-DQB1*06:02 alleles, and it is considered a reliable marker of the presence of this haplotype. Native Americans have a null or low prevalence of MS. In this study, we sought to identify the frequency of rs3129934 in the Wixárika ethnic group as well as in Mestizo (mixed race) patients with MS and in controls from western Mexico. Through real-time polymerase chain reaction (PCR) using TaqMan probes, we analyzed the allele and genotype frequencies of rs3129934 in Mestizo individuals with and without MS and in 73 Wixárika subjects from the state of Jalisco, Mexico. The Wixárika subjects were homozygote for the C allele of rs3129934. The allele and genotype frequency in Mestizos with MS was similar to that of other MS populations with Caucasian ancestry. The absence of the T risk allele rs3129934 (associated with the haplotype HLA-DRB1*15:01, HLA-DQ1*06:02) in this sample of Wixárika subjects is consistent with the unreported MS in this Amerindian group, related to absence of such paramount genetic risk factor. DOI: 10.1007/s00251-018-1052-8 PMID: 29397401
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 148 – Multiple Sklerose: Veröffentlichungen Oktober 2013
147. Immunology. 2018 Feb 2. doi: 10.1111/imm.12903. [Epub ahead of print] The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders. Dopkins N(1), Nagarkatti PS(1), Nagarkatti M(1). Author information: (1)Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA. The importance of the gut microbiome in the regulation of non-infectious diseases has earned unprecedented interest from biomedical researchers. Widespread use of next-generation sequencing techniques has prepared a foundation for further research by correlating the presence of specific bacterial species with the onset or severity of a disease state, heralding paradigm-shifting results. This review covers the mechanisms through which a dysbiotic gut microbiota contributes to the pathological symptoms in an autoimmune neurodegenerative disorder, multiple sclerosis (MS). Although the central nervous system (CNS) is protected by the blood-brain barrier (BBB), it is unclear how gut dysbiosis can trigger potential immunological changes in the CNS in the presence of the BBB. This review focuses on the immunoregulatory functionality of microbial metabolites, which can cross the BBB and mediate their effects directly on immune cells within the CNS and/or indirectly through modulating the response of peripheral T cells to stimulate or inhibit pro-inflammatory chemokines and cytokines, which in turn regulate the autoimmune response in the CNS. Although more research is clearly needed to directly link the changes in gut microbiome with neuroinflammation, focusing research on microbiota that produce beneficial metabolites with the ability to attenuate chronic inflammation systemically as well as in the CNS, can offer novel preventive and therapeutic modalities against a wide array of inflammatory and autoimmune diseases. © 2018 John Wiley & Sons Ltd. DOI: 10.1111/imm.12903 PMID: 29392733
148. Immunology. 2018 Feb 2. doi: 10.1111/imm.12902. [Epub ahead of print] Immune modulatory effects of statins. Zeiser R(1). Author information: (1)Department of Haematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Centre, Freiburg, Germany. Despite major advances in recent years, immunosuppressive regimens for multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and graft-versus-host disease still have major adverse effects and immunomodulation rather than immune paralysis would be desirable. Statins inhibit the rate-limiting enzyme of the l-mevalonate pathway, the 3-hydroxy-3-methyl-glutaryl- coenzyme A reductase. It was shown that blocking the l-mevalonate pathway reduces inflammation through effects on downstream metabolites of the pathway including farnesylpyrophosphates and geranylgeranylpyrophosphates, which are essential for the attachment of GTPases like RhoA, Rac and Ras to the cell membrane. Therefore, l-mevalonate pathway downstream products play critical roles in the different steps of an immune response including immune cell activation, migration, cytokine production, immune metabolism and survival. This review discusses the relevance of the different metabolites for the immunomodulatory effect of statins and connects preclinical results with data from clinical studies that tested statins for the treatment of different inflammatory diseases. © 2018 John Wiley & Sons Ltd. DOI: 10.1111/imm.12902 PMID: 29392731
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149. Inflamm Res. 2018 Feb 22. doi: 10.1007/s00011-018-1136-9. [Epub ahead of print] Cathepsin H deficiency in mice induces excess Th1 cell activation and early-onset of EAE though impairment of toll-like receptor 3 cascade. Okada R(1)(2), Zhang X(3), Harada Y(1), Wu Z(1), Nakanishi H(4)(5). Author information: (1)Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka, 812-8582, Japan. (2)Department of Chemistry, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan. (3)Center of Implant Dentistry, School of Somatology, China Medical University, Shenyang, 110122, China. (4)Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka, 812-8582, Japan. [email protected]. (5)Department of Pharmacology, Faculty of Pharmaceutical Sciences, Yasuda Women's University, Hiroshima, 731-0153, Japan. [email protected]. OBJECTIVE: The objective of this study is to investigate the role of cathepsin H (CatH), a lysosomal cysteine protease, in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. METHODS: EAE was induced in CatH-deficient mice (CatH-/-) and wild-type littermates (+/+) using myelin oligodendrocyte glycoprotein (MOG) 35-55. The effects of CatH deficiency were determined by clinical scoring, mRNA expression levels of Tbx21, Rorc and FoxP3, protein levels of poly(I:C)-induced toll-like receptor 3 (TLR3) and phosphorylation of IRF3, and secretion of interferon-β (IFN-β) by splenocytes. RESULTS AND CONCLUSIONS: CatH-/- showed a significantly earlier disease onset of EAE and increased Th1 cell differentiation in splenocytes. Splenocytes prepared from immunized CatH-/- showed a significant decrease in poly(I:C)-induced increased TLR3 expression, interferon regulatory factor 3 (IRF3) phospholylation and IFN-β secretion. Therefore, CatH deficiency impaired TLR3-mediated activation of IRF3 and consequent secretion of IFN-β from dendritic cells, leading to the enhancement of Th1 cell differentiation and consequent early disease onset of EAE. DOI: 10.1007/s00011-018-1136-9 PMID: 29470604
150. Insights Biomed. 2017;2(2). pii: 11. doi: 10.21767/2572-5610.10027. Epub 2017 Jun 12. Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. Jason LA(1), Ohanian D(1), Brown A(1), Sunnquist M(1), McManimen S(1), Klebek L(1), Fox P(1), Sorenson M(1). Author information: (1)College of Science and Health, DePaul University, USA. Multiple Sclerosis (MS), Myalgic Encephalomyelitis (ME), and Chronic Fatigue syndrome are debilitating chronic illnesses, with some overlapping symptoms. However, few studies have compared and contrasted symptom and disability profiles for these illnesses for the purpose of further differentiating them. The current study was an online self-report survey that compared symptoms from a sample of individuals with MS (N = 120) with a sample of individuals with ME or CFS (N = 269). Respondents completed the self-report DePaul Symptom Questionnaire. Those individuals with ME or CFS reported significantly more functional limitations and significantly more severe symptoms than those with MS. The implications of these findings are discussed. DOI: 10.21767/2572-5610.10027 PMCID: PMC5800741 [Available on 2018-06-12] PMID: 29430570
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151. Int Endod J. 2018 Feb 26. doi: 10.1111/iej.12914. [Epub ahead of print] Reparative bone-like tissue formation in the tooth of a systemic sclerosis patient. Matsuda S(1), Memida T(1), Mizuno N(1), Ogawa I(2), Ouhara K(1), Kajiya M(1), Fujita T(1), Sugiyama E(3), Kurihara H(1)(2). Author information: (1)Department of Periodontal Medicine, Applied Life Sciences, Institute of Biomedical & Health Sciences. (2)Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan. (3)Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan. Aim, To report a case of reparative bone-like tissue formation in the tooth of a patient with systemic sclerosis. A 58-year-old Japanese female patient with systemic sclerosis was referred because of tooth fracture. Cone beam computerized tomography (CBCT) revealed multiple root resorption and the unclear transition from alveolar bone to root profile. A sample from a fractured tooth was analyzed histologically. Haematoxylin and eosin-stained sections revealed the irregular replacement of pulp and dentine by bone-like tissue. Calcinosis was noted in various parts of the body and a histological analysis identified it as dystrophic calcification on sclerosed fibrous connective tissue. Bite force and the occlusal area were markedly weaker than the means for female of the same age. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/iej.12914 PMID: 29480950
152. Int J Neurosci. 2018 Feb 21:1-7. doi: 10.1080/00207454.2018.1435538. [Epub ahead of print] Relation of serum levels of homocysteine, vitamin B12 and folate to cognitive functions in multiple sclerosis patients. Fahmy EM(1), Elfayoumy NM(1), Abdelalim AM(1), Sharaf SA(2), Ismail RS(1), Elshebawy H(1). Author information: (1)a Department of Neurology , Faculty of Medicine, Cairo University , Cairo , Egypt. (2)b Department of Clinical Pathology , Faculty of Medicine, Cairo University , Cairo , Egypt. BACKGROUND: Hyperhomocysteinemia, vitamin B12 and folate deficiency have been linked to cognitive dysfunction in multiple sclerosis (MS) patients. OBJECTIVE: This study aimed to investigate the relation of serum homocysteine (Hcy), vitamin B12 and folate to cognitive functions in MS patients. SUBJECTS AND METHODS: Forty-five MS patients and twenty matched healthy controls were included. Subjects were submitted to cognitive assessment using a selected psychometric battery and measurement of serum levels of homocysteine, B12 and folic acid. RESULTS: MS patients showed significant worse performance in cognitive scales compared to controls (P ≤ 0.05). Serum homocysteine, vitamin B12 and folate showed no significant difference between patients and controls (P > 0.05). Serum homocysteine was negatively correlated with total score of Addenbrooke's Cognitive Examination (ACE), paced auditory serial addition test and controlled oral word association test scores. Serum vitamin B12 was positively correlated with ACE language, visuospatial and total scores and negatively correlated with trail making B score. Serum folate was significantly positively correlated with ACE language and total scores. Homocysteine was the only significant predictor for cognitive impairment in MS patients. CONCLUSION: Serum homocysteine may play a role in cognitive dysfunction in MS patients. DOI: 10.1080/00207454.2018.1435538 PMID: 29384421
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153. Int J Rehabil Res. 2018 Jan 30. doi: 10.1097/MRR.0000000000000270. [Epub ahead of print] The role of robotic gait training coupled with virtual reality in boosting the rehabilitative outcomes in patients with multiple sclerosis. Russo M, Dattola V, De Cola MC, Logiudice AL, Porcari B, Cannavò A, Sciarrone F, De Luca R, Molonia F, Sessa E, Bramanti P, Calabrò RS. Motor impairment is the most common symptom in multiple sclerosis (MS). Thus, a variety of new rehabilitative strategies, including robotic gait training, have been implemented, showing their effectiveness. The aim of our study was to investigate whether an intensive robotic gait training, preceding a traditional rehabilitative treatment, could be useful in improving and potentiating motor performance in MS patients. Forty-five patients, who fulfilled the inclusion criteria, were enrolled in this study and randomized into either the control group (CG) or the experimental group (EG). A complete clinical evaluation, including the Expanded Disability Severity Scale, the Functional Independence Measure, the Hamilton Rating Scale for Depression, the time up and go test (TUG), and the Tinetti balance scale, was performed at baseline (T0), after 6 week (T1), at the end of rehabilitative training (T2), and 1 month later (T3). A significant improvement was observed in the EG for all the outcome measures, whereas the CG showed an improvement only in TUG. In contrast, from T1 to T2, only CG significantly improved in all outcomes, whereas the EG had an improvement only regarding TUG. From T2 to T3, no significant differences in Functional Independence Measure scores emerged for both the groups, but a significant worsening in Tinetti balance scale and TUG was observed for the CG and in TUG for the EG. Our study provides evidence that robotic rehabilitationn coupled with two- dimensional virtual reality may be a valuable tool in promoting functional recovery in patients with MS. DOI: 10.1097/MRR.0000000000000270 PMID: 29384762
154. Int J STD AIDS. 2018 Jan 1:956462418754972. doi: 10.1177/0956462418754972. [Epub ahead of print] Multiple sclerosis and HIV: a case of multiple sclerosis-immune reconstitution inflammatory syndrome associated with antiretroviral therapy initiation. Anand P(1), Saylor D(1). Author information: (1)Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Studies have suggested that the incidence of multiple sclerosis (MS) in HIV-infected (HIV+) patients is lower than that of the general population. Here, we present a case of MS in an HIV+ patient with a relatively suppressed CD4 cell count who developed clinical and radiographic disease worsening in the setting of antiretroviral therapy (ART) initiation. A 47-year-old HIV+ woman (CD4 cell count 216 cells/µl) presented with decreased vision in her right eye. Magnetic resonance imaging (MRI) revealed optic nerve enhancement and open ring-enhancing lesions in the brain concerning for demyelinating disease. Cerebrospinal fluid was tested extensively for infection and malignancy with no abnormal findings. She received five days of intravenous methylprednisolone. Nine days later, she was restarted on ART. Three weeks later, she was readmitted with left eye vision loss and left hemiplegia (CD4 cell count 342 cells/µl). Repeat imaging showed multiple new enhancing lesions. Several cases have described severe MS relapses and unusually widespread demyelinating lesions on MRI after withdrawal of immunosuppressive drugs. We posit that the clinical and radiographic progression that occurred in our patient after initiation of ART represented an immune reconstitution response to ART. Caution may be warranted when initiating ART in HIV+ patients with suppressed CD4 cell count and active MS. DOI: 10.1177/0956462418754972 PMID: 29466918
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155. Int Ophthalmol. 2018 Feb 1. doi: 10.1007/s10792-018-0838-x. [Epub ahead of print] Impairment of acquired color vision in multiple sclerosis: an early diagnostic sign linked to the greatness of disease. Piro A(1), Tagarelli A(2), Nicoletti G(2), Scannapieco S(3), Polidoro S(3), Valentino P(3), Quattrone A(2). Author information: (1)National Researches Council, Institute of Molecular Bioimaging and Physiology, Research Section, Viale Europa, 88100, Germaneto (Catanzaro), Italy. [email protected]. (2)National Researches Council, Institute of Molecular Bioimaging and Physiology, Research Section, Viale Europa, 88100, Germaneto (Catanzaro), Italy. (3)Institute of Neurology, Magna Graecia University, Catanzaro, Italy. OBJECTIVE: To assess the type and degree of both red-green and blue-yellow color vision deficiencies of Calabrian males affected by multiple sclerosis. MATERIAL: Eighty Calabrian male patients were enrolled (age range 18-70 years; mean age 40.6 ± 12.4 years) showing a disease duration mean of 10.6 ± 8.2 years (range = 0.5-46 years) coming from the Institute of Neurology, Magna Graecia University, Catanzaro. Optic neuritis present in the medical histories of the 21 patients does not influence color vision. Excluding seven colorblind subjects and one affected by a bilateral maculopathy, the analyzed sample group was 72. Seventy controls were matched for age and sex. METHOD: An ophthalmologist examined all patients and controls in order to rule out diabetic retinopathy, cataracts, senile maculopathy, or ocular fundus' anomalies. The Ishihara test identified the colorblind patients. The City University Test screened for people with abnormal color vision by grading the severity of color vision deficiency. The second part of the City University Test as well as the Farnsworth Test confirmed both the color vision deficiency type and degree. RESULTS: Fifty-one percentage (37/72) of the patients showing a color vision deficiency were subdivided into two subgroups: subgroup one showed red-green deficiency (57%, 21/37); subgroup two showed a coupled red-green and blue-yellow deficiency (43%, 16/37). Furthermore, we found two distinct curves showing a groove within the first 10 years of the disease. Both monocular and binocular analyses allowed us to identify the patients showing the monocular color vision deficiency, but they were well compensated by binocular vision. CONCLUSION: We think that the majority of the patients with the red-green deficiency will develop the coupled red-green and blue-yellow deficiency in the latter years of multiple sclerosis. DOI: 10.1007/s10792-018-0838-x PMID: 29392642
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156. Iran Biomed J. 2018 Feb 7. [Epub ahead of print] Effect of Multiple Intraperitoneal Injections of Human Bone Marrow Mesenchymal Stem Cells on Cuprizone Model of Multiple Sclerosis Marzban M(1), Mousavizadeh K(2), Bakhshayesh M(2), Vousooghi N(1)(3), Vakilzadeh G(1), Torkaman-Boutorabi A(1)(3). Author information: (1)Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran. (2)Cellular and Molecular Research Center and Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. (3)Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran. Background: Bone marrow mesenchymal stem cells (BM-MSCs) elicit neuroprotective effects, and their repair ability has been investigated in different experimental models. We aimed to investigate the effect of multiple i.p. BM-MSCs injections in the cuprizone model of multiple sclerosis in mice. Methods: Adult male C57BL/6 mice (n = 40) were fed a regular diet or a diet containing cuprizone (0.2% w/w) for 6 six weeks. Bone marrow samples were taken from patients with spinal cord injury. BM-MSCs (2 × 106 in 1 milliliter medium) were administered intraperitoneally for two consecutive weeks at the end of the forth weeks of cuprizone administration. Animals (n = 12) were perfused with 10% paraformaldehyde at the end of sixth week. The brains were sectioned coronally in 6-8-μm thickness (-2.3 to 1.8 mm from bregma). The sections were stained by luxol fast blue-cresyl violet, and images were captured via a microscope. Demyelination ratio was estimated in corpus callosum in a blind manner. A quantitative real-time PCR was used to measure the myelin basic protein gene expression at sixth week. Results: Histologically, cuprizone induced demyelination in the corpus callosum. Demyelinated area was diminished in the corpus callosum of cell-administered group. Cuprizone could decrease myelin-binding protein mRNAs expression in corpus callosum, which was significantly recovered after BM-MSCs injections. Conclusion: Our data indicated a remyelination potency of multiple i.p. BM-MSCs in the cuprizone model of multiple sclerosis in mice. PMID: 29409311
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157. Isr Med Assoc J. 2018 Feb;20(2):86-90. Seroepidemiological Study of Epstein-Barr Virus in Different Population Groups in Croatia. Beader N(1)(2), Kolarić B(3)(4), Slačanac D(1), Tabain I(5), Vilibić-Čavlek T(1)(5). Author information: (1)Department of Microbiology, School of Medicine, University of Zagreb, Zagreb, Croatia. (2)Department of Clinical and Molecular Microbiology, University Hospital Centre Zagreb, Zagreb, Croatia. (3)Department for Social Medicine and Epidemiology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia. (4)Department of Epidemiology, Andrija Stampar Teaching Institute of Public Health, Zagreb Croatia. (5)Department of Virology, Croatian National Institute of Public Health, Zagreb, Croatia. BACKGROUND: The Epstein-Barr virus (EBV) is one of the most common viruses found in humans, causing lifelong infection in up to 95% of the world population. OBJECTIVES: To analyze the seroprevalence of EBV infection in different population groups in Croatia. METHODS: During a 2 year period (2015-2016), a total of 2022 consecutive serum samples collected from Croatian residents were tested for the presence of EBV-specific viral capsid antigen (VCA) immunoglobulin M (IgM) and IgG antibodies using an enzyme-linked immunoassay. IgM/IgG-positive samples were further tested for IgG avidity. RESULTS: The overall prevalence of EBV IgG antibodies was 91.4%. Females had significantly higher IgG seroprevalence than males (93.1% vs. 89.9%, P = 0.008). According to age, IgG seropositivity increased progressively from 59.6% in children age < 9 years to 98.3% in 30-39 year olds, and remained stable thereafter (P < 0.001). The IgG seroprevalence differed significantly among groups: 68.1% in children/adolescents and 95.9% in adults; multiple sclerosis (100%), hemodialysis patients (97.7%), heart transplant recipients (93.8%), hematological malignancies (91.2%), and Crohn's disease (88.5%), P < 0.001. IgM antibodies were detected in 9% of participants. Using IgG avidity, recent primary EBV infection was documented in 83.8% of IgM-positive subjects < 9 years old, 69.2% age 10-19, 33.3% age 20-29, and 3.6-4.2% > 40. All IgM positive participants > 40 years showed high IgG avidity. Logistic regression showed that age is associated with EBV IgG seropositivity. CONCLUSIONS: EBV is widespread in the Croatian population. Older age appears to be the main risk factor for EBV seropositivity. PMID: 29431301
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158. J Altern Complement Med. 2018 Feb 6. doi: 10.1089/acm.2017.0030. [Epub ahead of print] Using the International Classification of Functioning, Disability, and Health Model to Gain Perspective of the Benefits of Yoga in Stroke, Multiple Sclerosis, and Children to Inform Practice for Children with Cerebral Palsy: A Meta-Analysis. Veneri D(1), Gannotti M(2), Bertucco M(3), Fournier Hillman SE(2). Author information: (1)1 Department of Physical Therapy, Sacred Heart University , Fairfield, CT. (2)2 Department of Rehabilitation Sciences, University of Hartford , West Hartford, CT. (3)3 Department of Neuroscience, Biomedicine and Movement, University of Verona , Verona, Italy . OBJECTIVE: Research pertaining to yoga and children with cerebral palsy (CP) is negligible. The primary purpose of this study was to determine the domains of the International Classification of Functioning, Disability, and Health (ICF) model and levels of evidence for yoga and adults with stroke and multiple sclerosis (MS), and children. A secondary purpose was to decide whether any inferences could be made for children with CP. DESIGN: This study included a meta-analysis. INTERVENTIONS: A systematic review was performed of yoga and said populations. Outcome measures were categorized according to the ICF model domains of body structures and function, activity, and quality of life. Effect sizes (ESs) were calculated by using Cohen's d. Since there were few commonalities among outcome measures and reporting of outcomes within and among diagnostic groups, direct comparisons of ESs were difficult. Hence, we chose to evaluate the impact of yoga as compared with the control group or other physical exercise by using a General Linear Mixed Model. RESULTS: There were 5 yoga studies with stroke, 15 with MS, and 12 with children. Studies with children used outcomes related to body structure and function, whereas those with stroke and MS used outcomes across all three domains of the ICF. ESs varied from negligible to medium for stroke, from negligible to large for MS and children. CONCLUSIONS: The findings of this meta-analysis indicate that yoga is no better or worse than other exercise modalities as a treatment intervention for adults with stroke and MS, and children. Group yoga classes are typically social environments that can contribute to increased physical progress and feelings that contribute to quality of life, which may benefit individuals with CP. More research on yoga and particularly in children and adults with CP would yield valuable information for creating effective and safe yoga programs with a rich array of benefits. DOI: 10.1089/acm.2017.0030 PMID: 29406768
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159. J Alzheimers Dis. 2018;62(2):687-697. doi: 10.3233/JAD-170913. The First Historically Reported Italian Family with FTD/ALS Teaches a Lesson on C9orf72 RE: Clinical Heterogeneity and Oligogenic Inheritance. Giannoccaro MP(1), Bartoletti-Stella A(1)(2)(3), Piras S(3), Casalena A(4), Oppi F(3), Ambrosetto G(1), Montagna P(1), Liguori R(1)(3), Parchi P(3)(5), Capellari S(1)(3). Author information: (1)Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Italy. (2)Dipartimento Neuroscienze, Psicologia, Area del farmaco e Salute del bambino, Università di Firenze, Firenze, Italy. (3)IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy. (4)Dipartimento di Neurologia, Università dell'Aquila, L'Aquila, Italy. (5)Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Italy. BACKGROUND: In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline. OBJECTIVE: To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE). METHODS: We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals. RESULTS: Eight patients presented with ALS, four with FTD, and one with schizophrenia. The C9orf72 RE was found in three patients but not in the healthy survivor. Additionally, we found a novel possible pathogenic variant in the ITM2B gene in one patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy. The neuropathological examination of this patient did not show the classical features of ITM2B mutation related dementias suggesting that the putative pathogenic mechanism does not involve cellular mislocalization of the protein or the formation of amyloid plaques. CONCLUSION: We showed that the original Italian pedigree described with FTD/ALS carries the C9orf72 RE. Moreover, the finding of an additional mutation in another dementia causing gene in a patient with a more complex phenotype suggests a possible role of genetic modifiers in the disease. Together with other reports showing the coexistence of mutations in multiple ALS/FTD causative genes in the same family, our study supports an oligogenic etiology of ALS/FTD. DOI: 10.3233/JAD-170913 PMID: 29480190
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160. J Autoimmun. 2018 Jan 21. pii: S0896-8411(18)30007-6. doi: 10.1016/j.jaut.2018.01.001. [Epub ahead of print] Th17 cells, γδ T cells and their interplay in EAE and multiple sclerosis. McGinley AM(1), Edwards SC(1), Raverdeau M(1), Mills KHG(2). Author information: (1)School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. (2)School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: [email protected]. Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) that shares many features with the human disease. This review will focus on the role of IL-17-secreting CD4 and γδ T cells in EAE and MS, the plasticity of Th17 cells in vivo and the application of these findings to the understating of the pathogenesis and the development of new treatments for MS. There is convincing evidence that IL-17-secreting CD4 T cells (Th17 cells) and IL-17-secreting γδ T cells play a critical pathogenic role in central nervous system (CNS) inflammation in EAE and MS. Indeed a significant number of the major discoveries on the pathogenic role of IL-17-secreting T cells in autoimmunity were made in the EAE model. These included the first demonstration that IL-23- activated IL-17-secreting T cells are the key T cells in driving autoimmune disease pathology. Although the early studies on IL-17 focused on Th17 cells, it was later demonstrated that γδ T cells were an important early source of IL-17 and IL-21 that helped amplify IL-17 production by Th17 cells in autoimmune diseases. Furthermore, it emerged that Th1 cells can also have encephalitogenic activity and that there was considerable plasticity in these T cell responses, with Th17 cells reverting to a Th1 phenotype in vivo. This questioned the pathogenic role of IL-17 and suggested that other cytokines, such as IFN-γ, GM-CSF and TNF, may be important. Nevertheless, biological drugs that target the IL- 23-IL-17 pathway are highly effective in treating human psoriasis and are showing promise in the treatment of relapsing remitting MS and other T-cell mediated autoimmune diseases. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.jaut.2018.01.001 PMID: 29395738
161. J Clin Apher. 2018 Feb 12. doi: 10.1002/jca.21616. [Epub ahead of print] Do we have enough evidence for recommending therapeutic apheresis for natalizumab-related progressive multifocal leukoencephalopathy patients? Comment on "Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for apheresis: The seventh special issue." Landi D(1)(2), Centonze D(1)(2), Marfia GA(1)(2), Capra R(3), Scarpazza C(3). Author information: (1)Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University, Rome, Italy. (2)IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, Isernia, Italy. (3)Multiple Sclerosis Center, Spedali Civili di Brescia, Montichiari, Brescia, Italy. DOI: 10.1002/jca.21616 PMID: 29430694
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162. J Clin Med. 2018 Feb 20;7(2). pii: E36. doi: 10.3390/jcm7020036. Blood Mononuclear Cell Mitochondrial Respiratory Chain Complex IV Activity Is Decreased in Multiple Sclerosis Patients: Effects of β-Interferon Treatment. Hargreaves I(1)(2), Mody N(3)(4), Land J(5), Heales S(6)(7). Author information: (1)WC1N 3BG, UK. [email protected]. (2)L3 5UA, UK. [email protected]. (3)WC1N 3BG, UK. [email protected]. (4)AB24 3FX, UK. [email protected]. (5)WC1N 3BG, UK. [email protected]. (6)WC1N 3BG, UK. [email protected]. (7)UCL Great Ormond Street Institute of Child Health, University College London, London WC1E 6BT, UK. [email protected]. OBJECTIVES: Evidence of mitochondrial respiratory chain (MRC) dysfunction and oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS). However, at present, there is no reliable low invasive surrogate available to evaluate mitochondrial function in these patients. In view of the particular sensitivity of MRC complex IV to oxidative stress, the aim of this study was to assess blood mononuclear cell (BMNC) MRC complex IV activity in MS patients and compare these results to age matched controls and MS patients on β-interferon treatment. METHODS: Spectrophotometric enzyme assay was employed to measure MRC complex IV activity in blood mononuclear cell obtained multiple sclerosis patients and aged matched controls. RESULTS: MRC Complex IV activity was found to be significantly decreased (p < 0.05) in MS patients (2.1 ± 0.8 k/nmol × 10-3; mean ± SD] when compared to the controls (7.2 ± 2.3 k/nmol × 10-3). Complex IV activity in MS patients on β- interferon (4.9 ± 1.5 k/nmol × 10-3) was not found to be significantly different from that of the controls. CONCLUSIONS: This study has indicated evidence of peripheral MRC complex IV deficiency in MS patients and has highlighted the potential utility of BMNCs as a potential means to evaluate mitochondrial function in this disorder. Furthermore, the reported improvement of complex IV activity may provide novel insights into the mode(s) of action of β-interferon. DOI: 10.3390/jcm7020036 PMID: 29461488
Conflict of interest statement: The authors declare no conflict of interest.
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163. J Clin Neurosci. 2018 Feb 10. pii: S0967-5868(17)32021-0. doi: 10.1016/j.jocn.2018.01.060. [Epub ahead of print] Symptom-associated change of motor-related neuromagnetic fields in a patient with multiple sclerosis: A case report. Kim JH(1), Kim BS(2), Hwang SJ(3), Chang WS(3), Kim KW(4), Kwon HC(4), Lee YH(4), Chang JW(5). Author information: (1)Department of Neurosurgery, Hallym University Sacred Heart Hospital, Anyang, Gyeonggi-do, Republic of Korea. (2)EIT/LOFUS R&D Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon, Republic of Korea. (3)Department of Neurosurgery, Brain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. (4)Korean Research Institute of Standard and Science (KRISS), Daejeon, Republic of Korea. (5)Department of Neurosurgery, Brain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: [email protected]. The objective of this study was to investigate functional abnormalities of the brain in a patient with multiple sclerosis (MS) by using magnetoencephalography (MEG) and a finger-tapping task. A 46- year-old woman that presented with motor weakness of left hand and was diagnosed with MS. Conventional magnetic resonance imaging demonstrated a white matter lesion with hyperintensity on T2-weighted images in the right motor area. MEG recordings were performed during the period of motor weakness and after clinical improvement. Neuromagnetic brain activation was elicited by a simple, visually cued finger movement. The Equivalent current dipole (ECD) strength of the movement-evoked field (MEF) in the affected hemisphere was significantly decreased relative to the unaffected hemisphere. After improvement in motor weakness, we found that the lower amplitude of the readiness field and decreased ECD strength of the MEF observed in affected hemisphere during motor weakness had recovered. Analysis of motor-related neuromagnetic fields revealed that MEG may be used to detect diffuse changes in the brain that are not observable by conventional imaging of white matter regions in MS. We further found that brain activities can change after improvement in motor weakness. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.jocn.2018.01.060 PMID: 29439908
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164. J Clin Rheumatol. 2018 Jan 30. doi: 10.1097/RHU.0000000000000686. [Epub ahead of print] Evaluation of Vitamin B12 Deficiency and Associated Factors in Patients With Systemic Sclerosis. Tas Kilic D, Akdogan A, Kilic L, Sari A, Erden A, Armagan B, Kilickaya M, Kalyoncu U, Turhan T, Kiraz S, Karaahmetoglu S. BACKGROUND/OBJECTIVE: In patients with systemic sclerosis (SSc) gastrointestinal (GI) involvement, nutritional status and medications may lead to cobalamin (Vit B12) deficiency. We aimed to determine the frequency and the potential causes of Vit B12 deficiency in SSc patients. METHODS: We conducted a cross-sectional analysis of 62 SSc patients in a single center in 1 year period. Medical history and physical examination of patients were reevaluated. Data about organ involvements were obtained from hospital file records. The nutritional status of the patients was assessed with Malnutrition Universal Screening Tool (MUST). Vit B12, homocysteine (except in three patients) and Helicobacter Pylori Immunoglobulin G (H. Pylori IgG) levels were measured in all patients. Vit B12 deficiency was considered as serum Vit B12 level <200 pg/mL or being on Vit B12 replacement therapy. Serum Vit B12 levels of the patients were also grouped as low (<200 pg/mL), borderline (200-300 pg/mL) and normal (>300 pg/mL). Plasma homocysteine levels of the patients were classified as elevated (>9 μmol/L) and hyperhomocysteinemia (>15 μmol/L). Mann-Whitney U and Kruskal-Wallis tests were used to compare parameters among the groups. Correlation was tested by Spearman's correlation coefficient. RESULTS: Forty-four (71.0%) patients were defined as Vit B12 deficient; 22 had Vit B12 level <200 pg/mL (four were on Vit B12 replacement therapy) and the remaining 22 had Vit B12 >200 pg/mL and were already on Vit B12 replacement therapy. The percentage of the patients with hyperhomocysteinemia was significantly higher in the group with Vit B12 <200 pg/mL as compared to other groups (P = 0.004) but only 33.3% (7/21) of the patients with Vit B12 <200 pg/mL had hyperhomocysteinemia. There were no statistically significant differences between patients with and without Vit B12 deficiency regarding age, mean disease duration, MUST scores, mean hemoglobin levels, H. Pylori IgG positivity and organ involvements (P > 0.05 for all). CONCLUSIONS: Vit B12 deficiency is frequent in SSc and has multiple causes. All patients should be monitored for Vit B12 deficiency. The homocysteine levels seem unlikely to be helpful for confirmation of Vit B12 deficiency. DOI: 10.1097/RHU.0000000000000686 PMID: 29384828
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165. J Coll Physicians Surg Pak. 2018 Mar;28(3):S16-S18. doi: 10.29271/jcpsp.2018.03.S16. Tuberous Sclerosis Complex with Gingival Enlargement in an Adolescent. Nath S(1), Prakash J(2), Singh NN(3), Prajapati VK(4). Author information: (1)Department of Dentistry, Rajendra Institute of Medical Sciences, Ranchi, India. (2)Private Practice, Ranchi, India. (3)Department of Oral Pathology, Microbiology and Forensic Odontology, Dental Institute, Rajendra Institute of Medical Sciences, Ranchi, India. (4)Department of Oral Maxillofacial Surgery, Dental Institute, Rajendra Institute of Medical Sciences, Ranchi, India. Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem genetic disorder. It is characterised by formation of benign hamartomas, neurofibromas, and angiofibromas located in different organs. We describe a case of a 13-year boy who complained of gingival enlargement. Clinical examination showed distinctive dermatological signs like hypopigmented macules, shagreen plaques, miliary fibromas, fibrous plaques and multiple angiofibromas. Oral manifestation included localised gingival enlargement. Gingivectomy was performed and the excised tissue was submitted for histopathological examination. The microscopic examination of gingival tissue revealed multiple bundles of collagen fibres with proliferating fibroblast and multiple proliferating blood vessels in the connective tissue. The clinical and histopathological findings were consistent with gingival angiofibromas of TSC. Gingivectomy allowed the patient to have better function and aesthetics. Periodontal examination in conjunction with dermatological examination is important for early diagnosis of TSC. DOI: 10.29271/jcpsp.2018.03.S16 PMID: 29482692
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166. J Ethnopharmacol. 2018 Feb 8;217:36-48. doi: 10.1016/j.jep.2018.02.014. [Epub ahead of print] Bu Shen Yi Sui capsule promotes remyelination correlating with Sema3A/NRP-1, LIF/LIFR and Nkx6.2 in mice with experimental autoimmune encephalomyelitis. Zhao PY(1), Wang YQ(1), Liu XH(1), Zhu YJ(1), Zhao H(1), Zhang QX(1), Qi F(1), Li JL(1), Zhang N(1), Fan YP(2), Li KN(2), Zhao YY(3), Lei JF(3), Wang L(4). Author information: (1)School of Traditional Chinese Medicine, Beijing Key Lab of TCM Collateral Disease Theory Research, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing 100069, China. (2)Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China. (3)Core Facility Center, Capital Medical University, Beijing 100069, China. (4)School of Traditional Chinese Medicine, Beijing Key Lab of TCM Collateral Disease Theory Research, Capital Medical University, No.10 Xitoutiao, You An Men, Beijing 100069, China. Electronic address: [email protected]. ETHNOPHARMACOLOGICAL RELEVANCE: Bu Shen Yi Sui capsule (BSYSC), based on traditional Chinese formula Liu Wei Di Huang pill, is effective for the treatment of multiple sclerosis (MS) in clinical experience and trials. Our previous studies confirmed that BSYSC had the neuroprotective effect in MS and its animal model, experimental autoimmune encephalomyelitis (EAE); however, its mechanism of action was not clear. Thus, the effect of BSYSC on remyelination and the underlying mechanisms were investigated in the EAE mice. MATERIALS AND METHODS: The EAE model was established by injecting subcutaneously myelin oligodendrocyte protein (MOG) 35-55 in mice. Mice were treated with BSYSC (3.02 g/kg) or vehicle daily by oral gavage for 40 days. The body weight and clinical score of mice were evaluated. Brain was observed by magnetic resonance imaging. The inflammation infiltrate of brain and spinal cord was determined by hematoxylin-eosin staining, while the structure of myelin sheath was visualized by transmission electron microscopy on days 23 and 40 post immunization (dpi), respectively. The protein and mRNA levels of platelets-derived growth factor receptor (PDGFR) α and 2', 3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) were measured by immunohistochemistry, western blot and quantitative real-time polymerase chain reaction. The protein expressions of semaphorins (Sema) 3A, Neuropilin (NRP) - 1, leukemia inhibitory factor (LIF), LIF receptor (LIFR) and Nkx6.2 were further investigated by western blot. RESULTS: BSYSC treatment improved the body weight and clinical score of EAE mice, alleviated inflammatory infiltration and nerve fiber injuries. It also protected the ultrastructural integrity of myelin sheath. BSYSC significantly increased expressions of PDGFRα and CNPase in mice with EAE on 40 dpi. Furthermore, BSYSC treatment increased the expressions of LIF, LIFR and Nkx6.2 and reduced Sema3A and NRP-1 in EAE mice on 40 dpi. CONCLUSIONS: The data demonstrated that BSYSC exhibited the neuroprotective effect against EAE by promoting oligodendrocyte progenitor cells (OPCs) proliferation and differentiation, thus facilitating remyelination. Sema3A/NRP-1, LIF/LIFR and Nkx6.2 are likely contributed to the effects of BSYSC on OPCs. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jep.2018.02.014 PMID: 29428242
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167. J Eur Acad Dermatol Venereol. 2018 Feb 25. doi: 10.1111/jdv.14887. [Epub ahead of print] Altered epigenetic pathways and cell cycle dysregulation in healthy appearing skin of patients with koebnerized squamous cell carcinomas following skin surgery. Gambichler T(1), Rüddel I(1), Hessam S(1), Bechara FG(1), Stockfleth E(1), Schmitz L(1). Author information: (1)Skin Cancer Center, Department of Dermatology, Ruhr-University Bochum, Germany. BACKGROUND: Koebnerized non-melanoma skin cancer following skin trauma represents a rare and obscure event. OBJECTIVES: To study molecularpathological parameters in koebnerized squamous cell carcinomas (K-SCCs) occurring after complete tumour removal. METHODS: We assessed two patients with multiple sclerosis who were on treatment with dimethylfumarate (DMF) preceded by long- term azathioprine therapy. Both patients rapidly developed several K-SCCs following histopathologically proven complete excision of cutaneous SCCs. We performed immunohistochemistry for p53, p16, Ki-67, TET-2, IDH-2, 5-hmc, and 5-mc. PCR was carried out for the detection of human papilloma viruses. Mutation analysis was performed for BRAF, K-RAS, and EGFR. RESULTS: All lesions investigated were negative for HPV DNA. Mutations were not detected. Healthy appearing skin of both patients showed relatively high Ki-67, p16, and p53 expression which was comparable to the expression observed in primary SCCs as well as K-SCCs. Protein expression of Ki-67, p16, and mutant p53 was barely detected in the specimens of the healthy controls. A decreased protein expression of TET-2 enzyme was seen in all tumours and healthy appearing skin when compared to the skin of healthy controls. CONCLUSIONS: We observed two patients with K- SCCs developing under DMF treatment. In healthy appearing skin of patients with K-SCCs, wound healing processes, including induction of proliferation and growth factor release, might promote the growth of pre-neoplastic keratinocytes and cancer formation on the basis of pre-existing altered epigenetic pathways and cell cycle dysregulation. Although fumarates can reduce TET-2 expression, the role of DMF intake in the development of K-SCCs remains unclear. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/jdv.14887 PMID: 29478287
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168. J Evid Based Integr Med. 2018 Jan-Dec;23:2515690X17748744. doi: 10.1177/2515690X17748744. Guided Imagery Improves Mood, Fatigue, and Quality of Life in Individuals With Multiple Sclerosis: An Exploratory Efficacy Trial of Healing Light Guided Imagery. Case LK(1)(2), Jackson P(1), Kinkel R(1), Mills PJ(1). Author information: (1)1 University of California San Diego, La Jolla, CA, USA. (2)Current affiliation: National Center for Complementary and Integrative Health, Bethesda, MD, USA. Multiple sclerosis is a disabling and progressive neurological disease that has significant negative effects on health-related quality of life. This exploratory efficacy study examined the effects of Healing Light Guided Imagery (HLGI), a novel variant of guided imagery, compared with a wait-list control in patients with relapsing-remitting multiple sclerosis. Changes in the Beck Depression Inventory, Fatigue Severity Scale, and Multiple Sclerosis Quality of Life instrument (physical and mental components) were compared between groups. Patients who completed HLGI (N = 9) showed significant reductions in depressed mood ( P < .05) and fatigue ( P < .01) and showed significant gains in physical ( P = .01) and mental ( P < .01) quality of life compared with journaling (N = 8). Our results suggest that HLGI can improve self-reported physical and mental well-being in patients with relapsing-remitting multiple sclerosis. Further research is needed to study the effectiveness of this therapy, as well as its mind- body mechanisms of action. DOI: 10.1177/2515690X17748744 PMID: 29405761
169. J Health Psychol. 2018 Feb 1:1359105318755262. doi: 10.1177/1359105318755262. [Epub ahead of print] Neurological, physical and sociodemographic correlates of employment in multiple sclerosis: A meta- analysis. Gerhard L(1), Dorstyn DS(1), Murphy G(2), Roberts RM(1). Author information: (1)1 Faculty of Health and Medical Sciences, School of Psychology, The University of Adelaide, Australia. (2)2 College of Science, Health and Engineering, School of Psychology and Public Health, La Trobe University Australia. Illness severity and sociodemographic characteristics of 7,053 employees with multiple sclerosis and 11,043 peers not in the workforce were compared (Hedges' g with 95% confidence interval and p values). Pooled findings from 25 studies confirmed the main role of a relapsing-remitting disease course and higher education to employment. To a lesser extent, disease duration, fatigue and pain symptoms and age also differentiated the two groups. Vocational interventions for persons with multiple sclerosis should focus on job retention, including mechanisms to accommodate and facilitate functional independence. Longitudinal data are needed to distinguish the characteristics of those who achieve and maintain competitive employment. DOI: 10.1177/1359105318755262 PMID: 29460636
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170. J Hum Genet. 2018 Feb 23. doi: 10.1038/s10038-018-0416-0. [Epub ahead of print] Pattern of TSC1 and TSC2 germline mutations in Russian patients with tuberous sclerosis. Suspitsin EN(1)(2), Yanus GA(3)(4), Dorofeeva MY(5), Ledashcheva TA(6), Nikitina NV(7), Buyanova GV(8), Saifullina EV(9), Sokolenko AP(3)(4), Imyanitov EN(3)(4)(10)(11). Author information: (1)St. Petersburg Pediatric Medical University, St. Petersburg, Russia. [email protected]. (2)N.N. Petrov Institute of Oncology, St. Petersburg, Russia. [email protected]. (3)St. Petersburg Pediatric Medical University, St. Petersburg, Russia. (4)N.N. Petrov Institute of Oncology, St. Petersburg, Russia. (5)Center of Epileptology, N.N. Pirogov National Research Medical University, Moscow, Russia. (6)City Center of Medical Genetics, St. Petersburg, Russia. (7)Clinical center "Mother and Child Health Protection", Ekaterinburg, Russia. (8)Pediatric Regional Hospital, Chelyabinsk, Russia. (9)Perinatal Center of Republic of Baschkortostan, Ufa, Russia. (10)I.I. Mechnikov North-Western Medical University, St. Petersburg, Russia. (11)St. Petersburg State University, St. Petersburg, Russia. Tuberous sclerosis (TS) is a rare autosomal-dominant genetic disease. TS is manifested by the development of multiple hamartomas, which affect brain, kidneys, retina, skin and other organs. This study aimed to reveal specific features of molecular epidemiology of TS in Russia. Blood DNA samples from 61 patients with definite (n = 53) or probable (n = 8) clinical diagnosis of TS were tested for mutations in TSC1 and TSC2 genes using Sanger sequencing and MLPA analysis. Five TSC1/2 mutation-negative patients were further analyzed by exome sequencing. TSC1/2 mutations were detected in 53/61 patients (87%): 39 (74%) carried mutations in the TSC2 and 14 (26%) in the TSC1. Large rearrangements (exon deletions/duplications) affected exclusively TSC2, accounting for 15% of lesions of this gene. 6/8 (75%) patients with incomplete clinical manifestation of TS carried TSC1/2 gene lesion. Overall, 96% of detected germline TSC1/2 mutations occurred de novo. Patients with no mutation identified (NMI) differed from TSC1/2 mutation carriers, being lacking cortical tubers and subependymal nodules but having higher frequencies of renal angiomyolipomas, rhabdomyomas, and lymphangioleiomyomatosis. Exome sequencing failed to identify overt disease-causing mutation candidates among NMI patients. Russian patients with TS have increased frequency of TSC2 large gene rearrangements and TSC1/2 mutations occurring de novo as compared to other studies. Patients with suspected TS diagnosis but NMI status may represent a distinct disease entity. DOI: 10.1038/s10038-018-0416-0 PMID: 29476190
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171. J Immunol Methods. 2018 Feb 8. pii: S0022-1759(17)30509-4. doi: 10.1016/j.jim.2018.02.002. [Epub ahead of print] A sensitive and selective ELISA methodology quantifies a demyelination marker in experimental and clinical samples. Remacle AG(1), Dolkas J(2), Angert M(2), Hullugundi SK(2), Chernov AV(1), Jones RCW 3rd(3), Shubayev VI(4), Strongin AY(5). Author information: (1)Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (2)Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA; VA San Diego Healthcare System, La Jolla, CA 92037, USA. (3)Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA; Center for Pain Medicine, University of California, San Diego, La Jolla, CA 92093, USA; VA San Diego Healthcare System, La Jolla, CA 92037, USA. (4)Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA; VA San Diego Healthcare System, La Jolla, CA 92037, USA. Electronic address: [email protected]. (5)Infectious and Inflammatory Disease Center/Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: [email protected]. Sciatic nerve chronic constriction injury (CCI) in rodents produces nerve demyelination via proteolysis of myelin basic protein (MBP), the major component of myelin sheath. Proteolysis releases the cryptic MBP epitope, a demyelination marker, which is hidden in the native MBP fold. It has never been established if the proteolytic release of this cryptic MBP autoantigen stimulates the post-injury increase in the respective circulating autoantibodies. To measure these autoantibodies, we developed the ELISA that employed the cryptic 84-104 MBP sequence (MBP84-104) as bait. This allowed us, for the first time, to quantify the circulating anti-MBP84-104 autoantibodies in rat serum post-CCI. The circulating IgM (but not IgG) autoantibodies were detectable as soon as day 7 post-CCI. The IgM autoantibody level continually increased between days 7 and 28 post-injury. Using the rat serum samples, we established that the ELISA intra-assay (precision) and inter-assay (repeatability) variability parameters were 2.87% and 4.58%, respectively. We also demonstrated the ELISA specificity by recording the autoantibodies to the liberated MBP84-104 epitope alone, but not to intact MBP in which the 84-104 region is hidden. Because the 84-104 sequence is conserved among mammals, we tested if the ELISA was applicable to detect demyelination and quantify the respective autoantibodies in humans. Our limited pilot study that involved 16 female multiple sclerosis and fibromyalgia syndrome patients demonstrated that the ELISA was efficient in measuring both the circulating IgG- and IgM-type autoantibodies in patients exhibiting demyelination. We believe that the ELISA measurements of the circulating autoantibodies against the pathogenic MBP84-104 peptide may facilitate the identification of demyelination in both experimental and clinical settings. In clinic, these measurements may assist neurologists to recognize patients with painful neuropathy and demyelinating diseases, and as a result, to personalize their treatment regimens. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jim.2018.02.002 PMID: 29428829
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172. J Immunol Res. 2017;2017:5150678. doi: 10.1155/2017/5150678. Epub 2017 Dec 19. The Role of Microglia and Macrophages in CNS Homeostasis, Autoimmunity, and Cancer. Yin J(1)(2)(3), Valin KL(1)(2), Dixon ML(1)(2), Leavenworth JW(1)(2). Author information: (1)Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA. (2)Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA. (3)Department of Cell Biology, Tianjin Medical University, Tianjin 300070, China. Macrophages are major cell types of the immune system, and they comprise both tissue-resident populations and circulating monocyte-derived subsets. Here, we discuss microglia, the resident macrophage within the central nervous system (CNS), and CNS-infiltrating macrophages. Under steady state, microglia play important roles in the regulation of CNS homeostasis through the removal of damaged or unnecessary neurons and synapses. In the face of inflammatory or pathological insults, microglia and CNS-infiltrating macrophages not only constitute the first line of defense against pathogens by regulating components of innate immunity, but they also regulate the adaptive arms of immune responses. Dysregulation of these responses contributes to many CNS disorders. In this overview, we summarize the current knowledge regarding the highly diverse and complex function of microglia and macrophages during CNS autoimmunity-multiple sclerosis and cancer-malignant glioma. We emphasize how the crosstalk between natural killer (NK) cells or glioma cells or glioma stem cells and CNS macrophages impacts on the pathological processes. Given the essential role of CNS microglia and macrophages in the regulation of all types of CNS disorders, agents targeting these subsets are currently applied in preclinical and clinical trials. We believe that a better understanding of the biology of these macrophage subsets offers new exciting paths for therapeutic intervention. DOI: 10.1155/2017/5150678 PMCID: PMC5749282 PMID: 29410971
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173. J Int Adv Otol. 2018 Feb 20. doi: 10.5152/iao.2018.4467. [Epub ahead of print] Repeated Attacks of Dizziness Caused by a Rare Mitochondrial Encephalomyopathy. Toi T(1), Nomura Y(1), Kishino A(1), Shigihara S(1), Oshima T(1), Ishikawa H(2), Kamei S(3), Miyazaki H(4). Author information: (1)Department of Otolaryngology-Head and Neck Surgery, Nihon University School of Medicine, Tokyo, Japan. (2)Department of Neurology, National Hospital Organization Saitama National Hospital, Saitama, Japan. (3)Department of Medicine, Division of Neurology, Nihon University School of Medicine, Tokyo, Japan. (4)Department of Otolaryngology, Tokyo Women's Medical University Medical Center East, Tokyo, Japan. Cases of dizziness caused by multiple sclerosis are commonly reported, but those caused by mitochondrial encephalomyopathy have been rarely reported. Particularly, the description of eye nystagmography (ENG) using caloric and optokinetic nystagmus tests has not been reported to date. We encountered the case of a 40-year-old woman with mitochondrial encephalomyopathy who visited us with the chief complaint of dizziness. At first, we considered multiple sclerosis based on the magnetic resonance imaging (MRI) findings and dizziness. Repeated attacks of dizziness and serum lactic acid levels suggested mitochondrial encephalomyopathy. A muscle biopsy confirmed the diagnosis. ENG findings suggested central vestibular disorder of the cerebellum and brainstem. This case suggests that we should not rule out the differential diagnosis of a very rare mitochondrial encephalomyopathy in patients who experience dizziness with MRI findings indicative of multiple sclerosis. DOI: 10.5152/iao.2018.4467 PMID: 29460827
174. J Med Chem. 2018 Feb 27. doi: 10.1021/acs.jmedchem.7b01647. [Epub ahead of print] Discovery of 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine Derivatives as Potent, Orally Available, and Brain-penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors; Analysis of Structure-Kinetic Relationships. Yoshikawa M, Saitoh M, Katoh T, Seki T, Bigi SV, Shimizu Y, Ishii T, Okai T, Kuno M, Hattori H, Watanabe E, Saikatendu KS, Zou H, Nakakariya M, Tatamiya T, Nakada Y, Yogo T. We report herein the discovery and optimization of 7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine derivatives as a novel class of brain-penetrating receptor interacting protein 1 (RIP1) kinase inhibitors. Based on the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1, we identified 4-oxo-6,7- dihydro-1H-imidazo[4,5-c]pyridine derivative 11, possessing moderate RIP1 inhibitory activity and P- gp mediated efflux. The optimization of the core structure, the exploration of appropriate substituents utilizing SBDD approach led to the discovery of 22, a highly potent, orally available, and brain- penetrating RIP1 kinase inhibitor with excellent PK profiles. Compound 22 significantly suppressed necroptotic cell death both in mouse and human cells. Furthermore, oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). We also analyzed structure-kinetic relationship (SKR) for our novel chemical series and discussed the importance of evaluating drug-target residence time for lead optimization. DOI: 10.1021/acs.jmedchem.7b01647 PMID: 29485864
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175. J Med Internet Res. 2018 Feb 12;20(2):e36. doi: 10.2196/jmir.8371. A Multidimensional Tool Based on the eHealth Literacy Framework: Development and Initial Validity Testing of the eHealth Literacy Questionnaire (eHLQ). Kayser L(1), Karnoe A(1)(2), Furstrand D(1)(3), Batterham R(4)(5), Christensen KB(1), Elsworth G(4), Osborne RH(1)(4). Author information: (1)Department of Public Health, University of Copenhagen, Copenhagen, Denmark. (2)The Danish Multiple Sclerosis Society, Valby, Denmark. (3)Danish Cancer Research Center, The Danish Cancer Society, Copenhagen, Denmark. (4)Health Systems Improvement Unit, Centre for Population Health Research, Faculty of Health, Deakin University, Geelong, Australia. (5)Faculty of Public Health, Thammasat University, Bangkok, Thailand. BACKGROUND: For people to be able to access, understand, and benefit from the increasing digitalization of health services, it is critical that services are provided in a way that meets the user's needs, resources, and competence. OBJECTIVE: The objective of the study was to develop a questionnaire that captures the 7-dimensional eHealth Literacy Framework (eHLF). METHODS: Draft items were created in parallel in English and Danish. The items were generated from 450 statements collected during the conceptual development of eHLF. In all, 57 items (7 to 9 items per scale) were generated and adjusted after cognitive testing. Items were tested in 475 people recruited from settings in which the scale was intended to be used (community and health care settings) and including people with a range of chronic conditions. Measurement properties were assessed using approaches from item response theory (IRT) and classical test theory (CTT) such as confirmatory factor analysis (CFA) and reliability using composite scale reliability (CSR); potential bias due to age and sex was evaluated using differential item functioning (DIF). RESULTS: CFA confirmed the presence of the 7 a priori dimensions of eHLF. Following item analysis, a 35-item 7-scale questionnaire was constructed, covering (1) using technology to process health information (5 items, CSR=.84), (2) understanding of health concepts and language (5 items, CSR=.75), (3) ability to actively engage with digital services (5 items, CSR=.86), (4) feel safe and in control (5 items, CSR=.87), (5) motivated to engage with digital services (5 items, CSR=.84), (6) access to digital services that work (6 items, CSR=.77), and (7) digital services that suit individual needs (4 items, CSR=.85). A 7-factor CFA model, using small-variance priors for cross-loadings and residual correlations, had a satisfactory fit (posterior productive P value: .27, 95% CI for the difference between the observed and replicated chi-square values: -63.7 to 133.8). The CFA showed that all items loaded strongly on their respective factors. The IRT analysis showed that no items were found to have disordered thresholds. For most scales, discriminant validity was acceptable; however, 2 pairs of dimensions were highly correlated; dimensions 1 and 5 (r=.95), and dimensions 6 and 7 (r=.96). All dimensions were retained because of strong content differentiation and potential causal relationships between these dimensions. There is no evidence of DIF. CONCLUSIONS: The eHealth Literacy Questionnaire (eHLQ) is a multidimensional tool based on a well-defined a priori eHLF framework with robust properties. It has satisfactory evidence of construct validity and reliable measurement across a broad range of concepts (using both CTT and IRT traditions) in various groups. It is designed to be used to understand and evaluate people's interaction with digital health services. DOI: 10.2196/jmir.8371 PMID: 29434011
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 170 – Multiple Sklerose: Veröffentlichungen Oktober 2013
176. J Mol Neurosci. 2018 Feb;64(2):233-241. doi: 10.1007/s12031-017-1022-x. Epub 2018 Feb 15. Neuroprotective Effects of Melatonin on Experimental Allergic Encephalomyelitis Mice Via Anti- Oxidative Stress Activity. Long T(1), Yang Y(1), Peng L(2), Li Z(3). Author information: (1)Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China. (2)Department of Emergency, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China. (3)Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China. [email protected]. Multiple sclerosis (MS) is a chronic auto-inflammatory disease of the central nervous system (CNS) and hard to heal. This study aimed to investigate the effect of melatonin on mice with experimental autoimmune encephalomyelitis (EAE), a widely used MS model, and its potential mechanism underlying the action of MT on anti-oxidative stress. Female C57BL/6 mice were injected with MOG35-55 peptide to set up the EAE model, and for detection of the effect of melatonin (10 mg/kg i.p.) on the development and progression of EAE. Combining immunohistochemistry, biochemical technology and western blot approaches, the potential molecular mechanism of melatonin on EAE was evaluated as the levels of oxidative stress and the expression of Nrf2/ARE signal pathway. Our experiments showed a change of oxidative stress and Nrf2/ARE pathway expression in different groups, demonstrating that oxidative stress is associated with the pathophysiology of EAE. The administration of melatonin exerts neuroprotective effects against EAE, notably in suppressing the progression of EAE and pathological changes (lymphocytic infiltration). Furthermore, the effect of melatonin was probably related to decrease of the levels of oxidative stress, by activation of the Nrf2/ARE pathway and increased levels of anti-oxidant enzymes HO-1 and NQO1 expression. So, melatonin may be a promising reagent for intervention for multiple sclerosis in the future, and even for other autoimmune diseases. DOI: 10.1007/s12031-017-1022-x PMID: 29450696
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 171 – Multiple Sklerose: Veröffentlichungen Oktober 2013
177. J Neurochem. 2018 Feb 23. doi: 10.1111/jnc.14324. [Epub ahead of print] Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis. Ingwersen J(1), De Santi L(1)(2), Wingerath B(1), Graf J(1), Koop B(1), Schneider R(1), Hecker C(1), Schröter F(1), Bayer M(1), Engelke AD(1), Dietrich M(1), Albrecht P(1), Hartung HP(1), Annunziata P(2), Aktas O(1), Prozorovski T(1). Author information: (1)Department of Neurology Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. (2)Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy. Multiple sclerosis (MS) is characterized by inflammatory neurodegeneration, with axonal injury and neuronal cell death occurring in parallel to demyelination. Regarding the molecular mechanisms responsible for demyelination and axonopathy, energy failure, aberrant expression of ion channels and excitotoxicity have been suggested to lead to Ca2+ overload and subsequent activation of calcium-dependent damage pathways. Thus, the inhibition of Ca2+ influx by pharmacological modulation of Ca2+ channels may represent a novel neuroprotective strategy in the treatment of secondary axonopathy. We therefore investigated the effects of the L-type voltage-gated calcium channel (VGCC) blocker nimodipine in two different models of mouse experimental autoimmune encephalomyelitis (EAE), an established experimental paradigm for MS. We show that preventive application of nimodipine (10 mg/kg per day) starting on the day of induction had ameliorating effects on EAE in SJL/J mice immunized with encephalitic myelin peptide PLP139-151 , specifically in late- stage disease. Furthermore, supporting these data, administration of nimodipine to MOG35-55 - immunized C57BL/6 mice starting at the peak of pre-established disease, also led to a significant decrease in disease score, indicating a protective effect on secondary CNS damage. Histological analysis confirmed that nimodipine attenuated demyelination, axonal loss and pathological axonal β- APP accumulation in cerebellum and spinal cord in the chronic phase of disease. Of note, we observed no effects of nimodipine on the peripheral immune response in EAE mice with regard to distribution, antigen-specific proliferation or activation patterns of lymphocytes. Taken together, our data suggest a CNS-specific effect of L-type VGCC blockade to inflammation-induced neurodegeneration. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/jnc.14324 PMID: 29473171
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 172 – Multiple Sklerose: Veröffentlichungen Oktober 2013
178. J Neuroimaging. 2018 Feb 5. doi: 10.1111/jon.12500. [Epub ahead of print] Classic Block Design "Pseudo"-Resting-State fMRI Changes After a Neurorehabilitation Program in Patients with Multiple Sclerosis. Pareto D(1), Sastre-Garriga J(2), Alonso J(1), Galán I(2), Arévalo MJ(2), Renom M(2), Montalban X(2), Rovira À(1). Author information: (1) Section of Neuroradiology, Department of Radiology, University Hospital Vall d'Hebron, Barcelona, Spain. (2)Department of Neurology-Neuroimmunology, Multiple Sclerosis Centre of Catalonia (Cemcat), University Hospital Vall d'Hebron, Barcelona, Spain. BACKGROUND AND PURPOSE: The goal of this study was to assess changes in the resting-state networks (RSNs) of patients with multiple sclerosis (MS) after a cognitive rehabilitation program (CRP), by retrospectively analyzing functional magnetic resonance imaging (fMRI) studies using the classical block design. METHODS: Fifteen patients with MS (2 primary progressive, 3 relapsing- remitting, 10 secondary progressive) were scanned before and after the CRP on a 1.5T MRI scanner. In addition, patients underwent pre- and post-CRP neuropsychological assessment using a battery of standardized tests. Five healthy individuals were scanned at the same time points to confirm the test- retest reliability of the imaging technique. For each study, the individual fMRI blocks of rest were merged to produce a "pseudo"-resting-state (pseudo-RS) of 3 minutes duration. RS studies were analyzed with the MELODIC toolbox. A dual regression analysis was applied to estimate the longitudinal changes in RSNs of patients and test controls relative to a set of predefined RSNs used as templates. RESULTS: In healthy individuals, there were no significant differences in RSN results between the two time points studied. In the group of patients with MS, significant differences were found post-CRP in the visual medial, cerebellar, auditory, and frontal-executive RSNs. Furthermore, synchronization increases in the frontal-executive RSN were associated with cognitive improvement on neuropsychological testing. CONCLUSIONS: Results obtained using a pseudo-RS approach to analyze data from block-design fMRI studies suggest that a CRP of 5 weeks' duration induces measurable changes in specific RSNs of patients with MS. Copyright © 2018 by the American Society of Neuroimaging. DOI: 10.1111/jon.12500 PMID: 29400912
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 173 – Multiple Sklerose: Veröffentlichungen Oktober 2013
179. J Neuroimaging. 2018 Feb 27. doi: 10.1111/jon.12505. [Epub ahead of print] The Role of High-Frequency MRI Monitoring in the Detection of Brain Atrophy in Multiple Sclerosis. Uher T(1), Krasensky J(2), Sobisek L(3), Seidl Z(2), Bergsland N(4), Dwyer MG(4), Kubala Havrdova E(1), Zivadinov R(4)(5), Horakova D(1), Vaneckova M(2). Author information: (1)Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. (2)Department of Radiodiagnostic, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. (3)Department of Statistics and Probability, University of Economics in Prague, Prague, Czech Republic. (4)Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY. (5)Translational Imaging Center at Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, NY. BACKGROUND AND PURPOSE: A relatively high intraindividual variability of longitudinal magnetic resonance imaging (MRI) of brain volume loss (BVL) measurements over time renders challenging its application to individual multiple sclerosis (MS) patients. Objective of this study was to investigate if high-frequency brain MRI monitoring affects identification of pathological BVL in an individual patient. METHODS: One hundred fifty-seven relapsing-remitting MS patients had seven MRI scans over 12 months follow-up. All 1,585 MRI scans were performed on the same 1.5T scanner using an identical scanning protocol. Volumetric analysis was performed by ScanView and SIENA software. Linear regression analysis was used for estimation of annualized BVL, with a cutoff greater than .4% defined as pathological. We compared proportions of patients with pathological BVL obtained by analysis of different number of MRI time-points. RESULTS: An analysis of seven MRI scans (months 0, 2, 4, 6, 8, 10, and 12) showed pathological BVL in 105 (65%) of patients. When three MRI scans were included (months 0, 6, and 12), we found 10 (6.4%) false negative and 9 (5.7%) false positive results compared with the analysis of seven MRI scans, used as a reference for assessment of pathological BVL. Analysis of two MRI time-points (months 0 and 12) showed 10 (6.4%) false negative and 13 (8.3%) false positive results compared with analysis of seven MRI time-points. Change in the accuracy of pathological BVL between results obtained by analysis of seven and two time-points was 14.7%. CONCLUSIONS: High-frequency MRI monitoring may have a considerable effect on improving the precision of precisely identifying pathological BVL in individual patients. However, limitations in translation to clinical practice remain. Copyright © 2018 by the American Society of Neuroimaging. DOI: 10.1111/jon.12505 PMID: 29485230
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 174 – Multiple Sklerose: Veröffentlichungen Oktober 2013
180. J Neuroimmunol. 2018 Jan 31. pii: S0165-5728(17)30560-X. doi: 10.1016/j.jneuroim.2018.01.016. [Epub ahead of print] Cholinergic imbalance in lumbar spinal cord of a rat model of multiple sclerosis. Liu C(1), Liu H(1), Jin H(1), Yue X(1), Luo Z(1), Tu Z(2). Author information: (1)Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. (2)Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: [email protected]. Cholinergic dysfunction in the central nervous system is an important characteristic of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). By using a rat EAE model, upregulation of vesicular acetylcholine transporter (VAChT) level in the EAE rat lumbar spinal cord was detected by western blot and immunostaining, and was associated with lymphocyte filtration and glial activation. Ex vivo and in vitro autoradiography studies with [18F]VAT, a VAChT-specific radioligand, also revealed increased tracer uptake in EAE rat lumbar spinal cord compared with shams. These studies on VAChT expression suggest central cholinergic imbalance during EAE progression. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.01.016 PMID: 29397207
181. J Neuroimmunol. 2018 Feb 8. pii: S0165-5728(17)30498-8. doi: 10.1016/j.jneuroim.2018.02.002. [Epub ahead of print] Differentiation of remitting neuromyelitis optica spectrum disorders from multiple sclerosis by integrating parameters from serum proteins and lymphocyte subsets. Ip PP(1), Chung CY(1), Chang CC(1), Lee YF(2), Wang HM(1), Lian IB(3), Fann CS(1), Yang CC(4), Liao F(5). Author information: (1)Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. (2)Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan. (3)Department of Mathematics, National Changhua University of Education, Changhua, Taiwan. (4)Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: [email protected]. (5)Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: [email protected]. Differential diagnosis for neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) is always doubtful. To differentiate these diseases, we studied the immune status in the blood of patients with MS (n = 45) or NMOSD (n = 23) at remission phase. Remitting NMOSD patients had increased levels of CXCL13 and memory B cells, while remitting MS patients had elevated levels of galectin-9 and Th1 cells. A diagnostic model with these four variables is built to distinguish remitting NMOSD from MS with a sensitivity of 91.30%. Our diagnostic model may help to improve the differentiation of remitting NMOSD from MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.02.002 PMID: 29455925
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 175 – Multiple Sklerose: Veröffentlichungen Oktober 2013
182. J Neuroinflammation. 2018 Jan 30;15(1):26. doi: 10.1186/s12974-018-1075-y. Laquinimod attenuates inflammation by modulating macrophage functions in traumatic brain injury mouse model. Katsumoto A(1)(2), Miranda AS(3)(4), Butovsky O(5), Teixeira AL(6), Ransohoff RM(3), Lamb BT(7)(8). Author information: (1)Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. [email protected]. (2)Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 W 15th St, Indianapolis, IN, 46202, USA. [email protected]. (3)Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. (4)Laboratory of Neurobiology, Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. (5)Center of Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA. (6)Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. (7)Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. [email protected]. (8)Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 W 15th St, Indianapolis, IN, 46202, USA. [email protected]. BACKGROUND: Traumatic brain injury (TBI) is a critical public health and socio-economic problem worldwide. A growing body of evidence supports the involvement of inflammatory events in TBI. It has been reported that resident microglia and infiltrating monocytes promote an inflammatory reaction that leads to neuronal death and eventually behavioral and cognitive impairment. Currently, there is no effective treatment for TBI and the development of new therapeutic strategies is a scientific goal of highest priority. Laquinimod, an orally administered neuroimmunomodulator initially developed for the treatment of multiple sclerosis, might be a promising neuroprotective therapy for TBI. Herein, we aim to investigate the hypothesis that laquinimod will reduce the central nervous system (CNS) damage caused by TBI. METHODS: To test our hypothesis, Ccr2rfp/+ Cx3cr1 gfp/+ mice were submitted to a moderate TBI induced by fluid percussion. Sham controls were submitted only to craniotomy. Mice were treated daily by oral gavage with laquinimod (25 mg/kg) 7 days before and 3 days after TBI. The brains of mice treated or not treated with laquinimod were collected at 3 and 120 days post injury, and brain morphological changes, axonal injury, and neurogenesis were evaluated by microscopy analysis. We also isolated microglia from infiltrating monocytes, and the expression of immune gene mRNAs were analyzed by employing a quantitative NanoString nCounter technique. RESULTS: Laquinimod prevented ventricle enlargement caused by TBI in the long term. Immunohistochemical analyses revealed decreased axonal damage and restored neurogenesis in the laquinimod-treated TBI group at early stage (3 days post injury). Notably, laquinimod inhibited the monocytes infiltration to the brain. Hierarchial clustering demonstrated that the microglial gene expression from the TBI group treated with laquinimod resembles the sham group more than the TBI-water control group. CONCLUSIONS: Administration of laquinimod reduced lesion volume and axonal damage and restored neurogenesis after TBI. Laquinimod might be a potential therapy strategy to improve TBI long-term prognosis. DOI: 10.1186/s12974-018-1075-y PMCID: PMC5791334 PMID: 29382353
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 176 – Multiple Sklerose: Veröffentlichungen Oktober 2013
183. J Neuroinflammation. 2018 Feb 5;15(1):33. doi: 10.1186/s12974-017-1044-x. 18F-VC701-PET and MRI in the in vivo neuroinflammation assessment of a mouse model of multiple sclerosis. Belloli S(1)(2)(3), Zanotti L(4), Murtaj V(2)(5)(6), Mazzon C(7)(8), Di Grigoli G(1)(2), Monterisi C(6), Masiello V(6), Iaccarino L(9), Cappelli A(10), Poliani PL(11), Politi LS(2)(12)(13), Moresco RM(14)(15)(16). Author information: (1)IBFM-CNR, Segrate, Italy. (2)Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. (3)Milan Center for Neuroscience (NeuroMI) University of Milano-Bicocca, Milan, Italy. (4)Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy. (5)PhD Program in Neuroscience, University of Milan-Bicocca, Monza, Italy. (6)Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza, 20900, Italy. (7)Humanitas Clinical and Research Centre, Rozzano, Italy. (8)Biomedical Sciences Department, University of Padua, Padua, Italy. (9)Vita-Salute San Raffaele University and In Vivo Human Molecular and Structural Neuroimaging Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy. (10)Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy. (11)Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy. (12)Advanced MRI Center, University of Massachusetts Medical School, Worcester, MA, USA. (13)Neuroimaging Research, Boston Children's Hospital, Boston, MA, USA. (14)IBFM-CNR, Segrate, Italy. [email protected]. (15)Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. [email protected]. (16)Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza, 20900, Italy. [email protected]. BACKGROUND: Positron emission tomography (PET) using translocator protein (TSPO) ligands has been used to detect neuroinflammatory processes in neurological disorders, including multiple sclerosis (MS). The aim of this study was to evaluate neuroinflammation in a mouse MS model (EAE) using TSPO-PET with 18F-VC701, in combination with magnetic resonance imaging (MRI). METHODS: MOG35-55/CFA and pertussis toxin protocol was used to induce EAE in C57BL/6 mice. Disease progression was monitored daily, whereas MRI evaluation was performed at 1, 2, and 4 weeks post-induction. Microglia activation was assessed in vivo by 18F-VC701 PET at the time of maximum disease score and validated by radioligand ex vivo distribution and immunohistochemistry at 2 and 4 weeks post-immunization. RESULTS: In vivo and ex vivo analyses show that 18F-VC701 significantly accumulates within the central nervous system (CNS), particularly in the cortex, striatum, hippocampus, cerebellum, and cervical spinal cord of EAE compared to control mice, at 2 weeks post- immunization. MRI confirmed the presence of focal brain lesions at 2 weeks post-immunization in both T1-weighted and T2 images. Of note, MRI abnormalities attenuated in later post-immunization phase. Neuropathological analysis confirmed the presence of microglial activation in EAE mice, consistent with the in vivo increase of 18F-VC701 uptake. CONCLUSION: Increase of 18F-VC701 uptake in EAE mice is strongly associated with the presence of microglia activation in the acute phase of the disease. The combined use of TSPO-PET and MRI provided complementary evidence on the ongoing disease process, thus representing an attractive new tool to investigate neuronal damage and neuroinflammation at preclinical levels. DOI: 10.1186/s12974-017-1044-x PMCID: PMC5800080 PMID: 29402285
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 177 – Multiple Sklerose: Veröffentlichungen Oktober 2013
184. J Neuroinflammation. 2018 Feb 22;15(1):55. doi: 10.1186/s12974-018-1080-1. [18F]FSPG-PET reveals increased cystine/glutamate antiporter (xc-) activity in a mouse model of multiple sclerosis. Hoehne A(1), James ML(1)(2), Alam IS(1), Ronald JA(1), Schneider B(1), D'Souza A(1), Witney TH(1), Andrews LE(1), Cropper HC(1), Behera D(1), Gowrishankar G(1), Ding Z(2), Wyss-Coray T(2), Chin FT(1), Biswal S(1), Gambhir SS(3)(4). Author information: (1)Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, Stanford, CA, 94305, USA. (2)Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA. (3)Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, Stanford, CA, 94305, USA. [email protected]. (4)Department of Bioengineering, Department of Materials Science & Engineering, Stanford University, Stanford, CA, 94305, USA. [email protected]. BACKGROUND: The cystine/glutamate antiporter (xc-) has been implicated in several neurological disorders and, specifically, in multiple sclerosis (MS) as a mediator of glutamate excitotoxicity and proinflammatory immune responses. We aimed to evaluate an xc-specific positron emission tomography (PET) radiotracer, (4S)-4-(3-[18F]fluoropropyl)-L-glutamate ([18F]FSPG), for its ability to allow non-invasive monitoring of xc- activity in a mouse model of MS. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG35-55) peptide in complete Freund's adjuvant (CFA) followed by pertussis toxin. Control mice received CFA emulsion and pertussis toxin without MOG peptide, while a separate cohort of naïve mice received no treatment. PET studies were performed to investigate the kinetics and distribution of [18F]FSPG in naïve, control, pre-symptomatic, and symptomatic EAE mice, compared to 18F-fluorodeoxyglucose ([18F]FDG). After final PET scans, each mouse was perfused and radioactivity in dissected tissues was measured using a gamma counter. Central nervous system (CNS) tissues were further analyzed using ex vivo autoradiography or western blot. [18F]FSPG uptake in human monocytes, and T cells pre- and post-activation was investigated in vitro. RESULTS: [18F]FSPG was found to be more sensitive than [18F]FDG at detecting pathological changes in the spinal cord and brain of EAE mice. Even before clinical signs of disease, a small but significant increase in [18F]FSPG signal was observed in the spinal cord of EAE mice compared to controls. This increase in PET signal became more pronounced in symptomatic EAE mice and was confirmed by ex vivo biodistribution and autoradiography. Likewise, in the brain of symptomatic EAE mice, [18F]FSPG uptake was significantly higher than controls, with the largest changes observed in the cerebellum. Western blot analyses of CNS tissues revealed a significant correlation between light chain of xc- (xCT) protein levels, the subunit of xc- credited with its transporter activity, and [18F]FSPG-PET signal. In vitro [18F]FSPG uptake studies suggest that both activated monocytes and T cells contribute to the observed in vivo PET signal. CONCLUSION: These data highlight the promise of [18F]FSPG-PET as a technique to provide insights into neuroimmune interactions in MS and the in vivo role of xc- in the development and progression of this disease, thus warranting further investigation. DOI: 10.1186/s12974-018-1080-1 PMCID: PMC5822551 PMID: 29471880
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185. J Neuroinflammation. 2018 Feb 17;15(1):46. doi: 10.1186/s12974-018-1084-x. Cerebrospinal fluid level of Nogo receptor 1 antagonist lateral olfactory tract usher substance (LOTUS) correlates inversely with the extent of neuroinflammation. Takahashi K(1)(2), Takeuchi H(1), Kurihara Y(2), Doi H(1), Kunii M(1), Tanaka K(1), Nakamura H(1), Fukai R(1), Tomita-Katsumoto A(1), Tada M(1), Higashiyama Y(1), Joki H(1), Koyano S(1), Takei K(3), Tanaka F(4). Author information: (1)Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-Ku, Yokohama, 236-0004, Japan. (2)Molecular Medical Bioscience Laboratory, Department of Medical Life Science, Yokohama City University Graduate School of Medical Life Science, Suehiro-cho 1-7-29, Tsurumi-Ku, Yokohama, 230-0045, Japan. (3)Molecular Medical Bioscience Laboratory, Department of Medical Life Science, Yokohama City University Graduate School of Medical Life Science, Suehiro-cho 1-7-29, Tsurumi-Ku, Yokohama, 230-0045, Japan. [email protected]. (4)Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-Ku, Yokohama, 236-0004, Japan. [email protected]. BACKGROUND: Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral olfactory tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. METHODS: CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. RESULTS: Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. CONCLUSIONS: CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases. DOI: 10.1186/s12974-018-1084-x PMCID: PMC5816545 PMID: 29454354
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186. J Neurol. 2018 Feb 8. doi: 10.1007/s00415-018-8759-1. [Epub ahead of print] Defining spasticity: a new approach considering current movement disorders terminology and botulinum toxin therapy. Dressler D(1), Bhidayasiri R(2), Bohlega S(3), Chana P(4), Chien HF(5), Chung TM(6), Colosimo C(7), Ebke M(8), Fedoroff K(9), Frank B(10), Kaji R(11), Kanovsky P(12), Koçer S(13), Micheli F(14), Orlova O(15), Paus S(16), Pirtosek Z(17), Relja M(18), Rosales RL(19), Sagástegui-Rodríguez JA(20), Schoenle PW(21), Shahidi GA(22), Timerbaeva S(23), Walter U(24), Saberi FA(25). Author information: (1)Head of Movement Disorders Section, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. [email protected]. (2)Chulalongkorn Centre for Excellence on Parkinson's Disease and Related Disorders, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. (3)Department of Neurology, King Faisal Specialist Hospital, Riyyad, Kingdom of Saudi Arabia. (4)Department of Neurology, University of Santiago de Chile, Santiago de Chile, Chile. (5)Department of Neurology, University of Sao Paulo, Sao Paulo, Brazil. (6)University of Sao Paulo, Sao Paulo, Brazil. (7)Azienda Ospedaliera Santa Maria di Terni, Terni, Italy. (8)Median-Klinik Bad Salzuflen, Bad Salzuflen, Germany. (9)Gailtal-Klinik, Hermagor, Austria. (10)Helios-Klinik Leezen, Leezen, Germany. (11)Department of Neurology, University of Tokushima, Tokushima, Japan. (12)Department of Neurology, Palacky University, Olomouc, Czech Republic. (13)Centre de Rééducation et Medicine Physique, Hôpital du Jura, Porrentruy, Switzerland. (14)Department of Neurology, Hospital de Clínicas José de San Martín, University of Buenos Aires, Buenos Aires, Argentina. (15)Clinic 'Cecil Plus', Moscow, Russia. (16)Department of Neurology, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany. (17)Department of Neurology, Ljubljana University Medical Centre, Ljubljana, Slovenia. (18)Department of Neurology, University of Zagreb, Zagreb, Croatia. (19)Department of Neurology, University of Santo Tomas Hospital, Manila, Philippines. (20)Department of Neurology, University of Monterrey, Monterrey, Nueva Leon, Mexico. (21)Maternus-Klinik für Rehabilitation, Bad Oeynhausen, Germany. (22)Movement Disorders Clinic, Department of Neurology, Rasoul-e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran. (23)Federal State Hospital for Treatment and Rehabilitation of the Ministry of Health and Social Development of the Russian Federation, Moscow, Russia. (24)Department of Neurology, Rostock University, Rostock, Germany. (25)IAB- Interdisciplinary Working Group for Movement Disorders, Hamburg, Germany. Spasticity is a symptom occurring in many neurological conditions including stroke, multiple sclerosis, hypoxic brain damage, traumatic brain injury, tumours and heredodegenerative diseases. It affects large numbers of patients and may cause major disability. So far, spasticity has merely been described as part of the upper motor neurone syndrome or defined in a narrowed neurophysiological sense. This consensus organised by IAB-Interdisciplinary Working Group Movement Disorders wants to provide a brief and practical new definition of spasticity-for the first time-based on its various forms of muscle hyperactivity as described in the current movement disorders terminology. We propose the following new definition system: Spasticity describes involuntary muscle hyperactivity in the presence of central paresis. The involuntary muscle hyperactivity can consist of various forms of muscle hyperactivity: spasticity sensu strictu describes involuntary muscle hyperactivity triggered by rapid passive joint movements, rigidity involuntary muscle hyperactivity triggered by slow passive joint movements, dystonia spontaneous involuntary muscle hyperactivity and spasms complex involuntary movements usually triggered by sensory or acoustic stimuli. Spasticity can be described by a documentation system grouped along clinical picture (axis 1), aetiology (axis 2), localisation (axis 3) and additional central nervous system deficits (axis 4). Our new definition allows distinction of spasticity components accessible to BT therapy and those inaccessible. The documentation sheet presented provides essential information for planning of BT therapy. DOI: 10.1007/s00415-018-8759-1 PMID: 29423615
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187. J Neurol. 2018 Feb 8. doi: 10.1007/s00415-018-8781-3. [Epub ahead of print] MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein. Baumann M(1), Grams A(2), Djurdjevic T(2), Wendel EM(3), Lechner C(4), Behring B(5), Blaschek A(6), Diepold K(7), Eisenkölbl A(8), Fluss J(9), Karenfort M(10), Koch J(11), Konuşkan B(12), Leiz S(13), Merkenschlager A(14), Pohl D(15), Schimmel M(16), Thiels C(17), Kornek B(18), Schanda K(19), Reindl M(19), Rostásy K(20). Author information: (1)Division of Pediatric Neurology, Department of Pediatrics I, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. [email protected]. (2)Department of Neuroradiology, Medical University of Innsbruck, Innsbruck, Austria. (3)Department of Pediatrics, Olga Hospital, Stuttgart, Germany. (4)Division of Pediatric Neurology, Department of Pediatrics I, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. (5)Department of Pediatrics, Klinikum Nuremberg, Nuremberg, Germany. (6)Department of Pediatric Neurology and Developmental Medicine, Dr. von Hauner's Children's Hospital, University of Munich, Munich, Germany. (7)Division of Pediatric Neurology, Department of Pediatrics, Klinikum Kassel, Kassel, Germany. (8)Department of Pediatrics, Women's and Children's Hospital, Linz, Austria. (9)Pediatric Neurology, Geneva Children's Hospital, Geneva, Switzerland. (10)Department of General Paediatrics, Neonatology and Paediatric Cardiology, Heinrich Heine Universität, Düsseldorf, Germany. (11)Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria. (12)Department of Pediatric Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey. (13)Division of Pediatric Neurology, Department of Pediatrics, Klinikum Dritter Orden, Munich, Germany. (14)Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany. (15)Department of Neurology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada. (16)Division of Pediatric Neurology, Children's Hospital, Klinikum Augsburg, Augsburg, Germany. (17)Department of Neuropediatrics, University Children's Hospital, Ruhr-University Bochum, Bochum, Germany. (18)Institute of Neurology, Medical University of Vienna, Vienna, Austria. (19)Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. (20)Department of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln, Germany. Antibodies against the myelin oligodendrocyte glycoprotein (MOG-Ab) can be detected in various pediatric acquired demyelinating syndromes (ADS). Here, we analyze the spectrum of neuroradiologic findings in children with MOG-Ab and a first demyelinating event. The cerebral and spinal MRI of 69 children with different ADS was assessed in regard to the distribution and characteristics of lesions. Children with acute disseminated encephalomyelitis (n = 36) or neuromyelitis optica spectrum disorder (n = 5) presented an imaging pattern characterized predominantly by poorly demarcated lesions with a wide supra- and infratentorial distribution. Younger children also tended to have poorly defined and widespread lesions. The majority of patients with an isolated optic neuritis (n = 16) only presented small non-specific brain lesions or none at all. A longitudinally extensive transverse myelitis mainly affecting the cervical, and less often so the thoracic, lumbar, and conus regions, was detected in 31 children. The three children of our cohort who were then finally diagnosed with multiple sclerosis had at onset already demarcated white matter lesions as well as transverse myelitis. In conclusion, children with MOG seropositive ADS present disparate, yet characteristic imaging patterns. These patterns have been seen to correlate to the disease entity as well as to age of symptom onset. DOI: 10.1007/s00415-018-8781-3 PMID: 29423614
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188. J Neurol. 2018 Feb 8. doi: 10.1007/s00415-018-8783-1. [Epub ahead of print] Up-to-date knowledge about the association between multiple sclerosis and the reactivation of human endogenous retrovirus infections. Arneth B(1). Author information: (1)Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, University Hospital of the University of Marburg UKGM, Justus Liebig University, Feulgenstr. 12, 35392, Giessen, Germany. [email protected]. BACKGROUND: Although existing studies show that reactivation of the human endogenous retrovirus (HERVs) plays a leading role in multiple sclerosis (MS) progression, the practitioners are yet to establish effective approaches for managing MS without jeopardizing the patients' immune systems. AIM: To provide up-to-date knowledge on the specific roles played by the reactivation of the HERVs in the pathogenesis of MS. MATERIALS AND METHODS: A systematic review of 70 peer-reviewed journals accessed via PubMed was conducted. The searches generated more than 600 sources that were evaluated based on three step in and exclusion criteria. The selected sources were critically analyzed vis-à-vis the paper's hypothesis which posits that the HERVs reactivation does not directly cause the MS, but triggers a demyelination process by promoting the pathogenic effects of the retroviruses. The paper further documents the advancements in the therapeutic applications resulting from the immunohistological analysis and pathological studies aimed at minimizing the adverse consequences of the HERVs reactivation. RESULTS AND DISCUSSIONS: Only three out of the 70 reviewed sources did not find provide evidence linking the reactivation of HERV and MS progression. On the other hand, overwhelming pieces of evidence confirm that the reactivations often drive the demyelinating plaques by initiating microglial inflammation. Pathological examinations reveal that the inflammatory monocytes (Ly6ChiCCR2 + CX3CR1lo) trigger the reactivation of the malignant T cells that are responsible for the progression of MS. These findings are promoting new discoveries as far as managing MS is concerned. DOI: 10.1007/s00415-018-8783-1 PMID: 29423611
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189. J Neurol. 2018 Feb 5. doi: 10.1007/s00415-018-8758-2. [Epub ahead of print] Identifying neuropathic pain in patients with multiple sclerosis: a cross-sectional multicenter study using highly specific criteria. Solaro C(1), Cella M(2), Signori A(3), Martinelli V(4), Radaelli M(4), Centonze D(5)(6), Sica F(5)(6), Grasso MG(7), Clemenzi A(7), Bonavita S(8), Esposito S(8), Patti F(9), D'Amico E(9), Cruccu G(10), Truini A(10); Neuropathic Pain Special Interest Group of the Italian Neurological Society. Author information: (1)Department of Rehabilitation, Mons Luigi Novarese Novarese, Moncrivello, Italy. [email protected]. (2)Department of Neurology, ASL3 Genovese, Genoa, Italy. (3)Section of Biostatistics, Department of Health Sciences, University of Genova, Genoa, Italy. (4)Department of Neurology, San Raffaele Scientific Institute, Milan, Italy. (5)Neurology Clinic, Department of Systems Medicine, Tor Vergata University, Rome, Italy. (6)Istituto Neurologico Mediterraneo Neuromed, IRCCS, Pozzilli (IS), Italy. (7)Santa Lucia Foundation, IRCCS, Rome, Italy. (8)Clinic of Neurology, Second University of Naples, Naples, Italy. (9)Department of Neurosciences, University of Catania, Catania, Italy. (10)Department of Neurology and Psychiatry, University of Rome-La Sapienza, Rome, Italy. BACKGROUND: Pain is a common and heterogeneous complication of multiple sclerosis (MS). In this multicenter, cross sectional study, we aimed at investigating the prevalence of pain in MS using highly specific criteria for distinguishing the different types of pain. MATERIALS AND METHODS: After a structured interview, in patients with pain, clinical examination and DN4 questionnaire were used for distinguishing neuropathic and nociceptive pain. In subjects with neuropathic pain, the Neuropathic Pain Symptom Inventory was used for differentiating neuropathic pain symptoms. RESULTS: We enrolled 1249 participants (832 F, 417 M, mean age 33.9 years, mean disease duration 8 years, mean EDSS 3.2); based on clinical evaluation and DN4 score 429 patients (34.34%) were classified with pain (470 pain syndromes): 286 nociceptive pain syndromes and 184 neuropathic pain syndromes. Multivariate analysis showed that pain was associated with age, gender and disease severity and that neuropathic pain was distinctly associated with EDSS. CONCLUSIONS: Our study, providing definite information on the prevalence, characteristics and variables associated with neuropathic pain due to MS, shows that a more severe disease course is associated with a higher risk of neuropathic pain. Our findings might, therefore, provide a basis for improving the clinical management of this common MS complication. DOI: 10.1007/s00415-018-8758-2 PMID: 29404736
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190. J Neurol. 2018 Feb 20. doi: 10.1007/s00415-018-8796-9. [Epub ahead of print] Positive effects of fampridine on cognition, fatigue and depression in patients with multiple sclerosis over 2 years. Broicher SD(1), Filli L(2), Geisseler O(2), Germann N(2), Zörner B(3), Brugger P(2), Linnebank M(4). Author information: (1)Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland. [email protected]. (2)Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland. (3)Spinal Cord Injury Center, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland. (4)Department of Neurology, Helios-Klinik Hagen-Ambrock, Ambrocker Weg 60, 58091, Hagen, Germany. OBJECTIVE: To assess the effects of PR-fampridine on cognitive functioning, fatigue and depression in patients with multiple sclerosis (PwMS). METHODS: Thirty-two PwMS were included in this trial. Cognitive performance was assessed in an open-label and randomized double-blind, placebo- controlled study design using a comprehensive neuropsychological test battery as well as questionnaires examining depression and fatigue. RESULTS: We found significant improvements in cognitive measures assessing alertness (tonic alertness, p = 0.0244 and phasic alertness, p = 0.0428), psychomotor speed (p = 0.0140) as well as verbal fluency (p = 0.0002) during open-label treatment with PR-fampridine. These effects of performance were paralleled by patients' perception of reduced fatigue (physical, p = 0.0131; cognitive, p = 0.0225; total, p = 0.0126). Fampridine-induced improvements in phasic alertness (p = 0.0010) and measures of fatigue (physical, p = 0.0014; cognitive, p = 0.0003; total, p = 0.0005) were confirmed during randomized, double-blind, placebo- controlled assessment in the second year. In addition, we found positive effects of PR-fampridine on depressive symptoms (p = 0.0049). We demonstrated persisting beneficial effects of PR-fampridine on fatigue in PwMS over a period of more than 2 years. Drug responsiveness regarding cognitive performance and fatigue was not limited to walking responders. CONCLUSIONS: Our data demonstrate significant positive effects of treatment with PR-fampridine over 2 years on different cognitive domains as well as fatigue and depression in a cohort of PwMS. These findings imply that PR-fampridine should be considered as symptomatic treatment improving aspects of cognition, fatigue and depression in PwMS. DOI: 10.1007/s00415-018-8796-9 PMID: 29464379
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191. J Neurol. 2018 Feb 20. doi: 10.1007/s00415-018-8780-4. [Epub ahead of print] Smoking at time of CIS increases the risk of clinically definite multiple sclerosis. van der Vuurst de Vries RM(1), Mescheriakova JY(1), Runia TF(1), Siepman TAM(1), Wokke BHA(1), Samijn JPA(2), Hintzen RQ(3). Author information: (1)Department of Neurology, MS Centre ErasMS, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. (2)Department of Neurology, Maasstad Hospital, Rotterdam, The Netherlands. (3)Department of Neurology, MS Centre ErasMS, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. [email protected]. BACKGROUND: Cigarette smoking is a modifiable risk factor that influences the disease course of patients with multiple sclerosis (MS). However, in patients with a clinically isolated syndrome (CIS), there are conflicting results about the association between smoking and the risk of a subsequent MS diagnosis. The aim of this study was to determine the risk of clinically definite MS (CDMS) in smoking and non-smoking patients at time of a first demyelinating event. METHODS: Two hundred and fifty patients, aged 18-50 years, were included in our prospective CIS cohort. At time of the first neurological symptoms, patients completed a questionnaire about smoking habits. Cox regression analyses were performed to calculate univariate and multivariate hazard ratios for CDMS diagnosis in smoking and non-smoking CIS patients. RESULTS: One hundred and fourteen (46%) CIS patients were diagnosed with CDMS during a mean follow-up of 58 months. In total, 79 (32%) patients smoked at time of CIS. Sixty-seven % of the smoking CIS patients were diagnosed with CDMS during follow- up compared to 36% of the non-smoking CIS patients (p < 0.001). Smoking at time of CIS was an independent predictor for CDMS diagnosis (HR 2.3; p = 0.002). Non-smoking CIS patients who had a history of smoking did not have a higher risk for CDMS than those who had never smoked. CONCLUSIONS: Smoking at time of CIS was an independent risk factor for a future CDMS diagnosis. This is an additional argument to quit smoking at time of the first attack of suspected MS. DOI: 10.1007/s00415-018-8780-4 PMID: 29464378
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192. J Neurol. 2018 Feb 2. doi: 10.1007/s00415-018-8774-2. [Epub ahead of print] Cerebellum and cognition in multiple sclerosis: the fall status matters. Kalron A(1)(2), Allali G(3)(4)(5), Achiron A(6)(7). Author information: (1)Department of Physical Therapy, Sackler Faculty of Medicine, School of Health Professions, Tel-Aviv University, Tel Aviv, Israel. [email protected]. (2)Sagol School of Neurosciences, Tel-Aviv University, Tel Aviv, Israel. [email protected]. (3)Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospitals, Geneva, Switzerland. (4)Division of Cognitive and Motor Aging, Department of Neurology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA. (5)Faculty of Medicine, University of Geneva, Geneva, Switzerland. (6)Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Israel. (7)Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel. Cerebellar volume has been linked with cognitive performances in MS; however, the association in terms of fall status has never been compared. Therefore, the objective of the current study was to compare cognitive performance with cerebellar volume between MS fallers and non-fallers. The cross- sectional study included 140 PwMS (96 women). MRI volumetric analysis was based on the FreeSurfer image analysis suite. Volumes of the cerebellar gray and white matter were identified as the region of interest. Cognitive function included scores obtained from a computerized cognitive battery of tests. The sample was divided into fallers and non-fallers. MS fallers demonstrated a lower global cognitive performance and reduced gray and white matter cerebellar volumes compared to non- fallers. A significant association was found between total gray and white matter cerebellar volume and visual spatial subdomain (P value = 0.044 and 0.032, respectively) in the non-fallers group. The association remained significant after controlling for the total cranial volume and neurological disability (P value = 0.026 and 0.047, respectively). A relationship was found between the visual spatial score and the left gray matter cerebellum volume; R2 = 0.44, P value = 0.021. We believe that a unique relationship exists between the cerebellum structure and cognitive processing according to fall history in PwMS and should be considered when investigating the association between brain functioning and cognitive performances in MS. DOI: 10.1007/s00415-018-8774-2 PMID: 29396679
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193. J Neurol. 2018 Feb 17. doi: 10.1007/s00415-018-8771-5. [Epub ahead of print] Treatment of neuromyelitis optica with rituximab: a 2-year prospective multicenter study. Cabre P(1), Mejdoubi M(2), Jeannin S(3), Merle H(4), Plumelle Y(5), Cavillon G(6), Smadja D(3), Marignier R(6); Francophone Society of Multiple Sclerosis and OFSEP investigators. Collaborators: Rouzaud C, Heinzlef O, Dinh A, Creange A, Abdullatif A, Audouin B, Tourbah A, Berger E, Hautecoeur P, Donze C, Bourre B, Brochet B, Mekies C, Papeix C, Casez O, Brassat D, Defer G, Derache N, De Seze J, Dive D, LePage E, Fromont A, Gouider R, Edan G, Pelletier J, Grimaud J, Guennoc AM, Camdessanché JP, Kwiatkowski A, Laplaud D, Lebrun C, Debouverie M, Coustans M, Gout O, La Rochelle O, Heinzlef O, Ouallet JC, Cavelou P, Labauge P, Vermersch P, Wiertlewski S, Vukusic S, Marignier R, Schluep M, Seeldrayers P, Slassi I, Stankoff B, Thaite F, Moreau T, Thouvenot E, Zephir H, Ciron J, Collongues N, Kerschen P, Ruet A, Mouzawakh C, Pittion S, Cohen M, Gueguen A, Mathey G, Carra C, Bernady P, Faucheux JM, Planque E. Author information: (1)Department of Neurology, Pierre Zobda-Quitman University Hospital, 97261, Fort de France, Martinique. [email protected]. (2)Department of Radiology, Pierre Zobda-Quitman University Hospital, 97261, Fort de France, Martinique. (3)Department of Neurology, Pierre Zobda- Quitman University Hospital, 97261, Fort de France, Martinique. (4)Department of Ophthalmology, Pierre Zobda-Quitman University Hospital, 97261, Fort de France, Martinique. (5)Department of Biological Hematology, Pierre Zobda-Quitman University Hospital, 97261, Fort de France, Martinique. (6)Department of Neurology, Pierre-Wertheimer Hospital, Civilian Hospices of Lyon, Lyon, France. OBJECTIVE: Neuromyelitis optica (NMO) is a very severe autoimmune disorder of the central nervous system. It affects young subjects and has a poor prognosis both on a functional and vital level. Therefore, it is imperative to reduce the frequency of relapses. The purpose of this study was to evaluate the clinical and neuroradiological effectiveness of rituximab (RTX) on active forms of NMO. METHODS: We conducted a 2-year open prospective multicenter study that included 32 patients treated with RTX at a dose of 375 mg/m2/week for 1 month. When the number of circulating CD19+ B cells reached 1%, a maintenance therapy was started, consisting of two infusions of 1 g of RTX, administered at a 15-day interval. The primary objective was to reduce the annual relapse rate (ARR), in comparison to that observed in the 2 years before treatment onset. RESULTS: Rituximab administration reduced the ARR from 1.34 to 0.56 (p = 0.0005). The average Expanded Disability Status Scale (EDSS) score significantly improved by 1.1 point, from 5.9 (2-9) to 4.8 (0-9) after 2 years (p = 0.03). Anti-aquaporin-4 antibodies' level predicted treatment failure (p = 0.03). Frequency of Gad+ lesions in spinal cord decreased from 23.3 to 14.2%. RTX treatment did not prevent the death of three patients (treatment failure in two patients and acute myeloid leukemia in a patient previously treated with mitoxantrone). CONCLUSION: Rituximab is clinically effective in active forms of NMO, although few patients are resistant to the treatment. DOI: 10.1007/s00415-018-8771-5 PMID: 29455361
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194. J Neurol. 2018 Feb 13. doi: 10.1007/s00415-017-8727-1. [Epub ahead of print] The cortical blood-brain barrier in multiple sclerosis: a gateway to progression? Bell JS(1), Spencer JI(1), Yates RL(1)(2), DeLuca GC(3). Author information: (1)University of Oxford Medical School, Level 2 Academic Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK. (2)Nuffield Department of Clinical Neurosciences, Level 1 West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK. (3)Nuffield Department of Clinical Neurosciences, Level 1 West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK. [email protected]. DOI: 10.1007/s00415-017-8727-1 PMID: 29442176
195. J Neurol. 2018 Feb 12. doi: 10.1007/s00415-018-8791-1. [Epub ahead of print] Effectiveness and baseline factors associated to fingolimod response in a real-world study on multiple sclerosis patients. Esposito F(1)(2), Ferrè L(3)(4), Clarelli F(4), Rocca MA(3)(5), Sferruzza G(3)(4), Storelli L(5), Radaelli M(3), Sangalli F(3), Moiola L(3), Colombo B(3), Martinelli Boneschi F(3)(4), Comi G(3)(4), Filippi M(3)(5), Martinelli V(3). Author information: (1)Department of Neurology, San Raffaele Scientific Institute, Via Olgettina, 48, 20132, Milan, Italy. [email protected]. (2)Laboratory of Human Genetics of Neurological Disorders, CNS Inflammatory Unit and INSPE, San Raffaele Scientific Institute, Milan, Italy. [email protected]. (3)Department of Neurology, San Raffaele Scientific Institute, Via Olgettina, 48, 20132, Milan, Italy. (4)Laboratory of Human Genetics of Neurological Disorders, CNS Inflammatory Unit and INSPE, San Raffaele Scientific Institute, Milan, Italy. (5)Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. BACKGROUND: Treatment choice in multiple sclerosis (MS) is crucial for optimizing risk-benefit profile. OBJECTIVE: To assess fingolimod (FTY) effectiveness and identify baseline features associated to disease activity in a large Italian cohort of Relapsing-Remitting (RR) MS patients. METHODS: Three-hundred sixty-seven RRMS patients starting FTY treatment at San Raffaele Hospital (Milan-Italy) underwent clinical and MRI evaluations for 2 years. Treatment response was assessed considering the proportion of patients with no evidence of disease activity (NEDA) and recording the time to first relapse. Primary analyses were performed stratifying for Natalizumab (NTZ) treatment in the year before (NO_NTZ vs NTZ group), to account for post-NTZ reactivation. RESULTS: Almost half of patients were NEDA after 2 years, 53.4% in the NO_NTZ group and 36.2% in the NTZ group. Despite an opposite trend during the first 6-12 months, at 2-year follow-up the two groups were comparable for relapses and number of new/enlarging T2 and Gd-enhancing lesions. Baseline parameters of higher disease activity (ARR, Gd enhancing lesions and age at onset) were associated with increased likelihood of failing NEDA criteria or with shorter time to relapse (p < 0.05). CONCLUSIONS: Our data strengthen FTY effectiveness in everyday clinical practice, even in patients switching from NTZ treatment. Baseline parameters of inflammatory activity are the most important prognostic factors for mid-term disease reactivation also during second-line treatment with FTY, providing hints on how to select therapies towards a more personalized management. DOI: 10.1007/s00415-018-8791-1 PMID: 29435643
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196. J Neurol. 2018 Feb 1. doi: 10.1007/s00415-018-8763-5. [Epub ahead of print] Insular multiple sclerosis lesions are associated with erectile dysfunction. Winder K(1), Linker RA(1), Seifert F(1), Deutsch M(1), Engelhorn T(2), Dörfler A(2), Lee DH(1), Hösl KM(3), Hilz MJ(4). Author information: (1)Department of Neurology, University Hospital Erlangen, Friedrich-Alexander- University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany. (2)Department of Neuroradiology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. (3)Department of Psychiatry and Psychotherapy, Paracelsus Medical University, Nuremberg, Germany. (4)Department of Neurology, University Hospital Erlangen, Friedrich-Alexander- University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany. max.hilz@uk- erlangen.de. Erectile function (EF) is frequently compromised in men with multiple sclerosis (MS). Functional neuroimaging in healthy men identified a network of brain areas, such as the insula, visual and somatosensory association areas, cingulate gyrus, prefrontal cortex, as well as subcortical regions, contributing to EF. This study intended to determine associations between EF deterioration during MS and cerebral MS-associated lesion sites. In 31 men with MS (mean age 38.2 ± 11.2 years), we evaluated MS-related EF deterioration by comparing scores of the 5-item International Index of Erectile Function-5 questionnaire (IIEF5) at the time of study and retrospectively, 3 months prior to MS diagnosis, by calculating score differences as DeltaIIEF5 (DeltaIIEF5 score < 0 indicated EF deterioration). To assess the impact of confounding factors of EF, patient age, disease duration, disease severity, depressiveness, bladder and bowel symptoms, and total cerebral MS lesion volume were correlated with DeltaIIEF5 scores (Spearman rank correlation) and compared between patients with and without EF deterioration (t tests or Mann-Whitney U test). MS lesions were assessed on T2- weighted magnetic resonance imaging (MRI; 1.5 or 3 T). We determined the lesion overlap (prevalence of identical lesion sites among patients), subtracted lesion overlaps in patients without EF deterioration from overlaps in patients with EF deterioration, and compared DeltaIIEF5 scores voxel- wise between patients with and without lesions in a given voxel (t test; significance: p < 0.05). In 14 patients (45.2%), DeltaIIEF5 scores indicated EF deterioration. DeltaIIEF5 scores were not associated with age (ρ = 0.06; p = 0.74), disease duration (ρ = 0.26; p = 0.15), disease severity (ρ = - 0.19; p = 0.31), depressiveness (ρ = 0.07; p = 0.72), bladder symptoms (ρ = - 0.11; p = 0.57), bowel symptoms (ρ = 0.17; p = 0.37), and total lesion volume (ρ = - 0.13; p = 0.47). The voxel-wise analysis showed associations between EF deterioration and MS lesions primarily in the bilateral, and predominantly left juxtacortical insular region. In conclusion, MS lesions particularly in the left insular region, which is activated with sexual arousal, contribute to erectile dysfunction. DOI: 10.1007/s00415-018-8763-5 PMID: 29392463
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197. J Neurol. 2018 Feb 1. doi: 10.1007/s00415-018-8764-4. [Epub ahead of print] The long-term impact of early treatment of multiple sclerosis on the risk of disability pension. Landfeldt E(1)(2), Castelo-Branco A(3), Svedbom A(3), Löfroth E(4), Kavaliunas A(5), Hillert J(5). Author information: (1)Mapi Group, Stockholm, Sweden. [email protected]. (2)Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, 17177, Stockholm, Sweden. [email protected]. (3)Mapi Group, Stockholm, Sweden. (4)Novartis, Stockholm, Sweden. (5)Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. OBJECTIVE: The objective of this retrospective, observational study was to estimate the long-term impact of early treatment of multiple sclerosis (MS) on the risk of disability pension. METHODS: Our cohort comprised patients with MS in Sweden, identified in a nationwide disease-specific register (the Swedish Multiple Sclerosis Registry), who started treatment with a disease-modifying drug (DMD) between January 1, 2002, and December 31, 2012. We analyzed the association between time from onset of MS to treatment initiation and full-time disability pension using survival analysis. RESULTS: Our sample comprised 2477 patients. Unadjusted Kaplan-Meier failure functions showed that patients who started treatment within six months after onset had a lower risk of disability pension across follow- up compared with patients initiating therapy after 12 months. Outcomes from the univariate Cox proportional hazards model showed that time from onset to treatment initiation (in years) was significantly associated with disability pension (HR 1.03, p < 0.001). Outcomes from the multivariable Cox proportional hazards model showed that patients who started treatment within 6 months after onset had, on average, a 36% lower risk (HR 0.74, p = 0.010) of full-time disability pension during follow-up compared with patients starting treatment after 18 months when controlling for age, sex, marital status, university education, and prevalent comorbidities. CONCLUSIONS: We show that early treatment with DMDs of MS is associated with a significantly reduced risk of disability pension. Our findings highlight the potential long-term benefits of early treatment of MS and should be helpful to inform ongoing discussion on the optimum medical management of the disease. DOI: 10.1007/s00415-018-8764-4 PMID: 29392457
198. J Neurol Neurosurg Psychiatry. 2018 Feb 7. pii: jnnp-2017-317566. doi: 10.1136/jnnp-2017- 317566. [Epub ahead of print] Worldwide prevalence of neuromyelitis optica spectrum disorders. Mori M(1), Kuwabara S(1), Paul F(2). Author information: (1)Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan. (2)Charité - Universitätsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin and Berlin Institute of Health, NeuroCure Cluster of Excellence and Experimental and Clinical Research Center, Max Delbruck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany. DOI: 10.1136/jnnp-2017-317566 PMID: 29436488
Conflict of interest statement: Competing interests: None declared.
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199. J Neurol Sci. 2018 Mar 15;386:19-22. doi: 10.1016/j.jns.2018.01.011. Epub 2018 Jan 10. Cognition in multiple sclerosis: Between cognitive reserve and brain volume. Fenu G(1), Lorefice L(2), Arru M(2), Sechi V(3), Loi L(3), Contu F(3), Cabras F(3), Coghe G(2), Frau J(2), Fronza M(2), Sbrescia G(3), Lai V(3), Boi M(3), Mallus S(3), Murru S(3), Porcu A(3), Barracciu MA(3), Marrosu MG(2), Cocco E(2). Author information: (1)Multiple Sclerosis Center, Binaghi Hospital, ATS Sardegna, Department of Medical Sciences and Public Health, University of Cagliari, Italy. Electronic address: [email protected]. (2)Multiple Sclerosis Center, Binaghi Hospital, ATS Sardegna, Department of Medical Sciences and Public Health, University of Cagliari, Italy. (3)Radiology Unit, Binaghi Hospital, ATS Sardegna, Cagliari, Italy. BACKGROUND: Several correlations between cognitive impairment (CI), radiologic markers and cognitive reserve (CR) have been documented in MS. OBIECTIVE: To evaluate correlation between CI and brain volume (BV) considering CR as possibile mitigating factor. METHODS: 195 relapsing MS patients underwent a neuropsychological assessment using BICAMS. BV was estimated using SIENAX to obtain normalized volume of brain (NBV), white matter (NWV), gray matter (NGV) and cortical gray matter (CGV). CR was estimated using a previously validated tool. RESULTS: Pearson test showed a correlation between the symbol digit modality test (SDMT) score and NBV (r=0.38; p<0.000) NGV(r=0.31; p<0.000), CGV (r=0.35; p<0.000) and CRI score(r=0.42; p<0.000). Linear regression (dependent variable:SDMT) showed a relationship with CR scores (p=0.000) and NGV(p<0.000). A difference was detected between cognitive impaired and preserved patients regarding mean of NBV(p=0.002), NGV(p=0.007), CGV(p=0.002) and CR Scores (p=0.007). Anova showed a association between the presence of CI (dependent variable) and the interaction term CRIQ × CGV (p=0.004) whit adjustment for age and disability evaluated by EDSS. CONCLUSIONS: Our study shows a correlation between cognition and BV, in particular gray matter volume. Cognitive reserve is also confirmed as an important element playing a role in the complex interaction to determine the cognitive functions in MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jns.2018.01.011 PMID: 29406960
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200. J Neurol Sci. 2018 Feb 15;385:39-44. doi: 10.1016/j.jns.2017.11.028. Epub 2017 Nov 22. Anti-cholinergic medications for bladder dysfunction worsen cognition in persons with multiple sclerosis. Morrow SA(1), Rosehart H(2), Sener A(3), Welk B(4). Author information: (1)Department of Clinical Neurological Sciences, Western University, London Health Sciences Center, LHSC-UH, 339 Windermere Rd, London N6A 5A5, ON, Canada. Electronic address: [email protected]. (2)Department of Clinical Neurological Sciences, London Health Sciences Center, London, ON, Canada. (3)Western University, London Health Sciences Center, London, ON, Canada. (4)Department of Epidemiology and Biostatistics, Western University, London Health Sciences Center, London, ON, Canada. Bladder dysfunction is common in persons with MS (PwMS), often due to detrusor muscle overactivity. Anticholinergic medications are considered the first line treatment for bladder dysfunction and are known to worsen cognition in healthy older adults and in persons with dementia. Yet, it is not known if these medications have the same effect on PwMS. Thus, the Objective of this prospective matched- cohort study was to determine if anticholinergic medications affect objective measures of cognition in PwMS. We recruited PwMS starting either oxybutynin or tolterodine (cases). Cases and controls were tested with the Brief International Cognitive Assessment for MS (BiCAMS) battery prior to starting anticholinergic medications and 12weeks later. The primary outcome was change on the Symbol Digit Modalities Test (SDMT) between groups; secondary outcomes were changes on the other BiCAMS measures. Analysis of Covariance with baseline measures as covariates to assess the significance of between group differences was performed at 12weeks. Forty eight PwMS starting anticholinergic medications and 21 matched PwMS controls were recruited. There was a significant difference (p<0.001) in the change on the cognitive measures over 12weeks between groups. The controls demonstrated improvement, consistent with practice effect, while the cases remained unchanged. This study demonstrates that anticholinergic medications may have a negative effect on cognition in PwMS; further confirmatory studies are needed. Copyright © 2017 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jns.2017.11.028 PMID: 29406911
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201. J Neurol Sci. 2018 Feb 15;385:30-33. doi: 10.1016/j.jns.2017.12.004. Epub 2017 Dec 6. Neuroinflammation following disease modifying therapy in multiple sclerosis: A pilot positron emission tomography study. Bunai T(1), Terada T(1), Kono S(2), Yokokura M(3), Yoshikawa E(4), Futatsubashi M(4), Miyajima H(2), Ouchi Y(5). Author information: (1)Department of Biofunctional Imaging, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan. (2)First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan. (3)Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan. (4)Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan. (5)Department of Biofunctional Imaging, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: [email protected]. INTRODUCTION: Chronic activation of microglia accelerates the neurodegenerative process in multiple sclerosis (MS). Although disease modifying therapy (DMT) is reportedly effective for neuroinflammatory responses in MS, the progression of neuroinflammation after DMT remains unclear. METHODS: We evaluated microglial activation in six clinically stable relapsing-remitting MS patients after DMT by quantifying changes in translocator protein (TSPO) density using PET with [11C]DPA713, a selective TSPO tracer for microglial activation. All patients underwent [11C]DPA713 PET scans twice, and the scans were conducted one year apart. The binding potential (BPND) of the tracer was estimated using a simplified reference tissue model. RESULTS: [11C]DPA713 BPND measured at 6months after DMT was significantly higher in the MS group than that in the control group. Compared with the first PET measurement, the one-year PET measurement revealed significantly elevated [11C]DPA713 BPND in broader brain regions covering the temporal and parietal cortices after one year of DMT. CONCLUSIONS: The current results indicate that microglial activation may proceed in the entire brain of clinically stable MS patients even after receiving DMT. Copyright © 2017 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jns.2017.12.004 PMID: 29406909
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202. J Neurol Sci. 2018 Feb 15;385:217-224. doi: 10.1016/j.jns.2018.01.004. Epub 2018 Jan 4. Argentinean recommendations on the identification of treatment failure in relapsing remitting multiple sclerosis patients. Cristiano E(1), Alonso R(2), Alvez Pinheiro A(3), Bacile EA(4), Balbuena ME(5), Ballario C(6), Barboza AG(7), Bestoso S(8), Burgos M(9), Cáceres F(10), Carnero Contentti E(11), Carrá A(12), Crespo E(13), Curbelo MC(14), Deri N(15), Fernandez J(16), Fernández Liguori N(17), Fiol M(18), Gaitán MI(18), Garcea O(19), Giunta D(20), Halfon MJ(21), Hryb JP(22), Jacobo M(23), Kohler E(24), Linares R(25), Luetic GG(26), Martínez AD(27), Míguez J(28), Nofal PG(29), Patrucco L(28), Piedrabuena R(30), Rojas JI(28), Rotta Escalante R(31), Saladino ML(10), Silva BA(19), Sinay V(32), Steinberg JD(27), Tarulla A(33), Vétere SA(34), Villa A(35), Vrech C(36), Ysrraelit MC(18), Correale J(18). Author information: (1)Centro de esclerosis múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Argentina. Electronic address: [email protected]. (2)Clínica de Esclerosis Múltiple, Hospital Ramos Mejía, Buenos Aires, Argentina; Sanatorio Guemes, Buenos Aires, Argentina. (3)Hospital San Martín, Paraná, Entre Ríos, Argentina. (4)Instituto Neurociencias Cordoba, Argentina. (5)Seccion de Neuroinmunologia y Enfermedades Desmielinizantes, Servicio de Neurologia, Hospital de clinicas Jose de San Martin, Argentina. (6)NeuroRosario, Rosario, Argentina. (7)Hospital Central de Mendoza, Argentina. (8)Servicio Neurología, Hospital Escuela Corrientes, Argentina. (9)Hospital San Bernardo, Salta, Argentina. (10)INEBA, Institute of Neuoscience Buenos Aires, Argentina. (11)Department of Neuroscience - Neuroimmunology Unit, Hospital Alemán, Buenos Aires, Argentina. (12)MS Section Hospital Britanico Buenos Aires, Argentina; Fundación Favaloro/INECO, Buenos Aires, Argentina. (13)Universisad Nacional del sur, Bahia Blanca, Buenos Aires, Argentina. (14)MS Section Hospital Britanico Buenos Aires, Argentina; Policlinico Municipal Sofía T. de Santamarina, Buenos Aires, Argentina. (15)Centro de Investigaciones Diabaid, Argentina; Hospital Fernández de Buenos Aires, Argentina. (16)Práctica Privada, Argentina. (17)Hospital Enrique Tornu, Buenos Aires, Argentina; Sanatorio Guemes, Buenos Aires, Argentina. (18)Department of Neurology, Institute for Neurological Research Dr Raul Carrea, FLENI, Argentina. (19)Clínica de Esclerosis Múltiple, Hospital Ramos Mejía, Buenos Aires, Argentina. (20)Clinical Research Section, Hospital Italiano de Buenos Aires, Argentina. (21)Hospital Británico de Buenos Aires, Argentina; Hospital Municipal de Vicente López Prof. Dr. Bernardo Houssay, Argentina. (22)Servicio de Neurología, Hospital Cárlos G. Durand, CABA, Buenos Aires, Argentina. (23)RIAPEM (Red Integral Asistencial al Paciente con EM), Santiago del Estero, Argentina. (24)Fundación Sinapsis Santa Rosa La Pampa, Argentina. (25)Axis Neurociencias Bahia Blanca, Argentina. (26)Instituto de Neurociencias de Rosario, Argentina. (27)MS Section Hospital Britanico Buenos Aires, Argentina. (28)Centro de esclerosis múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Argentina. (29)Hospital de Clínicas Ntra Sra del Carmen, San Miguel de Tucumán, Argentina. (30)Instituto Lennox/Clinica Reina Fabiola, Córdoba, Argentina. (31)Fundación FACENE, Buenos Aires, Argentina. (32)Fundación Favaloro/INECO, Buenos Aires, Argentina. (33)Hospital de Agudos Parmenio Piñero, Municipalidad de Ciudad de Buenos Aires, MCBA, Argentina. (34)Sección de Enfermedades Desmielinizantes HIGA "Gral. San Martín" de la ciudad de La Plata, Argentina. (35)Sección Neuroinmunología, Hospital Ramos Mejia, Buenos Aires, Argentina. (36)Departamento de Enfermedades desmielinizantes, Sanatorio Allende Cordoba, Argentina. Erratum in J Neurol Sci. 2018 Feb 12;:. One of the biggest challenges in multiple sclerosis (MS) is the definition of treatment response/failure in order to optimize treatment decisions in affected patients. The objective of this consensus was to review how disease activity should be assessed and to propose recommendations on the identification of treatment failure in RRMS patients in Argentina.METHODS: A panel of experts in neurology from Argentina, dedicated to the diagnosis and care of MS patients, gathered both virtually and in person during 2016 and 2017 to carry out a consensus recommendation on the identification of treatment failure in RRMS patients. To achieve consensus, the methodology of "formal consensus-RAND/UCLA method" was used. RESULTS: Recommendations were established based on published evidence and the expert opinion. Recommendations focused on disease management, disease activity markers and treatment failure identification were determined. Main consensus were: ≥2 relapses during the first year of treatment and/or ≥3 new or enlarged T2 or T1 GAD+ lesions and/or sustained increase of ≥2 points in EDSS or ≥100% in T25FW defines treatment failure in RRMS patients. CONCLUSIONS: The recommendations of this consensus guidelines attempts to optimize the health care and management of patients with MS in Argentina. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jns.2018.01.004 PMID: 29406907
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203. J Neurol Sci. 2018 Feb 15;385:198-214. doi: 10.1016/j.jns.2017.12.022. Epub 2017 Dec 22. Autoimmunity in multiple sclerosis: role of sphingolipids, invariant NKT cells and other immune elements in control of inflammation and neurodegeneration. Podbielska M(1), O'Keeffe J(2), Hogan EL(3). Author information: (1)Department of Neurology and Neurosurgery, Medical University of South Carolina Charleston, SC, USA; Laboratory of Signal Transduction Molecules, Ludwik Hirszfeld Institute of Immunology & Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland. Electronic address: [email protected]. (2)Department of Biopharmaceutical & Medical Science, School of Science & Computing, Galway-Mayo Institute of Technology, Galway, Ireland. (3)Department of Neurology and Neurosurgery, Medical University of South Carolina Charleston, SC, USA. Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is classified as being an autoimmune response in the genetically susceptible individual to a persistent but unidentified antigen(s). Both the adaptive and the innate immune systems are likely to contribute significantly to MS pathogenesis. This review summarizes current understanding of the characteristics of MS autoimmunity in the initiation and progression of the disease. In particular we find it timely to classify the autoimmune responses by focusing on the immunogenic features of myelin-derived lipids in MS including molecular mimicry; on alterations of bioactive sphingolipids mediators in MS; and on functional roles for regulatory effector cells, including innate lymphocyte populations, like the invariant NKT (iNKT) cells which bridge adaptive and innate immune systems. Recent progress in identifying the nature of sphingolipids recognition for iNKT cells in immunity and the functional consequences of the lipid-CD1d interaction opens new avenues of access to the pathogenesis of demyelination in MS as well as design of lipid antigen-specific therapeutics. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jns.2017.12.022 PMID: 29406905
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204. J Neurol Sci. 2018 Feb 15;385:126-130. doi: 10.1016/j.jns.2017.12.029. Epub 2017 Dec 24. Demyelination with preferential MAG loss: A complex message from MS paraffin blocks. Rahmanzadeh R(1), Sahraian MA(1), Rahmanzade R(1), Rodriguez M(2). Author information: (1)MS Research Center, Neuroscience Institute, Tehran University of Medical Science, Tehran, Iran. (2)Department of Neurology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. Electronic address: rodriguez.moses@mayo.edu. Multiple sclerosis (MS) is generally considered to be a demyelinating autoimmune disorder. However, neuropathological examinations of MS lesions do not support this concept. Demyelination with preferential loss of myelin-associated glycoprotein (MAG) is a common finding in MS tissues and has been reported by several groups. As MAG is located in ad-axonal myelin layers and is not accessible to infiltrating immune cells, demyelination with preferred loss of MAG may be suggestive of a primary oligodendrocytopathy in MS. Moreover, it has been shown that oligodendrocytopathy may precede the infiltration of inflammatory cells at the lesion site. In this paper, we review studies of neuropathology of MS tissues that reported this type of demyelination and then we discuss three emerging explanations that are trying to interpret this mismatched observation. Published by Elsevier B.V. DOI: 10.1016/j.jns.2017.12.029 PMID: 29406891
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205. J Neurol Sci. 2018 Feb 15;385:1-6. doi: 10.1016/j.jns.2017.11.037. Epub 2017 Dec 2. Preliminary evidence of the cerebellar role on cognitive performances in clinically isolated syndrome. Moroso A(1), Ruet A(1), Lamargue-Hamel D(2), Munsch F(2), Deloire M(3), Ouallet JC(3), Cubizolle S(3), Charré-Morin J(3), Saubusse A(3), Tourdias T(1), Dousset V(1), Brochet B(4). Author information: (1)CHU de Bordeaux, INSERM-CHU CIC-P 0005, Service de Neurologie, Bordeaux F-33076, France; Université de Bordeaux, Bordeaux F-33076, France; Neurocentre Magendie, INSERM U1215, Team Glia-neuron Interactions, Bordeaux F-33077, France. (2)Université de Bordeaux, Bordeaux F-33076, France; Neurocentre Magendie, INSERM U1215, Team Glia-neuron Interactions, Bordeaux F-33077, France. (3)CHU de Bordeaux, INSERM-CHU CIC-P 0005, Service de Neurologie, Bordeaux F-33076, France. (4)CHU de Bordeaux, INSERM-CHU CIC-P 0005, Service de Neurologie, Bordeaux F-33076, France; Université de Bordeaux, Bordeaux F-33076, France; Neurocentre Magendie, INSERM U1215, Team Glia-neuron Interactions, Bordeaux F-33077, France. Electronic address: [email protected]. BACKGROUND: Cerebellar and cognitive dysfunction can occur early in clinically isolated syndrome (CIS). Eye tracking is a reliable tool for the evaluation of both subtle cerebellar symptoms and cognitive impairment. OBJECTIVES: To investigate the early cognitive profile using neuropsychological and ocular motor (OM) testing in CIS with and without cerebellar dysfunction with OM testing compared to healthy subjects (HS). METHODS: Twenty-eight patients and 12 HC underwent OM and neuropsychological testing. Cerebellar impairment was defined by the registration of saccadic intrusions and/or at least 10% of dysmetria during ocular motor recording. Visually guided saccade (VGS), memory-guided saccade (MGS) and antisaccade (AS) paradigms were compared to neuropsychological assessments. RESULTS: The group of patients with cerebellar dysfunction (n=16) performed worse on MGS latencies and error rates, and had worse working memory, executive function and information processing speed (IPS) z scores than patients without cerebellar dysfunction. IPS was correlated with the AS error rate in all patients and with the VGS error rate and the MGS final eye position ratio in cerebellar patients. CONCLUSION: Eye tracking is a sensitive tool to assess cognitive and cerebellar dysfunctions in CIS. In CIS patients, cerebellar impairment is associated with working memory, executive functions and IPS slowness. Copyright © 2017 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jns.2017.11.037 PMID: 29406885
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206. J Neurol Sci. 2018 Feb 12. pii: S0022-510X(18)30061-3. doi: 10.1016/j.jns.2018.02.003. [Epub ahead of print] Corrigendum to "Argentinean recommendations on the identification of treatment failure in relapsing remitting multiple sclerosis patients" [J. Neurol. Sci. 385C (2018) 217-224]. Cristiano E(1), Alonso R(2), Alvez Pinheiro A(3), Bacile EA(4), Balbuena ME(5), Ballario C(6), Barboza AG(7), Bestoso S(8), Burgos M(9), Cáceres F(10), Carnero Contentti E(11), Carrá A(12), Crespo E(13), Curbelo MC(14), Deri N(15), Fernandez J(16), Fernández Liguori N(17), Fiol M(18), Gaitán MI(18), Garcea O(19), Giunta D(20), Halfon MJ(21), Hryb JP(22), Jacobo M(23), Kohler E(24), Linares R(25), Luetic GG(26), Martínez AD(27), Míguez J(28), Nofal PG(29), Patrucco L(28), Piedrabuena R(30), Rojas JI(28), Rotta Escalante R(31), Saladino ML(10), Silva BA(19), Sinay V(32), Steinberg JD(27), Tarulla A(33), Vétere SA(34), Villa A(35), Vrech C(36), Ysrraelit MC(18), Correale J(18). Author information: (1)Centro de esclerosis múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Argentina. Electronic address: [email protected]. (2)Clínica de Esclerosis Múltiple, Hospital Ramos Mejía, Buenos Aires, Argentina; Sanatorio Guemes, Buenos Aires, Argentina. (3)Hospital San Martín, Paraná, Entre Ríos, Argentina. (4)Instituto Neurociencias Cordoba, Argentina. (5)Seccion de Neuroinmunologia y Enfermedades Desmielinizantes, Servicio de Neurologia, Hospital de clinicas Jose de San Martin, Argentina. (6)NeuroRosario, Rosario, Argentina. (7)Hospital Central de Mendoza, Argentina. (8)Servicio Neurología, Hospital Escuela Corrientes, Argentina. (9)Hospital San Bernardo, Salta, Argentina. (10)INEBA, Institute of Neuoscience Buenos Aires, Argentina. (11)Department of Neuroscience, Neuroimmunology Unit, Hospital Alemán, Buenos Aires, Argentina. (12)MS SectionHospital Britanico Buenos Aires, Argentina; Fundación Favaloro/INECO, Buenos Aires, Argentina. (13)Universisad Nacional del sur, Bahia Blanca, Buenos Aires, Argentina. (14)MS SectionHospital Britanico Buenos Aires, Argentina; Policlinico Municipal Sofía T. de Santamarina, Buenos Aires, Argentina. (15)Centro de Investigaciones Diabaid, Argentina; Hospital Fernández de Buenos Aires, Argentina. (16)Práctica Privada, Argentina. (17)Hospital Enrique Tornu, Buenos Aires, Argentina; Sanatorio Guemes, Buenos Aires, Argentina. (18)Department of Neurology, Institute for Neurological Research Dr Raul Carrea, FLENI,Argentina. (19)Clínica de Esclerosis Múltiple, Hospital Ramos Mejía, Buenos Aires, Argentina. (20)Clinical Research Section, Hospital Italiano de Buenos Aires, Argentina. (21)Hospital Británico de Buenos Aires, Argentina; Hospital Municipal de Vicente López Prof. Dr. Bernardo Houssay, Argentina. (22)Servicio de Neurología, Hospital Cárlos G. Durand, CABA, Buenos Aires, Argentina. (23)RIAPEM (Red Integral Asistencial al Paciente con EM), Santiago del Estero, Argentina. (24)Fundación Sinapsis Santa Rosa La Pampa, Argentina. (25)Axis Neurociencias Bahia Blanca, Argentina. (26)Instituto de Neurociencias de Rosario, Argentina. (27)MS SectionHospital Britanico Buenos Aires, Argentina. (28)Centro de esclerosis múltiple de Buenos Aires, Hospital Italiano de Buenos Aires, Argentina. (29)Hospital de Clínicas Ntra Sra del Carmen, San Miguel de Tucumán, Argentina. (30)Instituto Lennox/Clinica Reina Fabiola, Córdoba, Argentina. (31)Fundación FACENE, Buenos Aires, Argentina. (32)Fundación Favaloro/INECO, Buenos Aires, Argentina. (33)Hospital de Agudos Parmenio Piñero, Municipalidad de Ciudad de Buenos Aires, MCBA,Argentina. (34)Sección de Enfermedades Desmielinizantes HIGA "Gral. San Martín" de la ciudad de La Plata, Argentina. (35)Sección Neuroinmunología, Hospital Ramos Mejia, Buenos Aires, Argentina. (36)Departamento de Enfermedades desmielinizantes, Sanatorio Allende Cordoba, Argentina. Erratum for J Neurol Sci. 2018 Feb 15;385:217-224. DOI: 10.1016/j.jns.2018.02.003 PMID: 29449007
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207. J Neuroophthalmol. 2018 Mar;38(1):91-100. doi: 10.1097/WNO.0000000000000633. New Ways of "Seeing" the Mechanistic Heterogeneity of Multiple Sclerosis Plaque Pathogenesis. Meltzer EI(1), Costello FE, Frohman EM, Frohman TC. Author information: (1)Department of Neurology (EM), Partner's Neurology Residency Training Program, Massachusetts General and Brigham and Women's Hospitals, Harvard Medical School, Massachusetts; The Department of Neurology (TCF, EMF), The Dell Medical School, The University of Texas, Austin, Texas; and Department of Neurology (FC), University of Calgary, Calgary, Canada. BACKGROUND: Over the past few decades, we have witnessed a transformation with respect to the principles and pathobiological underpinnings of multiple sclerosis (MS). From the traditional rubric of MS as an inflammatory and demyelinating disorder restricted to central nervous system (CNS) white matter, our contemporary view has evolved to encompass a broader understanding of the variable mechanisms that contribute to tissue injury, in a disorder now recognized to affect white and grey matter compartments. EVIDENCE ACQUISITION: A constellation of inflammation, ion channel derangements, bioenergetic supply: demand mismatches within the intra-axonal compartment, and alterations in the dynamics and oximetry of blood flow in CNS tissue compartments are observed in MS. These findings have raised questions regarding how histopathologic heterogeneity may influence the diverse clinical spectrum of MS; and, accordingly, how individual treatment needs vary from 1 patient to the next. RESULTS: We are now on new scaffolding in MS; one that promises to translate key clinical and laboratory observations to the application of emerging patient-centered therapies. CONCLUSIONS: This review highlights our current knowledge of the underlying disease mechanisms in MS, explores the inflammatory and neurodegenerative consequences of tissue damage, and examines physiologic factors that contribute to bioenergetic homeostasis within the CNS of affected patients. DOI: 10.1097/WNO.0000000000000633 PMID: 29438266
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208. J Neuroophthalmol. 2018 Mar;38(1):85-90. doi: 10.1097/WNO.0000000000000634. Keep Your Eyes Wide Open: On Visual- and Vision-Related Measurements to Better Understand Multiple Sclerosis Pathophysiology. Backner Y(1), Levin N. Author information: (1)fMRI Unit, Neurology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel. BACKGROUND: Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is multifaceted. It manifests as acute episodes as well as an accumulative chronic disability; myelin involvement as well as axonal damage; local as well as global effects; and disease load elements as well as compensatory mechanisms. The visual system, with its clear structural organization and relatively direct reflection of damage, may serve as an appropriate model to study MS. METHODS: In recent years, we have witnessed a blossoming in the field of visual measures in MS. Because it is impossible to cover all different aspects of these measures, we chose to focus on several hot topics in MS literature and shed light on them through studies conducted in the visual system. RESULTS: We argue that numerous methods can be used to study axonal and demyelinating aspects of the disease. Although optical coherence tomography and static visual functions better reflect the axonal aspects of the disease, conduction velocity as measured by visual-evoked potential latencies and dynamic visual function mirrors myelin levels. We also posit that the classic disease load parameters cannot be the only means by which we assess a patient's condition. Novel imaging methods such as diffusion tensor imaging and functional magnetic resonance imaging can be used to assess the global effects of local damage on neighboring white matter and compensatory abilities of the brain. CONCLUSIONS: There have been great advances in therapeutic research in MS. However, the stratification of patients according to their prognosis and predictive outcomes in response to treatment is still in its infancy. The many facets of MS make it difficult to piece all the data together into one cohesive conclusion for the individual patient. The visual system, with our ability to assess both structure and function, offers a promising opportunity to study both pathophysiologic mechanisms and novel therapies. DOI: 10.1097/WNO.0000000000000634 PMID: 29438265
209. J Neuroophthalmol. 2018 Mar;38(1):81-84. doi: 10.1097/WNO.0000000000000631. Multiple Sclerosis: Eyes on the Future. Costello FE(1), Burton JM. Author information: (1)Departments of Clinical Neurosciences (FC, JMB), Surgery (FC), and Community Health Sciences (JMB), University of Calgary, Calgary, Alberta, Canada. DOI: 10.1097/WNO.0000000000000631 PMID: 29438264
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210. J Neuroophthalmol. 2018 Jan 29. doi: 10.1097/WNO.0000000000000629. [Epub ahead of print] Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis. Nolan RC(1), Galetta SL, Frohman TC, Frohman EM, Calabresi PA, Castrillo-Viguera C, Cadavid D, Balcer LJ. Author information: (1)Departments of Neurology (RCN, SLG, and LJB), Population Health (LJB), and Ophthalmology (SLG and LJB), New York University School of Medicine, New York, New York; Department of Neurology (TCF and EMF), Dell Medical School at University of Texas Austin, Austin, Texas; Department of Neurology (PAC), Johns Hopkins University School of Medicine, Baltimore, Maryland; Clinical Development Department (CCV), Biogen, Cambridge, Massachusetts; and Clinical Development Group (DC), Fulcrum Therapeutics, Cambridge, Massachusetts. BACKGROUND: The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion. METHODS: We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360°) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined. RESULTS: Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 μm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6-μm threshold value in a 2 × 2 table analysis with the application of χ tests (P < 0.0001). The 6-μm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 μm for identifying unilateral ON in the MS cohort. CONCLUSIONS: An intereye difference of 5-6 μm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS. DOI: 10.1097/WNO.0000000000000629 PMID: 29384802
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211. J Neuropathol Exp Neurol. 2018 Feb 10. doi: 10.1093/jnen/nly011. [Epub ahead of print] Early Nodal and Paranodal Disruption in Autoimmune Optic Neuritis. Stojic A(1), Bojcevski J(1), Williams SK(1), Diem R(1), Fairless R(1). Author information: (1)Department of Neurology, University Clinic Heidelberg, Heidelberg, Germany. Disturbances in the nodes of Ranvier are an early phenomenon in many CNS disorders, including the autoimmune demyelinating disease multiple sclerosis (MS). Using an animal model of optic neuritis, a common early symptom of MS, we have investigated nodal and paranodal compartments in the optic nerve during disease progression. Both nodes and paranodes, as identified by immunohistochemistry against sodium channels (Nav) and Caspr, respectively, were observed to increase in length during the late induction phase of the disease, prior to onset of the demyelination and immune cell infiltration characteristic of optic neuritis. These changes were correlated with both axonal stress and microglial/macrophage activation, and were most apparent in the vicinity of the retrobulbar optic nerve head, the unmyelinated region of the optic nerve where retinal ganglion cell axons exit the retina. Using intravitreal glutamate injection as a model of a primary retinal insult, we demonstrate that this can induce similar nodal and paranodal changes. This may suggest that onset of neurodegeneration in the absence of demyelination, as reported in several studies into the nonaffected eyes of MS patients, may give rise to subtle disturbances in the axo-glial junction. © 2018 American Association of Neuropathologists, Inc. All rights reserved. DOI: 10.1093/jnen/nly011 PMID: 29444299
212. J Neurosci Res. 2018 Feb 15. doi: 10.1002/jnr.24224. [Epub ahead of print] Animal models of multiple sclerosis: Focus on experimental autoimmune encephalomyelitis. Bjelobaba I(1), Begovic-Kupresanin V(2), Pekovic S(1), Lavrnja I(1). Author information: (1)Institute for Biological Research "Sinisa Stankovic," Department of Neurobiology, University of Belgrade, Belgrade, Serbia. (2)Clinic for Infectious and Tropic Diseases, Military Medical Academy, Belgrade, Serbia. Multiple sclerosis (MS) is a chronic, progressive disorder of the central nervous system (CNS) that affects more than two million people worldwide. Several animal models resemble MS pathology; the most employed are experimental autoimmune encephalomyelitis (EAE) and toxin- and/or virus- induced demyelination. In this review we will summarize our knowledge on the utility of different animal models in MS research. Although animal models cannot replicate the complexity and heterogeneity of the MS pathology, they have proved to be useful for the development of several drugs approved for treatment of MS patients. This review focuses on EAE because it represents both clinical and pathological features of MS. During the past decades, EAE has been effective in illuminating various pathological processes that occur during MS, including inflammation, CNS penetration, demyelination, axonopathy, and neuron loss mediated by immune cells. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/jnr.24224 PMID: 29446144
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213. J Neurosurg. 2018 Feb 23:1-12. doi: 10.3171/2017.8.JNS17749. [Epub ahead of print] Stereotactic radiosurgery for tremor: systematic review. Martínez-Moreno NE(1), Sahgal A(2), De Salles A(3), Hayashi M(4), Levivier M(5), Ma L(6), Paddick I(7), Régis J(8), Ryu S(9), Slotman BJ(10), Martínez-Álvarez R(1). Author information: (1)Department of Radiosurgery and Functional Neurosurgery, Ruber International Hospital, Madrid, Spain. (2)Department of Radiation Oncology, University of Toronto, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada. (3)Department of Neurosurgery, University of California, Los Angeles, California. (4)Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan. (5)Neurosurgery Service and Gamma Knife Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. (6)Division of Physics, Department of Radiation Oncology, University of California, San Francisco, California. (7)Division of Physics, National Hospital for Neurology and Neurosurgery, London, United Kingdom. (8)Department of Functional Neurosurgery, Timone University Hospital, Aix-Marseille University, Marseille, France. (9)Department of Radiation Oncology, Stony Brook University, Stony Brook, New York; and. (10)Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands. OBJECTIVE The aim of this systematic review is to offer an objective summary of the published literature relating to stereotactic radiosurgery (SRS) for tremor and consensus guideline recommendations. METHODS This systematic review was performed up to December 2016. Article selection was performed by searching the MEDLINE (PubMed) and EMBASE electronic bibliographic databases. The following key words were used: "radiosurgery" and "tremor" or "Parkinson's disease" or "multiple sclerosis" or "essential tremor" or "thalamotomy" or "pallidotomy." The search strategy was not limited by study design but only included key words in the English language, so at least the abstract had to be in English. RESULTS A total of 34 full-text articles were included in the analysis. Three studies were prospective studies, 1 was a retrospective comparative study, and the remaining 30 were retrospective studies. The one retrospective comparative study evaluating deep brain stimulation (DBS), radiofrequency thermocoagulation (RFT), and SRS reported similar tremor control rates, more permanent complications after DBS and RFT, more recurrence after RFT, and a longer latency period to clinical response with SRS. Similar tremor reduction rates in most of the reports were observed with SRS thalamotomy (mean 88%). Clinical complications were rare and usually not permanent (range 0%-100%, mean 17%, median 2%). Follow-up in general was too short to confirm long-term results. CONCLUSIONS SRS to the unilateral thalamic ventral intermediate nucleus, with a dose of 130-150 Gy, is a well-tolerated and effective treatment for reducing medically refractory tremor, and one that is recommended by the International Stereotactic Radiosurgery Society. DOI: 10.3171/2017.8.JNS17749 PMID: 29473775
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214. J Pharmacol Sci. 2018 Feb 2. pii: S1347-8613(18)30004-5. doi: 10.1016/j.jphs.2018.01.001. [Epub ahead of print] LPA5 signaling is involved in multiple sclerosis-mediated neuropathic pain in the cuprizone mouse model. Tsukahara R(1), Yamamoto S(2), Yoshikawa K(2), Gotoh M(3), Tsukahara T(1), Neyama H(1), Ishii S(4), Akahoshi N(4), Yanagida K(5), Sumida H(5), Araki M(6), Araki K(6), Yamamura KI(6), Murakami- Murofushi K(7), Ueda H(8). Author information: (1)Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. (2)Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Saitama, Japan. (3)Endowed Research Division of Human Welfare Sciences, Ochanomizu University, Tokyo, Japan; Institute for Human Life Innovation, Ochanomizu University, Tokyo, Japan. (4)Department of Immunology, Akita University Graduate School of Medicine, Akita, Japan. (5)Department of Biochemistry and Molecular Biology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. (6)Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan. (7)Endowed Research Division of Human Welfare Sciences, Ochanomizu University, Tokyo, Japan. (8)Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: [email protected]. Lysophosphatidic acid (LPA) and LPA1 receptor signaling play a crucial role in the initiation of peripheral nerve injury-induced neuropathic pain through the alternation of pain-related genes/proteins expression and demyelination. However, LPA and its signaling in the brain are still poorly understood. In the present study, we revealed that the LPA5 receptor expression in corpus callosum elevated after the initiation of demyelination, and the hyperalgesia through Aδ-fibers following cuprizone-induced demyelination was mediated by LPA5 signaling. These data suggest that LPA5 signaling may play a key role in the mechanisms underlying neuropathic pain following demyelination in the brain. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved. DOI: 10.1016/j.jphs.2018.01.001 PMID: 29409686
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215. J Psychosom Res. 2018 Mar;106:13-24. doi: 10.1016/j.jpsychores.2017.12.014. Epub 2017 Dec 28. Cognitive behavioural therapy for MS-related fatigue explained: A longitudinal mediation analysis. van den Akker LE(1), Beckerman H(2), Collette EH(3), Knoop H(4), Bleijenberg G(5), Twisk JW(6), Dekker J(7), de Groot V(2); TREFAMS-ACE study group. Author information: (1)Department of Rehabilitation Medicine, VU University Medical Center, Amsterdam, The Netherlands; EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands; MS Center Amsterdam, Amsterdam, The Netherlands. Electronic address: [email protected]. (2)Department of Rehabilitation Medicine, VU University Medical Center, Amsterdam, The Netherlands; EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands; MS Center Amsterdam, Amsterdam, The Netherlands. (3)Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands. (4)Expert Centre for Chronic Fatigue, Radboud University Medical Centre, Nijmegen, The Netherlands; Department of Medical Psychology, Academic Medical Centre (AMC), University of Amsterdam, Amsterdam, The Netherlands. (5)Expert Centre for Chronic Fatigue, Radboud University Medical Centre, Nijmegen, The Netherlands. (6)EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands; Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. (7)Department of Rehabilitation Medicine, VU University Medical Center, Amsterdam, The Netherlands; Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands. BACKGROUND: Cognitive behavioural therapy (CBT) effectively reduces fatigue directly following treatment in patients with Multiple Sclerosis (MS), but little is known about the process of change during and after CBT. DESIGN: Additional analysis of a randomized clinical trial. OBJECTIVE: To investigate which psychological factors mediate change in fatigue during and after CBT. METHODS: TREFAMS-CBT studied the effectiveness of a 16-week CBT treatment for MS-related fatigue. Ninety- one patients were randomized (44 to CBT, 47 to the MS-nurse consultations). Mediation during CBT treatment was studied using assessments at baseline, 8 and 16weeks. Mediation of the change in fatigue from post-treatment to follow-up was studied separately using assessments at 16, 26 and 52weeks. Proposed mediators were: changes in illness cognitions, general self-efficacy, coping styles, daytime sleepiness, concentration and physical activity, fear of disease progression, fatigue perceptions, depression and physical functioning. Mediators were separately analysed according to the product-of-coefficients approach. Confidence intervals were calculated with a bootstrap procedure. RESULTS: During treatment the decrease in fatigue brought on by CBT was mediated by improved fatigue perceptions, increased physical activity, less sleepiness, less helplessness, and improved physical functioning. Post-treatment increases in fatigue levels were mediated by reduced physical activity, reduced concentration, and increased sleepiness. CONCLUSION: These results suggests that focusing on improving fatigue perceptions, perceived physical activity, daytime sleepiness, helplessness, and physical functioning may further improve the effectiveness of CBT for fatigue in patients with MS. Maintenance of treatment effects may be obtained by focusing on improving physical activity, concentration and sleepiness. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.jpsychores.2017.12.014 PMID: 29455894
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216. J Steroid Biochem Mol Biol. 2018 Feb 12. pii: S0960-0760(18)30079-7. doi: 10.1016/j.jsbmb.2018.02.005. [Epub ahead of print] Estrogen serum concentration affects blood immune cell composition and polarization in human females under controlled ovarian stimulation. Habib P(1), Dreymueller D(2), Rösing B(3), Botung H(4), Slowik A(4), Zendedel A(4), Habib S(5), Hoffmann S(6), Beyer C(7). Author information: (1)Department of Neurology, Institute of Neuroanatomy, Medical Clinic, RWTH Aachen University, 52074 Aachen, Germany. (2)Institute of Pharmacology and Toxicology, Medical Clinic, RWTH Aachen University, 52074 Aachen, Germany. (3)Clinic for Gynecological Endocrinology and Reproductive Medicine, RWTH Aachen University Clinics, 52074 Aachen, Germany. (4)Institute of Neuroanatomy, Medical Clinic, RWTH Aachen University, 52074 Aachen, Germany. (5)Medical Biochemistry, Department of Biochemistry, University of Leicester, Leicester, United Kingdom. (6)Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Clinic, RWTH Aachen University, 52074 Aachen, Germany. (7)Institute of Neuroanatomy, Medical Clinic, RWTH Aachen University, 52074 Aachen, Germany. Electronic address: [email protected]. Estrogens modulate the immune system and possess anti-inflammatory properties. In line, immune cells express a variety of estrogen receptors (ER) including ER-alpha and -beta. In the present study, we examined the influence of 17beta-estradiol (E2) serum concentrations on blood leukocyte composition and their ex vivo polarization/activation status by FACS analysis in sub-fertile human females under controlled ovarian stimulation (COS). Using a set of cell-type and polarization-specific markers, we demonstrate that increased 17ß-estradiol (E2) serum concentrations yield an overall increase in leukocytes, neutrophils and monocytes but decreased lymphocytes. There was a clear ratio shift towards an increase in M2 monocytes with a protective quality and an increase in T-helper cells compared to a decrease in cytotoxic T-cells. These data support experimental findings and clinical trials, i.e. related to multiple sclerosis and other autoimmune-related diseases, that have shown a down-regulation of CD8(+) T cells and up-regulation of T-regulatory cells. Further studies have to pinpoint to which extent the immune system/-responsiveness of otherwise healthy female patients is affected by medium-term systemic E2 variations. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.jsbmb.2018.02.005 PMID: 29448043
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217. JAMA Dermatol. 2018 Feb 16. doi: 10.1001/jamadermatol.2017.5799. [Epub ahead of print] Association Between Pemphigus and Neurologic Diseases. Kridin K(1), Zelber-Sagi S(2), Comaneshter D(3), Cohen AD(3)(4). Author information: (1)Department of Dermatology, Rambam Health Care Campus, Haifa, Israel. (2)School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel. (3)Department of Quality Measurements and Research, Chief Physician's Office, Clalit Health Services, Tel Aviv, Israel. (4)Siaal Research Center for Family Medicine and Primary Care, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheeva, Israel. Importance: The association between pemphigus and neurologic diseases was not evaluated systematically in the past. In a recent uncontrolled cross-sectional study, Parkinson disease was found to be significantly associated with pemphigus; in the same study, epilepsy had a nonsignificant association with pemphigus. Several case reports have suggested that pemphigus coexists with multiple sclerosis and dementia. Objective: To estimate the association between pemphigus and 4 neurologic conditions (dementia, epilepsy, Parkinson disease, and multiple sclerosis), using one of the largest cohorts of patients with pemphigus. Design, Setting, and Participants: A retrospective population-based cross-sectional study was performed between January 1, 2004, and December 31, 2014, using the database of Clalit Health Services, the largest public health care organization in Israel, in the setting of general community clinics, primary care and referral centers, and ambulatory and hospitalized care. A total of 1985 patients with a new diagnosis of pemphigus and 9874 controls were included in the study. Main Outcomes and Measures: The proportion of dementia, epilepsy, Parkinson disease, and multiple sclerosis was compared between patients diagnosed with pemphigus and age-, sex-, and ethnicity-matched control participants. Logistic regression was used to calculate odds ratios (ORs) for dementia, epilepsy, Parkinson disease, and multiple sclerosis. The association was examined after a sensitivity analysis that included only patients treated with long-term, pemphigus- specific medications (corticosteroids, immunosuppressants, or rituximab) and after adjustment for several confounding factors. Results: When comparing the 1985 cases (1188 women and 797 men; mean [SD] age, 72.1 [18.5] years) with the 9874 controls (5912 women and 3962 men; mean [SD] age, 72.1 [18.5] years), dementia was seen in 622 cases (31.3%) vs 1856 controls (18.8%), with an OR of 1.97 (95% CI, 1.77-2.20). Epilepsy was present in 74 cases (3.7%) vs 210 controls (2.1%), with an OR of 1.78 (95% CI, 1.36-2.33). Parkinson disease was seen in 175 cases (8.8%) vs 437 controls (4.4%), with an OR of 2.09 (95% CI, 1.74-2.51). Multiple sclerosis was present in 2 cases (0.1%) vs 6 controls (0.01%), with an OR of 1.65 (95% CI, 0.34-8.22). Study findings were robust to sensitivity analysis that included patients receiving pemphigus-specific treatments. Estimates were not altered significantly after controlling for comorbidities and overuse of health care. Conclusions and Relevance: An association was observed between pemphigus and specific neurologic diseases, including dementia, Parkinson disease, and epilepsy. Physicians treating patients with pemphigus should be aware of this possible association. Patients with pemphigus should be carefully assessed for comorbid neurologic disorders and receive appropriate treatment. DOI: 10.1001/jamadermatol.2017.5799 PMID: 29453873
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218. JAMA Neurol. 2018 Feb 5. doi: 10.1001/jamaneurol.2017.4842. [Epub ahead of print] Differences in the Reponses to Apheresis Therapy of Patients With 3 Histopathologically Classified Immunopathological Patterns of Multiple Sclerosis. Stork L(1), Ellenberger D(2), Beißbarth T(2), Friede T(2), Lucchinetti CF(3), Brück W(1), Metz I(1). Author information: (1)Institute of Neuropathology, University Medical Center Goettingen, Goettingen, Germany. (2)Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany. (3)Department of Neurology, Mayo Clinic, Rochester, Minnesota. Importance: Plasma exchange and immunoadsorption are second-line apheresis therapies for patients experiencing multiple sclerosis relapses. Early active multiple sclerosis lesions can be classified into different histopathological patterns of demyelination. Pattern 1 and 2 lesions show T-cell- and macrophage-associated demyelination, and pattern 2 is selectively associated with immunoglobulin and complement deposits, suggesting a humoral immune response. Pattern 3 lesions show signs of oligodendrocyte degeneration. Thus it is possible that pathogenic heterogeneity might predict therapy response. Objective: To evaluate the apheresis response in relation to histopathologically defined immunopathological patterns of multiple sclerosis. Design, Setting and Participants: This single-center cohort study recruited 69 patients nationwide between 2005 and 2016. All included patients had a diagnosis of early active inflammatory demyelination consistent with multiple sclerosis; were classified into patterns 1, 2, or 3 based on brain biopsy analysis; and underwent apheresis treatments. Patients who had concomitant severe disease, neuromyelitis optica, or acute disseminated encephalomyelitis were excluded. Main Outcomes and Measures: The primary therapy outcome was a functionally relevant improvement of the relapse-related neurological deficit. Radiological and Expanded Disability Status Scale changes were secondary outcome parameters. Results: The mean (SD) age of patients was 36.6 (13.3) years; 46 of the 69 participants (67%) were female. Overall, 16 patients (23%) exhibited pattern 1 lesions, 40 (58%) had pattern 2 lesions, and 13 (19%) had pattern 3 lesions. A functional therapy response was observed in 5 of the 16 patients with pattern 1 disease (31%) and 22 of the 40 patients with pattern 2 disease (55%), but none of the 13 patients with pattern 3 disease exhibited improvement (pattern 2 vs 3 P < .001). Radiological improvements were found in 4 (25%), 22 (56%), and 1 (11%) of patients with patterns 1, 2, and 3, respectively. The respective rates of response measured by changes in Expanded Disability Status Scale scores were 25%, 40%, and 0%. Brainstem involvement was a negative predictive factor for the functional therapy response (logarithmic odds ratio [logOR], -1.43; 95% CI, -3.21 to 0.17; P = .03), while immunoadsorption (as compared with plasma exchange) might be a positive predictive factor (logOR, 3.26; 95% CI, 0.75 to 8.13; P = .01). Conclusions and Relevance: This cohort study provides evidence that the response to apheresis treatment is associated with immunopathological patterns. Patients with both patterns 1 and 2 improved clinically after apheresis treatment, but pattern 2 patients who showed signs of a humoral immune response benefited most. Apheresis appears unlikely to benefit patients with pattern 3 lesions. DOI: 10.1001/jamaneurol.2017.4842 PMID: 29404583
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219. JAMA Neurol. 2018 Feb 5. doi: 10.1001/jamaneurol.2017.4850. [Epub ahead of print] Tissue Markers for Acute Multiple Sclerosis Treatment Response-A Step Toward Personalized Medicine. Fox RJ(1). Author information: (1)Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, Ohio. DOI: 10.1001/jamaneurol.2017.4850 PMID: 29404560
220. JAMA Ophthalmol. 2018 Feb 22. doi: 10.1001/jamaophthalmol.2017.6757. [Epub ahead of print] Prevalence of Myelin Oligodendrocyte Glycoprotein and Aquaporin-4-IgG in Patients in the Optic Neuritis Treatment Trial. Chen JJ(1)(2), Tobin WO(2), Majed M(3), Jitprapaikulsan J(3), Fryer JP(3), Leavitt JA(1), Flanagan EP(2), McKeon A(2)(3), Pittock SJ(2)(3). Author information: (1)Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota. (2)Department of Neurology, Mayo Clinic, Rochester, Minnesota. (3)Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Importance: Autoantibodies to aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) are recently established biomarkers of autoimmune optic neuritis whose frequency and accompanying phenotype, especially for MOG-IgG, are still being characterized. The Optic Neuritis Treatment Trial (ONTT) was a well-known randomized clinical trial in optic neuritis; therefore, knowledge of the serostatus and accompanying phenotype of these patients would be useful to determine the frequency of these antibodies in patients presenting with typical monocular optic neuritis and their outcomes. Objectives: To determine the AQP4-IgG and MOG-IgG serostatus of patients within the ONTT and describe the clinical features of seropositive patients. Design, Setting, and Participants: In this follow- up study of the randomized clinical trial, ONTT, conducted between July 1, 1988, and June 30, 1991, analysis of serum for AQP4-IgG and MOG-IgG was performed from January 1 to April 30, 2017. A total of 177 patients from the ONTT with acute optic neuritis and serum available for analysis were enrolled from 13 academic referral centers. Interventions: Analysis of serum for AQP4-IgG and MOG- IgG was performed at Mayo Clinic Neuroimmunology Laboratory in 2017 with a flow cytometry, live cell, AQP4- and MOG-transfected cell-based assay. Main Outcomes and Measures: Aquaporin-4-IgG and MOG-IgG serostatus. Results: Of the 177 patients in the study (135 women and 42 men; mean [SD] age, 32.8 [6.9] years), 3 were positive for MOG-IgG (1.7%) and none were positive for AQP4- IgG. All 3 patients positive for MOG-IgG had disc edema at presentation. Two patients later had a single episode of recurrent optic neuritis. All 3 patients had complete recovery of visual acuity, and none were corticosteroid dependent, although peripheral visual field loss persisted in 1 patient. None of the 3 patients positive for MOG-IgG had demyelinating lesions on magnetic resonance imaging scans, and none had developed multiple sclerosis at the 15-year follow-up. Conclusions and Relevance: Frequency of MOG-IgG was rare in the ONTT, and AQP4-IgG was not found in patients in the ONTT. Characteristics of patients positive for MOG-IgG in the ONTT support the previously described phenotype of MOG-IgG optic neuritis. Myelin oligodendrocyte glycoprotein-related disease appears to be a different entity than multiple sclerosis. Overall, AQP4-IgG and MOG-IgG may be less common in isolated optic neuritis than previously reported. DOI: 10.1001/jamaophthalmol.2017.6757 PMID: 29470571
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221. JMIR Mhealth Uhealth. 2018 Feb 9;6(2):e37. doi: 10.2196/mhealth.8996. Exploring the Specific Needs of Persons with Multiple Sclerosis for mHealth Solutions for Physical Activity: Mixed-Methods Study. Giunti G(1)(2), Kool J(3), Rivera Romero O(4), Dorronzoro Zubiete E(4). Author information: (1)Salumedia Tecnologias, Seville, Spain. (2)University of Oulu, Oulu, Finland. (3)Kliniken Valens, Valens, Switzerland. (4)Universidad de Sevilla, Seville, Spain. BACKGROUND: Multiple sclerosis (MS) is one of the world's most common neurologic disorders, with symptoms such as fatigue, cognitive problems, and issues with mobility. Evidence suggests that physical activity (PA) helps people with MS reduce fatigue and improve quality of life. The use of mobile technologies for health has grown in recent years with little involvement from relevant stakeholders. User-centered design (UCD) is a design philosophy with the goal of creating solutions specific to the needs and tasks of the intended users. UCD involves stakeholders early and often in the design process. In a preliminary study, we assessed the landscape of commercially available MS mobile health (mHealth) apps; to our knowledge, no study has explored what persons with MS and their formal care providers think of mHealth solutions for PA. OBJECTIVE: The aim of this study was to (1) explore MS-specific needs for MS mHealth solutions for PA, (2) detect perceived obstacles and facilitators for mHealth solutions from persons with MS and health care professionals, and (3) understand the motivational aspects behind adoption of mHealth solutions for MS. METHODS: A mixed-methods design study was conducted in Kliniken Valens, Switzerland, a clinic specializing in neurological rehabilitation. We explored persons with MS and health care professionals who work with them separately. The study had a qualitative part comprising focus groups and interviews, and a quantitative part with standardized tools such as satisfaction with life scale and electronic health (eHealth) literacy. RESULTS: A total of 12 persons with relapsing-remitting MS and 12 health care professionals from different backgrounds participated in the study. Participants were well-educated with an even distribution between genders. Themes identified during analysis were MS-related barriers and facilitators, mHealth design considerations, and general motivational aspects. The insights generated were used to create MS personas for design purposes. Desired mHealth features were as follows: (1) activity tracking, (2) incentives for completing tasks and objectives, (3) customizable goal setting, (4) optional sociability, and (5) game-like attitude among others. Potential barriers to mHealth apps adoption were as follows: (1) rough on-boarding experiences, (2) lack of clear use benefits, and (3) disruption of the health care provider-patient relationship. Potential facilitators were identified: (1) endorsements from experts, (2) playfulness, and (3) tailored to specific persons with MS needs. A total of 4 MS personas were developed to provide designers and computer scientists means to help in the creation of future mHealth solutions for MS. CONCLUSIONS: mHealth solutions for increasing PA in persons with MS hold promise. Allowing for realistic goal setting and positive feedback, while minimizing usability burdens, seems to be critical for the adoption of such apps. Fatigue management is especially important in this population; more attention should be brought to this area. DOI: 10.2196/mhealth.8996 PMID: 29426814
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222. Klin Monbl Augenheilkd. 2018 Feb 16. doi: 10.1055/s-0043-124756. [Epub ahead of print] Efficacy of Natalizumab in Intermediate Uveitis Related to Multiple Sclerosis: A Case Report. Roemer S(1), Bissig A(1), Rocca A(2), Du Pasquier R(3), Guex-Crosier Y(1). Author information: (1)Department of Ophthalmology, Jules Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland. (2)Department of Clinical Neurosciences, Neurosurgery Unit, University Hospital CHUV, Lausanne, Switzerland. (3)Laboratory of Neuroimmunology, Service of Neurology, Department of Clinical Neurosciences, University of Lausanne, CHUV, Lausanne, Switzerland. DOI: 10.1055/s-0043-124756 PMID: 29452449
Conflict of interest statement: The authors declare no conflict of interest.
223. Lab Anim. 2018 Jan 1:23677218756156. doi: 10.1177/0023677218756156. [Epub ahead of print] Differential anxiety-like responses in NOD/ShiLtJ and C57BL/6J mice following experimental autoimmune encephalomyelitis induction and oral gavage. Kocovski P(1)(2), Dang PT(2), D'Souza CS(2), Stamper CE(3), Hale MW(1), Orian JM(2). Author information: (1)1 School of Psychology and Public Health, La Trobe University, Australia. (2)2 Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Australia. (3)3 Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, USA. Oral gavage is commonly used in pre-clinical drug evaluation, but is potentially aversive and may induce behavioral effects independent of compounds under investigation. This study examined the combined effects of repeated oral gavage and disease induction on anxiety-like behavior in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. The C57BL/6J and NOD/ShiLtJ EAE variants were exposed to sham-EAE induction or untreated control conditions, and either daily oral gavage or home cage conditions. Anxiety-like behavior was subsequently assessed in the elevated plus maze. C57BL/6J mice exhibited increased anxiety-like behavior, relative to NOD/ShiLtJ mice, in response to repeated gavage, whereas sham-EAE induction and repeated gavage were associated with increased anxiety-like behavior in NOD/ShiLtJ mice. Thus, exposure to the induction procedure and repeated gavage differentially altered subsequent anxiety-like behavior in the two EAE variants. Future pre-clinical studies should rely on prior evaluation of parameters of the experimental design using sham-EAE mice. Additionally, less aversive administration routes should be utilized wherever possible to ensure that procedures do not distort effects of the therapeutic under investigation. DOI: 10.1177/0023677218756156 PMID: 29444620
224. Lancet Neurol. 2018 Feb;17(2):118. doi: 10.1016/S1474-4422(17)30463-5. Evolving diagnostic criteria for multiple sclerosis. Chataway J. DOI: 10.1016/S1474-4422(17)30463-5 PMID: 29413308
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225. Matrix Biol. 2018 Jan 31. pii: S0945-053X(17)30410-9. doi: 10.1016/j.matbio.2018.01.015. [Epub ahead of print] Role of proteoglycans in neuro-inflammation and central nervous system fibrosis. Heindryckx F(1), Li JP(2). Author information: (1)Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. Electronic address: [email protected]. (2)Department of Medical Biochemistry and Microbiology/SciLifeLab, Uppsala University, Uppsala, Sweden. Fibrosis is defined as the thickening and scarring of connective tissue, usually as a consequence of tissue damage. The central nervous system (CNS) is special in the sense that fibrogenic cells are restricted to vascular and meningeal areas. Inflammation and the disruption of the blood-brain barrier can lead to the infiltration of fibroblasts and trigger fibrotic response. While the initial function of the fibrotic tissue is to restore the blood-brain barrier and to limit the site of injury, it also demolishes the structure of extracellular matrix and impedes the healing process by producing inhibitory molecules and forming a physical and biochemical barrier that prevents axon regeneration. As a major constituent in the extracellular matrix, proteoglycans participate in the neuro-inflammation, modulating the fibrotic process. In this review, we will discuss the pathophysiology of fibrosis during acute injuries of the CNS, as well as during chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and age-related neurodegeneration with focus on the functional roles of proteoglycans. Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.matbio.2018.01.015 PMID: 29382609
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226. Med Arch. 2018 Feb;72(1):58-61. doi: 10.5455/medarh.2017.72.58-61. Analysis of Vitamin D Receptor Polymorphisms in Patients with Familial Multiple Sclerosis. Yucel FE(1), Kamıslı O(1), Acar C(2), Sozen M(2), Tecellioğlu M(1), Ozcan C(1). Author information: (1)Inonu University, School of Medicine, Department of Neurology Malatya, Turkey. (2)Inonu University, Department of Molecular Biology and Genetics Malatya, Turkey. Objective: Genetic and environmental factors are important in the development of the multiple sclerosis (MS). Vitamin D shows its effects on the immune system with the vitamin D receptor (VDR) in the nucleus. Single nucleotide polymorphisms (SNPs) in the VDR gene can lead to alterations in vitamin D functions and metabolism.Taq I, Apa I, Fok I and Bsm I polymorphisms and MS associations have been investigated in many studies. VDR gene polymorphism has not been previously studied in patients with familial MS. Aim: We aimed to investigate the relationship between familial MS patients present in Turkish population and VDR genotypes Taq I, Apa I and Fok I polymorphisms. Methods: 29 patients with a family history of MS and 120 healthy control subjects were included in the present study. We studied present VDR genotypes Taq I, Apa I and Fok I polymorphisms. Results: We observed a significant difference between controls and patient group only in Taq I polymorphism (p: 0.025). Homozygousity of G allele was not seen in the patients whereas in controls frequency of that genotype was p:0.208. When gender was considered males show significant difference for GG genotype. There were no significant association for the Apa I and Fok I polymorphisms. Conclusion: Although our findings suggest association between VDR Taq I polymorphism and the familial MS, additional studies are needed to establish detailed relationships. DOI: 10.5455/medarh.2017.72.58-61 PMCID: PMC5789553 PMID: 29416220
227. Med Chem. 2018 Feb 6;14(2):104-105. doi: 10.2174/157340641402180206092504. Editorial: Multiple Sclerosis: Pathogenesis and Therapeutics. Katsara M(1), Apostolopoulos V(2). Author information: (1)Novartis (Hellas) SACI, Medical Department, National Road No1 (12th Km). GR-144 51, Metamorphosis-Athens, Greece. (2)Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Werribee Campus, VIC 3030, Australia. DOI: 10.2174/157340641402180206092504 PMID: 29453907
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228. Med J Islam Repub Iran. 2017 Aug 2;31:43. doi: 10.14196/mjiri.31.43. eCollection 2017. Catastrophic health expenditure among households with members with special diseases: A case study in Kurdistan. Moradi G(1), Safari H(2), Piroozi B(1), Qanbari L(3), Farshadi S(4), Qasri H(5), Farhadifar F(1). Author information: (1)Social Determinants of Health Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran. (2)Department of Health Management and Economics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. (3)Special Disease Department, Deputy of Treatment, Kurdistan University of Medical Sciences, Sanandaj, Iran. (4)Health Economics Department, Deputy of Treatment, Kurdistan University of Medical Sciences, Sanandaj, Iran. (5)Deputy of Treatment, Kurdistan University of Medical Sciences, Sanandaj, Iran. Background: One of the main goals of health systems is to protect people against financial risks associated with diseases that can be catastrophic for patients. In 2014, Health Sector Evolution Plan (HSEP) was implemented in Iran; one of the objectives of HSEP was to reduce out-of-pocket payments and provide more financial protection for people. Therefore, the present study aimed at exploring the likelihood of facing catastrophic health expenditures (CHE) among households with members suffering from dialysis, kidney transplant, or multiple sclerosis (MS) after the implementation of HSEP. Methods: A total number of 385 households were selected using stratified random sampling and were asked to complete the World Health Survey questionnaire through telephone conversations. As outlined by the World Health Organization (WHO), when household out-of-pocket expense for health services is ≥40% of its capacity to pay, then that household is considered to be facing CHE. Furthermore, determinants of CHE were identified using logistic regression. Results: The percentage of facing catastrophic health care expenditures for households with a MS, dialysis, and kidney transplant patient was 20.6%, 18.7%, and 13.8%, respectively. Results of logistic regression analysis revealed that patient's economic status, level of education, supplementary insurance status, type of disease, multiple members with special diseases in the household, rural residence, use of inpatient, dental, and rehabilitation services were effective factors for determining the likelihood of facing CHE. Conclusion: Despite the implementation of HSEP, the percentage of CHE is still high for households that have members who suffer from special diseases. However, basic health insurance packages should be amended and more cost-sharing exemptions should be granted to provide more financial protection for the vulnerable households. DOI: 10.14196/mjiri.31.43 PMCID: PMC5804459 PMID: 29445672
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229. Medicina (Kaunas). 2018 Feb 3. pii: S1010-660X(18)30006-5. doi: 10.1016/j.medici.2018.01.003. [Epub ahead of print] Characteristics of headache in relation to the manifestation of Susac syndrome. Obelienienė D(1), Macaitytė R(2), Balnytė R(2), Pėstininkaitė R(2), Gleiznienė R(3), Balčiūnienė J(4). Author information: (1)Department of Neurology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania. Electronic address: [email protected]. (2)Department of Neurology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania. (3)Department of Radiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania. (4)Department of Ophthalmology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania. Susac syndrome is characterized by a clinical triad of encephalopathy, branch retinal artery occlusion, and hearing loss. Due to the absence of the whole complex of the triad in the majority of cases at disease presentation, the syndrome often remains underdiagnosed and untreated. Headache is estimated to affect up to 80% of Susac syndrome patients, but the relevance of headache characteristics and profile is not yet clear. The proposed diagnostic criteria of the European Susac Consortium acknowledge headache as a possible brain manifestation if it is new, described as migrainous or oppressive, and precedes the other symptoms by not more than 6 months. Herein, a case series of different migraine-like headache associations attributed to Susac syndrome is presented and discussed in relevance with previously published literature. Our patients experienced different presentations of migraine-like headache related with Susac syndrome: exacerbation and chronification of headache just before the manifestation of the first symptoms of Susac syndrome, the manifestation of headache during the first episode of the syndrome, and an increasing frequency of headache during the course of the disease. The diagnosis of Susac syndrome in all three cases was confirmed by typical clinical symptoms and findings in retinal fluorescein angiography, audiometry, and brain magnetic resonance imaging, based on the diagnostic criteria of the European Susac Consortium. Based on the analysis of our presented cases, we conclude that headache attributed to Susac's syndrome is of migraine-like type but could be of different presentations in relation to the onset of the syndrome. Copyright © 2018 The Lithuanian University of Health Sciences. Production and hosting by Elsevier Sp. z o.o. All rights reserved. DOI: 10.1016/j.medici.2018.01.003 PMID: 29449066
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230. Medicine (Baltimore). 2018 Feb;97(8):e9908. doi: 10.1097/MD.0000000000009908. Efficacy of alemtuzumab and natalizumab in the treatment of different stages of multiple sclerosis patients. Wang L(1), Qi CH(2), Zhong R(3), Yuan C(2), Zhong QY(2). Author information: (1)Department of Pharmacy, Jining No.1 People's Hospital, Jining. (2)Department of Pharmacy, Weifang People's Hospital, Weifang. (3)Department of Neurology, Zhucheng People's Hospital, Zhucheng, P.R. China. BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease, in which the insulating covers of nerve cells in the brain and spinal cord are demyelinated. This study was conducted to compare the efficacy of alemtuzumab and natalizumab in the treatment of different stages of MS patients. METHODS: A total of 585 patients diagnosed with MS and hospitalized were included and analyzed after which they were divided into the primary progressive MS A and B groups, the relapsing-remitting MS (RRMS) C and D groups, and the secondary progressive MS E and F groups. Patients in A, C, and E groups were administered alemtuzumab while those in B, D, and F groups were administered natalizumab for the treatment. The expanded disability status scale (EDSS) scores and the EDSS difference were calculated before and after treatment. The number of head magnetic resonance imaging enhanced lesions in the patients, recurrence time and recurrence rate were measured before and after treatment. RESULTS: The EDSS score of the RRMS group was significantly lower than that of the primary progressive MS group and the secondary progressive MS group. After 12 months of treatment, the EDSS score of RRMS patients treated with natalizumab was significantly lower compared with the patients with alemtuzumab, and the difference before and after treatment was significantly higher than alemtuzumab. The recurrence rate of the RRMS-D group was significantly lower than the RRMS-C group. After 12 months of treatment, compared with the RRMS-C group, a significant reduction was observed in the number of head magnetic resonance imaging enhanced lesions and longer recurrence time in the RRMS-D group. CONCLUSION: The efficacy of natalizumab was better than alemtuzumab in the treatment of patients in the RRMS group, while there was no significant difference among other stages of MS patients, which provided the theoretical basis and clinical guidance for the treatment of different stages of MS. DOI: 10.1097/MD.0000000000009908 PMID: 29465579 [Indexed for MEDLINE]
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231. Met Ions Life Sci. 2018 Feb 5;18. pii: /books/9783110470734/9783110470734- 022/9783110470734-022.xml. doi: 10.1515/9783110470734-022. Copper Complexes in Cancer Therapy. Denoyer D, Clatworthy SAS, Cater MA. Copper homeostasis is tightly regulated in both prokaryotic and eukaryotic cells to ensure sufficient amounts for cuproprotein biosynthesis, while limiting oxidative stress production and toxicity. Over the last century, copper complexes have been developed as antimicrobials and for treating diseases involving copper dyshomeostasis (e.g., Wilson's disease). There now exists a repertoire of copper complexes that can regulate bodily copper through a myriad of mechanisms. Furthermore, many copper complexes are now being appraised for a variety of therapeutic indications (e.g., Alzheimer's disease and amyotrophic lateral sclerosis) that require a range of copper-related pharmacological affects. Cancer therapy is also drawing considerable attention since copper has been recognized as a limiting factor for multiple aspects of cancer progression including growth, angiogenesis, and metastasis. Consequently, 'old copper complexes' (e.g., tetrathiomolybdate and clioquinol) have been repurposed for cancer therapy and have demonstrated anticancer activity in vitro and in preclinical models. Likewise, new tailor-made copper complexes have been designed based on structural and biological features ideal for their anticancer activity. Human clinical trials continue to evaluate the therapeutic efficacy of copper complexes as anticancer agents and considerable progress has been made in understanding their pharmacological requirements. In this chapter, we present a historical perspective on the main copper complexes that are currently being repurposed for cancer therapy and detail several of the more recently developed compounds that have emerged as promising anticancer agents. We further provide an overview of the known mechanisms of action, including molecular targets and we discuss associated clinical trials. DOI: 10.1515/9783110470734-022 PMID: 29394035
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232. Metab Brain Dis. 2018 Feb 2. doi: 10.1007/s11011-017-0171-5. [Epub ahead of print] Fractional anisotropy of white matter, disability and blood iron parameters in multiple sclerosis. Herbert E(1), Engel-Hills P(2), Hattingh C(3), Fouche JP(4)(5), Kidd M(6), Lochner C(4), Kotze MJ(3), van Rensburg SJ(3). Author information: (1)Department of Medical Imaging and Therapeutic Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Cape Town, South Africa. [email protected]. (2)Department of Medical Imaging and Therapeutic Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Cape Town, South Africa. (3)Division of Chemical Pathology, Department of Pathology, National Health Laboratory Service (NHLS) and Stellenbosch University, Cape Town, South Africa. (4)MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch University, Cape Town, South Africa. (5)Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa. (6)Centre for Statistical Consultation, Stellenbosch University, Cape Town, South Africa. Multiple sclerosis (MS) is a disorder related to myelin damage, which can be investigated by neuroimaging techniques such as fractional anisotropy (FA), a measure of microstructural white matter properties. The objectives of this study were to investigate (1) the relationship between FA and disability using an extremes of outcome approach, and (2) whether blood iron parameters were associated with FA and/or disability. Patients diagnosed with MS (n = 107; 14 males and 93 females) had iron parameter tests and disability determinations using the Expanded Disability Status Scale (EDSS). FA was recorded in 48 white matter tracts in 11 of the female patients with MS and 12 female controls.RESULTS: In patients with high disability scores the mean FA was significantly lower (0.34 ± 0.067) than in the control group (0.45 ± 0.036; p = 0.04), while patients with low disability had mean FA values (0.44 ± 0.014) similar to controls (p = 0.5). Positive associations were found between FA and the iron parameters serum iron, ferritin and percentage transferrin saturation (%Tfsat) in all the white matter tracts. For % Tfsat, the associations were highly significant in 14 tracts (p < 0.01; r-values 0.74-0.84) and p < 0.001 (r = 0.83) in the superior fronto occipital fasciculus (LH). In the whole patient group a trend was found towards an inverse association between the EDSS and the %Tfsat (r = -0.26, p = 0.05) after excluding male gender and smoking as confounders, suggesting reduced disability in the presence of higher blood iron parameters. Additionally, significant inverse associations between disease duration and haemoglobin (p = 0.04) as well as %Tfsat (p = 0.02) suggested that patients with MS may experience a decrease in blood iron concentrations over time. DOI: 10.1007/s11011-017-0171-5 PMID: 29396631
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233. Mol Psychiatry. 2018 Feb 9. doi: 10.1038/s41380-017-0011-3. [Epub ahead of print] Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model. Pan H(1), Oliveira B(1), Saher G(2), Dere E(1), Tapken D(3), Mitjans M(1), Seidel J(1), Wesolowski J(1), Wakhloo D(1), Klein-Schmidt C(3), Ronnenberg A(1), Schwabe K(4), Trippe R(3), Mätz-Rensing K(5), Berghoff S(2), Al-Krinawe Y(4), Martens H(6), Begemann M(1), Stöcker W(7), Kaup FJ(5), Mischke R(8), Boretius S(9), Nave KA(2)(10), Krauss JK(4), Hollmann M(3), Lühder F(11), Ehrenreich H(12)(13). Author information: (1)Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. (2)Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany. (3)Department of Biochemistry I-Receptor Biochemistry, Ruhr University, Bochum, Germany. (4)Department of Neurosurgery, Hannover Medical School, Hannover, Germany. (5)Department of Pathology, Leibniz Institute for Primate Research, Göttingen, Germany. (6)Synaptic Systems GmbH, Göttingen, Germany. (7)Institute for Experimental Immunology, affiliated to Euroimmun, Lübeck, Germany. (8)Small Animal Clinic, University of Veterinary Medicine, Hannover, Germany. (9)Functional Imaging Laboratory, Leibniz Institute for Primate Research, Göttingen, Germany. (10)DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. (11)Department of Neuroimmunology, Institute for Multiple Sclerosis Research and Hertie Foundation, University Medicine Göttingen, Göttingen, Germany. (12)Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. [email protected]. (13)DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany. [email protected]. Autoantibodies of the IgG class against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1-AB) were considered pathognomonic for anti-NMDAR encephalitis. This view has been challenged by the age-dependent seroprevalence (up to >20%) of functional NMDAR1-AB of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. These findings question a merely encephalitogenic role of NMDAR1-AB. Here, we show that NMDAR1-AB belong to the normal autoimmune repertoire of dogs, cats, rats, mice, baboons, and rhesus macaques, and are functional in the NMDAR1 internalization assay based on human IPSC-derived cortical neurons. The age dependence of seroprevalence is lost in nonhuman primates in captivity and in human migrants, raising the intriguing possibility that chronic life stress may be related to NMDAR1-AB formation, predominantly of the IgA class. Active immunization of ApoE-/- and ApoE+/+ mice against four peptides of the extracellular NMDAR1 domain or ovalbumin (control) leads to high circulating levels of specific AB. After 4 weeks, the endogenously formed NMDAR1-AB (IgG) induce psychosis-like symptoms upon MK-801 challenge in ApoE-/- mice, characterized by an open blood-brain barrier, but not in their ApoE+/+ littermates, which are indistinguishable from ovalbumin controls. Importantly, NMDAR1-AB do not induce any sign of inflammation in the brain. Immunohistochemical staining for microglial activation markers and T lymphocytes in the hippocampus yields comparable results in ApoE-/- and ApoE+/+ mice, irrespective of immunization against NMDAR1 or ovalbumin. These data suggest that NMDAR1-AB of the IgG class shape behavioral phenotypes upon access to the brain but do not cause brain inflammation on their own. DOI: 10.1038/s41380-017-0011-3 PMID: 29426955
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234. Molecules. 2018 Jan 31;23(2). pii: E304. doi: 10.3390/molecules23020304. A Cyclic Altered Peptide Analogue Based on Myelin Basic Protein 87-99 Provides Lasting Prophylactic and Therapeutic Protection Against Acute Experimental Autoimmune Encephalomyelitis. Emmanouil M(1), Tseveleki V(2), Triantafyllakou I(3), Nteli A(4), Tselios T(5), Probert L(6). Author information: (1)Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave., 11521 Athens, Greece. [email protected]. (2)Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave., 11521 Athens, Greece. [email protected]. (3)Department of Chemistry, University of Patras, 26504 Patras, Greece. [email protected]. (4)Department of Chemistry, University of Patras, 26504 Patras, Greece. [email protected]. (5)Department of Chemistry, University of Patras, 26504 Patras, Greece. [email protected]. (6)Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave., 11521 Athens, Greece. [email protected]. In this report, amide-linked cyclic peptide analogues of the 87-99 myelin basic protein (MBP) epitope, a candidate autoantigen in multiple sclerosis (MS), are tested for therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). Cyclic altered peptide analogues of MBP87-99 with substitutions at positions 91 and/or 96 were tested for protective effects when administered using prophylactic or early therapeutic protocols in MBP72-85-induced EAE in Lewis rats. The Lys91 and Pro96 of MBP87-99 are crucial T-cell receptor (TCR) anchors and participate in the formation of trimolecular complex between the TCR-antigen (peptide)-MHC (major histocompability complex) for the stimulation of encephalitogenic T cells that are necessary for EAE induction and are implicated in MS. The cyclic peptides were synthesized using Solid Phase Peptide Synthesis (SPPS) applied on the 9-fluorenylmethyloxycarboxyl/tert-butyl Fmoc/tBu methodology and combined with the 2-chlorotrityl chloride resin (CLTR-Cl). Cyclo(91-99)[Ala96]MBP87-99, cyclo(87-99)[Ala91,96]MBP87-99 and cyclo(87-99)[Arg91, Ala96]MBP87-99, but not wild-type linear MBP87-99, strongly inhibited MBP72- 85-induced EAE in Lewis rats when administered using prophylactic and early therapeutic vaccination protocols. In particular, cyclo(87-99)[Arg91, Ala96]MBP87-99 was highly effective in preventing the onset and development of clinical symptoms and spinal cord pathology and providing lasting protection against EAE induction. DOI: 10.3390/molecules23020304 PMID: 29385090
Conflict of interest statement: The authors declare no conflicts of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
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235. Mov Disord. 2018 Feb 13. doi: 10.1002/mds.27284. [Epub ahead of print] Relationship between cerebrospinal fluid biomarkers and structural brain network properties in Parkinson's disease. Abbasi N(1)(2), Mohajer B(1)(2), Abbasi S(3), Hasanabadi P(3), Abdolalizadeh A(1)(2), Rajimehr R(4). Author information: (1)Interdisciplinary Neuroscience Research Program (INRP), Tehran University of Medical Sciences, Tehran, Iran. (2)Multiple Sclerosis Research Center (MSRC), Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. (3)Mashhad University of Medical Sciences, Mashhad, Iran. (4)McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. BACKGROUND: Pathological accumulation of α-synuclein, amyloid-β42 , and tau proteins in the brain is considered critical for development of various neurodegenerative diseases. OBJECTIVES: We investigated the association between CSF levels of these biomarkers, brain structural connectivity, and the UPDRS in PD. METHODS: Diffusion tensor images and CSF biomarkers (α-synuclein, amyloid-β42 , total tau, and phosphorylated tau181) from 132 drug-naïve, nondemented PD patients and 61 healthy controls were obtained from the Parkinson's Progression Markers Initiative database. After network reconstruction of structural connectivity patterns, global interconnectivity measures (including global efficiency, clustering coefficient, and characteristic path length) and local efficiency were calculated. Network properties and CSF biomarkers were compared between PD patients and healthy controls. The association of CSF biomarkers with network properties and UPDRS-III score was investigated. RESULTS: Global measures (but not local efficiency) and CSF α-synuclein were significantly lower in PD patients. Global efficiency and clustering coefficient correlated positively with α-synuclein, Aβ42 , and total tau CSF levels. Furthermore, these CSF biomarkers showed no significant association with the UPDRS-III score. CONCLUSIONS: This study examined the association of CSF biomarkers that reflect the brain pathology, with structural brain connectivity and UPDRS-III in PD. Our results revealed an association between the abnormal aggregation of α- synuclein, Aβ42 , and tau proteins and structural connectivity disruption in PD patients. In summary, a combination of structural imaging and measurement of CSF biomarkers provide a better understanding of the pathogenesis of PD. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society. DOI: 10.1002/mds.27284 PMID: 29436735
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236. Mult Scler. 2018 Jan 1:1352458518757089. doi: 10.1177/1352458518757089. [Epub ahead of print] The contribution of secondhand tobacco smoke exposure to pediatric multiple sclerosis risk. Lavery AM(1), Collins BN(2), Waldman AT(3), Hart CN(4), Bar-Or A(5), Marrie RA(6), Arnold D(7), O'Mahony J(8), Banwell B(3); Canadian Pediatric Demyelinating Disease Network. Author information: (1)Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA/Department of Social and Behavioral Sciences, College of Public Health, Temple University, Philadelphia, PA, USA. (2)Department of Social and Behavioral Sciences, College of Public Health, Temple University, Philadelphia, PA, USA. (3)Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (4)Department of Social and Behavioral Sciences, College of Public Health, Temple University, Philadelphia, PA, USA/Center for Obesity Research and Education, College of Public Health, Temple University, Philadelphia, PA, USA. (5)Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada/Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (6)Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. (7)McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada. (8)Institute of Health Policy, Management, and Evaluation, University of Toronto and The Hospital for Sick Children, Toronto, ON, Canada. BACKGROUND: Pediatric acquired demyelinating syndromes (ADSs) are monophasic (mono-ADS) in 70% of cases and represent the first attack of multiple sclerosis (MS) in 30%. Secondhand tobacco smoke (SHS) exposure has been implicated as a risk factor for adult-onset MS. Little is known about whether SHS presents an additive risk beyond genetic factors and other environmental exposures associated with pediatric MS. METHODS: This study examined SHS exposure in 216 children with mono-ADS and 81 children with MS. Interactions between SHS, HLA-DRB1*15 alleles, serum 25- hydroxyvitamin D concentrations, and serological evidence of remote Epstein-Barr virus (EBV) exposure were evaluated. RESULTS: SHS exposure was more common in children with MS (37% exposed) compared to mono-ADS (29.5% exposed). Compared to mono-ADS, SHS exposure was not an independent risk factor for MS. When both SHS exposure and HLA-DRB1*15 were present, the odds for MS increased (odds ratio (OR) = 3.7; 95% confidence interval (CI): 1.17-11.9) compared to mono-ADS. Interactions between SHS and vitamin D or EBV did not associate with MS. CONCLUSION: Exposure to SHS is a risk factor for central nervous system (CNS) demyelination. Results suggest that SHS exposure and HLA-DRB1*15 interact to increase risk for MS in children diagnosed with mono-ADS. DOI: 10.1177/1352458518757089 PMID: 29393768
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237. Mult Scler. 2018 Feb 1:1352458518760715. doi: 10.1177/1352458518760715. [Epub ahead of print] Convergent effects of a functional C3 variant on brain atrophy, demyelination, and cognitive impairment in multiple sclerosis. Roostaei T(1), Sadaghiani S(2), Mashhadi R(3), Falahatian M(4), Mohamadi E(5), Javadian N(5), Nazeri A(6), Doosti R(5), Naser Moghadasi A(7), Owji M(5), Hashemi Taheri AP(8), Shakouri Rad A(8), Azimi A(7), Voineskos AN(9), Nazeri A(10), Sahraian MA(7). Author information: (1)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/Interdisciplinary Neuroscience Research Program, Tehran University of Medical Sciences, Tehran, Iran/Kimel Family Translational Imaging- Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada/Department of Psychiatry, University of Toronto, Toronto, ON, Canada/Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA. (2)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/Interdisciplinary Neuroscience Research Program, Tehran University of Medical Sciences, Tehran, Iran. (3)Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran. (4)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. (5)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran. (6)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA. (7)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. (8)Department of Radiology, Tehran University of Medical Sciences, Tehran, Iran. (9)Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada/Department of Psychiatry, University of Toronto, Toronto, ON, Canada. (10)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/Interdisciplinary Neuroscience Research Program, Tehran University of Medical Sciences, Tehran, Iran/Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA. BACKGROUND: Complement system activation products are present in areas of neuroinflammation, demyelination, and neurodegeneration in brains of patients with multiple sclerosis (MS). C3 is a central element in the activation of complement cascades. A common coding variant in the C3 gene (rs2230199, C3R102G) affects C3 activity. OBJECTIVES: To assess the effects of rs2230199 on MS severity using clinical, cognitive, and imaging measures. METHODS: In total, 161 relapse-onset MS patients (Expanded Disability Status Scale (EDSS) ≤ 6) underwent physical assessments, cognitive tests (Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and California Verbal Learning Test (CVLT)), and magnetic resonance imaging (MRI). Lesion volumes were quantified semi-automatically. Voxel-wise analyses were performed to assess the effects of rs2230199 genotype on gray matter (GM) atrophy ( n = 155), white matter (WM) fractional anisotropy (FA; n = 105), and WM magnetization transfer ratio (MTR; n = 90). RESULTS: While rs2230199 minor- allele dosage (C3-102G) showed no significant effect on EDSS and Multiple Sclerosis Functional Composite (MSFC), it was associated with worse cognitive performance ( p = 0.02), lower brain parenchymal fraction ( p = 0.003), and higher lesion burden ( p = 0.02). Moreover, voxel-wise analyses showed lower GM volume in subcortical structures and insula, and lower FA and MTR in several WM areas with higher copies of rs2230199 minor allele. CONCLUSION: C3-rs2230199 affects white and GM damage as well as cognitive impairment in MS patients. Our findings support a causal role for complement system activity in the pathophysiology of MS. DOI: 10.1177/1352458518760715 PMID: 29485352
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238. Mult Scler. 2018 Feb 1:1352458518761187. doi: 10.1177/1352458518761187. [Epub ahead of print] Online meditation training for people with multiple sclerosis: A randomized controlled trial. Cavalera C(1), Rovaris M(2), Mendozzi L(2), Pugnetti L(3), Garegnani M(3), Castelnuovo G(4), Molinari E(4), Pagnini F(5). Author information: (1)Department of Psychology, Università Cattolica del Sacro Cuore, Milan, Italy. (2)Multiple Sclerosis Center and Rehabilitation Unit, Scientific Institute (IRCCS), don C. Gnocchi Foundation, Milan, Italy. (3)Laboratory of Clinical Neurophysiology, Scientific Institute (IRCCS) S. Maria Nascente, don C. Gnocchi Foundation, Milan, Italy. (4)Department of Psychology, Università Cattolica del Sacro Cuore, Milan, Italy; Psychology Research Laboratory, Istituto Auxologico Italiano (IRCCS), Piancavallo, Italy. (5)Department of Psychology, Università Cattolica del Sacro Cuore, Milan, Italy; Department of Psychology, Harvard University, Cambridge, MA, USA. BACKGROUND: Multiple sclerosis (MS) has a relevant impact on quality of life (QOL) and is associated with increased risks of psychological morbidity. Mindfulness-based interventions (MBIs) are among the most studied interventions, although few well-conducted studies have tested them in this field. Furthermore, the participation in typical MBIs may be impaired by time and logistics. OBJECTIVE: We aimed to test the efficacy of an online MBI to improve QOL, psychological well- being, sleep, and fatigue. METHODS: We conducted a randomized controlled trial, in which 139 participants were randomly assigned to an MS-specific online mindfulness meditation intervention or to a psychoeducational (active control) group. Participants were assessed for QOL, depression, anxiety, sleep problems, and fatigue, at three different times: at recruitment, after 2 months, and after 6 months. RESULTS: In comparison to the control group, the experimental subjects reported higher QOL and lower depression, anxiety, and sleep problems at the end of intervention. However, after 6 months these group differences were no longer significant. CONCLUSION: An online MBI could be an effective psychological treatment for the promotion of well-being in MS in short-term. However, the lack of lasting effects requires the development of new strategies to support long-term changes. DOI: 10.1177/1352458518761187 PMID: 29485319
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239. Mult Scler. 2018 Feb 1:1352458518761185. doi: 10.1177/1352458518761185. [Epub ahead of print] Severe hypertriglyceridemia associated with teriflunomide in a patient with multiple sclerosis: A case report. Camara-Lemarroy CR(1), Castilló J(2), Sastre-Garriga J(2), Tintore M(2), Montalban X(2). Author information: (1)Department of Clinical Neurosciences and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada/Servicio de Neurología, Hospital Universitario "Dr. José E. González," Universidad Autónoma de Nuevo León, Monterrey, México. (2)Servei de Neurología-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. OBJECTIVE: To describe a case of severe hypertriglyceridemia in a patient receiving teriflunomide. METHODS: This is a case study. RESULTS: Our patient developed severe hypertriglyceridemia (>5000 mg/dL) while on teriflunomide. The drug was withdrawn. Resolution began over 3 weeks later. CONCLUSION: We describe the first probable case of teriflunomide-associated severe hypertriglyceridemia in a patient with multiple sclerosis, an adverse event previously associated with leflunomide in patients with rheumatologic diseases. Clinicians should be aware of this rare but potentially dangerous adverse event. DOI: 10.1177/1352458518761185 PMID: 29473796
240. Mult Scler. 2018 Feb 1:1352458518761188. doi: 10.1177/1352458518761188. [Epub ahead of print] Clinical commentary on 'Severe hypertriglyceridemia associated with teriflunomide in a patient with multiple sclerosis'. Faissner S(1), Gold R(1). Author information: (1)Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany. DOI: 10.1177/1352458518761188 PMID: 29473795
241. Mult Scler. 2018 Feb 1:1352458518757930. doi: 10.1177/1352458518757930. [Epub ahead of print] Rituximab is an acceptable alternative to ocrelizumab for treating multiple sclerosis - Yes. Piehl F(1), Hillert J(2). Author information: (1)Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden/Department of Neurology, Karolinska University Hospital, Stockholm, Sweden/Neuroimmunology Unit, Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden. (2)Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden/Department of Neurology, Karolinska University Hospital, Stockholm, Sweden. DOI: 10.1177/1352458518757930 PMID: 29468952
242. Mult Scler. 2018 Feb 1:1352458518760717. doi: 10.1177/1352458518760717. [Epub ahead of print] Rituximab is an acceptable alternative to ocrelizumab for treating multiple sclerosis - Commentary. Cree BA(1). Author information: (1)Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. DOI: 10.1177/1352458518760717 PMID: 29468947
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243. Mult Scler. 2018 Feb 1:1352458518757931. doi: 10.1177/1352458518757931. [Epub ahead of print] Rituximab is an acceptable alternative to ocrelizumab for treating multiple sclerosis - No. Wallin MT(1)(2). Author information: (1)VA Multiple Sclerosis Center of Excellence-East, Washington, DC, USA. (2)School of Medicine, Georgetown University, Washington, DC, USA. DOI: 10.1177/1352458518757931 PMID: 29468931
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244. Mult Scler. 2018 Feb 1:1352458518758911. doi: 10.1177/1352458518758911. [Epub ahead of print] Multiple sclerosis-related fatigue: Altered resting-state functional connectivity of the ventral striatum and dorsolateral prefrontal cortex. Jaeger S(1), Paul F(2), Scheel M(1), Brandt A(1), Heine J(3), Pach D(4), Witt CM(4), Bellmann-Strobl J(5), Finke C(6). Author information: (1)NeuroCure Cluster of Excellence and NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany. (2)NeuroCure Cluster of Excellence and NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany/Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany/Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany/Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. (3)Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany. (4)Institute for Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Berlin, Germany; Institute for Complementary and Integrative Medicine, University of Zurich and University Hospital Zurich, Zurich, Switzerland. (5)NeuroCure Cluster of Excellence and NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany/Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany/Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. (6)Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany/Berlin School of Mind and Brain, Humboldt- Universität zu Berlin, Berlin, Germany. OBJECTIVE: Since recent studies suggested a role of the striatum and prefrontal cortex for multiple sclerosis (MS)-related fatigue, we investigated resting-state functional connectivity alterations of striatal subdivisions and the dorsolateral prefrontal cortex (dlPFC). METHODS: Resting-state functional magnetic resonance imaging was acquired in 77 relapsing-remitting MS patients (38 fatigued (F-MS), 39 non-fatigued (NF-MS)) and 41 matched healthy controls (HC). Fatigue severity was assessed using the fatigue severity scale. Seed-based connectivity analyses were performed using subregions of the striatum and the dlPFC as regions of interest applying non-parametric permutation testing. RESULTS: Compared to HC and NF-MS patients, F-MS patients showed reduced caudate nucleus and ventral striatum functional connectivity with the sensorimotor cortex (SMC) and frontal, parietal, and temporal cortex regions. Fatigue severity correlated negatively with functional connectivity of the caudate nucleus and ventral striatum with the SMC and positively with functional connectivity of the dlPFC with the rostral inferior parietal gyrus and SMC. CONCLUSION: MS-related fatigue is associated with reduced functional connectivity between the striatum and sensorimotor as well as attention and reward networks, in which the ventral striatum might be a key integration hub. Together with increased connectivity between the dlPFC and sensory cortical areas, these connectivity alterations shed light on the mechanisms of MS-related fatigue. DOI: 10.1177/1352458518758911 PMID: 29464981
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245. Mult Scler. 2018 Feb 1:1352458518758927. doi: 10.1177/1352458518758927. [Epub ahead of print] Measurement of soluble CD59 in CSF in demyelinating disease: Evidence for an intrathecal source of soluble CD59. Zelek WM(1), Watkins LM(2), Howell OW(2), Evans R(2), Loveless S(3), Robertson NP(3), Beenes M(4), Willems L(4), Brandwijk R(4), Morgan BP(1). Author information: (1)Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, UK. (2)Institute of Life Science (ILS), Swansea University Medical School, Swansea, UK. (3)Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. (4)Hycult Biotech, Uden, The Netherlands. BACKGROUND: CD59, a broadly expressed glycosylphosphatidylinositol-anchored protein, is the principal cell inhibitor of complement membrane attack on cells. In the demyelinating disorders, multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), elevated complement protein levels, including soluble CD59 (sCD59), were reported in cerebrospinal fluid (CSF). OBJECTIVES: We compared sCD59 levels in CSF and matched plasma in controls and patients with MS, NMOSD and clinically isolated syndrome (CIS) and investigated the source of CSF sCD59 and whether it was microparticle associated. METHODS: sCD59 was quantified using enzyme-linked immunosorbent assay (ELISA; Hycult; HK374-02). Patient and control CSF was subjected to western blotting to characterise anti-CD59-reactive materials. CD59 was localised by immunostaining and in situ hybridisation. RESULTS: CSF sCD59 levels were double those in plasma (CSF, 30.2 ng/mL; plasma, 16.3 ng/mL). Plasma but not CSF sCD59 levels differentiated MS from NMOSD, MS from CIS and NMOSD/CIS from controls. Elimination of microparticles confirmed that CSF sCD59 was not membrane anchored. CONCLUSION: CSF levels of sCD59 are not a biomarker of demyelinating diseases. High levels of sCD59 in CSF relative to plasma suggest an intrathecal source; CD59 expression in brain parenchyma was low, but expression was strong on choroid plexus (CP) epithelium, immediately adjacent the CSF, suggesting that this is the likely source. DOI: 10.1177/1352458518758927 PMID: 29421990
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246. Mult Scler. 2018 Feb;24(2):214-221. doi: 10.1177/1352458517717808. Radiologically isolated syndrome or subclinical multiple sclerosis: MAGNIMS consensus recommendations. De Stefano N(1), Giorgio A(1), Tintoré M(2), Pia Amato M(3), Kappos L(4), Palace J(5), Yousry T(6), Rocca MA(7), Ciccarelli O(6), Enzinger C(8), Frederiksen J(9), Filippi M(7), Vrenken H(10), Rovira À(11); MAGNIMS study group. Author information: (1)Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy. (2)Neurology/Neuroimmunology Department, Vall d'Hebron University Hospital, Barcelona, Spain. (3)Department NEUROFARBA, Section Neurosciences, University of Florence, Florence, Italy. (4)Department of Neurology, University Hospital, Kantonsspital, Basel, Switzerland. (5)Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. (6)Institute of Neurology, University College London, London, UK. (7)Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. (8)Department of Neurology and Division of Neuroradiology, Vascular and Interventional Radiology, Department of Radiology, Medical University of Graz, Graz, Austria. (9)Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark. (10)Department of Radiology and Nuclear Medicine and Department of Physics and Medical Technology, VU University Medical Center, Amsterdam, The Netherlands. (11)Section of Neuroradiology, Vall d'Hebron University Hospital, Barcelona, Spain. DOI: 10.1177/1352458517717808 PMID: 29451440
247. Mult Scler J Exp Transl Clin. 2018 Feb 14;4(1):2055217318756688. doi: 10.1177/2055217318756688. eCollection 2018 Jan-Mar. A randomized study to evaluate the effect of exercise on fatigue in people with relapsing-remitting multiple sclerosis treated with fingolimod. Mäurer M(1), Schuh K(2), Seibert S(2), Baier M(2), Hentschke C(2), Streber R(3), Tallner A(3), Pfeifer K(3). Author information: (1)Klinik für Neurologie, Klinikum Würzburg Mitte gGmbH, Standort Juliusspital, Würzburg, Germany. (2)Novartis Pharma GmbH, Germany. (3)Institute of Sport Science and Sport, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Germany. Background: Fatigue is a major symptom of multiple sclerosis (MS) in patients, and it has been shown to improve with physical exercise. Although fingolimod might lessen fatigue, it is unclear how patients treated with fingolimod react to physical activity regarding fatigue. Objective: This study evaluated the effect of an exercise intervention on fatigue in relapsing-remitting MS patients receiving fingolimod. Methods: People with MS (PwMS) were randomized to either a structured internet-based exercise program (e-training) or no e-training intervention. The primary endpoint was the change in the Modified Fatigue Impact Scale (mFIS) after six months. Results: The primary analysis showed no statistically significant difference between groups in the mFIS change. Subgroup analyses revealed a beneficial effect of physical exercise for PwMS with low aerobic capacity and with low aerobic capacity plus more severe fatigue. The incidence of adverse events was similar in both groups. No cardiovascular events were reported. The majority of PwMS were relapse free. Conclusion: Physical exercise benefits on fatigue may depend on the physical capacity of the patient and requires individualized training. Consistent with previous studies, these results suggest that physical exercise generally does not impose a risk and that this holds true also for patients receiving fingolimod.Trial registration: ClinicalTrials.gov, NCT01490840. DOI: 10.1177/2055217318756688 PMCID: PMC5818099 PMID: 29479457
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248. Mult Scler J Exp Transl Clin. 2018 Jan 23;4(1):2055217317753465. doi: 10.1177/2055217317753465. eCollection 2018 Jan-Mar. Movement measurements at home for multiple sclerosis: walking speed measured by a novel ambient measurement system. Smith VM(1), Varsanik JS(2), Walker RA(2), Russo AW(1), Patel KR(1), Gabel W(3), Phillips GA(3), Kimmel ZM(2), Klawiter EC(1). Author information: (1)Massachusetts General Hospital, Harvard Medical School, USA. (2)Atlas5D, Inc., USA. (3)Value-based Medicine Group, Biogen, USA. Background: Gait disturbance is a major contributor to clinical disability in multiple sclerosis (MS). A sensor was developed to assess walking speed at home for people with MS using infrared technology in real-time without the use of wearables. Objective: To develop continuous in-home outcome measures to assess gait in adults with MS. Methods: Movement measurements were collected continuously for 8 months from six people with MS. Average walking speed and peak walking speed were calculated from movement data, then analyzed for variability over time, by room (location), and over the course of the day. In-home continuous gait outcomes and variability were correlated with standard in-clinic gait outcomes. Results: Measured in-home average walking speed of participants ranged from 0.33 m/s to 0.96 m/s and peak walking speed ranged from 0.89 m/s to 1.51 m/s. Mean total within-participant coefficient of variation for daily average walking speed and peak walking speed were 10.75% and 10.93%, respectively. Average walking speed demonstrated a moderately strong correlation with baseline Timed 25-Foot Walk (rs = 0.714, P = 0.111). Conclusion: New non-wearable technology provides reliable and continuous in-home assessment of walking speed. DOI: 10.1177/2055217317753465 PMCID: PMC5784463 PMID: 29383266
249. Mult Scler Relat Disord. 2018 Jan 31;20:223-227. doi: 10.1016/j.msard.2018.01.018. [Epub ahead of print] LIF and multiple sclerosis: One protein with two healing properties. Metcalfe SM(1). Author information: (1)Cambridge University, Clinical School Biomedical Campus & LIFNano Rx, Cambridge, UK. Electronic address: [email protected]. DOI: 10.1016/j.msard.2018.01.018 PMID: 29448112
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250. Mult Scler Relat Disord. 2018 Jan 31;20:194-198. doi: 10.1016/j.msard.2018.01.026. [Epub ahead of print] Multiple sclerosis in pediatric patients in Slovenia. Krajnc N(1), Oražem J(2), Rener-Primec Z(2), Kržan MJ(3). Author information: (1)University Children's Hospital, Department of Child, Adolescent & Developmental Neurology, Bohoričeva 20, 1525 Ljubljana, Slovenia; Department of Pediatrics, General Hospital Slovenj Gradec, Gosposvetska cesta 1, 2380 Slovenj Gradec, Slovenia. Electronic address: [email protected]. (2)University Children's Hospital, Department of Child, Adolescent & Developmental Neurology, Bohoričeva 20, 1525 Ljubljana, Slovenia. (3)University Children's Hospital, Department of Child, Adolescent & Developmental Neurology, Bohoričeva 20, 1525 Ljubljana, Slovenia; Neurology Revita, Kidričeva 47a, 4000 Kranj, Slovenia. AIM: The purpose of this study is to review the Slovenian experience with the diagnostics, treatment and outcome in pediatric multiple sclerosis (MS) patients. METHODS: Children and adolescent diagnosed with MS and followed by Department of Child, Adolescent and Developmental Neurology, University Childrens' Hospital Ljubljana, between 1 January 2000 and 31 December 2012 were included. Data from patients' documentation were analyzed retrospectively to record demographic data, clinical presentation, paraclinical findings, disability progression, relapse rate and treatment strategies. RESULTS: The study includes 38 patients up to 18 years with MS diagnosis, with female: male ratio 2.8:1 and the incidence of 0.81 per 100.000 children of 0-18 years. The mean age at the time of diagnosis was 15 years 4 months. Most frequent presenting symptoms were sensory, motor, brain-stem, visual and ataxia and 65% of patients had a relapse in the first year. The value of paraclinical findings was asessed. 74% of patients with definite MS and 36% of those with clinically isolated syndrome received disease modifyng therapy and 68% of them was not affected at the follow- up. INTERPRETATION: The characteristics of pediatric MS patients in Slovenia disclose higher annual relapse rates than in adults but also favorable impact of disease modifying treatment on a clinical course. Our data suggest a good treatment tolerance but also the influence of the formulation on a decision to start or switch the treatment. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.026 PMID: 29414298
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251. Mult Scler Relat Disord. 2018 Jan 31;20:186-191. doi: 10.1016/j.msard.2018.01.023. [Epub ahead of print] Investigating the dynamic plantar pressure distribution and loading pattern in subjects with multiple sclerosis. Keklicek H(1), Cetin B(2), Salci Y(3), Balkan AF(4), Altinkaynak U(5), Armutlu K(6). Author information: (1)Trakya University, Faculty Of Health Sciences, Department Of Physiotherapy and Rehabilitation, Edirne, Turkey. Electronic address: [email protected]. (2)Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Ankara, Turkey. Electronic address: [email protected]. (3)Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Ankara, Turkey. Electronic address: [email protected]. (4)Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Ankara, Turkey. Electronic address: [email protected]. (5)Gercek Prosthetics and Orthotics Research and Development Group, Ankara, Turkey. Electronic address: [email protected]. (6)Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Ankara, Turkey. Electronic address: [email protected]. BACKGROUND: Multiple sclerosis (MS) is a complex disorder affecting subjects by multiple system impairments. Gait problems are common in subjects with MS and various factors such as; ataxia, hypertonic muscles or/and seconder musculoskeletal system deformities affect the normal plantigrade contact by disturbing accommodation of foot to the ground while walking. The aim of this study was investigating the dynamic plantar pressure distribution and time of maximum pressure in subjects with MS and determining the differences from healthy subjects (HS). METHODS: Fifty-five subjects with MS (110 foot) and 20 HS (40 foot) were the participants of the study. The dynamic pedobarograph was utilized for evaluation of dynamic loading parameters; maximum pressure (N/cm2) and time of maximum pressure (ms) collected from heel medial, heel lateral, midfoot, heads of first, second, third, fourth and fifth metatarsal bones. RESULTS: There were differences between the groups in maximum pressure of heel medial (p < .001) and heel lateral (p < .001) was higher in HS. Also, there were differences between the groups the time of maximum pressure of all metatarsal head areas, midfoot, heel medial and heel lateral (p < .001). Subjects with MS spent lesser time to reach maximum pressure for forefoot loading and longer time for hindfoot loading. CONCLUSION: The study provided basic data about foot pressure distribution and time of maximum pressure in subjects with MS. Results of the study showed that the hindfoot loading was disrupted and inappropriate timing during load transfer from hindfoot to forefoot is exist in subjects with MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.023 PMID: 29414296
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252. Mult Scler Relat Disord. 2018 Jan 29;20:164-168. doi: 10.1016/j.msard.2018.01.019. [Epub ahead of print] Uncovering the link between reproductive factors and multiple sclerosis: A case-control study on Iranian females. Salehi F(1), Abdollahpour I(2), Nedjat S(3), Sahraian MA(4), Memari AH(5), Rahnama M(5), Mansournia MA(6). Author information: (1)Cohort study Center, Shahrekord University of Medical Sciences, Iran. (2)Department of Epidemiology, School of Public Health, Arak University of Medical Sciences, Iran. (3)Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Iran; Knowledge Utilization Research Center, Tehran University of Medical Science, Iran. (4)MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Iran. (5)Sports Medicine Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Iran. (6)Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Iran. Electronic address: [email protected]. BACKGROUND: Increase of MS prevalence in females compared to males, especially in reproductive age, highlights the important role of reproductive factors in MS pathology. OBJECTIVES: We examined the association between females' reproductive age-related factors and MS risk. METHODS: A case-control study including 399 cases and 541 controls was carried out. The adjusted associations between MS risk and reproductive variables including age at menarche, oral contraceptive pills (OCPs) use history, OCP usage duration and age at first use, history of assisted reproductive technologies (ARTs) use, parity history, age at first childbirth and the number of parities, abortion and exclusive breast feeding > 2 months were assessed. RESULTS: We found protective relationships between MS and older age at menarche (OR = 0.90 {95% CI = 0.82-0.98}), ART use history (OR = 0.45 {95% CI = 0.21-0.99}), older maternal age at first childbirth (OR = 0.94{95% CI = 0.89 - 0.99}) and higher number of parities(OR = 0.61 {95% CI = 0.49 - 0.75), whereas using OCPs was associated with higher risk of developing MS (OR = 1.80 {95% CI = 1.35-2.41}). CONCLUSIONS: Links were noted between a number of reproductive factors and risk of MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.019 PMID: 29414292
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253. Mult Scler Relat Disord. 2018 Jan 26;20:154-158. doi: 10.1016/j.msard.2018.01.015. [Epub ahead of print] Correlation between the corpus callosum index and brain atrophy, lesion load, and cognitive dysfunction in multiple sclerosis. Gonçalves LI(1), Dos Passos GR(2), Conzatti LP(2), Burger JLP(3), Tomasi GH(2), Zandoná MÉ(2), Azambuja LS(3), Gomes I(3), Franco A(3), Sato DK(4), Becker J(5). Author information: (1)School of Medicine; Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil. (2)São Lucas Hospital, Neurology Service; Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil. (3)Brain Institute (BraIns) of Rio Grande do Sul; Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil. (4)School of Medicine; Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; São Lucas Hospital, Neurology Service; Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; Brain Institute (BraIns) of Rio Grande do Sul; Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil. (5)School of Medicine; Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; São Lucas Hospital, Neurology Service; Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil; Brain Institute (BraIns) of Rio Grande do Sul; Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: [email protected]. BACKGROUND: The corpus callosum index (CCI) can be easily and reliably obtained from conventional magnetic resonance imaging (MRI) and has been proposed as a possible marker of brain atrophy in MS. However, further validation of its correlation with volumetric measurements is still warranted. OBJECTIVE: To assess the correlation of the CCI with the corpus callosum volume (CCV), brain and lesion volumes, and level of disability in MS. METHODS: Cross-sectional, exploratory study including patients with relapsing-remitting MS. Clinical assessment comprised of physical and cognitive disability scales. MRI parameters included conventional volumetric measurements, the CCI (manual), and the CCV (automated). RESULTS: Twenty-four patients were included. There was a strong correlation between the CCI and CCV. The CCI correlated strongly with the white matter and lesion volumes, and moderately with the whole brain volume and scores on the Paced Auditory Serial Addition Test and MS Functional Composite. There were no correlations between the CCI and either gray matter volume or scores on the Expanded Disability Status Scale, the 9-Hole Peg Test, or the Timed 25-Foot Walk test. CONCLUSION: The findings support the validity of the CCI as an easy-to- obtain marker of brain atrophy, lesion load, and cognitive dysfunction in patients with MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.015 PMID: 29414290
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 234 – Multiple Sklerose: Veröffentlichungen Oktober 2013
254. Mult Scler Relat Disord. 2018 Jan 25;20:136-143. doi: 10.1016/j.msard.2018.01.014. [Epub ahead of print] Symbol Digit Modalities Test adaptation for Magnetic Resonance Imaging environment: A systematic review and meta-analysis. Silva PHR(1), Spedo CT(2), Barreira AA(2), Leoni RF(3). Author information: (1)Dept. of Physics, FFCLRP, University of Sao Paulo, Ribeirao Preto, SP, Brazil. (2)Dept. of Neuroscience and Behavioral Sciences, FMRP, University of Sao Paulo, Ribeirao Preto, SP, Brazil. (3)Dept. of Physics, FFCLRP, University of Sao Paulo, Ribeirao Preto, SP, Brazil. Electronic address: [email protected]. BACKGROUND: The Symbol Digit Modalities Test (SDMT) is widely used for cognitive evaluation of information processing speed (IPS), required in many cognitive operations. Despite being unspecific for different neurological disorders, it is sensitive to assess impaired performance related to stroke, Parkinson's disease, traumatic brain injury, and multiple sclerosis. However, in addition to evaluate the presence and severity of IPS impairment, it is of interest to determine the localization and integration of brain regions responsible for the functions assessed by the SDMT. OBJECTIVE: To review the studies that adapted the SDMT to the magnetic resonance environment and obtain the brain areas associated with the performance of the task in healthy subjects with a meta-analysis. METHODOLOGY: A systematic review was performed using ten studies published between 1990 and 2017, and selected from four databases. All studies included participants of both genders and age between 18 and 50 years, used Functional Magnetic Resonance Imaging (fMRI) and SDMT adaptation and reported brain regions associated with the task. Six of them also reported the region coordinates in a standard space, so they were included in a meta-analysis. Activation Likelihood Estimation algorithm, with significance for p < 0.05 corrected for multiple comparisons, was used to identify areas that are robustly related to the performance of the SDMT. RESULTS: The areas predominantly reported in the studies of our meta-analysis were regions of the frontoparietal attentional network and occipital cortex, as well as cuneus, precuneus, and cerebellum. Individually all regions that survived the statistical threshold are consistent with what is expected after reviewing prospective studies. CONCLUSIONS: The present study allowed the identification of brain areas activated during the performance of the SDMT in healthy subjects, and therefore it will help understanding the differences in brain activation by this task in clinical populations. Moreover, it may guide future studies of therapeutic strategies and interventions in those populations. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.014 PMID: 29414287
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 235 – Multiple Sklerose: Veröffentlichungen Oktober 2013
255. Mult Scler Relat Disord. 2018 Jan 25;20:132-135. doi: 10.1016/j.msard.2018.01.016. [Epub ahead of print] A longitudinal study of JC virus serostatus stability among multiple sclerosis patients. Alroughani R(1), Akhtar S(2), Ahmed S(3), Al-Hashel J(4). Author information: (1)Division of Neurology, Amiri Hospital, Arabian Gulf Street, Sharq 13041, Kuwait; Neurology Clinic, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait. Electronic address: [email protected]. (2)Department of Community Medicine & Behavioural Sciences, Faculty of Medicine, University of Kuwait, PO Box 24923, Safat 13110, Kuwait. (3)Department of Neurology, Ibn Sina Hospital, P.O. Box 25427, Safat 13115, Kuwait; Department of Neurology and Psychiatry, Minia University, P.O. Box 61519, Minia 61111, Egypt. (4)Department of Neurology, Ibn Sina Hospital, P.O. Box 25427, Safat 13115, Kuwait; Department of Medicine, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110, Kuwait. BACKGROUND: Anti-JC virus (JCV) antibody testing has been used increasingly to stratify multiple sclerosis (MS) patients into different disease modifying therapies. OBJECTIVES: We assessed JCV serostatus stability longitudinally in MS patients who were regularly tested for anti-JCV antibody and examined the demographic and clinical factors associated with JCV serostatus. METHODS: The data of MS patients who were screened for anti-JCV antibody using the two-step second-generation ELISA were collected between 1st October 2014 and 31st October 2015 at the MS clinic, Kuwait. Demographics, disease characteristics and JCV serostatus, including antibody index (AI), were obtained for patients with at least 12-months of follow-up results. Stable JCV serostatus was defined as anti-JCV antibody status that remained consistently negative or positive throughout the observation period. A change in serostatus was confirmed by a follow-up test at 6 months. Patients were labeled as JCV seroconverters (negative to positive), JCV seroreverters (positive to negative) or intermittently seropositive. RESULTS: This study included 168 MS patients with anti-JCV antibody results for at least 1 year. Mean age and mean disease duration were 33.4 ± 9.8 and 8.1 ± 5.6 years respectively. In this cohort, 94% (n = 158) patients received natalizumab treatment with a mean of 27.2 ± 13.8 infusions. JCV stable serostatus (positive or negative) was observed in 84.5% (n = 142) with a mean follow-up duration of 23.8 ± 7.0 months. In this longitudinal study, relatively high frequencies of seroconverters (11.5%), intermittently seropositive (9.7%) and seroreverters (3.6%) were recorded. Age, gender, disease duration and number of natalizumab infusions did not influence JCV serostatus stability. JCV seroconversion risk was low with persistent AI < 0.9 beyond 18 months of initial testing. CONCLUSION: Anti-JCV antibody index at baseline predicted stable negative as well as stable positive JCV serostatus over the observational period. The AI < 0.9 appeared to have a significant implication in the longitudinal stability of JCV AI in patients who were intermittently seropositive. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.016 PMID: 29414286
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 236 – Multiple Sklerose: Veröffentlichungen Oktober 2013
256. Mult Scler Relat Disord. 2018 Jan 25;20:129-131. doi: 10.1016/j.msard.2018.01.009. [Epub ahead of print] Digital epidemiology confirms a latitude gradient of MS in France. Dalla Costa G(1), Giordano A(1), Romeo M(1), Sangalli F(1), Comi G(1), Martinelli V(2). Author information: (1)Neurological Department, San Raffaele Hospital, Milan, Italy. (2)Neurological Department, San Raffaele Hospital, Milan, Italy. Electronic address: [email protected]. BACKGROUND: A gradient of prevalence of MS has been previously reported, and this may be due to different environmental and genetic features of the different populations, but also to methodological issues. In France, for example, three studies analysed the presence of such a gradient with conflicting results. The aim of this study was to assess whether digital epidemiology could confirm the presence of such a gradient. METHODS: through Google Trends, we analysed the relative search volume (RSV) for 'multiple sclerosis' in France, from 2004 to 2017, and assessed if an association with the decimal degree of latitude existed. RESULTS: Latitude was correlated with crude RSV (r2 0.39, p 0.04) in the 21 regions considered, with a southwest/northeast gradient. A multiple linear regression model adjusted for sex and age confirmed the existence of such a latitudinal effect, with an increase of 2.43 RSV units for each unit increase in latitude (95% CIs 0.62-4.24, p < 0.01, adjusted r2 0.61). CONCLUSIONS: our study provides additional evidence for the existence of a latitude gradient in MS, and the value of Internet-acquired data as real-time surveillance tools and alerts for healthcare systems. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.009 PMID: 29414285
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 237 – Multiple Sklerose: Veröffentlichungen Oktober 2013
257. Mult Scler Relat Disord. 2018 Jan 25;20:122-128. doi: 10.1016/j.msard.2018.01.013. [Epub ahead of print] Relationship between Social Cognition and traditional cognitive impairment in Progressive Multiple Sclerosis and possible implicated neuroanatomical regions. Ciampi E(1), Uribe-San-Martin R(2), Vásquez M(3), Ruiz-Tagle A(4), Labbe T(5), Cruz JP(6), Lillo P(7), Slachevsky A(8), Reyes D(9), Reyes A(3), Cárcamo-Rodríguez C(3). Author information: (1)Neurology Department, Pontifical Catholic University of Chile, Santiago, Chile; Neurology, Hospital Sotero del Rio, Santiago, Chile. Electronic address: [email protected]. (2)Neurology Department, Pontifical Catholic University of Chile, Santiago, Chile; Neurology, Hospital Sotero del Rio, Santiago, Chile. (3)Neurology Department, Pontifical Catholic University of Chile, Santiago, Chile. (4)Centre for Advanced Research in Education, University of Chile, Santiago, Chile. (5)Pontifical Catholic University of Chile, Santiago, Chile. (6)Radiology Department, Pontifical Catholic University of Chile, Santiago, Chile. (7)Neurology Department South, Faculty of Medicine, University of Chile, Geroscience Center for Brain Health and Metabolism, Santiago, Chile. (8)Centre for Advanced Research in Education, University of Chile, Santiago, Chile; Gerosciences Center for Brain Health and Metabolism, Santiago, Chile; Physiopathology Department, ICBM and East Neuroscience Department Faculty of Medicine University of Chile, Santiago, Chile; Cognitive Neurology and Dementia, Neurology Department, Salvador Hospital, Santiago, Chile; Neurology Service, Medicine Department, Alemana Clinic and Universidad del Desarrollo, Santiago, Chile. (9)Faculty of Medicine, Pontifical Catholic University of Chile, Santiago, Chile. BACKGROUND: Cognitive impairment is a relevant contributor of the medical and social burden in Progressive MS. Social Cognition, the neurocognitive processes underlying social interaction, has been explored mainly in European and North American cohorts, influencing social aspects of quality of life (QOL) of early MS patients and families. Few studies have studied Social Cognition in Progressive MS and the literature on its neuroanatomical bases or brain atrophy measurements is still scarce. OBJECTIVES: To explore the relationship between Social Cognition performance and its correlations with traditional cognitive domains, brain atrophy and QOL in primary and secondary Progressive MS patients. METHODS: Cross-sectional analysis including: mini-Social-Cognition-and-Emotional- Assessment (mini-SEA), neuropsychological battery, disability, depression, fatigue, QOL, and brain volume. RESULTS: Forty-three MS patients, 23 primary and 20 secondary Progressive, 65% women, mean age and disease duration of 57.2 and 15.7 years, respectively, with high levels of disability (median EDSS 6.0) and a widespread impairment in traditional domains (mostly episodic verbal/visual and working memories) were assessed. The Mini-SEA score was correlated with executive functions (cognitive shifts Rho:0.55; p = 0.001) analyzing the whole group, and with visual episodic memory (Rho:0.58, p = 0.009) in the primary Progressive MS group. Mini-SEA score was also correlated with total normalized grey matter volume (Rho:0.48; p = 0.004). Particularly, atrophy within bilateral cortical regions of orbitofrontal, insula and cerebellum, and right regions of fusiform gyrus and precuneus were significantly associated with higher Social Cognition impairment. In this cohort, QOL was not correlated with Social Cognition, but with EDSS, fatigue and depression. CONCLUSIONS: In Progressive MS, Social Cognition is directly correlated with traditional cognitive domains such as executive function and episodic memory. It is also associated with global grey matter atrophy and regional atrophy within associative visual and executive cortical areas, but no correlations with QOL were found in this cohort. These findings may contribute to the understanding of the pathological bases behind Social Cognition in Progressive MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.013 PMID: 29414284
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 238 – Multiple Sklerose: Veröffentlichungen Oktober 2013
258. Mult Scler Relat Disord. 2018 Jan;19:168-170. doi: 10.1016/j.msard.2016.08.006. Epub 2016 Aug 12. Response to the commentary of Yates RL and DeLuca GC on the study: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis. Yaldizli Ö(1), Sethi V(2), Pardini M(3), Tur C(4), Mok KY(5), Muhlert N(6), Liu Z(7), Samson RS(2), Wheeler-Kingshott CAM(2), Yousry TA(8), Houlden H(9), Hardy J(9), Miller DH(10), Chard DT(10). Author information: (1)Queen Square MS Centre NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, London, UK; Department of Neurology, University Hospital Basel, Basel, Switzerland. Electronic address: [email protected]. (2)Queen Square MS Centre NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, London, UK. (3)Queen Square MS Centre NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, London, UK; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy. (4)Queen Square MS Centre NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, London, UK; MS Centre of Catalonia (Cemcat), Neurology-Neuroimmunology Department, Vall d'Hebron University Hospital, Barcelona, Spain. (5)Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Division of Life Science, Hong Kong University of Science and Technology, Hong Kong Special Administrative Region. (6)Queen Square MS Centre NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, London, UK; School of Psychology and Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, UK; School of Psychological Sciences, University of Manchester, Manchester, UK. (7)Queen Square MS Centre NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, London, UK; Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. (8)Queen Square MS Centre NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, London, UK; National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, UK; Brain Repair and Rehabilitation, UCL Institute of Neurology, London, UK; Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK. (9)Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. (10)Queen Square MS Centre NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology, London, UK; National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, UK. DOI: 10.1016/j.msard.2016.08.006 PMID: 29409599
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259. Mult Scler Relat Disord. 2018 Jan;19:166-167. doi: 10.1016/j.msard.2016.08.005. Epub 2016 Aug 9. Comment: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis. Yates RL(1), DeLuca GC(1). Author information: (1)Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK. DOI: 10.1016/j.msard.2016.08.005 PMID: 29409598
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 240 – Multiple Sklerose: Veröffentlichungen Oktober 2013
260. Mult Scler Relat Disord. 2018 Jan;19:161-165. doi: 10.1016/j.msard.2017.10.008. Epub 2017 Oct 14. The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and adults. Graves JS(1), Barcellos LF(2), Simpson S(3), Belman A(4), Lin R(5), Taylor BV(6), Ponsonby AL(7), Dwyer T(8), Krupp L(9), Waubant E(10), van der Mei IAF(11). Author information: (1)UCSF Pediatric MS Center, San Francisco, CA, USA; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. (2)Genetic Epidemiology and Genomics Lab, School of Public Health, and California Institute of Quantitative Biosciences, UC Berkeley, Berkeley, CA, USA; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. (3)Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. (4)National Pediatric MS Center, Stonybrook, NY, USA; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. (5)Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; Guangxi Center for Disease Prevention and Control, Nanning, China; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. (6)Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. (7)Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. (8)Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. (9)National Pediatric MS Center, Stonybrook, NY, USA; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. (10)UCSF Pediatric MS Center, San Francisco, CA, USA; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. (11)Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia; School of Medicine, University of Tasmania, Hobart, Australia. Electronic address: [email protected]. BACKGROUND: While common variant non-HLA (human leukocyte antigen) alleles have been associated with MS risk, their role in disease course is less clear. We sought to determine whether established multiple sclerosis (MS) genetic susceptibility factors are associated with relapse rate in children and an independent cohort of adults with MS. METHODS: Genotyping was performed for 182 children with MS or clinically isolated syndrome with high risk for MS from two Pediatric MS Centers. They were prospectively followed for relapses. Fifty-two non-HLA MS susceptibility single nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate. Cox regression models were adjusted for sex, genetic ancestry, disease-modifying therapy (DMT), 25-OH vitamin D level and HLA- DRB1*15:01/03 status. Investigation of pediatric subject SNP results was performed using a second cohort of 141 adult MS subjects of Northern European ancestry from the Southern Tasmanian Multiple Sclerosis Longitudinal Study. RESULTS: For pediatric subjects, 408 relapses were captured over 622 patient-years of follow-up. Four non-HLA risk SNPs (rs11154801, rs650258, rs12212193, rs2303759) were associated with relapses (p < 0.01) in the pediatric subjects. After adjustment for genetic ancestry, sex, age, vitamin D level, DMT use and HLA-DRB1*15 status, having two copies of the MS risk allele within AHI1 (rs11154801) was associated with increased relapses among children (HR = 1.75,95%CI = 1.18-2.48, p = 0.006) and this result was also observed among adults (HR = 1.81,95%CI = 1.05-3.03, p = 0.026). CONCLUSIONS: Our results suggest that the MS genetic risk variant within the gene AHI1 may contribute to disease course in addition to disease susceptibility. Copyright © 2017 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2017.10.008 PMCID: PMC5806144 [Available on 2019-01-01] PMID: 29409597
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 241 – Multiple Sklerose: Veröffentlichungen Oktober 2013
261. Mult Scler Relat Disord. 2018 Feb 9;21:11-18. doi: 10.1016/j.msard.2018.02.008. [Epub ahead of print] Humoral response to John Cunningham virus during pregnancy in multiple sclerosis. Saraste M(1), Atula S(2), Hedman K(3), Hurme S(4), Jalkanen A(5), Sneck M(6), Surcel HM(7), Maghzi AH(8), Airas L(5). Author information: (1)Department of Neurology, University of Turku, Turku, Finland. Electronic address: [email protected]. (2)Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. (3)Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. (4)Department of Biostatistics, University of Turku, Turku, Finland. (5)Division of Clinical Neurosciences, University of Turku and Turku University Hospital, Turku, Finland. (6)HUSLAB, Helsinki University Hospital, Helsinki, Finland. (7)National Institute for Health and Welfare, Oulu, Finland. (8)Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States. BACKGROUND: Pregnancy induces an immunosuppressive state in the mother to ensure immunological acceptance of the foetus. Impairment of cell-mediated immune responses may render the mother susceptible to intracellular pathogens. It is not presently known whether pregnancy alters the immunosurveillance for John Cunningham virus (JCV), an opportunistic pathogen associated with natalizumab treatment for multiple sclerosis (MS). OBJECTIVE: To evaluate whether the humoral immune response to JCV is altered during pregnancy among MS patients and healthy controls to get insight to potential pregnancy-induced alterations related to immune response to JCV during pregnancy. METHODS: Serum anti-JCV-antibody-indices (JCV-Ab-index) were determined by a two- step second-generation enzyme-linked immunosorbent assay in 49 MS patients during and after pregnancy and in 49 healthy controls during pregnancy. For comparison, total IgG levels and antibodies against Epstein-Barr, cytomegalo and measles viruses were similarly measured. RESULTS: The JCV-Ab-indices of MS patients were not altered during the pregnancy (1st vs. 3rd trimester, 0.62 vs. 0.77, p = 0.99). Contrary to this, in the healthy controls JCV-Ab-indices (p = 0.005), antibody levels to the other viruses, and total IgG levels (p < 0.0001) decreased significantly during pregnancy. CONCLUSIONS: JCV-Ab levels remain unaltered during MS pregnancy, while the total IgG concentration is reduced/diluted due to increasing plasma volumes during the course of pregnancy. This may imply a biologically significant alteration in the immune response to JCV during MS pregnancy. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.008 PMID: 29454151
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 242 – Multiple Sklerose: Veröffentlichungen Oktober 2013
262. Mult Scler Relat Disord. 2018 Feb 7;21:42-45. doi: 10.1016/j.msard.2018.02.007. [Epub ahead of print] Dimethyl fumarate in a patient with multiple sclerosis and type 1 diabetes mellitus: The importance of ketonuria. Krzystanek E(1), Jarosz-Chobot P(2). Author information: (1)Department of Neurology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. Electronic address: [email protected]. (2)Department of Children's Diabetology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. BACKGROUND: Dimethyl fumarate (DMF) is approved for use in patients with relapsing-remitting multiple sclerosis (MS). Its mechanism of action is still not well understood, but besides the immunological pathways in MS, it may also affect the metabolism of normally functioning internal organs, tissues and cells. CASE PRESENTATION: We report on the case of 29-year-old woman with satisfactorily-controlled type 1 diabetes (T1D), who was diagnosed as having MS. After administration of DMF she experienced intense, adverse gastro-intestinal reactions together with ketonuria up to 160 mg/dL. The highest ketone concentrations in the urine were observed approximately 2 h after each DMF dose and always with co-existing adverse reactions. Dose reduction did not improve symptoms and treatment had to be stopped. Twelve hours after the last dose of DMF all laboratory results returned to normal ranges and all gastro-intestinal adverse reactions were resolved within the following 24 h. CONCLUSION: This is a first report of ketonuria in a MS-patient with T1D treated with DMF. Patients with MS and co-existing metabolic diseases, which are not contraindicated for DMF treatment, represent a unique opportunity to address questions regarding the possible mechanisms of action of DMF on the cellular metabolism. The use of DMF in patients with metabolic diseases needs closer attention. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.007 PMID: 29455073
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 243 – Multiple Sklerose: Veröffentlichungen Oktober 2013
263. Mult Scler Relat Disord. 2018 Feb 6;21:30-34. doi: 10.1016/j.msard.2018.02.005. [Epub ahead of print] The use of satellite data to measure ultraviolet-B penetrance and its potential association with age of multiple sclerosis onset. Amram O(1), Schuurman N(2), Randall E(3), Zhu F(4), Saeedi J(5), Rieckmann P(6), Yee I(7), Tremlett H(8). Author information: (1)Department of Nutrition and Exercise Physiology, Elson S. Floyd College of Medicine, Washington State University, P O Box 1495, Spokane, WA 99210-1495, USA. (2)Department of Geography, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada V5A 1S6. (3)School of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, Canada V6T 1Z9. (4)Division of Neurology, Faculty of Medicine and the Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2221 Wesbrook Mall, Vancouver, Canada V6T 2B5. (5)Neurology Department, National Neuroscience Institute, King Fahad Medical City, P.O. Box 59046, M.B.N.020007, Riyadh 11525, Saudi Arabia. (6)Department of Neurology, Sozialstiftung Bamberg, Teaching Hospital of the Friedrich-Alexander Universität Erlangen, Buger Str. 80, D-96049 Bamberg, Germany. (7)Division of Neurology, Faculty of Medicine and the Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2221 Wesbrook Mall, Vancouver, Canada V6T 2B5; Department of Medical Genetics, Faculty of Medicine, University of British Columbia, C201 - 4500 Oak Street, Vancouver, Canada V6H 3N1. (8)Division of Neurology, Faculty of Medicine and the Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2221 Wesbrook Mall, Vancouver, Canada V6T 2B5. Electronic address: [email protected]. BACKGROUND: Studies have indicated an association between low Ultraviolet B (UVB) exposure and an increased risk of developing multiple sclerosis (MS). Few studies, however, have explored whether UVB exposure is associated with the age at MS symptom onset. OBJECTIVE: We investigated the potential association between cumulative early life ambient UVB exposure and age at MS onset, using satellite data to measure ambient UVB exposure. METHODS: Adult onset MS patients were selected from the University of British Columbia's MS genetic database (1980-2005). Patients' places of residence from birth to age 18 years were geocoded (latitude and longitude) and assigned UVB values using NASA's Total Ozone Mapping Spectrometer (TOMS) dataset. Linear regression was used to explore the relationship between cumulative UVB exposure (measured for age periods 0-6, 7-12, 13- 18, 0-12, and 0-18) and age at MS onset. RESULTS: 3226 patients were included in the analysis. Of these, 74% were female, with an overall mean symptom onset age of 33.3 years. At onset, a total of 2944 (91%) had a relapsing-remitting disease course, 254 (8%) had primary progressive and the disease course for 28 (1%) was unknown. No significant associations between cumulative early life ambient UVB exposure and age at MS onset were observed. Patient sex, MS phenotype, and immigration to Canada after age 18 were significantly associated with age of onset (p < 0.01). CONCLUSIONS: Early life ambient UVB, as measured by satellite imagery, was not significantly associated with the age at MS onset. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.005 PMID: 29455071
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 244 – Multiple Sklerose: Veröffentlichungen Oktober 2013
264. Mult Scler Relat Disord. 2018 Feb 6;21:1-8. doi: 10.1016/j.msard.2018.02.003. [Epub ahead of print] Structural MRI correlates of cognitive function in multiple sclerosis. Artemiadis A(1), Anagnostouli M(2), Zalonis I(2), Chairopoulos K(3), Triantafyllou N(2). Author information: (1)1st Department of Neurology, Aeginition Hospital, Faculty of Medicine, National Kapodistrian University of Athens, Vas. Sofias Ave. 72-74, GR-11528 Athens, Greece; Department of Neurology, Army Share Fund Hospital (NIMTS), Monis Petraki 10-12, GR-11521 Athens, Greece. Electronic address: [email protected]. (2)1st Department of Neurology, Aeginition Hospital, Faculty of Medicine, National Kapodistrian University of Athens, Vas. Sofias Ave. 72-74, GR-11528 Athens, Greece. (3)Department of Neurology, Army Share Fund Hospital (NIMTS), Monis Petraki 10- 12, GR-11521 Athens, Greece. BACKGROUND: Cognitive impairment (CI) has been associated with numerous magnetic resonance imaging (MRI) indices in multiple sclerosis (MS) patients. In this study we investigated the association of a large set of 2D and 3D MRI markers with cognitive function in MS. METHODS: A sample of 61 RRMS patients (mean age 41.8 ± 10.6 years old, 44 women, mean disease duration 137.9 ± 83.9 months) along with 51 age and gender matched healthy controls was used in this cross-sectional study. Neuropsychological and other tests, along with a large set of 2D/3D MRI evaluations were made. RESULTS: 44.3% of patients had CI. CI patients had more disability, physical fatigue than non- CI patients and more psychological distress than non-CI patients and HCs. Also, CI patients had significantly larger third ventricle width and volume, smaller coprus callosum index and larger lesion volume than non-CI patients. These MRI markers also significantly predicted cognitive scores after adjusting for age and education, explaining about 30.6% of the variance of the total cognitive score. CONCLUSIONS: Selected linear and volumetric MRI indices predict cognitive function in MS. Future studies should expand these results by exploring longitudinal changes and producing normative data. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.003 PMID: 29438835
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 245 – Multiple Sklerose: Veröffentlichungen Oktober 2013
265. Mult Scler Relat Disord. 2018 Feb 6;20:220-222. doi: 10.1016/j.msard.2018.02.004. [Epub ahead of print] Early relapse after RTX initiation in a patient with NMO/MS overlap syndrome: How long to conclude to a failure treatment? Maillart E(1), Lippi A(2), Lubetzki C(3), Louapre C(3), Papeix C(3). Author information: (1)AP-HP, Neurology Department, Pitié-Salpêtrière hospital, 47-83 Boulevard de l'Hôpital, F-75013 Paris, France. Electronic address: [email protected]. (2)AP-HP, Neurology Department, Pitié-Salpêtrière hospital, 47-83 Boulevard de l'Hôpital, F-75013 Paris, France; Neurology Department, Gui de Chauliac University Hospital, Montpellier, France. (3)AP-HP, Neurology Department, Pitié-Salpêtrière hospital, 47-83 Boulevard de l'Hôpital, F-75013 Paris, France. BACKGROUND: We report a dramatic clinical and radiological worsening within two months after rituximab initiation in a patient with NeuroMyelitis Optica/Multiple Sclerosis (NMO/MS) overlap syndrome. METHODS: Case study. RESULTS: A 45-year-old Caucasian woman with NMO/MS overlap syndrome experienced a severe myelitis nine weeks after first rituximab infusion, with extensive new gadolinium-enhanced spinal cord lesions. CONCLUSION: This case report illustrates the limits of MS and NMO-Spectrum Disorder classification and challenges the criteria of therapeutic failure within the 6 months after rituximab initiation. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.004 PMID: 29433095
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 246 – Multiple Sklerose: Veröffentlichungen Oktober 2013
266. Mult Scler Relat Disord. 2018 Feb 5;20:215-219. doi: 10.1016/j.msard.2018.02.002. [Epub ahead of print] Fingolimod reduces the clinical expression of active demyelinating lesions in MS. Signoriello E(1), Landi D(2), Monteleone F(3), Saccà F(4), Carolina NG(3), Buttari F(3), Sica F(5), Girolama AM(3), Di Iorio G(1), Lus G(1), Centonze D(3). Author information: (1)Multiple Sclerosis Center, II Division of Neurology, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Napoli, Italy. (2)Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University, Via Montpellier 1, 00133 Rome, Italy; IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Neurology and Neurorehabilitation Units, Via Atinense 18, 86077 Pozzilli, (IS), Italy. Electronic address: [email protected]. (3)Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University, Via Montpellier 1, 00133 Rome, Italy; IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Neurology and Neurorehabilitation Units, Via Atinense 18, 86077 Pozzilli, (IS), Italy. (4)Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, 80131, Napoli, Italy. (5)IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Neurology and Neurorehabilitation Units, Via Atinense 18, 86077 Pozzilli, (IS), Italy. BACKGROUND: Fingolimod is a modulator of Central and peripheral sphingosine pathways, which is currently approved for treatment of Multiple Sclerosis (MS). In animal models it reduces inflammation, but it is also able to potentiate glutamatergic transmission and synaptic plasticity. We aimed to explore whether Fingolimod is able to modify the clinical expression of new demyelinating lesions with respect to IFNβ-1a in relapsing remitting MS (RRMS) patients suboptimal responders to IFNβ-1a. METHODS: 103 patients with RRMS switching for inefficacy from IFNβ-1a to Fingolimod and treated for at least 12 months were included. Annualised Relapse Rate (ARR), EDSS and the number of new brain and spinal gadolinium enhancing (Gd +) and T2 lesions were retrospectively assessed in the whole group during each treatment period. The likelihood of co-occurrence of new Gd + lesions and clinical relapses during IFNβ-1a and Fingolimod treatment was analysed. RESULTS: The mean duration of treatment with IFNβ-1a and Fingolimod was 3.14 (SD 1.6) and 3.22 years (SD 1.1) respectively. Significant reduction of ARR (p < .001), total number of Gd + and T2 lesions (p < .001) was found switching from IFNβ-1a to Fingolimod. Gd + lesions occurring during treatment with Fingolimod were more likely to be asymptomatic compared with IFNβ-1a (88% vs 30.9%, p = < .025). CONCLUSION: Fingolimod reduces clinical and radiological inflammation in MS. Additionally, it limits the clinical expression of new Gd + lesions, possibly reducing local inflammatory processes and improving brain network plasticity in patients with suboptimal response to IFNβ-1a. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.002 PMID: 29433094
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 247 – Multiple Sklerose: Veröffentlichungen Oktober 2013
267. Mult Scler Relat Disord. 2018 Feb 5;20:210-214. doi: 10.1016/j.msard.2018.02.001. [Epub ahead of print] Why do people search Wikipedia for information on multiple sclerosis? Brigo F(1), Lattanzi S(2), Bragazzi N(3), Nardone R(4), Moccia M(5), Lavorgna L(6). Author information: (1)Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy; Department of Neurology, Franz Tappeiner Hospital, Merano, Italy. Electronic address: [email protected]. (2)Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy. (3)Department of Health Sciences, University of Genoa, Genoa, Italy. (4)Department of Neurology, Franz Tappeiner Hospital, Merano, Italy; Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria. (5)Department of Neuroscience, Federico II University of Naples, Naples, Italy. (6)Clinic of Neurology, University of Campania "Luigi Vanvitelli", Naples, Italy. BACKGROUND: Wikipedia is a frequently-accessed online source of health-related information. In this study we evaluated the number of views of the Italian Wikipedia articles related to multiple sclerosis (MS) and its treatment. METHODS: Using Pageviews Analysis we assessed the total views, and mean monthly and daily views of the Italian Wikipedia articles on MS and its treatments from 1 January 2015 to 31 October 2017. We compared the views of the article on MS with those for Alzheimer´s disease, epilepsy, migraine and stroke, and adjusted results for crude disease prevalence. RESULTS: The total views of the Italian Wikipedia article on MS was 929,983 (mean monthly views: 33,214; mean daily views: 1089). The adjusted views for the Italian Wikipedia article on MS were higher than those for the other neurological disorders. The normalized views for the MS article were 16, 7, 145 and 11 times higher than those of the articles on Alzheimer's disease, epilepsy, migraine and stroke, respectively. Peaks were temporally related to famous people with MS talking about their disease in talk shows on television or to news on novel treatments for MS. CONCLUSION: Wikipedia searches do not reliably reflect its actual epidemiology. Celebrities with MS acting as testimonials might effectively increase public knowledge on MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.001 PMID: 29428464
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268. Mult Scler Relat Disord. 2018 Feb 2;21:46-50. doi: 10.1016/j.msard.2018.01.020. [Epub ahead of print] The interplay of multiple sclerosis and menstrual cycle: Which one affects the other one? Mirmosayyeb O(1), Badihian S(1), Manouchehri N(1), Basiri AK(2), Barzegar M(2), Esmaeil N(3), Fayyazi E(2), Shaygannejad V(4). Author information: (1)Isfahan Neurosciences Research Center, Alzahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran; Student Research Committee, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. (2)Isfahan Neurosciences Research Center, Alzahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran. (3)Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. (4)Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: [email protected]. BACKGROUND: Menstruation is suggested to affect multiple sclerosis (MS) symptoms, while the effect of MS on menstruation is not studied before. Here, we aimed to compare the pattern of menstrual cycle and its symptoms between MS patients and healthy controls. METHODS: This is a cross-sectional study conducted during 2015-2016 in MS clinic of Kashani hospital, Isfahan, Iran. We included female patients > 14 years with diagnosis of relapsing-remitting MS, and healthy subjects as the control group. We collected data regarding menarche age, menstrual characteristics, history of premenstrual syndrome, the amount of menstrual bleeding, and the possible perimenstrual symptoms from all subjects. Also, MS patients were asked to report changes in menstrual characteristics after MS occurrence. RESULTS: The final study population contained 181 MS patients and 202 healthy subjects. The mean age in MS and control group were 36.04 ± 9.86 and 35.16 ± 11.30, respectively (P-value = 0.426). Menarche age in MS patients and control group were not statistically different (13.59 ± 1.87 and 13.29 ± 1.53, respectively; P-value = 0.087). Changing menstrual characteristics was reported in 70 MS patients (38.7%). Irregular menstrual cycle increased from 21% to 40.3% after occurrence of MS (P-value < 0.001) and was reported 24.7% in the control group. MS patients versus controls reported more symptoms before, during, and after their menstrual period (P-values < 0.001). CONCLUSION: We found no difference regarding menstrual characteristics in MS patients before onset of the disease and healthy controls. Irregular menstrual cycle was observed more after the disease occurrence while other menstrual characteristics did not change. Moreover, MS patients reported many more perimenstrual symptoms. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.01.020 PMID: 29455074
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 249 – Multiple Sklerose: Veröffentlichungen Oktober 2013
269. Mult Scler Relat Disord. 2018 Feb 2;20:199-203. doi: 10.1016/j.msard.2018.01.027. [Epub ahead of print] Predicting falls in multiple sclerosis: Do electrophysiological measures have a better predictive accuracy compared to clinical measures? Chinnadurai SA(1), Gandhirajan D(2), Srinivasan AV(3), Kesavamurthy B(3), Ranganathan LN(3), Pamidimukkala V(2). Author information: (1)Institute of Neurology, Madras Medical College, Chennai 600003, Tamilnadu, India. Electronic address: [email protected]. (2)Lalitha Super Specialty Hospital, Kothapet, Guntur 522001, Andhra Pradesh, India. (3)Institute of Neurology, Madras Medical College, Chennai 600003, Tamilnadu, India. BACKGROUND: The risk of falls in people with Multiple Sclerosis (MS) is much greater than that of the general population due to impaired coordination, gait, sensation, muscle tone, strength, and cognition. These MS related falls hamper the day to day living of these individuals and are one of the prime factors aggravating the disease related morbidity. The fear of falling itself may make these individuals more dependent and hinder their professional and leisurely activities. Hence, the significance of identifying individuals who are at risk of falling and instituting preventive counter- measures cannot be overemphasized. Various simple clinical tests and questionnaires have been recommended for this purpose, but are far from ideal. OBJECTIVE: The objective was to find accurate measures to predict a future fall in MS patients. We also aimed to enquire about the prevalence of falls in MS population and its clinical profile which included detailed history about the past falls, Expanded disability status scale (EDSS) scores, Timed 25 foot walk (T25FW) scores, Activities specific balance confidence (ABC) scores, Falls efficacy scale international (FESI) scores, Multiple Sclerosis Walking Scale 12 (MSWS12) questionnaire. DESIGN/METHODS: This was a prospective cohort study conducted at the Institute of Neurology, Chennai from January 2015 to August 2017. MS patients of any subtype attending Neurology OPD satisfying revised 2010 McDonald criteria were recruited. 134 subjects with MS consented to participate in this study and 113 of them who met the criteria were included. Baseline history was obtained about the number of falls in the previous year. EDSS, T25FW, ABC, FESI, and MSWS12 scores were obtained at the baseline. VEMP and SEP tests were done and the baseline P13/N23 cVEMP latencies, N10 oVEMP latency, and P37 lower limb SEP latency were obtained. These subjects were followed up for one year and were enquired if they had fallen during that period and the number of falls was recorded. Logistic regression models were used to compute the area under receiver operating characteristic curve (AUC) for each variable tested. Pearson correlation coefficients were calculated for each variable with the number of future falls. RESULTS: Among the 113 patients, 72% (n = 81) had one or more falls during follow-up. Among all variables tested P13 cervical VEMP latency had the highest predictive accuracy (AUC = 0.820) followed by N10 ocular VEMP latency (AUC = 0.794) and P37 SEP latency (AUC = 0.732). P13 latency also had the highest correlation coefficient (R = 0.689, R2 = 0.475) with the number of future falls. CONCLUSION: P13, N10 and P37 latencies were the most accurate in predicting a future fall when compared to clinical measures. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.027 PMID: 29414299
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 250 – Multiple Sklerose: Veröffentlichungen Oktober 2013
270. Mult Scler Relat Disord. 2018 Feb 2;20:181-185. doi: 10.1016/j.msard.2018.01.024. [Epub ahead of print] Knee flexor strength and balance control impairment may explain declines during prolonged walking in women with mild multiple sclerosis. Ramari C(1), Moraes AG(2), Tauil CB(3), von Glehn F(4), Motl R(5), de David AC(6). Author information: (1)Faculty of Physical Education, University of Brasília, DF, Brazil. Electronic address: [email protected]. (2)Faculty of Physical Education, University of Brasília, DF, Brazil. Electronic address: [email protected]. (3)Base Hospital, Department of Neurology, Brasília, DF, Brazil; Faculty of Medicine, University of Brasília, DF, Brazil. Electronic address: [email protected]. (4)Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected]. (5)Department of Physical Therapy, University of Alabama at Birmingham, AL, United States. Electronic address: [email protected]. (6)Faculty of Physical Education, University of Brasília, DF, Brazil. Electronic address: [email protected]. BACKGROUND: Physiological factors such as muscle weakness and balance could explain declines in walking distance by multiple sclerosis (MS) patients. The purpose of this study was to characterize levels and examine associations among decline in walking distance, balance and muscular strength in women with mild MS. METHODS: Participants included 28 women with mild relapsing-remitting MS and 21 women without MS. We executed the 6-min walk test (6MWT) to verify declines in walking distance. Isokinetic knee flexion (KF) and extension (KE) muscle strength was measured using a dynamometer. Balance was quantified using a force platform, with eyes open and closed, on a rigid and foam surface. RESULTS: The MS patients presented declines in walking, lower KF muscle strength, and worse balance than controls. KF strength and balance correlated with walking in the MS group. The KF strength explained differences between groups in walking. The KF strength and balance presented as predictors of walking slowing down in the 6MWT, in mild MS. CONCLUSION: Women with mild MS have strength impairment of knee flexor muscles and balance control impairment that may explain walking related motor fatigability during prolonged walking. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.024 PMID: 29414295
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 251 – Multiple Sklerose: Veröffentlichungen Oktober 2013
271. Mult Scler Relat Disord. 2018 Feb 14;21:69-70. doi: 10.1016/j.msard.2018.02.015. [Epub ahead of print] A case of dextrocardia following maternal exposure to generic Fingolimod during the first trimester of pregnancy. Navardi S(1), Sahraian MA(2). Author information: (1)MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Iranian Center for Neurological Research, Neuroscience Institute, Tehran University of Medical Science, Tehran, Iran. (2)MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Iranian Center for Neurological Research, Neuroscience Institute, Tehran University of Medical Science, Tehran, Iran. Electronic address: [email protected]. Fingolimod, taken orally once per day, is approved for the treatment of relapsing-remitting multiple sclerosis (MS). It should be stopped at least two months before conception as it is not considered safe during pregnancy or when breast feeding. In vitro and animal studies have found a possibly increased risk of congenital abnormalities following exposure to Fingolimod. Here, we report a 34-year-old female, with a 10-year history of MS who had unexpected pregnancy with exposure to generic Fingolimod during the first 7 weeks. The infant was born with dextrocardia, but without any further structural cardiac or other abnormalities. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.015 PMID: 29474980
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 252 – Multiple Sklerose: Veröffentlichungen Oktober 2013
272. Mult Scler Relat Disord. 2018 Feb 12;21:51-55. doi: 10.1016/j.msard.2018.02.016. [Epub ahead of print] Prevalence of multiple sclerosis in Poland. Kapica-Topczewska K(1), Brola W(2), Fudala M(2), Tarasiuk J(3), Chorazy M(3), Snarska K(4), Kochanowicz J(3), Kulakowska A(3). Author information: (1)Department of Neurology, Medical University of Bialystok, Bialystok, Poland. Electronic address: [email protected]. (2)Department of Neurology, Specialist Hospital, Konskie, Poland. (3)Department of Neurology, Medical University of Bialystok, Bialystok, Poland. (4)Department of Clinical Medicine, Medical University of Bialystok, Bialystok, Poland. OBJECTIVE: The prevalence of multiple sclerosis (MS)was previously unknown in Poland. The aim of this study was to determine the prevalence of MS in Poland. METHODS: MS prevalence was determined on the basis of data from the Swietokrzyskie (central Poland) and Podlaskie (northeastern Poland) Voivodeships. The area population on the prevalence study day (December 31, 2013) was 1,268,239 (649,007 women; 619,232 men) in central and 1,195,625 (612,979 women; 582,646 men) in northeastern Poland. RESULTS: The overall crude prevalence rate of confirmed MS patients was 109.1/100,000 (95% confidence interval[CI]103.5-115.0) in the Swietokrzyskie and 108.7/100,000 (95% CI 103.0-114.7) in the Podlaskie Voivodeships. A significantly higher prevalence was recorded in females (149.8/100,000, 95% CI 140.6-159.3 vs. 142.4/100,000, 95% CI 133.3-152.0) than in males (66.5/100,000, 95% CI 60.4-73.1 vs.57.8/100,000, 95% CI 52.0-64.2)(p < 0.001). Age-adjusted rates for the Polish Standard Population were the same in both regions (110.3/100,000 (95% CI 104.6- 116.1) vs.110.9/100,000 (95% CI 105.1-117.1)) and for the European Standard Population did not different statistically between both voivodeships (103.9/100,000 (95% CI 98.6-109.5) vs.108.5/100,000 (95% CI 102.7-114.5)). CONCLUSION: This is the first data that obtained the level of MS prevalence in Poland and confirmed that Poland is a high-risk area for multiple sclerosis. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.016 PMID: 29455075
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 253 – Multiple Sklerose: Veröffentlichungen Oktober 2013
273. Mult Scler Relat Disord. 2018 Feb 12;21:19-23. doi: 10.1016/j.msard.2018.02.012. [Epub ahead of print] The influence of biogenic amines on Th17-mediated immune response in multiple sclerosis. Melnikov M(1), Rogovskii V(2), Boyko A(3), Pashenkov M(4). Author information: (1)Department of Neurology, Neurosurgery and Medical Genetics of Pirogov Russian National Research Medical University, 117997 Moscow, Russia; Laboratory of Clinical Immunology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency, 115478 Moscow, Russia. Electronic address: [email protected]. (2)Department of Molecular Pharmacology and Radiobiology of Pirogov Russian National Research Medical University, 117997 Moscow, Russia. (3)Department of Neurology, Neurosurgery and Medical Genetics of Pirogov Russian National Research Medical University, 117997 Moscow, Russia. (4)Laboratory of Clinical Immunology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency, 115478 Moscow, Russia. Biogenic amines are direct mediators of interactions between immune and nervous systems implicated in the pathogenesis of multiple sclerosis (MS). Recently, great attention has been drawn to studying the effects of biogenic amines on Th17-cells, which play one of the central roles in the development of inflammatory lesions in MS. Results of these studies suggest that, depending on the activation of particular receptors, biogenic amines can both enhance and inhibit Th17-cell functions. Based on these data, targeting biogenic amines and their receptors could be explored as a new kind of additional disease-modifying treatment of MS. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.02.012 PMID: 29454152
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274. Mult Scler Relat Disord. 2018 Feb 11;21:56-62. doi: 10.1016/j.msard.2018.02.010. [Epub ahead of print] Predictors of retinal atrophy in multiple sclerosis: A longitudinal study using spectral domain optical coherence tomography with segmentation analysis. Behbehani R(1), Adnan H(2), Al-Hassan AA(2), Al-Salahat A(3), Alroughani R(4). Author information: (1)Al-Bahar Ophthalmology Center, Ibn Sina Hospital, Kuwait; Neurology Clinic, Dasman Institute, Dasman, Kuwait; Division of Neurology, Department of Medicine, Amiri Hospital, Kuwait. Electronic address: [email protected]. (2)Al-Bahar Ophthalmology Center, Ibn Sina Hospital, Kuwait; Neurology Clinic, Dasman Institute, Dasman, Kuwait. (3)Neurology Clinic, Dasman Institute, Dasman, Kuwait; Neurology Department, Farwaniya Hospital, Kuwait. (4)Neurology Department, Farwaniya Hospital, Kuwait; Division of Neurology, Amiri Hospital, Sharq, Kuwait; Division of Neurology, Department of Medicine, Amiri Hospital, Kuwait. BACKGROUND: Multiple sclerosis is an inflammatory demyelinating disease characterized by progressive axonal loss affecting mainly the inner retinal layers. Optical coherence tomography (OCT) provides in-vivo quantification of the retinal layers and allows measuring progressive retinal changes. Our objective was to assess the longitudinal changes in the retina using spectral domain OCT (SDOCT) and to identify independent predictors affecting retinal thinning in MS patients. METHODS: A prospective study in a tertiary care MS center was conducted to study the longitudinal retinal changes in MS patients. All subjects underwent baseline and follow up OCT assessment with segmentation analysis. Regression analysis was performed to assess clinical factors (age, sex, disease duration, history of optic neuritis before baseline, non-ocular clinical relapses) and MRI disease activity during the follow-up period. RESULTS: The study included 102 MS patients with a mean follow-up duration of 3.9 ± SD years. At the last follow-up assessments, there were significant thinning of the average macular thickness (AMT) (p < .001), macular nerve fiber layer (MRNFL) (p < .001), ganglion cell-inner plexiform layer (GCIPL) (p < .001), and the peripapillary nerve fiber layer (PRNFL) (p < .001), compared to baseline. Early disease duration up to 10 years was associated with thinning of AMT, PRNFL, and GCIPL, while longer disease duration (> 15 years) was associated with only GCIPL thinning. Prior optic neuritis was predictive of more thinning of PRNFL (p = < .01), while MRI activity and female gender were significantly associated with more MRNFL thinning (p = < .01). CONCLUSION: MS is associated with longitudinal thinning affecting AMT inner retinal layers (MRNFL, GCIPL, PRNFL). Early disease duration, female gender, MRI activity, and prior optic neuritis were predictive of faster rate of neuro-axonal loss. This may have implications in the design of future therapeutic trials. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.010 PMID: 29459346
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275. Mult Scler Relat Disord. 2018 Feb 11;21:24-29. doi: 10.1016/j.msard.2018.02.013. [Epub ahead of print] Muscle carnosine in experimental autoimmune encephalomyelitis and multiple sclerosis. Keytsman C(1), Blancquaert L(2), Wens I(3), Missine M(2), Noten PV(3), Vandenabeele F(3), Derave W(2), Eijnde BO(3). Author information: (1)REVAL Rehabilitation Research Center, BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Agoralaan Building A, Diepenbeek, Belgium. Electronic address: [email protected]. (2)Department of Movement and Sports Sciences, Ghent University, Ghent, Belgium. (3)REVAL Rehabilitation Research Center, BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Agoralaan Building A, Diepenbeek, Belgium. BACKGROUND: Muscle carnosine is related to contractile function (Ca++ handling) and buffering of exercise-induced acidosis. As these muscular functions are altered in Multiple Sclerosis (MS) it is relevant to understand muscle carnosine levels in MS. METHODS: Tibialis anterior muscle carnosine was measured in an animal MS model (EAE, experimental autoimmune encephalomyelitis, n = 40) and controls (CON, n = 40) before and after exercise training (EAEEX, CONEX, 10d, 1 h/d, 24 m/min treadmill running) or sedentary conditions (EAESED, CONSED). Human m. vastus lateralis carnosine of healthy controls (HC, n = 22) and MS patients (n = 24) was measured. RESULTS: EAE muscle carnosine levels were decreased (p < .0001) by ~ 40% to ~ 64% at 10d and 17d following EAE induction (respectively) regardless of exercise (p = .823). Similarly, human MS muscle carnosine levels were decreased (- 25%, p = .03). CONCLUSION: Muscle carnosine concentrations in an animal MS model and MS patients are substantially reduced. In EAE exercise therapy does not restore this. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.013 PMID: 29454153
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276. Mult Scler Relat Disord. 2018 Feb 10;21:71-77. doi: 10.1016/j.msard.2018.02.009. [Epub ahead of print] Factors associated with excessive sitting time in multiple sclerosis. Sasaki JE(1), Motl RW(2), Cutter G(3), Marrie RA(4), Tyry T(5), Salter A(6). Author information: (1)Department of Physical Therapy, School of Health Professions, University of Alabama at Birmingham, Birmingham, AL, United States. Electronic address: [email protected]. (2)Department of Physical Therapy, School of Health Professions, University of Alabama at Birmingham, Birmingham, AL, United States. (3)Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States. (4)Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. (5)Dignity Health, St Joseph's Hospital and Medical Center, Phoenix, AZ, United States. (6)Division of Biostatistics, School of Medicine, Washington University, St Louis, MO, United States. OBJECTIVE: The objective of this study was to examine the sociodemographic, clinical, and behavioral factors associated with excessive sitting time in persons with multiple sclerosis (MS). METHODS: Useful data were obtained from 6483 persons with MS who completed the semi-annual survey of the North American Research Committee on Multiple Sclerosis registry conducted in the spring of 2015. Sociodemographic, clinical, and behavioral data were collected using self-report questionnaires. Sitting time per day was determined using the International Physical Activity Questionnaire. We conducted data analyses in May-June 2017 and defined those classified above the 75th percentile of sitting time as excessive sitters. Multivariate binary logistic regression was used to calculate the odds ratios for being an excessive sitter for sociodemographic, clinical, and behavioral variables. RESULTS: The results indicated that participants who were moderately disabled, severely disabled but ambulatory, or severely disabled but non-ambulatory were 1.57, 2.62, and 8.70 times more likely to be excessive sitters than those reporting mild disability. Persons with MS who were insufficiently active were 2.61 times more likely to be excessive sitters than persons who were sufficiently active. CONCLUSION: This study identified disability status and physical activity levels as two prominent factors associated with the likelihood of being an excessive sitter in MS and this will inform the design of future interventions for reducing sedentary behavior in this population. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.02.009 PMID: 29477021
277. Mult Scler Relat Disord. 2018 Feb 10;21:63-68. doi: 10.1016/j.msard.2018.01.030. [Epub ahead of print] The value of tests evaluating visual functions in detecting overt or subclinical optic neuritis in multiple sclerosis. Öcek Ö(1), Gedizlioğlu M(2), Köşkderelioğlu A(2), Ortan PK(2), Yüksel B(3), Türe M(4), Gediz F(3). Author information: (1)Izmir Bozyaka Education and Research Hospital, Clinic of Neurology, Turkey. Electronic address: [email protected]. (2)Izmir Bozyaka Education and Research Hospital, Clinic of Neurology, Turkey. (3)Izmir Bozyaka Education and Research Hospital, Clinic of Ophthalmology, Turkey. (4)Atagoz Ophthalmological Diseases Hospital, Turkey. DOI: 10.1016/j.msard.2018.01.030 PMID: 29471193
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278. Mult Scler Relat Disord. 2018 Feb 1;20:205-209. doi: 10.1016/j.msard.2018.01.029. [Epub ahead of print] Cardiac repolarization evolves differently during the course of benign and disabling multiple sclerosis. Mikkola A(1), Ojanen A(2), Hartikainen JE(3), Remes AM(4), Simula S(5). Author information: (1)Department of Neurology, Kuopio University Hospital and Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland. Electronic address: [email protected]. (2)Department of Clinical Physiology and Nuclear Medicine, Mikkeli Central Hospital, Mikkeli, Finland. Electronic address: [email protected]. (3)Heart Center, Kuopio University Hospital and Institute of Clinical Medicine - Medicine, University of Eastern Finland, Kuopio, Finland. Electronic address: [email protected]. (4)Department of Neurology, Kuopio University Hospital and Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland; Medical Research Center, Oulu University Hospital, Oulu, Finland; Research Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland. Electronic address: [email protected]. (5)Department of Neurology, Mikkeli Central Hospital, Mikkeli, Finland. Electronic address: [email protected]. BACKGROUND: Cardiac repolarization is modulated by the autonomic nervous system. Even though multiple sclerosis associates with prolonged cardiac repolarization the physiology responsible for the phenomenon remains unknown. OBJECTIVE: To study in longitudinal setting whether the patients with confirmed benign and disabling outcome of relapsing-remitting multiple sclerosis (RRMS) differ in regard to changes of cardiac repolarization. METHODS: Total of 43 patients, 26% with benign (EDSS ≤2 at least 10y after onset symptom) and 74% with disabling (EDSS >2 at least 10y after onset symptom) RRMS, having 12-lead electrocardiogram (ECG) recorded at the time of onset symptom (ECG1) and for follow-up (ECG2), were studied. Heart rate (HR) corrected QT intervals (QTc) reflecting cardiac repolarization were assessed. RESULTS: The time interval between ECG1 and ECG2 showed no statistical difference between benign (7.8 ± 4.8y) and disabling (10.2 ± 5.6y; p = .211) RRMS. Patients with benign and disabling RRMS showed similar values of HR (66±9 bpm vs 73 ± 15 bpm; p=.146) and QTc (403 ± 13 ms vs 408 ± 19 ms; p = .450) at the time of ECG1. However, at the time of ECG2, HR was higher (79 ± 14 bpm vs 65 ± 10 bpm; p = .004) and QTc was longer (420 ± 24 ms vs 400 ± 15 ms; p = .012) in patients with disabling than benign RRMS. Correspondingly, HR increased (p = .063) and QTc prolonged (p = .014) during the disease course only in patients with disabling RRMS. CONCLUSIONS: Deterioration of cardiac autonomic regulation during the disease course associates with disabling but not with benign RRMS. Our findings suggest that assessment of cardiac autonomic regulation should be included in the evaluation of RRMS disease course. In addition, patients with disabling RRMS might be prone to unfavorable cardiovascular outcome also due to deterioration of autonomic nervous system. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.01.029 PMID: 29428463
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279. Mult Scler Relat Disord. 2018 Feb 1;20:204. doi: 10.1016/j.msard.2018.01.028. [Epub ahead of print] Letter to the Editors - Multiple sclerosis and related disorders - Birnbaum et al., 2017. Tourbah A(1), Sedel F. Author information: (1)Department of Neurology, CHU de Reims, and Faculté de Médecine de Reims, URCA, Reims, France, and Laboratoire de Psychopathologie et de Neuropsychologie, LPN 2027 Université Paris 8, Saint-Denis, France. Electronic address: [email protected]. DOI: 10.1016/j.msard.2018.01.028 PMID: 29414300
280. Mult Scler Relat Disord. 2018 Feb 1;20:178-180. doi: 10.1016/j.msard.2018.01.025. [Epub ahead of print] Multiple sclerosis onset after granulocyte macrophage colony-stimulating factor withdrawal. Chong J(1), Cohen M(2), Waubant E(3). Author information: (1)UCSF Multiple Sclerosis Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA. (2)Palo Alto Medical Foundation, 1501 Trousdale Drive, Burlingame, CA 94010, USA. (3)UCSF Multiple Sclerosis Center, 675 Nelson Rising Lane, San Francisco, CA 94158, USA. Electronic address: [email protected]. A 51-year old woman with stage III melanoma participated in a phase II clinical trial in which she received subcutaneous rhGM-CSF injections for 3 years. She was in remission by the end of the trial. Seven months after discontinuing GM-CSF she had her first MS event. The unique timeline of rh-GM- CSF injections in a melanoma trial, during which yearly MRI scans showed subtle stable demyelination followed by RRMS onset shortly after discontinuation of treatment, may provide some insight on the role of GM-CSF in MS. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.01.025 PMID: 29414294
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281. Mult Scler Relat Disord. 2018 Feb 1;20:169-177. doi: 10.1016/j.msard.2018.01.021. [Epub ahead of print] Physical activity and disability outcomes in multiple sclerosis: A systematic review (2011-2016). Charron S(1), McKay KA(2), Tremlett H(3). Author information: (1)Department of Medicine (Neurology) and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; School of Kinesiology, University of British Columbia, Vancouver, BC, Canada. (2)Department of Medicine (Neurology) and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada. (3)Department of Medicine (Neurology) and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada. Electronic address: [email protected]. BACKGROUND: Physical activity may be neuroprotective in multiple sclerosis (MS). One review (2011) of exercise and MS disability was inconclusive, but highlighted the need for more studies. OBJECTIVE: To perform an updated systematic literature review examining the relationship between physical activity and physical ability outcomes in persons with MS. METHODS: EMBASE and MEDLINE were searched for original interventional studies (2011-2016) evaluating exercise on quantitative outcomes of physical disability in MS. We also assessed any reported adverse outcomes. RESULTS: Of the 153 articles identified, 12 were included; 3 examined endurance training; 6 resistance training; and 3 explored less conventional exercises, specifically, tai chi, kickboxing, and vestibular rehabilitation, each lasting 5-24 weeks. In total, 568 unique individuals were included, and >10 different scales used to assess outcomes. Endurance training provided benefits in walking ability, while mindfulness exercises (tai chi and vestibular rehabilitation), and dynamic workouts (kickboxing) led to improvements in balance and coordination. Resistance training alone did not improve walking ability, but improved lower limb muscular strength and endurance. When resistance and endurance training were combined, improvements were seen in mobility, balance and coordination. Four studies assessed discontinuation; most reported a return to pre-intervention function. Adverse outcomes were reported in 6 studies, and appeared generally mild, ranging from mild muscle soreness to exacerbation of MS symptoms. CONCLUSIONS: Physical activity was associated with measurable benefits on ability outcomes, but continuation is likely required to maintain benefits. While adverse events were generally mild, approximately half of studies actually reported safety outcomes. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.01.021 PMID: 29414293
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282. Muscle Nerve. 2018 Feb 21. doi: 10.1002/mus.26106. [Epub ahead of print] Correlating serum microRNAs and clinical parameters in Amyotrophic lateral sclerosis. Raheja R(1), Regev K(2), Healy BC(1), Mazzola MA(1), Beynon V(1), von Glehn F(1), Paul A(1), Diaz- Cruz C(1), Gholipour T(1), Glanz BI(1), Kivisakk P(1), Chitnis T(1), Weiner HL(1), Berry JD(3), Gandhi R(1). Author information: (1)Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital, Harvard Medical School, Boston, USA. (2)Tel Aviv Sourasky Medical Center, Neurology, Tel Aviv, Israel. (3)Neurological Clinical Research Institute, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a debilitating neurologic disorder with poor survival rates and no clear biomarkers for disease diagnosis and prognosis. METHODS: We compared serum miRNA expression from patients with ALS to healthy controls and patients with multiple sclerosis and Alzheimer's disease. We also correlated miRNA expression in cross-sectional and longitudinal cohorts of ALS patients with clinical parameters. RESULTS: We identified 7 microRNAs (miR-192-5p, miR-192-3p, miR-1, miR-133a-3p, miR-133b, miR-144-5p and miR-19a-3p) that were upregulated and 6 microRNAs (miR-320c, miR-320a, let-7d-3p, miR-425-5p, miR-320b and miR-139-5p) that were downregulated in ALS patients compared to healthy controls, Alzheimer's disease and multiple sclerosis patients. Changes in 4 miRNAs (miR-136-3p, miR-30b-5p, miR-331-3p, and miR-496) correlated positively and change in 1 microRNA (miR-2110) correlated negatively with changes in clinical parameters in longitudinal analysis. DISCUSSION: Our findings identified serum microRNAs that can serve as biomarkers for ALS diagnosis and progression. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/mus.26106 PMID: 29466830
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283. Nat Commun. 2018 Feb 7;9(1):539. doi: 10.1038/s41467-018-02926-5. A transcriptomic atlas of aged human microglia. Olah M(1)(2), Patrick E(3), Villani AC(2)(4), Xu J(2), White CC(2), Ryan KJ(5), Piehowski P(6), Kapasi A(6), Nejad P(2), Cimpean M(5), Connor S(1)(2), Yung CJ(1), Frangieh M(5), McHenry A(5), Elyaman W(1)(2), Petyuk V(6), Schneider JA(7), Bennett DA(7), De Jager PL(8)(9), Bradshaw EM(10)(11). Author information: (1)Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, 10032, USA. (2)Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA. (3)School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales, 2006, Australia. (4)Massachusetts General Hospital, Boston, MA, 02114, USA. (5)Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. (6)Pacific Northwest National Laboratory, Richland, WA, 99354, USA. (7)Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, 60612, USA. (8)Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, 10032, USA. [email protected]. (9)Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA. [email protected]. (10)Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, 10032, USA. [email protected]. (11)Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA. [email protected]. With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding of what constitutes the phenotype of aged human microglia-the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neurodegenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer's disease and multiple sclerosis, to be increased with advancing age, and to be reduced by the protective APOEε2 haplotype. APOEε4 has no effect. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging. DOI: 10.1038/s41467-018-02926-5 PMCID: PMC5803269 PMID: 29416036
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284. Nat Commun. 2018 Feb 26;9(1):819. doi: 10.1038/s41467-018-03186-z. EGFL7 reduces CNS inflammation in mouse. Larochelle C(1)(2)(3), Uphaus T(1), Broux B(2)(3), Gowing E(2)(3), Paterka M(1), Michel L(2)(3), Dudvarski Stankovic N(4)(5)(6), Bicker F(4), Lemaître F(2)(3), Prat A(2)(3), Schmidt MHH(4), Zipp F(7). Author information: (1)Department of Neurology, Focus Program Translational Neuroscience (FTN), Research Center Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. (2)Neuroimmunology Unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada. (3)Department of Neuroscience, Faculty of Medicine, Université de Montréal, 900 rue St-Denis, Montréal, H2X OA9, QC, Canada. (4)Molecular Signal Transduction Laboratories, Institute of Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. (5)German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. (6)German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. (7)Department of Neurology, Focus Program Translational Neuroscience (FTN), Research Center Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. [email protected]. Extracellular matrix (ECM) proteins secreted by blood-brain barrier (BBB) endothelial cells (ECs) are implicated in cell trafficking. We discovered that the expression of ECM epidermal growth factor-like protein 7 (EGFL7) is increased in the CNS vasculature of patients with multiple sclerosis (MS), and in mice with experimental autoimmune encephalomyelitis (EAE). Perivascular CD4 T lymphocytes colocalize with ECM-bound EGFL7 in MS lesions. Human and mouse activated T cells upregulate EGFL7 ligand αvβ3 integrin and can adhere to EGFL7 through integrin αvβ3. EGFL7-knockout (KO) mice show earlier onset of EAE and increased brain and spinal cord parenchymal infiltration of T lymphocytes. Importantly, EC-restricted EGFL7-KO is associated with a similar EAE worsening. Finally, treatment with recombinant EGFL7 improves EAE, reduces MCAM expression, and tightens the BBB in mouse. Our data demonstrate that EGFL7 can limit CNS immune infiltration and may represent a novel therapeutic avenue in MS. DOI: 10.1038/s41467-018-03186-z PMID: 29483510
285. Nat Rev Neurol. 2018 Jan 31;14(2):72-74. doi: 10.1038/nrneurol.2018.3. Multiple sclerosis in 2017: Progress in multiple sclerosis - from diagnosis to therapy. Trojano M(1), Amato MP(2). Author information: (1)Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Italy. (2)Department NEUROFARBA, Section Neurosciences, University of Florence, Italy. DOI: 10.1038/nrneurol.2018.3 PMID: 29384150
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286. Nervenarzt. 2018 Feb 5. doi: 10.1007/s00115-018-0492-6. [Epub ahead of print] [Multiple sclerosis and hepatitis B vaccination : What does the verdict of the European Court of Justice on liability after vaccination mean?] [Article in German] Löbermann M(1), Handorn B(2), Winkelmann A(3), Reisinger EC(4), Hartung HP(5)(6), Zettl UK(3). Author information: (1)Abteilung für Tropenmedizin, Infektionskrankheiten und Sektion Nephrologie, Zentrum für Innere Medizin, Universitätsmedizin Rostock, Ernst Heydemann Straße 6, 18057, Rostock, Deutschland. [email protected]. (2)Simmons & Simmons LLP, München, Deutschland. (3)Zentrum für Nervenheilkunde, Klinik und Poliklinik für Neurologie, Universitätsmedizin Rostock, Rostock, Deutschland. (4)Abteilung für Tropenmedizin, Infektionskrankheiten und Sektion Nephrologie, Zentrum für Innere Medizin, Universitätsmedizin Rostock, Ernst Heydemann Straße 6, 18057, Rostock, Deutschland. (5)Klinik für Neurologie, UKD, Medizinische Fakultät, Heinrich-Heine- Universität Düsseldorf, Düsseldorf, Deutschland. (6)Zentrum für Neurologie und Neuropsychiatrie, LVR Kliniken der HHU, Düsseldorf, Deutschland. In June 2017 the European Court of Justice (ECJ) issued a verdict on the legal assessment of the association between hepatitis B immunization and the subsequent manifestation of multiple sclerosis (MS). This led to a high level of insecurity in the medical field as well as the normal population, especially in MS patients. The aim of this article is to briefly present the evidence-based medical facts and in particular to clearly highlight the legal aspects of the abovenamed ECJ verdict. DOI: 10.1007/s00115-018-0492-6 PMID: 29404651
287. Nervenarzt. 2018 Feb 5. doi: 10.1007/s00115-018-0491-7. [Epub ahead of print] [Coagulation factors and multiple sclerosis : Key factors in the pathogenesis?] [Article in German] Göbel K(1), Kleinschnitz C(2), Meuth SG(3). Author information: (1)Klinik für Allgemeine Neurologie, Universitätsklinikum Münster, Albert- Schweitzer-Campus 1, 48149, Münster, Deutschland. [email protected]. (2)Klinik für Neurologie, Universitätsklinikum Essen, Hufelandstr. 55, 45147, Essen, Deutschland. (3)Klinik für Allgemeine Neurologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Deutschland. Environmental factors and genetic predisposition influence the individual risk to develop multiple sclerosis (MS). Preclinical results in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE), prove a significant contribution of the corpuscular and plasmatic coagulation system for the severity of MS. It was recently shown that key molecules of the coagulation cascade, such as fibrinogen, thrombin and factor XII can influence neuroinflammatory disorders such as MS. The inhibition of both fibrinogen and factor XII led to a significantly improved disease course in animal models. Furthermore, in patients suffering from MS a dysregulation of diverse coagulation factors was demonstrated. The precise role of these changes for the pathogenesis of MS remains to be clarified. Nonetheless, the identification of molecular mechanisms between inflammation and the coagulation cascade might provide completely new perspectives for the therapy of MS; however, as most of the currently available data were obtained from animal models, this knowledge must be interpreted with an adequate degree of caution. DOI: 10.1007/s00115-018-0491-7 PMID: 29404650
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288. Neurobiol Aging. 2017 Dec 30;65:1-6. doi: 10.1016/j.neurobiolaging.2017.12.024. [Epub ahead of print] Estimates of age-dependent cutoffs for pathological brain volume loss using SIENA/FSL-a longitudinal brain volumetry study in healthy adults. Opfer R(1), Ostwaldt AC(2), Sormani MP(3), Gocke C(4), Walker-Egger C(5), Manogaran P(6), De Stefano N(7), Schippling S(5). Author information: (1)Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland; Jung diagnostics GmbH, Hamburg, Germany. Electronic address: [email protected]. (2)Jung diagnostics GmbH, Hamburg, Germany. (3)Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy. (4)Medical Prevention Center Hamburg (MPCH), Hamburg, Germany. (5)Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland. (6)Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland; Department of Information Technology and Electrical Engineering, Swiss Federal Institute of Technology, Zurich, Switzerland. (7)Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy. Brain volume loss (BVL) has gained increasing interest for monitoring tissue damage in neurodegenerative diseases including multiple sclerosis (MS). In this longitudinal study, 117 healthy participants (age range 37.3-82.6 years) received at least 2 magnetic resonance imaging examinations. BVL (in %) was determined with the Structural Image Evaluation using Normalisation of Atrophy/FMRIB Software Library and annualized. Mean BVL per year was 0.15%, 0.30%, 0.46%, and 0.61% at ages 45, 55, 65, and 75 years, respectively. The corresponding BVL per year values of the age-dependent 95th percentiles were 0.52%, 0.77%, 1.05% and 1.45%. Pathological BVL can be assumed if an individual BVL per year exceeds these thresholds for a given age. The mean BVL per year determined in this longitudinal study was consistent with results from a cross-sectional study that was published recently. The cut-off for a pathological BVL per year at the age of 45 years (0.52%) was consistent with the cut-off suggested previously to distinguish between physiological and pathological BVL in MS patients. Different cut-off values, however, need to be considered when interpreting BVL assessed in cohorts of higher ages. Copyright © 2017 Elsevier Inc. All rights reserved. DOI: 10.1016/j.neurobiolaging.2017.12.024 PMID: 29407463
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289. Neurochem Int. 2018 Feb 7. pii: S0197-0186(17)30550-8. doi: 10.1016/j.neuint.2018.02.006. [Epub ahead of print] The small heat shock proteins, especially HspB4 and HspB5 are promising protectants in neurodegenerative diseases. Zhu Z(1), Reiser G(2). Author information: (1)Institut für Inflammation und Neurodegeneration (Neurobiochemie), Otto-von- Guericke-Universität Magdeburg, Medizinische Fakultät, Leipziger Straße 44, 39120 Magdeburg, Germany; College of Medicine, Department of Physiology, University of Kentucky, Lexington, KY, USA. (2)Institut für Inflammation und Neurodegeneration (Neurobiochemie), Otto-von-Guericke- Universität Magdeburg, Medizinische Fakultät, Leipziger Straße 44, 39120 Magdeburg, Germany. Electronic address: [email protected]. Small heat shock proteins (sHsps) are a group of proteins with molecular mass between 12 and 43 kDa. Currently, 11 members of this family have been classified, namely HspB1 to HspB11. HspB1, HspB2, HspB5, HspB6, HspB7, and HspB8, which are expressed in brain have been observed to be related to the pathology of neurodegenerative diseases, including Parkinson's, Alzheimer's, Alexander's disease, multiple sclerosis, and human immunodeficiency virus-associated dementia. Specifically, sHsps interact with misfolding and damaging protein aggregates, like Glial fibrillary acidic protein in AxD, β-amyloid peptides aggregates in Alzheimer's disease, Superoxide dismutase 1 in Amyotrophic lateral sclerosis and cytosine-adenine-guanine/polyglutamine (CAG/PolyQ) in Huntington's disease, Spinocerebellar ataxia type 3, Spinal-bulbar muscular atrophy, to reduce the toxicity or increase the clearance of these protein aggregates. The degree of HspB4 expression in brain is still debated. For neuroprotective mechanisms, sHsps attenuate mitochondrial dysfunctions, reduce accumulation of misfolded proteins, block oxidative/nitrosative stress, and minimize neuronal apoptosis and neuroinflammation, which are molecular mechanisms commonly accepted to mirror the progression and development of neurodegenerative diseases. The increasing incidence of the neurodegenerative diseases enhanced search for effective approaches to rescue neural tissue from degeneration with minimal side effects. sHsps have been found to exert neuroprotective functions. HspB5 has been emphasized to reduce the paralysis in a mouse model of experimental autoimmune encephalomyelitis, providing a therapeutic basis for the disease. In this review, we discuss the current understanding of the properties and the mechanisms of protection orchestrated by sHsps in the nervous system, highlighting the promising therapeutic role of sHsps in neurodegenerative diseases. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.neuint.2018.02.006 PMID: 29425965
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290. Neurochem Res. 2018 Feb 1. doi: 10.1007/s11064-018-2484-0. [Epub ahead of print] PDGF Modulates Synaptic Excitability and Short-Latency Afferent Inhibition in Multiple Sclerosis. Mango D(1), Nisticò R(2)(3), Furlan R(4), Finardi A(4), Centonze D(5)(6), Mori F(7)(8). Author information: (1)Neuropharmacology Unit, EBRI Rita Levi-Montalcini Foundation, Rome, Italy. (2)Neuropharmacology Unit, EBRI Rita Levi-Montalcini Foundation, Rome, Italy. [email protected]. (3)Department of Biology, University of Rome "Tor Vergata", Rome, Italy. [email protected]. (4)Clinical Neuroimmunology Unit, Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy. (5)Neurology and Neurorehabilitation Units, IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, IS, Italy. [email protected]. (6)Multiple Sclerosis Research Unit, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy. [email protected]. (7)Neurology and Neurorehabilitation Units, IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, IS, Italy. (8)Multiple Sclerosis Research Unit, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy. Maintenance of synaptic plasticity reserve is crucial to contrast clinical deterioration in MS and PDGF plays a key role in this phenomenon. Indeed, higher cerebrospinal fluid PDGF concentration correlates with improved clinical recovery after a relapse, and the amplitude of LTP-like cortical plasticity in relapsing-remitting MS patients. However, LTP-like cortical plasticity varies depending on the individual level of inhibitory cortical circuits. Aim of this study was to explore whether PDGF-CSF concentration correlates with inhibitory cortical circuits explored by means of transcranial magnetic stimulation in patients affected by relapsing-remitting MS. We further performed electrophysiological experiments evaluating GABAergic transmission in the experimental autoimmune encephalomyelitis (EAE) hippocampus. Our results reveal that increased CSF PDGF concentration correlates with decreased short afferent inhibition in the motor cortex in MS patients and decreased GABAergic activity in EAE. These findings show that PDGF affects GABAergic activity both in MS patients and in EAE hippocampus. DOI: 10.1007/s11064-018-2484-0 PMID: 29392518
291. Neurodegener Dis Manag. 2018 Feb;8(1):13-15. doi: 10.2217/nmt-2017-0059. Epub 2018 Jan 31. The exciting field of neuro-repair in multiple sclerosis: an interview with Sarah I Sheikh. Sheikh SI(1). Author information: (1)Senior Medical Director, Late Stage Clinical Development at Biogen, Cambridge, MA 02142, USA. Sarah Isabel Sheikh speaks to Laura Dormer, Commissioning Editor: Sarah I Sheikh, MD, MSc, MRCP, is a Senior Medical Director in Late Stage Clinical Development at Biogen. Her current focus is on developing therapies for multiple sclerosis/neuroinflammation, remyelination and neuro-repair. Prior to Biogen, Dr Sheikh was an attending in Neurology at Brigham and Women's Hospital. She completed her internship at Massachusetts General Hospital and residency in Neurology and Neuromuscular fellowship at Massachusetts General Hospital and Brigham and Women's Hospital. She received her medical degree from Oxford University Medical School, and a Masters in cell physiology from Oxford University, Corpus Christi College. She is a member of the Royal College of Physicians, London. DOI: 10.2217/nmt-2017-0059 PMID: 29384036
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292. Neuroimage. 2018 Jan 31;172:357-368. doi: 10.1016/j.neuroimage.2018.01.061. [Epub ahead of print] Deciphering the microstructure of hippocampal subfields with in vivo DTI and NODDI: Applications to experimental multiple sclerosis. Crombe A(1), Planche V(2), Raffard G(3), Bourel J(2), Dubourdieu N(2), Panatier A(2), Fukutomi H(4), Dousset V(5), Oliet S(2), Hiba B(6), Tourdias T(7). Author information: (1)INSERM, U1215, Neurocentre Magendie, F-33000, Bordeaux, France; Univ. Bordeaux, F-33000, Bordeaux, France; CNRS UMR 5536, Centre de Résonance Magnétique des Systèmes Biologiques, F-33000, Bordeaux, France; CHU de Bordeaux, F-33000, Bordeaux, France. (2)INSERM, U1215, Neurocentre Magendie, F-33000, Bordeaux, France; Univ. Bordeaux, F-33000, Bordeaux, France. (3)Univ. Bordeaux, F-33000, Bordeaux, France; CNRS UMR 5536, Centre de Résonance Magnétique des Systèmes Biologiques, F-33000, Bordeaux, France. (4)Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. (5)INSERM, U1215, Neurocentre Magendie, F-33000, Bordeaux, France; Univ. Bordeaux, F- 33000, Bordeaux, France; CHU de Bordeaux, F-33000, Bordeaux, France. (6)Univ. Bordeaux, F- 33000, Bordeaux, France; CNRS UMR 5229, Centre de Neurosciences Cognitives, F-69675, Bron, France. Electronic address: [email protected]. (7)INSERM, U1215, Neurocentre Magendie, F- 33000, Bordeaux, France; Univ. Bordeaux, F-33000, Bordeaux, France; CHU de Bordeaux, F-33000, Bordeaux, France. Electronic address: [email protected]. The hippocampus contains distinct populations of neurons organized into separate anatomical subfields and layers with differential vulnerability to pathological mechanisms. The ability of in vivo neuroimaging to pinpoint regional vulnerability is especially important for better understanding of hippocampal pathology at the early stage of neurodegenerative disorders and for monitoring future therapeutic strategies. This is the case for instance in multiple sclerosis whose neurodegenerative component can affect the hippocampus from the early stage. We challenged the capacity of two models, i.e. the classical diffusion tensor imaging (DTI) model and the neurite orientation dispersion and density imaging (NODDI) model, to compute quantitative diffusion MRI that could capture microstructural alterations in the individual hippocampal layers of experimental-autoimmune encephalomyelitis (EAE) mice, the animal model of multiple sclerosis. To achieve this, the hippocampal anatomy of a healthy mouse brain was first explored ex vivo with high resolution DTI and NODDI. Then, 18 EAE mice and 18 control mice were explored 20 days after immunization with in vivo diffusion MRI prior to sacrifice for the histological quantification of neurites and glial markers in each hippocampal layer. Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) maps were computed from the DTI model while the orientation dispersion index (ODI), the neurite density index (NDI) and the volume fraction of isotropic diffusivity (isoVF) maps were computed from the NODDI model. We first showed in control mice that color-coded FA and ODI maps can delineate three main hippocampal layers. The quantification of FA, AD, RD, MD, ODI, NDI and isoVF presented differences within these 3 layers, especially within the molecular layer of the dentate gyrus which displayed a specific signature based on a combination of AD (or MD), ODI and NDI. Then, the comparison between EAE and control mice showed a decrease of AD (p = 0.036) and of MD (p = 0.033) selectively within the molecular layer of EAE mice while NODDI indices did not present any difference between EAE and control mice in any layer. Histological analyses confirmed the differential vulnerability of the molecular layer of EAE mice that exhibited decreased dendritic length and decreased dendritic complexity together with activated microglia. Dendritic length and intersections within the molecular layer were independent contributors to the observed decrease of AD (R2 = 0.37 and R2 = 0.40, p < 0.0001) and MD (R2 = 0.41 and R2 = 0.42, p < 0.0001). We therefore identified that NODDI maps can help to highlight the internal microanatomy of the hippocampus but NODDI still presents limitations in grey matter as it failed to capture selective dendritic alterations occurring at early stages of a neurodegenerative disease such as multiple sclerosis, whereas DTI maps were significantly altered. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.neuroimage.2018.01.061 PMID: 29409838
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293. Neuroimage. 2018 Feb 15. pii: S1053-8119(17)31105-9. doi: 10.1016/j.neuroimage.2017.12.081. [Epub ahead of print] Preserved canonicality of the BOLD hemodynamic response reflects healthy cognition: Insights into the healthy brain through the window of multiple sclerosis. Turner MP(1), Hubbard NA(2), Sivakolundu DK(1), Himes LM(1), Hutchison JL(1), Hart J Jr.(3), Spence J(1), Frohman E(4), Frohman T(4), Okuda D(4), Rypma B(5). Author information: (1)School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA. (2)McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA. (3)School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (4)Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (5)School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: [email protected]. The hemodynamic response function (HRF), a model of brain blood-flow changes in response to neural activity, reflects communication between neurons and the vasculature that supplies these neurons in part by means of glial cell intermediaries (e.g., astrocytes). Intact neural-vascular communication might play a central role in optimal cognitive performance. This hypothesis can be tested by comparing healthy individuals to those with known white-matter damage and impaired performance, as seen in Multiple Sclerosis (MS). Glial cell intermediaries facilitate the ability of neurons to adequately convey metabolic needs to cerebral vasculature for sufficient oxygen and nutrient perfusion. In this study, we isolated measurements of the HRF that could quantify the extent to which white-matter affects neural-vascular coupling and cognitive performance. HRFs were modeled from multiple brain regions during multiple cognitive tasks using piecewise cubic spline functions, an approach that minimized assumptions regarding HRF shape that may not be valid for diseased populations, and were characterized using two shape metrics (peak amplitude and time-to-peak). Peak amplitude was reduced, and time-to-peak was longer, in MS patients relative to healthy controls. Faster time-to-peak was predicted by faster reaction time, suggesting an important role for vasodilatory speed in the physiology underlying processing speed. These results support the hypothesis that intact neural-glial-vascular communication underlies optimal neural and cognitive functioning. Copyright © 2018. Published by Elsevier Inc. DOI: 10.1016/j.neuroimage.2017.12.081 PMID: 29454932
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294. Neuroimage Clin. 2018 Jan 28;18:143-148. doi: 10.1016/j.nicl.2018.01.013. eCollection 2018. Diagnostic accuracy of semiautomatic lesion detection plus quantitative susceptibility mapping in the identification of new and enhancing multiple sclerosis lesions. Zhang S(1)(2), Nguyen TD(2), Zhao Y(3), Gauthier SA(4)(5), Wang Y(2)(6), Gupta A(2)(5). Author information: (1)Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (2)Department of Radiology, Weill Cornell Medicine, New York, NY, USA. (3)Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA. (4)Department of Neurology, Weill Cornell Medicine, New York, NY, USA. (5)Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA. (6)Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA. Purpose: To evaluate the diagnostic accuracy of a novel non-contrast brain MRI method based on semiautomatic lesion detection using T2w FLAIR subtraction image, the statistical detection of change (SDC) algorithm (T2w + SDC), and quantitative susceptibility mapping (QSM). This method identifies new lesions and discriminates between enhancing and nonenhancing lesions in multiple sclerosis (MS). Methods: Thirty three MS patients who had MRIs at two different time points with at least one new Gd-enhancing lesion on the 2nd MRI were included in the study. For a reference standard, new lesions were identified by two neuroradiologists on T2w and post-Gd T1w images with the help of T2w + SDC. The diagnostic accuracy of the proposed method based on QSM and T2w + SDC lesion detection (T2w + SDC + QSM) for assessing lesion enhancement status was determined. Receiver operating characteristic (ROC) analysis was performed to compute the optimal lesion susceptibility cutoff value. Results: A total of 165 new lesions (54 enhancing, 111 nonenhancing) were identified. The sensitivity and specificity of T2w + SDC + QSM in predicting lesion enhancement status were 90.7% and 85.6%, respectively. For lesions ≥50 mm3, ROC analysis showed an optimal QSM cutoff value of 13.5 ppb with a sensitivity of 88.4% and specificity of 88.6% (0.93, 95% CI, 0.87-0.99). For lesions ≥15 mm3, the optimal QSM cutoff was 15.4 ppb with a sensitivity of 77.9% and specificity of 94.0% (0.93, 95% CI, 0.89-0.97). Conclusion: The proposed T2w + SDC + QSM method is highly accurate for identifying and predicting the enhancement status of new MS lesions without the use of Gd injection. DOI: 10.1016/j.nicl.2018.01.013 PMCID: PMC5790036 PMID: 29387531
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295. Neuroimage Clin. 2017 Dec 8;17:1028-1035. doi: 10.1016/j.nicl.2017.12.010. eCollection 2018. Evidence of progressive tissue loss in the core of chronic MS lesions: A longitudinal DTI study. Klistorner A(1)(2)(3), Wang C(3)(4), Yiannikas C(5), Parratt J(5), Dwyer M(6), Barton J(4), Graham SL(2), You Y(1)(2), Liu S(1)(3)(4), Barnett MH(3)(4). Author information: (1)Save Sight Institute, Sydney Medical School, University of Sydney, Sydney, Australia. (2)Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia. (3)Sydney Neuroimaging Analysis Centre, Sydney, NSW, Australia. (4)Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia. (5)Royal North Shore Hospital, Sydney, NSW, Australia. (6)Buffalo Neuroimaging Analysis Center, University at Buffalo, Buffalo, NY, USA. Objective: Using diffusion tensor imaging (DTI), we examined chronic stable MS lesions, peri-lesional white matter (PLWM) and normal appearing white matter (NAWM) in patients with relapsing-remitting multiple sclerosis (RRMS) for evidence of progressive tissue destruction and evaluated whether diffusivity change is associated with conventional MRI parameters and clinical findings. Method: Pre- and post-gadolinium T1, T2 and DTI images were acquired from 55 consecutive RRMS patients at baseline and 42.3 ± 9.7 months later. Chronic stable T2 lesions of sufficient size were identified in 43 patients (total of 134 lesions). Diffusivity parameters such as axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA) were compared at baseline and follow-up. MRI was also performed in 20 normal subjects of similar age and gender. Results: Within the core of chronic MS lesions the diffusion of water molecules significantly increased over the follow-up period, while in NAWM all diffusivity indices remained stable. Since increase of AD and RD in lesional core was highly concordant, indicating isotropic nature of diffusivity change, and considering potential effect of crossing fibers on directionally-selective indices, only MD, a directionally-independent measure, was used for further analysis. The significant increase of MD in the lesion core during the follow-up period (1.29 ± 0.19 μm2/ms and 1.34 ± 0.20 μm2/ms at baseline and follow-up respectively, P < 0.0001) was independent of age or disease duration, total brain lesion volume or new lesion activity, lesion size or location and baseline tissue damage (T1 hypointensity). Change of MD in the lesion core, however, was associated with progressive brain atrophy (r = 0.47, P = 0.002). A significant gender difference was also observed: the MD change in male patients was almost twice that of female patients (0.030 ± 0.04 μm2/ms and 0.058 ± 0.03 μm2/ms in female and male respectively, P = 0.01). Sub-analysis of lesions with lesion-free surrounding revealed the largest MD increase in the lesion core, while MD progression gradually declined towards PLWM. MD in NAWM remained stable over the follow-up period. Conclusion: The significant increase of isotropic water diffusion in the core of chronic stable MS lesions likely reflects gradual, self-sustained tissue destruction in demyelinated white matter that is more aggressive in males. DOI: 10.1016/j.nicl.2017.12.010 PMCID: PMC5772506 PMID: 29387524
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296. Neurol Genet. 2018 Jan 30;4(1):e213. doi: 10.1212/NXG.0000000000000213. eCollection 2018 Feb. Familial monophasic acute transverse myelitis due to the pathogenic variant in VPS37A. Mealy MA(1), Nam TS(1), Pardo SJ(1), Pardo CA(1), Sobreira NL(1), Avramopoulos D(1), Valle D(1), Burns KH(1), Levy M(1). Author information: (1)Department of Neurology (M.A.M., S.J.P., C.A.P., M.L.), Institute of Genetic Medicine (N.L.S., D.A., D.V., K.H.B.), and Department of Pathology (K.H.B.), Johns Hopkins University, Baltimore, MD; and Department of Neurology (T.-S.N.), Chonnam National University Medical School, Gwangju, South Korea. Objective: To identify genetic differences among siblings with a family history of idiopathic transverse myelitis (ITM). Methods: We compared whole-exome sequencing (WES) on germline samples from the 2 affected sisters with ITM with 3 of their healthy siblings. Results: The 2 sisters with ITM both had acute onset of sensory loss in the legs, weakness, and bowel/bladder dysfunction. The first developed ITM at age 15 years with a clinical nadir of complete paralysis, which slowly recovered over a few years. MRI demonstrated a persistent T2 lesion in the lower thoracic cord. The second developed ITM at age 50 years with a nadir of sensory loss from T6 down and paraparesis in the legs, associated with an MRI lesion at T6. She also made a partial recovery with treatment. Both sisters are homozygous for a missense variant in VPS37A (c.700C>A, p.Leu234Ile) identified by WES. We performed targeted sequencing of VPS37A in an additional 86 samples from patients with ITM and 175 with other diseases to investigate the p.Leu234Ile variant. We identified another patient with ITM homozygous for the same rare variant. No patients with multiple sclerosis, neuromyelitis optica, other neurologic conditions, or any healthy controls in public databases were homozygous for this variant. Conclusions: A rare missense variant in VPS37A may predispose to development of ITM. Further studies are necessary to determine the frequency of this variant in the patient population and the mechanism through which it contributes to the risk of disease. DOI: 10.1212/NXG.0000000000000213 PMCID: PMC5820602 PMID: 29473047
297. Neurol Neurochir Pol. 2017 Oct 31. pii: S0028-3843(17)30390-0. doi: 10.1016/j.pjnns.2017.10.009. [Epub ahead of print] Optical coherence tomography in diagnosis and monitoring multiple sclerosis. Kucharczuk J(1), Maciejek Z(2), Sikorski BL(3). Author information: (1)Department of Ophthalmology, 10th Military Research Hospital with Polyclinic, Bydgoszcz, Poland. (2)Department of Neurology, 10th Military Research Hospital with Polyclinic, Bydgoszcz, Poland. (3)Department of Ophthalmology, Nicolaus Copernicus University, Bydgoszcz, Poland. Electronic address: [email protected]. This paper presents application of optical coherence tomography (OCT) for diagnosis and monitoring of multiple sclerosis (MS). The peripapillary retinal nerve fibre layer thinning and the reduced total macular volume analysis are shown. With the course of the MS, the severity of these abnormalities increases which reflects the progressive degeneration of retinal ganglion cells and nerve fibres. The OCT parameters are sensitive, non-invasive indicators useful in assessing the progression of inflammation and neurodegeneration in MS. Copyright © 2017 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. DOI: 10.1016/j.pjnns.2017.10.009 PMID: 29395116
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298. Neurol Neuroimmunol Neuroinflamm. 2018 Jan 22;5(2):e435. doi: 10.1212/NXI.0000000000000435. eCollection 2018 Mar. Cervical spinal cord atrophy: An early marker of progressive MS onset. Zeydan B(1), Gu X(1), Atkinson EJ(1), Keegan BM(1), Weinshenker BG(1), Tillema JM(1), Pelletier D(1), Azevedo CJ(1), Lebrun-Frenay C(1), Siva A(1), Okuda DT(1), Kantarci K(1), Kantarci OH(1). Author information: (1)Department of Neurology (B.Z., X.G., B.M.K., B.G.W., J.-M.T., O.H.K.), Department of Radiology (B.Z., K.K.), and Department of Health Sciences Research (E.J.A.), Mayo Clinic College of Medicine, Rochester, MN; Department of Neurology (X.G.), The affiliated ZhongShan Hospital of DaLian University, LiaoNing, China; Multiple Sclerosis Center (D.P., C.J.A.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Neurology (C.L.-F.), Hopital Pasteur, Nice, France; Cerrahpasa School of Medicine (A.S.), Istanbul University, Turkey; and Department of Neurology & Neurotherapeutics (D.T.O.), Clinical Center for Multiple Sclerosis, University of Texas Southwestern Medical Center, Dallas. Objective: To assess whether cervical spinal cord atrophy heralds the onset of progressive MS. Methods: We studied 34 individuals with radiologically isolated syndrome (RIS) and 31 patients with relapsing-remitting MS (RRMS) age matched to 25 patients within a year of onset of secondary progressive MS (SPMS). Two raters independently measured (twice per rater) the cervical spinal cord average segmental area (CASA) (mm2) of axial T2-weighted images between C2 and C7 landmarks. The midsagittal T2-weighted image from the end of C2 to the end of C7 vertebra was used to measure the cervical spine (c-spine) length (mm). Sex, age at cervical MRI, number and location of cervical spinal cord lesions, c-spine length, and diagnoses were analyzed against the outcome measures of CASA and C2 and C7 slice segmental areas. Results: Intrarater and interrater agreement was excellent (intraclass correlation coefficient >0.97). The CASA area (p = 0.03) and C7 area (p = 0.002) were smaller in SPMS compared with RRMS. The C2 area (p = 0.027), CASA (p = 0.004), and C7 area (p = 0.003) were smaller in SPMS compared with RIS. The C2 area did not differ between SPMS and RRMS (p = 0.09). The C2 area (p = 0.349), CASA (p = 0.136), and C7 area (p = 0.228) did not differ between RIS and MS (SPMS and RRMS combined). In the multivariable model, ≥2 cervical spinal cord lesions were associated with the C2 area (p = 0.008), CASA (p = 0.009), and C7 area independent of disease course (p = 0.017). Progressive disease course was associated with the C7 area independent of the cervical spinal cord lesion number (p = 0.004). Conclusion: Cervical spinal cord atrophy is evident at the onset of progressive MS and seems partially independent of the number of cervical spinal cord lesions. Classification of evidence: This study provides Class III evidence that MRI cervical spinal cord atrophy distinguishes patients at the onset of progressive MS from those with RIS and RRMS. DOI: 10.1212/NXI.0000000000000435 PMCID: PMC5795903 PMID: 29435472
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299. Neurol Sci. 2018 Feb 23. doi: 10.1007/s10072-018-3295-4. [Epub ahead of print] Disability progression in multiple sclerosis: a Tunisian prospective cohort study. Hentati E(1)(2), Ben Sassi S(3)(4), Nabli F(1)(2), Mabrouk T(1)(2), Zouari M(1)(2), Hentati F(1)(2). Author information: (1)Neurology Department, Mongi Ben Hmida National Institute of Neurology, Tunis, Tunisia. (2)Neuroscience Department, Faculty of Medicine of Tunis, University Tunis El Manar, Tunis, Tunisia. (3)Neurology Department, Mongi Ben Hmida National Institute of Neurology, Tunis, Tunisia. [email protected]. (4)Neuroscience Department, Faculty of Medicine of Tunis, University Tunis El Manar, Tunis, Tunisia. [email protected]. Data regarding multiple sclerosis (MS) course in North Africans are scarce and mainly retrospective. To prospectively assess disability progression of multiple sclerosis in Tunisia. Analysis was performed in 600 patients from the MS database of the Mongi Ben Hmida National Institute of Neurology (Tunis, Tunisia), prospectively recorded over a 10-year period. Two MS phases were defined: phase 1, from MS clinical onset to Disability Status Scale (DSS) 3; and phase 2, from DSS 3 to DSS 6. Median durations of both phases and median ages at DSS 3 and DSS 6 were estimated using the Kaplan- Meier method. Median ages at DSS scores 3 and 6 were 48 years (95% confidence interval (CI), 45- 50) and 53 years (95% CI, 52-55), respectively. Median time from onset to DSS 3 (phase 1 duration) was 9 years (95% CI, 7-11) and median time to DSS 6 was 12 years (95% CI, 10-15). Median phase 2 duration was 3 years (95% CI, 2.4-3.6). Males and progressive-onset patients had faster disability worsening during the first phase of the disease. Conversely, disability progression during the second phase was independent of gender and MS phenotype at onset. Our study showed that disability progression followed a two-stage process in Tunisian MS patients with however a more aggressive course compared to that in Westerners. DOI: 10.1007/s10072-018-3295-4 PMID: 29476286
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300. Neurol Sci. 2018 Feb 15. doi: 10.1007/s10072-018-3267-8. [Epub ahead of print] An electroglottographical analysis-based discriminant function model differentiating multiple sclerosis patients from healthy controls. Vavougios GD(1)(2), Doskas T(1)(2), Konstantopoulos K(3)(4). Author information: (1)University of Thessaly, Biopolis, 41110, Larissa, Greece. (2)Department of Neurology, Athens Naval Hospital, Deinokratous 70, Athens, Greece. (3)Health Sciences Department, Speech Therapy, European University Cyprus, 6 Diogenous Street, Engomi, P.O. Box: 22006, 1516, Nicosia, Cyprus. [email protected]. (4)Cyprus Institute for Neurology and Genetics, Nicosia, Cyprus. [email protected]. Dysarthrophonia is a predominant symptom in many neurological diseases, affecting the quality of life of the patients. In this study, we produced a discriminant function equation that can differentiate MS patients from healthy controls, using electroglottographic variables not analyzed in a previous study. We applied stepwise linear discriminant function analysis in order to produce a function and score derived from electroglottographic variables extracted from a previous study. The derived discriminant function's statistical significance was determined via Wilk's λ test (and the associated p value). Finally, a 2 × 2 confusion matrix was used to determine the function's predictive accuracy, whereas the cross- validated predictive accuracy is estimated via the "leave-one-out" classification process. Discriminant function analysis (DFA) was used to create a linear function of continuous predictors. DFA produced the following model (Wilk's λ = 0.043, χ2 = 388.588, p < 0.0001, Tables 3 and 4): D (MS vs controls) = 0.728*DQx1 mean monologue + 0.325*CQx monologue + 0.298*DFx1 90% range monologue + 0.443*DQx1 90% range reading - 1.490*DQx1 90% range monologue. The derived discriminant score (S1) was used subsequently in order to form the coordinates of a ROC curve. Thus, a cutoff score of - 0.788 for S1 corresponded to a perfect classification (100% sensitivity and 100% specificity, p = 1.67e-22). Consistent with previous findings, electroglottographic evaluation represents an easy to implement and potentially important assessment in MS patients, achieving adequate classification accuracy. Further evaluation is needed to determine its use as a biomarker. DOI: 10.1007/s10072-018-3267-8 PMID: 29450761
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301. Neurol Sci. 2018 Feb 13. doi: 10.1007/s10072-018-3266-9. [Epub ahead of print] Natalizumab reduces serum pro-angiogenic activity in MS patients. Iaffaldano P(1), Ribatti D(1)(2), Trojano M(3). Author information: (1)Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy. (2)National Cancer Institute "Giovanni Paolo II", Bari, Italy. (3)Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy. [email protected]. Angiogenesis has been implicated in the pathobiology of multiple sclerosis (MS). Osteopontin exerts a pro-angiogenetic effect and is increased in body fluid of MS patients. To evaluate the effect of 1 year natalizumab treatment on serum pro-angiogenic activity and on plasma osteopontin levels in relapsing (RR) MS patients. Ten RRMS patients scheduled for natalizumab treatment were enrolled and evaluated at baseline and after 1-year natalizumab treatment. Pro-angiogenic activity was assessed by a chick embryo chorioallantoic membrane assay (CAM), osteopontin levels were evaluated by an enzyme-linked immunosorbent assay. Plasma and serum samples of 10 treatment-naïve RRMS and 10 healthy controls (HCs) were used as controls of baseline evaluations. Both treatment-naïve and natalizumab scheduled RRMS patients had higher baseline vessel density (22.0 ± 3.9 and 22.5 ± 2.6, p < 0.0001) and higher osteopontin levels (65.7 ± 24.3 ng/ml and 65.9 ± 16.6 ng/ml, p = 0.019 and p = 0.029, respectively) than HCs (9.0 ± 2.2; 48.5 ± 7.8 ng/ml, respectively). Baseline osteopontin levels and vessel density were significantly correlated (rs = 0.373, p = 0.043). After 1 year of treatment, the number of vessels and the osteopontin levels, were significantly reduced (11.9 ± 2.1, p < 0.005; 49.3 ± 20.0 ng/ml, p = 0.028). Our results suggest that natalizumab could exert its anti-inflammatory properties also by inhibiting the angiogenetic mechanisms in RRMS patients. DOI: 10.1007/s10072-018-3266-9 PMID: 29441483
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302. Neurology. 2018 Feb 9. pii: 10.1212/WNL.0000000000005055. doi: 10.1212/WNL.0000000000005055. [Epub ahead of print] Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Zesiewicz TA(1), Wilmot G(1), Kuo SH(1), Perlman S(1), Greenstein PE(1), Ying SH(1), Ashizawa T(1), Subramony SH(1), Schmahmann JD(1), Figueroa KP(1), Mizusawa H(1), Schöls L(1), Shaw JD(1), Dubinsky RM(1), Armstrong MJ(1), Gronseth GS(1), Sullivan KL(1). Author information: (1)From the Department of Neurology (T.A.Z., J.D. Shaw), University of South Florida, Tampa; Department of Neurology (G.W.), Emory University, Atlanta, GA; Department of Neurology (S.-H.K.), Columbia University, New York, NY; Department of Neurology (S.P.), University of California, Los Angeles; Department of Neurology (P.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; Shire (S.H.Y.), Lexington, MA, and the Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (T.A.), Houston Methodist Research Institute, TX; Department of Neurology (S.H.S., M.J.A.), University of Florida College of Medicine, Gainesville; Department of Neurology (J.D. Schmahmann), Massachusetts General Hospital, and Department of Neurology, Harvard Medical School, Boston, MA; Department of Neurology (K.P.F.), University of Utah, Salt Lake City; National Center of Neurology and Psychiatry (H.M.), Tokyo, Japan; Department of Neurology and Hertie-Institute for Clinical Brain Research (L.S.), Tübingen, Germany; Department of Neurology (R.M.D., G.S.D.), University of Kansas Medical Center, Kansas City; and Jiann-Ping Hsu College of Public Health (K.L.S.), Georgia Southern University, Statesboro. OBJECTIVE: To systematically review evidence regarding ataxia treatment. METHODS: A comprehensive systematic review was performed according to American Academy of Neurology methodology. CONCLUSIONS: For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis-associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study). © 2018 American Academy of Neurology. DOI: 10.1212/WNL.0000000000005055 PMID: 29440566
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303. Neurology. 2018 Feb 7. pii: 10.1212/WNL.0000000000005067. doi: 10.1212/WNL.0000000000005067. [Epub ahead of print] Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. Portaccio E(1), Annovazzi P(2), Ghezzi A(2), Zaffaroni M(2), Moiola L(2), Martinelli V(2), Lanzillo R(2), Brescia Morra V(2), Rinaldi F(2), Gallo P(2), Tortorella C(2), Paolicelli D(2), Pozzilli C(2), De Giglio L(2), Cavalla P(2), Cocco E(2), Marrosu MG(2), Patti F(2), Solaro C(2), Bellantonio P(2), Uccelli A(2), Laroni A(2), Pastò L(2), Giannini M(2), Trojano M(2), Comi G(2), Amato MP(2); MS Study Group of the Italian Neurological Society. Collaborators: Amato MP, Portaccio E, Hakiki B, Pastò L, Giannini M, Razzolini L, Righini I, Siracusa G, Ghezzi A, Annovazzi P, Zaffaroni M, Martinelli V, Radaelli M, Moiola L, Comi G, Protti A, Susani E, Marazzi R, Confalonieri P, Torri Clerici V, Cavalla P, Chiavazza C, Bergamaschi R, Mancardi G, Uccelli A, Capello E, Laroni A, Solaro C, Tola MR, Caniatti L, Granella F, Annunziata P, Plewnia K, Guidi L, Bartolozzi ML, Mazzoni M, Pozzilli C, De Giglio L, Totaro R, Carolei A, Rossi M, Lugaresi A, De Luca G, Di Tommaso V, Tortorella C, Paolicelli D, D'Onghia M, Trojano M, Marrosu MG, Cocco E, Melis M, Patti F, Leone C, Lo Fermo S, Bellantonio P, Fantozzi R, Gasperini C, Iudice A, Bosco A, Sartori A, Lanzillo R, Brescia Morra V. Author information: (1)From IRCCS Don Gnocchi Foundation (E.P.), Florence; Multiple Sclerosis Study Center (P.A., A.G., M.Z.), ASST Valle Olona, Gallarate Hospital (VA); Scientific Institute University Vita-Salute San Raffaele (L.M., V.M., G.C.), Milan; Department of Neurosciences, Reproductive and Odontostomatological Sciences (R.L., V.B.M.), Federico II University of Naples; Department of Neurosciences (F.R., P.G.), Multiple Sclerosis Centre-Veneto Region (CeSMuV), University Hospital of Padova; Department of Neurology (C.T., D.P., M.T.), University of Bari; Department of Neurology and Psychiatry (C.P., L.D.G.), "La Sapienza" University, Rome; Department of Neurology (P.C.), University of Torino; Department of Medical Sciences and Public Health (E.C., M.G.M.), University of Cagliari; Department of Neurology (F.P.), University of Catania; Department of Neurology (C.S.), ASL3 Genovese; Multiple Sclerosis Center (P.B.), IRCCS Neuromed, Pozzilli; Department of Neurology (A.U., A.L.), University of Genova; and Department of NEUROFARBA (L.P., M.G., M.P.A.), University of Florence, Italy. [email protected]. (2)From IRCCS Don Gnocchi Foundation (E.P.), Florence; Multiple Sclerosis Study Center (P.A., A.G., M.Z.), ASST Valle Olona, Gallarate Hospital (VA); Scientific Institute University Vita-Salute San Raffaele (L.M., V.M., G.C.), Milan; Department of Neurosciences, Reproductive and Odontostomatological Sciences (R.L., V.B.M.), Federico II University of Naples; Department of Neurosciences (F.R., P.G.), Multiple Sclerosis Centre- Veneto Region (CeSMuV), University Hospital of Padova; Department of Neurology (C.T., D.P., M.T.), University of Bari; Department of Neurology and Psychiatry (C.P., L.D.G.), "La Sapienza" University, Rome; Department of Neurology (P.C.), University of Torino; Department of Medical Sciences and Public Health (E.C., M.G.M.), University of Cagliari; Department of Neurology (F.P.), University of Catania; Department of Neurology (C.S.), ASL3 Genovese; Multiple Sclerosis Center (P.B.), IRCCS Neuromed, Pozzilli; Department of Neurology (A.U., A.L.), University of Genova; and Department of NEUROFARBA (L.P., M.G., M.P.A.), University of Florence, Italy. OBJECTIVE: To assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS), with a specific focus on spontaneous abortion (SA) and congenital anomalies (CA). METHODS: Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents. Rates of SA and CA were also compared with those reported in the Italian population. Multivariable logistic and linear regression models were performed. RESULTS: A total of 92 pregnancies were tracked in 83 women. In the multivariable analysis, natalizumab exposure was associated with SA (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.9-8.5, p < 0.001). However, the rate of SA (17.4%) was within the estimates for the general population, as well as the rate of major CA (3.7%). Moreover, exposure to natalizumab and interferon-β (IFN-β) was associated with lower length and weight of the babies (p < 0.001). CONCLUSION: Our results showed that natalizumab exposure to up 12 weeks of gestation is associated with an increased risk of SA, although within the limits expected in the general population, whereas the risk of CA needs further investigation. Taking into account the high risk of disease reactivation after natalizumab suspension, pregnancy could be planned continuing natalizumab while strictly monitoring conception. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in women with MS, natalizumab exposure increases the risk of spontaneous abortion as compared to IFN-β-exposed or untreated patients (OR 3.9, 95% CI 1.9-8.5). © 2018 American Academy of Neurology. DOI: 10.1212/WNL.0000000000005067 PMID: 29438046 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 278 – Multiple Sklerose: Veröffentlichungen Oktober 2013
304. Neurology. 2018 Feb 7. pii: 10.1212/WNL.0000000000005068. doi: 10.1212/WNL.0000000000005068. [Epub ahead of print] Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Portaccio E(1), Moiola L(2), Martinelli V(2), Annovazzi P(2), Ghezzi A(2), Zaffaroni M(2), Lanzillo R(2), Brescia Morra V(2), Rinaldi F(2), Gallo P(2), Tortorella C(2), Paolicelli D(2), Pozzilli C(2), De Giglio L(2), Cavalla P(2), Cocco E(2), Marrosu MG(2), Solaro C(2), Uccelli A(2), Laroni A(2), Pastò L(2), Giannini M(2), Trojano M(2), Comi G(2), Amato MP(2); MS Study Group of the Italian Neurological Society. Collaborators: Amato MP, Portaccio E, Hakiki B, Pastò L, Giannini M, Razzolini L, Righini I, Siracusa G, Ghezzi A, Annovazzi P, Zaffaroni M, Martinelli V, Radaelli M, Moiola L, Comi G, Protti A, Susani E, Marazzi R, Confalonieri P, Torri Clerici V, Cavalla P, Chiavazza C, Bergamaschi R, Mancardi G, Uccelli A, Capello E, Laroni A, Solaro C, Tola MR, Caniatti L, Granella F, Annunziata P, Plewnia K, Guidi L, Bartolozzi ML, Mazzoni M, Pozzilli C, De Giglio L, Totaro R, Carolei A, Rossi M, Lugaresi A, De Luca G, Di Tommaso V, Tortorella C, Paolicelli D, D'Onghia M, Trojano M, Marrosu MG, Cocco E, Melis M, Patti F, Leone C, Lo Fermo S, Bellantonio P, Fantozzi R, Gasperini C, Iudice A, Bosco A, Sartori A, Lanzillo R, Brescia Morra V. Author information: (1)From IRCCS Don Gnocchi Foundation (E.P.), Florence; Scientific Institute University Vita-Salute San Raffaele (L.M., V.M., G.C.), Milan; Multiple Sclerosis Study Center (P.A., A.G., M.Z.), ASST Valle Olona, Gallarate Hospital (VA); Department of Neurosciences, Reproductive and Odontostomatological Sciences (R.L., V.B.M.), Federico II University of Naples; Department of Neurosciences (F.R., P.G.), Multiple Sclerosis Centre-Veneto Region (CeSMuV), University Hospital of Padova; Department of Neurology (C.T., D.P., M.T.), University of Bari; Department of Neurology and Psychiatry (C.P., L.D.G.), "La Sapienza" University, Rome; Department of Neurology (P.C.), University of Torino; Department of Medical Sciences and Public Health (E.C., M.G.M.), University of Cagliari; Department of Neurology (C.S.), ASL3 Genovese; Department of Neurology (A.U., A.L.), University of Genova; and Department of NEUROFARBA (L.P., M.G., M.P.A.), University of Florence, Italy. [email protected]. (2)From IRCCS Don Gnocchi Foundation (E.P.), Florence; Scientific Institute University Vita-Salute San Raffaele (L.M., V.M., G.C.), Milan; Multiple Sclerosis Study Center (P.A., A.G., M.Z.), ASST Valle Olona, Gallarate Hospital (VA); Department of Neurosciences, Reproductive and Odontostomatological Sciences (R.L., V.B.M.), Federico II University of Naples; Department of Neurosciences (F.R., P.G.), Multiple Sclerosis Centre-Veneto Region (CeSMuV), University Hospital of Padova; Department of Neurology (C.T., D.P., M.T.), University of Bari; Department of Neurology and Psychiatry (C.P., L.D.G.), "La Sapienza" University, Rome; Department of Neurology (P.C.), University of Torino; Department of Medical Sciences and Public Health (E.C., M.G.M.), University of Cagliari; Department of Neurology (C.S.), ASL3 Genovese; Department of Neurology (A.U., A.L.), University of Genova; and Department of NEUROFARBA (L.P., M.G., M.P.A.), University of Florence, Italy. OBJECTIVE: To assess the risk of disease reactivation during pregnancy after natalizumab suspension in women with multiple sclerosis (MS). METHODS: Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents through a 2-factor repeated measures analysis. Predictors of disease activity were assessed through stepwise multivariable logistic regression models. RESULTS: A total of 92 pregnancies were tracked in 83 women receiving natalizumab. Among these pregnancies, 74 in 70 women resulted in live births, with a postpartum follow-up of at least 1 year, and were compared with 350 previously published pregnancies. Relapse rate during and after pregnancy was higher in women treated with natalizumab (p < 0.001). In multivariable analysis, longer natalizumab washout period was the only predictor of relapse occurrence during pregnancy (p = 0.001). Relapses in the postpartum year were related to relapses during pregnancy (p = 0.019) and early reintroduction of disease-modifying drugs (DMD; p = 0.021). Disability progression occurred in 16.2% of patients and was reduced by early reintroduction of DMD (p = 0.024). CONCLUSIONS: Taken as a whole, our findings indicate that the combination of avoiding natalizumab washout and the early resumption of DMD after delivery could be the best option in the perspective of maternal risk. This approach must take into account possible fetal risks that need to be discussed with the mother and require further investigation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in women with MS, the risk of relapses during pregnancy is higher in those who had been using natalizumab as compared to those who had been using interferon-β or no treatment. © 2018 American Academy of Neurology.
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DOI: 10.1212/WNL.0000000000005068 PMID: 29438041
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305. Neurology. 2018 Feb 27;90(9):403-404. doi: 10.1212/WNL.0000000000005038. Epub 2018 Jan 31. An intervention to improve balance in persons with multiple sclerosis. Bennett S(1), Leavitt VM(2). Author information: (1)From Rehabilitation Science Department (S.B.), University at Buffalo; and Multiple Sclerosis Cognitive Neuroscience Laboratory (V.M.L.), Department of Neurology, Columbia University Medical Center, New York, NY. [email protected]. (2)From Rehabilitation Science Department (S.B.), University at Buffalo; and Multiple Sclerosis Cognitive Neuroscience Laboratory (V.M.L.), Department of Neurology, Columbia University Medical Center, New York, NY. DOI: 10.1212/WNL.0000000000005038 PMID: 29386278
306. Neurology. 2018 Feb 27;90(9):e797-e807. doi: 10.1212/WNL.0000000000005013. Epub 2018 Jan 31. Efficacy of Balance and Eye-Movement Exercises for Persons With Multiple Sclerosis (BEEMS). Hebert JR(1), Corboy JR(2), Vollmer T(2), Forster JE(2), Schenkman M(2). Author information: (1)From the Department of Physical Medicine and Rehabilitation (J.R.H., J.E.F., M.S.) and Department of Neurology (J.R.H., J.R.C., T.V.), University of Colorado School of Medicine, Aurora. [email protected]. (2)From the Department of Physical Medicine and Rehabilitation (J.R.H., J.E.F., M.S.) and Department of Neurology (J.R.H., J.R.C., T.V.), University of Colorado School of Medicine, Aurora. OBJECTIVE: To determine whether a multifaceted vestibular-related rehabilitation program (Balance and Eye-Movement Exercises for Persons with Multiple Sclerosis; BEEMS) improves balance in persons with MS and whether there are differences in outcomes based on brainstem/cerebellar lesion involvement. METHODS: A 2-arm, examiner-blinded, stratified (involvement vs no involvement of brainstem/cerebellar structures), randomized controlled trial was implemented. Eighty-eight participants were allocated to BEEMS or no treatment control. Computerized Dynamic Posturography- Sensory Organization Test (CDP-SOT) measured balance control. The Dizziness Handicap Inventory (DHI), Modified Fatigue Impact Scale (MFIS), and Short Form-36 Health Status Questionnaire (SF- 36) were also administered. Linear mixed models were used to investigate the primary and secondary aims. RESULTS: From baseline to 6 weeks, BEEMS participants experienced greater improvements compared to control participants in CDP-SOT composite (model-estimated difference in change 4.9, 95% confidence interval 1.39-8.38, p = 0.006), DHI total (-13.5, -17.7 to -7.25, p < 0.0001), MFIS total (-11.4, -15.7 to -7.0, p < 0.0001), SF-36 Mental (5.6, 2.43-8.71, p = 0.0006), and SF-36 Physical (3.5, 1.12-5.81, p = 0.004) scores and from baseline to 14 weeks in CDP-SOT composite (8.3, 4.73-11.9, p < 0.0001), DHI total (-13.9, -19.3 to -8.62, p < 0.0001), MFIS total (-12.3, -16.7 to -7.79, p < 0.0001), SF-36 Mental (3.9, 0.70-7.16, p = 0.02), and SF-36 Physical (3.2, 0.79-5.62, p = 0.01) scores. From baseline to 6 weeks, BEEMS participants with brainstem/cerebellar lesion involvement experienced greater improvements compared to those without in CDP-SOT composite (5.26, 0.34-10.2, p = 0.04) and MFIS total (-7.6, -14.0 to -1.33, p = 0.02) scores. CONCLUSION: BEEMS improved multiple outcomes regardless of whether brainstem/cerebellar lesions were present, supporting the generalizability of BEEMS for ambulatory people with MS who have at least minimally impaired balance and fatigue. CLINICAL TRIALSGOV IDENTIFIER: NCT01698086. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that BEEMS training improves dynamic posturography-based balance, dizziness, fatigue, and quality of life in persons with MS. © 2018 American Academy of Neurology. DOI: 10.1212/WNL.0000000000005013 PMID: 29386274
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307. Neurology. 2018 Feb 21. pii: 10.1212/WNL.0000000000005118. doi: 10.1212/WNL.0000000000005118. [Epub ahead of print] Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis. Chataway J(1), Martin K(2), Barrell K(2), Sharrack B(2), Stolt P(2), Wraith DC(2); ATX-MS1467 Study Group. Collaborators: Maslova NN, Fitilev SB, Makarov NS, Trinitatskiy YV, Belskaya G, Khabirov FA, Poverennova IE, Amelina OA, Stolyarov ID, Skoromets AA, Belova A, Karelis G. Author information: (1)From the Queen Square Multiple Sclerosis Centre (J.C.), Department of Neuroinflammation, UCL Institute of Neurology, University College London; Apitope Technology (Bristol) Ltd. (K.M., K.B., D.W.), Chepstow; Academic Department of Neuroscience (B.S.), NIHR Sheffield Neuroscience Biomedical Research Centre, University of Sheffield, UK; MagliaRotta (P.S.), Basel, Switzerland; and Institute of Immunology and Immunotherapy (D.C.W.), Birmingham, UK. [email protected]. (2)From the Queen Square Multiple Sclerosis Centre (J.C.), Department of Neuroinflammation, UCL Institute of Neurology, University College London; Apitope Technology (Bristol) Ltd. (K.M., K.B., D.W.), Chepstow; Academic Department of Neuroscience (B.S.), NIHR Sheffield Neuroscience Biomedical Research Centre, University of Sheffield, UK; MagliaRotta (P.S.), Basel, Switzerland; and Institute of Immunology and Immunotherapy (D.C.W.), Birmingham, UK. OBJECTIVE: To assess safety, tolerability, and efficacy of the antigen-specific immunotherapy ATX- MS-1467 in participants with relapsing multiple sclerosis using different treatment protocols to induce tolerance. METHODS: Two open-label trials in adult participants with relapsing multiple sclerosis were conducted. Study 1 was a multicenter, phase 1b safety evaluation comparing intradermal (i.d.) (cohort 1) with subcutaneous (cohort 2) administration in 43 participants. Both cohorts received ATX-MS-1467 dosed at 25, 50, 100, 400, and 800 μg at 14-day intervals over 8 weeks, followed by 8 weeks with 4 additional 800-μg doses at 14-day intervals and 32 weeks off study medication. Study 2 was a phase 2a, multicenter, single-arm trial enrolling 37 participants. ATX-MS-1467 was titrated from 50 μg i.d. on day 1 to 200 μg on day 15 and 800 μg on day 29 followed by biweekly administration of 800 μg for 16 weeks and 16 weeks off study medication. Efficacy was evaluated on MRI parameters and clinical variables. Safety endpoints included treatment-emergent adverse events and injection-site reactions. RESULTS: In study 1, there was a significant decrease in new/persisting T1 gadolinium-enhanced (GdE) lesions in cohort 1 from baseline to week 16, returning to baseline values at week 48. In study 2, the number of T1 GdE lesions were significantly reduced on treatment and remained reduced at study completion. Safety results were unremarkable in both studies. CONCLUSION: Relatively slow ATX-MS-1467 titration and a longer full-dose i.d. treatment period is associated with reduction in GdE lesions and a sustained effect post treatment. Further trials of ATX-MS-1467 are warranted. CLASSIFICATION OF EVIDENCE: This work provides Class IV evidence that for patients with relapsing multiple sclerosis, slow ATX-MS-1467 titration and a longer full-dose i.d. treatment period is associated with reduction in GdE lesions. © 2018 American Academy of Neurology. DOI: 10.1212/WNL.0000000000005118 PMID: 29467307
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308. Neurology. 2018 Feb 20;90(8):e724-e726. doi: 10.1212/WNL.0000000000005001. Journal Club: MRI reveals acute inflammation in cortical lesions during early MS. Bateman EM(1), Schleicher WE(1), Smith EJ(1), Sweet DR(1), Gaudet AD(2). Author information: (1)From the Department of Psychology and Neuroscience (E.M.B., W.E.S., E.J.S., A.D.G.), University of Colorado Boulder; and Medical Scientist Training Program (D.R.S.), Department of Pathology, Case Western Reserve University, Cleveland, OH. (2)From the Department of Psychology and Neuroscience (E.M.B., W.E.S., E.J.S., A.D.G.), University of Colorado Boulder; and Medical Scientist Training Program (D.R.S.), Department of Pathology, Case Western Reserve University, Cleveland, OH. [email protected]. Early multiple sclerosis is characterized by immune-associated demyelination of CNS axons. In a recent Neurology® article, Maranzano et al. evaluated MRI scans of patients with early multiple sclerosis to study the evolution of leukocortical lesions. Their novel data suggest that acute inflammation after blood-brain barrier leakage may contribute to gray matter cortical lesions in early multiple sclerosis. © 2018 American Academy of Neurology. DOI: 10.1212/WNL.0000000000005001 PMCID: PMC5818168 [Available on 2019-02-20] PMID: 29459454
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309. Neurology. 2018 Feb 2. pii: 10.1212/WNL.0000000000005065. doi: 10.1212/WNL.0000000000005065. [Epub ahead of print] Relapse occurrence in women with multiple sclerosis during pregnancy in the new treatment era. Alroughani R(1), Alowayesh MS(2), Ahmed SF(2), Behbehani R(2), Al-Hashel J(2). Author information: (1)From the Division of Neurology (R.A.), Department of Medicine, Amiri Hospital, Sharq; Department of Pharmacy Practice (M.S.A.), School of Pharmacy, Kuwait University, Jabriya; Department of Neurology (S.F.A., J.A.-H.), Ibn Sina Hospital, Sabah Medical Area, Kuwait; Department of Neurology and Psychiatry (S.F.A.), Minia University, Egypt; Department of Ophthalmology (R.B.), Al-Bahar Eye Center, Sabah Medical Area; and Department of Medicine (J.A.- H.), Faculty of Medicine, Kuwait University, Jabriya. [email protected]. (2)From the Division of Neurology (R.A.), Department of Medicine, Amiri Hospital, Sharq; Department of Pharmacy Practice (M.S.A.), School of Pharmacy, Kuwait University, Jabriya; Department of Neurology (S.F.A., J.A.-H.), Ibn Sina Hospital, Sabah Medical Area, Kuwait; Department of Neurology and Psychiatry (S.F.A.), Minia University, Egypt; Department of Ophthalmology (R.B.), Al-Bahar Eye Center, Sabah Medical Area; and Department of Medicine (J.A.-H.), Faculty of Medicine, Kuwait University, Jabriya. OBJECTIVE: To determine the rate of relapse occurrence during pregnancy and postpartum. METHODS: In a cross-sectional study using the national multiple sclerosis (MS) registry, pregnant women with relapsing MS were identified. Data on demographics, clinical characteristics, and disease- modifying therapies (DMTs), including washout periods, were collected. Timings and durations of relapses were extracted. A multivariate logistic regression was used to assess the relationship between relapses and prior use of different DMTs. RESULTS: Completed data were available for 99 pregnancies (87 patients). Mean age and mean age at onset were 31.8 ± 5 and 24.4 ± 5.6 years, respectively, while the mean disease duration was 7.4 ± 4.6 years. Most pregnancies (89.9%) occurred in patients who were on DMTs in the year preceding pregnancy with a mean treatment duration of 63.4 ± 29 months. The rates of occurrence of relapses during pregnancy and postpartum were 17.2% and 13.7%, respectively. Most of the relapses occurred during the first (n = 6) and third (n = 7) trimesters. Rate of relapse was highest among patients receiving natalizumab and fingolimod before pregnancy. A longer washout period was significantly associated with relapse occurrence. CONCLUSION: The relapse occurrence during pregnancy is higher than the previously published rates. The use of high-efficacy therapies with long washout periods before conception was associated with an increased risk of relapses during pregnancy. Postpartum relapse occurrence was similar to that in previous reports. © 2018 American Academy of Neurology. DOI: 10.1212/WNL.0000000000005065 PMID: 29429970
310. Neuromolecular Med. 2018 Feb 10. doi: 10.1007/s12017-018-8481-2. [Epub ahead of print] Cardiovascular Autonomic Dysfunction: Link Between Multiple Sclerosis Osteoporosis and Neurodegeneration. Sternberg Z(1). Author information: (1)Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 100 High Street, Buffalo, NY, 14203-1126, USA. [email protected]. The high prevalence of osteoporosis, observed in multiple sclerosis (MS) patients, has been attributed to reduced mobility and or the use of disease-modifying drugs. However, MS-impaired cardiovascular autonomic nervous system (ANS) function has the potential of reducing bone mass density (BMD) by altering the expression and/or function of the neuronal, systemic, and local mediators of bone remodeling. This review describes the complex regulation of bone homeostasis with a focus on MS, providing evidence that ANS dysfunction and low BMD are intertwined with MS inflammatory and neurodegenerative processes, and with other MS-related morbidities, including depression, fatigue, and migraine. Strategies for improving ANS function could reduce the prevalence of MS osteoporosis and slow the rate of MS progression, with a significant positive impact on patients' quality of life. DOI: 10.1007/s12017-018-8481-2 PMID: 29429076
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311. Neuron. 2018 Feb 21;97(4):742-768. doi: 10.1016/j.neuron.2018.01.021. Multiple Sclerosis: Mechanisms and Immunotherapy. Baecher-Allan C(1), Kaskow BJ(1), Weiner HL(2). Author information: (1)Department of Neurology, Ann Romney Center for Neurologic Diseases, Partners MS Center, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (2)Department of Neurology, Ann Romney Center for Neurologic Diseases, Partners MS Center, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected]. Multiple sclerosis (MS) is an autoimmune disease triggered by environmental factors that act on a genetically susceptible host. It features three clinical stages: a pre-clinical stage detectable only by MRI; a relapsing-remitting (RRMS) stage characterized by episodes of neurologic dysfunction followed by resolution; and a progressive stage, which usually evolves from the relapsing stage. Advances in our understanding of the immune mechanisms that contribute to MS have led to more than ten FDA- approved immunotherapeutic drugs that target effector T cells, regulatory cells, B cells, and cell trafficking into the nervous system. However, most drugs for relapsing MS are not effective in treating progressive disease. Progressive MS features a compartmentalized immune response in the central nervous system, involving microglia cells and astrocytes, as well as immune-independent processes that drive axonal dysfunction. Major challenges for MS research involve understanding the mechanisms of disease progression, developing treatment for progressive MS, and determining the degree to which progressive disease can be prevented by early treatment. Key priorities for MS research include developing biomarkers, personalized medicine and advanced imaging, and a better understanding of the microbiome. With a better understanding of the genetic and epidemiological aspects of this disease, approaches to prevent MS are now also being considered. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.neuron.2018.01.021 PMID: 29470968
312. Neuropediatrics. 2018 Feb 26. doi: 10.1055/s-0038-1635123. [Epub ahead of print] Imaging Pediatric Multiple Sclerosis-Challenges and Recent Advances. Parmar K(1), Banwell BL(2), Akbar N(3), Bigi S(4). Author information: (1)Department of Neurology, University Hospital Basel, Basel, Switzerland. (2)Division of Neurology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, United States. (3)School of Rehabilitation Therapy, Queen's University, Kingston, Ontario, Canada. (4)Division of Child Neurology, Department of Pediatrics, University Children's Hospital Bern, University of Bern, Bern, Switzerland. Pediatric onset multiple sclerosis (POMS) is a rare disease with an incidence of 0.07 to 2.9/100'000 children per year. It follows a relapsing-remitting disease course and is characterized by rapid accrual of inflammatory lesions, high relapse frequency, and early cognitive impairment. Magnetic resonance imaging (MRI) plays a pivotal role in the diagnosis of POMS, and in the exclusion of other disorders mimicking POMS. Furthermore, MRI aids in disease monitoring, and in the evaluation of therapeutic efficacy in both clinical practice and clinical trials. Volumetric MRI studies, diffusion tensor imaging, resting-state, and task-based functional MRI provide deeper insight into the impact of POMS on maturing neural networks. This review article aims to highlight the importance of MRI in the care of POMS patients and to provide an overview on the different MRI techniques used in the management of POMS. Georg Thieme Verlag KG Stuttgart · New York. DOI: 10.1055/s-0038-1635123 PMID: 29482255
Conflict of interest statement: Dr. Parmar received travel support from Novartis Switzerland unrelated to this work. Dr. Banwell receives financial compensation for work as a consultant to Novartis on clinical trial work unrelated to this work. Dr. Akbar and Dr. Bigi declare that they have no conflict of interest.
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313. NeuroRehabilitation. 2018;42(1):69-79. doi: 10.3233/NRE-172225. Mildly disabled persons with multiple sclerosis use similar net joint power strategies as healthy controls when walking speed increases. Brincks J(1), Christensen LE(1), Rehnquist MV(1), Petersen J(2), Sørensen H(2), Dalgas U(2). Author information: (1)Department of Rehabilitation and Health Promotion Research, Faculty of Health Science, VIA University College, Aarhus N, Denmark. (2)Department of Public Health - Section of Sport Science, Aarhus University, Aarhus, Denmark. BACKGROUND: To improve walking in persons with multiple sclerosis (MS), it is essential to understand the underlying mechanisms of walking. This study examined strategies in net joint power generated or absorbed by hip flexors, hip extensors, hip abductors, knee extensors, and plantar flexors in mildly disabled persons with MS and healthy controls at different walking speeds. METHODS: Thirteen persons with MS and thirteen healthy controls participated and peak net joint power was calculated using 3D motion analysis. RESULTS: In general, no differences were found between speed-matched healthy controls and persons with MS, but the fastest walking speed was significantly higher in healthy controls (2.42 m/s vs. 1.70 m/s). The net joint power increased in hip flexors, hip extensors, hip abductors, knee extensors and plantar flexors in both groups, when walking speed increased. Significant correlations between changes in walking speed and changes in net joint power of plantar flexors, hip extensors and hip flexors existed in healthy controls and persons with MS, and in net knee extensor absorption power of persons with MS only. CONCLUSION: In contrast to previous studies, these findings suggest that mildly disabled persons with MS used similar kinetic strategies as healthy controls to increase walking speed. DOI: 10.3233/NRE-172225 PMID: 29400680
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314. NeuroRehabilitation. 2018;42(1):81-92. doi: 10.3233/NRE-172222. What is the opinion of patients with multiple sclerosis and their healthcare professionals about lower limb orthoses? A qualitative study using focus group discussions. Swinnen E(1)(2)(3), Deliens T(1)(4), Dewulf E(1), Van Overstraeten S(1), Lefeber N(1)(2)(3), Van Nieuwenhoven J(5), Ilsbroukx S(5), Kerckhofs E(1)(2)(3). Author information: (1)Vrije Universiteit Brussel, Faculty of Physical Education and Physiotherapy, Rehabilitation Research - Neurological Rehabilitation (RERE-Neuro), Brussels, Belgium. (2)Vrije Universiteit Brussel, Center for Neurosciences (C4N), Brussels, Belgium. (3)Vrije Universiteit Brussel, Brubotics, Brussels, Belgium. (4)Vrije Universteit Brussel, Faculty of Physical Education and Physiotherapy, Department of Movement and Sport Sciences, Brussels, Belgium. (5)National Multiple Sclerosis Center, Melsbroek, Belgium. OBJECTIVE: The aim of this study was to collect patients' and healthcare professionals' opinions about lower limb orthoses (LL-orthoses): 1) the positive and negative aspects; 2) the differences in wearing them according to location; and 3) their recommendations for future modifications. METHODS: Four focus group discussions were performed, with in total twenty patients with MS with a prescribed LL-orthosis and seven healthcare professionals. Audiotaped discussions were transcribed and qualitatively processed (NVivo11). RESULTS: Healthcare professionals and patients state that a LL-orthosis improves gait and reduces the risk of falling. Some negative aspects were indicated like stigmatization, difficulties to put on and off the LL-orthosis and the aesthetic aspects. Several patients mentioned that they did not get enough or no correct information about the adaptability and use of the orthoses. Opinions regarding differences in wearing according to location (e.g. in and outside the rehabilitation center) were diverse. Recommendations for future changes were e.g. more refined and firmer orthoses. CONCLUSIONS: The opinions collected are interesting for taking into account in the process of construction and delivering of LL-orthoses. Future research should focus on the opinions concerning different types of LL-orthosis in relation with the severity of the limitations of the patients. DOI: 10.3233/NRE-172222 PMID: 29400679
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315. NeuroRehabilitation. 2018;42(1):121-130. doi: 10.3233/NRE-172214. Male and female opinions about orthotic devices of the lower limb: A multicentre, observational study in patients with central neurological movement disorders. Swinnen E(1)(2)(3), Lefeber N(1)(2)(3), Werbrouck A(1)(2)(3), Gesthuizen Y(1), Ceulemans L(1), Christiaens S(1), De Wael L(1), Buyl R(4), Ilsbroukx S(5), Van Nieuwenhoven J(5), Michielsen M(6), Lafosse C(7), Kerckhofs E(1)(2)(3). Author information: (1)Faculty of Physical Education and Physiotherapy, Rehabilitation Research- Neurological Rehabilitation (RERE-NEURO), Vrije Universiteit Brussel, Brussels, Belgium. (2)C4N, Center For Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium. (3)BRUBOTICS, Brussels Human Robotics Research Center, Vrije Universiteit Brussel, Brussels, Belgium. (4)Faculty of Medicine and Pharmacy, Department of Biostatistics and Medical Informatics, Vrije Universiteit Brussel, Brussels, Belgium. (5)National Multiple Sclerosis Center, Melsbroek, Belgium. (6)Sint Ursula Rehabilitation Center, Jessa Hospital, Herk-de-Stad, Belgium. (7)Rehabilitation Hospital RevArte, Edegem, Belgium. BACKGROUND AND OBJECTIVE: Because user-satisfaction and acceptance may partly determine the grade of compliance to an orthotic device (OD), the aim of this multicentre observational study was to inquire the reasons for acceptance and the user-satisfaction of an OD of the lower limb in male and female central neurological movement disorders (CNMD) patients. METHODS: Persons with CNMD having at least one prescribed OD of the lower limb were included. Two questionnaires were used: the MIRAD-ACCORT-II (reasons for acceptance) and a modified version of the D-QUEST 2.0 (user- satisfaction). Descriptive analyses were performed and to analyse the differences between the males' and females' answers Chi2- and Mann-Whitney U tests were used. RESULTS: Twenty-six stroke and 23 multiple sclerosis patients participated (53% males). "Comfort", "safety", "effectiveness" and "ease of use" were reported as most important aspects. 86% of the patients were (very) satisfied about their OD. Only for the aspect safety, compared to males, significant more females reported that if the OD is not safe enough they will not use it. CONCLUSION: For both, males and females, aspects related to comfort and functionality were reported as much more important than the esthetical aspects, and in general they are quite satisfied with the OD and the process of providing the OD. Orthopaedic technicians and health care providers can take these aspects into account when developing, constructing and providing OD's. DOI: 10.3233/NRE-172214 PMID: 29400677
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316. Neuroreport. 2018 Mar 7;29(4):317-327. doi: 10.1097/WNR.0000000000000962. Beneficial effect of atorvastatin-modified dendritic cells pulsed with myelin oligodendrocyte glycoprotein autoantigen on experimental autoimmune encephalomyelitis. Chen Z(1), Yang D(2), Peng X(1)(3), Lin J(1), Su Z(4), Li J(1), Zhang X(1), Weng Y(1). Author information: (1)Department of Neurology, the First Affiliated Hospital of Wenzhou Medical University. (2)Department of Endocrinology, Ruian People's Hospital, the Third Affiliated Hospital of Wenzhou Medical University. (3)Department of Neurology, Lishui Central Hospital, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang Province, People's Republic of China. (4)Department of Neurology, Wenzhou Central Hospital, Wenzhou. It is well known that dendritic cells play a key role in producing antigen-specific responses. Inversely, tolerogenic dendritic cells (TolDCs), a specialized subset, induce immune tolerance and negatively regulate autoimmune responses. Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the mevalonate pathway for cholesterol biosynthesis, might be a promising inductive agent for inducing TolDCs. This study aimed to investigate the effectiveness of TolDCs induced by atorvastatin pulsed with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55) in experimental autoimmune encephalomyelitis mice established by MOG35-55 immunization and to investigate the potential effects on Th17/Treg balance in the murine model of multiple sclerosis. Our results showed that atorvastatin-treated dendritic cells maintained a steady semimature phenotype with a low level of costimulatory molecules and proinflammatory cytokines. Upon an intraperitoneal injection into experimental autoimmune encephalomyelitis mice, TolDCs pulsed with MOG (TolDCs- MOG) significantly alleviated disease activity and regulated Th17/Treg balance with a marked decrease in Th17 cells and an obvious increase in regulatory T cells. Taken together, TolDCs-MOG modified by atorvastatin showed a characteristic tolerogenic phenotype and the antigen-specific TolDCs might represent a new promising strategy for the future treatments for multiple sclerosis. DOI: 10.1097/WNR.0000000000000962 PMID: 29394220
317. Neuroreport. 2018 Feb 20. doi: 10.1097/WNR.0000000000000976. [Epub ahead of print] Subcortical grey matter structures in multiple sclerosis: what is their role in cognition? Cruz-Gómez ÁJ(1), Aguirre N, Sanchis-Segura C, Ávila C, Forn C. Author information: (1)Department of Basic Psychology, Clinic and Psychobiology, Jaume I University, Castelló de la Plana, Spain. The present study aimed to investigate altered grey matter (GM) and functional connectivity (FC) in deep subcortical areas, such as the thalamus and basal ganglia, and their relationship with cognitive impairment (CI) in multiple sclerosis (MS). Thirty-six patients were neuropsychologically assessed, classified as cognitive preserved (CP) and CI, and were compared with 18 healthy controls. GM atrophy and FC were observed in 10 predefined functional areas of the thalamus and in six of basal ganglia. GM atrophy was prominent in the basal ganglia in CI patients compared with CP MS patients. Increased FC was observed between the right caudate and the bilateral orbitofrontal cortex in CI versus CP patients. The discriminant and correlation analyses showed that the enhanced FC observed between the right caudate and the orbitofrontal cortex was closely associated with CI in MS patients. In conclusion, reduced GM volume and enhanced frontobasal ganglia connectivity are related to cognition in MS patients. DOI: 10.1097/WNR.0000000000000976 PMID: 29465624
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318. Neurosci Biobehav Rev. 2018 Mar;86:99-107. doi: 10.1016/j.neubiorev.2018.01.006. Examining the effectiveness of acetylcholinesterase inhibitors and stimulant-based medications for cognitive dysfunction in multiple sclerosis: A systematic review and meta-analysis. Cotter J(1), Muhlert N(2), Talwar A(3), Granger K(3). Author information: (1)Cambridge Cognition, Cambridge, UK. Electronic address: [email protected]. (2)Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine & Health, University of Manchester, UK; Neurodegenerative Imaging Group, King's College London, UK; School of Psychological Sciences, Cardiff University, UK. (3)Cambridge Cognition, Cambridge, UK. We sought to examine the effectiveness of acetylcholinesterase inhibitors (AChEIs) and stimulant- based medications for improving cognitive performance in patients with multiple sclerosis (MS). An electronic database search was conducted on 25th March 2017. Eligible studies were double-blind, randomised, placebo-controlled trials that examined the efficacy of compounds that act primarily as AChEIs or stimulants (administered daily for ≥1 week) on cognitive outcome measures in patients with MS. Where suitable data was reported, we generated effect sizes and corresponding 95% confidence intervals and performed meta-analyses using random-effects models to investigate the effectiveness of these drug types across cognitive domains. Sixteen trials were included in the systematic review, with eleven trials (N = 734 MS patients) providing sufficient data for meta-analysis. Whilst there was only a limited pool of relatively small trials and a number of different compounds, we found that collectively, both AChEIs (donepezil and rivastigmine) and stimulants (methylphenidate, modafinil, l- amphetamine sulfate and lisdexamfetamine dimesylate) offered no significant benefits over placebo on measures of processing speed, working memory, verbal fluency, verbal memory, visuospatial memory or executive functioning. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.neubiorev.2018.01.006 PMID: 29406017
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319. Neurosci Biobehav Rev. 2018 Feb 22. pii: S0149-7634(17)30639-5. doi: 10.1016/j.neubiorev.2018.02.012. [Epub ahead of print] The Role of the Cerebellum in Multiple Sclerosis - 150 years after Charcot. Parmar K(1), Stadelmann C(2), Rocca MA(3), Langdon D(4), D'Angelo E(5), D'Souza M(6), Burggraaff J(7), Wegner C(2), Sastre-Garriga J(8), Barrantes-Freer A(2), Dorn J(9), Uitdehaag BMJ(7), Montalban X(10), Wuerfel J(11), Enzinger C(12), Rovira A(10), Tintore M(10), Filippi M(10), Kappos L(6), Sprenger T(6); MAGNIMS study group. Author information: (1)Department of Neurology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address: [email protected]. (2)Institute for Neuropathology, University of Goettingen Medical Center, Robert-Koch-Str. 40, D-37099 Göttingen, Germany. (3)Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, I-20132 Milan, Italy. (4)Department of Psychology, Royal Holloway, University of London, Surrey, TW20 0EX, UK. (5)Department of Brain and Behavioral Sciences, University of Pavia, and Brain Connectivity Center - IRCCS C. Mondino, 27100 Pavia, Italy. (6)Department of Neurology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. (7)Department of Neurology, VU University Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. (8)Department of Neurology/Neuroimmunology, Multiple Sclerosis Centre of Catalonia, Hospital Vall d'Hebron, Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. (9)Novartis Pharma AG, Forum 1, Novartis Campus, CH- 4056 Basel, Switzerland. (10)Department of Radiology, Magnetic Resonance Unit, Hospital Vall d'Hebron, Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. (11)Medical Imaging Analysis Center (MIAC) AG, Mittlere Strasse 83, CH- 4056 Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Gewerbestrasse 14, CH-4123 Allschwil, Switzerland. (12)Research Unit for Neuronal Plasticity & Repair, Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, A-8036 Graz, Austria. Despite its functional importance and well known clinical impact in Multiple Sclerosis (MS), the cerebellum has only received significant attention over the past few years. It is now established that the cerebellum plays a key role not only in various sensory-motor networks, but also in cognitive- behavioural processes, domains primarily affected in patients with MS. Evidence from histopathological and magnetic resonance imaging (MRI) studies on cerebellar involvement in MS is increasingly available, however linking these pathological findings with clinical dysfunction remains challenging. There are promising advances in technology that are likely to improve the detection of pathological changes within the cerebellum, which may elucidate how pathology relates to disability. Copyright © 2018. Published by Elsevier Ltd. DOI: 10.1016/j.neubiorev.2018.02.012 PMID: 29477616
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320. Neurosciences (Riyadh). 2018 Jan;23(1):13-17. doi: 10.17712/nsj.2018.1.20170207. Stroke and seizure continue to be the major brunt of in patient neurology care. An observation from teaching hospital. Zafar A(1), Alabdali M, Shahid R, Aljaafari D, Al-Khamis FA, Albakr AI, Nazish S, Al-Sulaiman AA, Abraham A. Author information: (1)Department of Neurology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Kingdom of Saudi Arabia. E-mail: [email protected]. OBJECTIVE: To assess the burden and describe the pattern of neurological disorders requiring admissions in a teaching hospital of Al Khobar. METHODS: This is a retrospective, cross sectional study, carried out in the Neurology Department of King Fahd Hospital of the University from January 2009 to December 2016. Neurological disorders were grouped as ischemic stroke, intracerebral hemorrhage, transient ischemic attack, cerebral venous sinus thrombosis, seizure disorders, central nervous system infection, multiple sclerosis, neuropathies, myopathies, headache, dementia and miscellaneous group. Data was entered and analyzed by Statistical Package for the Social Science (SPSS) version 22.0 (IBM Corp., Armonk, NY, USA). RESULTS: The records of 1,317 patients admitted under Neurology Service were analyzed. Out of that, 740 (56.2%) were male and 577 (43.8%) were female. Mean age was 46.9+\-24 years (mean+\-standard deviation). Ischemic stroke was the most common diagnosis (32%) followed by seizures (20%). Multiple sclerosis accounted for around 8% and central nervous system infections 5% of neurological admission. CONCLUSION: Ischemic stroke was found to be the most common etiology for hospitalization in our study. The results of our study are similar to previous literature. An urgent need to control major risk factors such as diabetes and hypertension is warranted to minimize the burden of stroke. PMID: 29455215
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321. Neurosurg Focus. 2018 Feb;44(2):E7. doi: 10.3171/2017.11.FOCUS17614. Preliminary experience with a transcranial magnetic resonance-guided focused ultrasound surgery system integrated with a 1.5-T MRI unit in a series of patients with essential tremor and Parkinson's disease. Iacopino DG(1), Gagliardo C(2), Giugno A(1), Giammalva GR(1), Napoli A(3), Maugeri R(1), Graziano F(1), Valentino F(4), Cosentino G(4), D'Amelio M(4), Bartolotta TV(2), Catalano C(3), Fierro B(4), Midiri M(2), Lagalla R(2). Author information: (1)Unit of Neurosurgery, Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo. (2)Section of Radiological Sciences, Department of Biopathology and Medical Biotechnologies, University of Palermo. (3)Radiology Section, Department of Radiological, Oncological and Anatomopathological Sciences, "Sapienza" University of Rome; and. (4)Unit of Neurology, Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Italy. OBJECTIVE Transcranial magnetic resonance-guided focused ultrasound surgery (tcMRgFUS) is one of the emerging noninvasive technologies for the treatment of neurological disorders such as essential tremor (ET), idiopathic asymmetrical tremor-dominant Parkinson's disease (PD), and neuropathic pain. In this clinical series the authors present the preliminary results achieved with the world's first tcMRgFUS system integrated with a 1.5-T MRI unit. METHODS The authors describe the results of tcMRgFUS in a sample of patients with ET and with PD who underwent the procedure during the period from January 2015 to September 2017. A monolateral ventralis intermedius nucleus (VIM) thalamic ablation was performed in both ET and PD patients. In all the tcMRgFUS treatments, a 1.5-T MRI scanner was used for both planning and monitoring the procedure. RESULTS During the study period, a total of 26 patients underwent tcMRgFUS thalamic ablation for different movement disorders. Among these patients, 18 were diagnosed with ET and 4 were affected by PD. All patients with PD were treated using tcMRgFUS thalamic ablation and all completed the procedure. Among the 18 patients with ET, 13 successfully underwent tcMRgFUS, 4 aborted the procedure during ultrasound delivery, and 1 did not undergo the tcMRgFUS procedure after stereotactic frame placement. Two patients with ET were not included in the results because of the short follow-up duration at the time of this study. A monolateral VIM thalamic ablation in both ET and PD patients was performed. All the enrolled patients were evaluated before the treatment and 2 days after, with a clinical control of the treatment effectiveness using the graphic items of the Fahn-Tolosa-Marin tremor rating scale. A global reevaluation was performed 3 months (17/22 patients) and 6 months (11/22 patients) after the treatment; the reevaluation consisted of clinical questionnaires, neurological tests, and video recordings of the tests. All the ET and PD treated patients who completed the procedure showed an immediate amelioration of tremor severity, with no intra- or posttreatment severe permanent side effects. CONCLUSIONS Although this study reports on a small number of patients with a short follow- up duration, the tcMRgFUS procedure using a 1.5-T MRI unit resulted in a safe and effective treatment option for motor symptoms in patients with ET and PD. To the best of the authors' knowledge, this is the first clinical series in which thalamotomy was performed using tcMRgFUS integrated with a 1.5-T magnet. DOI: 10.3171/2017.11.FOCUS17614 PMID: 29385927
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322. Neurourol Urodyn. 2018 Feb 2. doi: 10.1002/nau.23501. [Epub ahead of print] Value of urodynamic findings in predicting upper urinary tract damage in neuro-urological patients: A systematic review. Musco S(1), Padilla-Fernández B(2), Del Popolo G(1), Bonifazi M(1), Blok BFM(3), Groen J(3), 't Hoen L(3), Pannek J(4), Bonzon J(4), Kessler TM(5), Schneider MP(5), Gross T(6), Karsenty G(7), Phé V(8), Hamid R(9), Ecclestone H(9), Castro-Diaz D(2). Author information: (1)Department of Neuro-Urology, Careggi University Hospital, Florence, Italy. (2)Department of Urology, Hospital Universitario de Canarias, Universidad de La Laguna, Santa Cruz de Tenerife, Spain. (3)Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands. (4)Neuro-Urology, Swiss Paraplegic Center, Nottwil, Switzerland. (5)Neuro-Urology, Spinal Cord Injury Center & Research, University of Zürich, Balgrist University Hospital, Zürich, Switzerland. (6)Department of Urology, University of Bern, Inselspital, Bern, Switzerland. (7)Department of Urology, Aix Marseille University, Marseille, France. (8)Department of Urology, Pitié-Salpêtrière Academic Hospital, Paris 6 University, Paris Cedex 13, France. (9)Department of Neuro-Urology, London Spinal Injuries Centre, Stanmore, UK. AIM: The main goals of neurogenic lower urinary tract dysfunction (NLUTD) management are preventing upper urinary tract damage (UUTD), improving continence, and quality of life. Here, we aimed to systematically assess all available evidence on urodynamics predicting UUTD in patients with NLUTD. METHODS: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was performed in March 2017. Only neuro-urological patients assessed by urodynamics were included. Any outcome of upper urinary tract function were evaluated. RESULTS: Forty-nine studies (1 randomized controlled trial, 9 prospective, and 39 retrospective case series) reported urodynamic data on 4930 neuro-urological patients. Of those, 2828 (98%) were spina bifida (SB) children. The total number of adults was 2044, mainly having spinal cord injury (SCI) (60%). A low bladder compliance was found in 568 (46.3%) and 341 (29.3%) of the paediatric and adult population, respectively. Hydronephrosis (HDN) was detected in 557 children (27.8%) in 19/28 studies and 178 adults (14.6%), mainly SCI, in 14/21 studies. Nine out of 30 multiple sclerosis (MS) patients affected by HDN (16.8%) showed low compliance in 4/14 studies. CONCLUSIONS: Patients with SB and SCI have a higher risk of developing UUTD (mainly reported as HDN) compared to those with MS. Reduced compliance and high DLPP were major risk factors for UUTD. Although our findings clarify the mandatory role of urodynamics in the management of NLUTD, standardization and better implementation of assessments in daily practice may further improve outcomes of neuro-urological patients based on objective measurements, that is, urodynamics. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/nau.23501 PMID: 29392753
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323. NMR Biomed. 2018 Feb 1. doi: 10.1002/nbm.3894. [Epub ahead of print] Multi-compartmental diffusion characterization of the human cervical spinal cord in vivo using the spherical mean technique. By S(1)(2)(3), Xu J(1)(2)(4), Box BA(2), Bagnato FR(5), Smith SA(1)(2)(4). Author information: (1)Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA. (2)Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA. (3)Philips Healthcare, Gainesville, FL, USA. (4)Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. (5)Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA. The purpose of this work was to evaluate the feasibility and reproducibility of the spherical mean technique (SMT), a multi-compartmental diffusion model, in the spinal cord of healthy controls, and to assess its ability to improve spinal cord characterization in multiple sclerosis (MS) patients at 3 T. SMT was applied in the cervical spinal cord of eight controls and six relapsing-remitting MS patients. SMT provides an elegant framework to model the apparent axonal volume fraction vax , intrinsic diffusivity Dax , and extra-axonal transverse diffusivity Dex_perp (which is estimated as a function of vax and Dax ) without confounds related to complex fiber orientation distribution that reside in diffusion MRI modeling. SMT's reproducibility was assessed with two different scans within a month, and SMT- derived indices in healthy and MS cohorts were compared. The influence of acquisition scheme on SMT was also evaluated. SMT's vax , Dax , and Dex_perp measurements all showed high reproducibility. A decrease in vax was observed at the site of lesions and normal appearing white matter (p < 0.05), and trends towards a decreased Dax and increased Dex_perp were seen. Importantly, a twofold reduction in acquisition yielded similarly high accuracy with SMT. SMT provides a fast, reproducible, and accurate method to improve characterization of the cervical spinal cord, and may have clinical potential for MS patients. Copyright © 2018 John Wiley & Sons, Ltd. DOI: 10.1002/nbm.3894 PMID: 29388719
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324. Nutr Neurosci. 2018 Feb 15:1-13. doi: 10.1080/1028415X.2018.1436237. [Epub ahead of print] Vitamin D down-regulates the expression of some Th17 cell-related cytokines, key inflammatory chemokines, and chemokine receptors in experimental autoimmune encephalomyelitis. Jafarzadeh A(1)(2)(3), Azizi SV(1), Arabi Z(1), Ahangar-Parvin R(1), Mohammadi-Kordkhayli M(4), Larussa T(5), Khatami F(6), Nemati M(3)(7). Author information: (1)a Molecular Medicine Research Center , Rafsanjan University of Medical Sciences , Rafsanjan , Iran. (2)b Department of Immunology, Medical School , Rafsanjan University of Medical Sciences , Rafsanjan , Iran. (3)c Department of Immunology, Medical School , Kerman University of Medical Sciences , Kerman , Iran. (4)d Department of Immunology, Medical School , Tehran University of Medical Sciences , Tehran , Iran. (5)e Department of Health Science , University of Catanzaro 'Magna Graecia' , Catanzaro , Italy. (6)f Department of Pathology, Medical School , Rafsanjan University of Medical Sciences , Rafsanjan , Iran. (7)g Department of Laboratory Sciences, Para-Medicine School , Kerman University of Medical Sciences , Kerman , Iran. OBJECTIVES: A spectrum of immunomodulatory properties was attributed to vitamin D (VD). Here, the VD effects on expression of some Th17 cell- related cytokines, chemokines and chemokine receptors were investigated in experimental autoimmune encephalomyelitis (EAE). METHODS: One group of C57BL/6 mice, considered as healthy group, was treated with phosphate buffered saline (PBS). EAE was induced in other three groups and treated from day +3 to +30 with PBS, olive oil (VD vehicle) or 200 ng of VD. At day 31, the expression of interleukin-17 (IL-17), IL-23, chemokine (C-C motif) ligand 20 (CCL20), CCL22, CC chemokine receptor 4 (CCR4) and CCR6 in spinal cord and serum IL-17 and IL-23 levels were measured by real-time PCR and ELISA, respectively. RESULTS: The expression of IL-17, IL-23 P19, IL-23 P40, CCL20, CCL22 and CCR4 in spinal cord and serum IL-17 and IL-23 levels in PBS-administrated EAE mice were significantly increased compared with healthy group. In EAE mice treated with VD, the expression of aforementioned parameters was significantly reduced in comparison with PBS-administrated EAE mice. CONCLUSION: VD down- regulates the expression of some inflammatory cytokines, chemokines and chemokine receptors in EAE mice. The possible therapeutic potential of VD in multiple sclerosis can be considered in future investigation. DOI: 10.1080/1028415X.2018.1436237 PMID: 29447086
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325. Nutrients. 2018 Feb 7;10(2). pii: E184. doi: 10.3390/nu10020184. Vitamin D-Binding Protein Polymorphisms, 25-Hydroxyvitamin D, Sunshine and Multiple Sclerosis. Langer-Gould A(1), Lucas RM(2), Xiang AH(3), Wu J(4), Chen LH(5), Gonzales E(6), Haraszti S(7)(8), Smith JB(9), Quach H(10), Barcellos LF(11). Author information: (1)Los Angeles Medical Center, Neurology Department, Southern California Permanente Medical Group, 1505 N Edgemont Street, Los Angeles, CA 90027, USA. [email protected]. (2)College of Medicine, Biology & Environment, Australian National University, Canberra, ACT 2000, Australia. [email protected]. (3)Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles Avenue, Pasadena, CA 91101, USA. [email protected]. (4)Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles Avenue, Pasadena, CA 91101, USA. [email protected]. (5)Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles Avenue, Pasadena, CA 91101, USA. [email protected]. (6)Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles Avenue, Pasadena, CA 91101, USA. [email protected]. (7)Department of Research & Evaluation, Kaiser Permanente Southern California, 100 S. Los Robles Avenue, Pasadena, CA 91101, USA. [email protected]. (8)Philadelphia College of Osteopathic Medicine, 4000 Presidential Blvd., Apt. 819, Philadelphia, PA 19131, USA. [email protected]. (9)Department of Research & Evaluation, Kaiser Permanente2 Southern California, 100 S. Los Robles Avenue, Pasadena, CA 91101, USA. [email protected]. (10)QB3 Genetic Epidemiology and Genomics Lab, School of Public Health, University of California Berkeley, 209 Hildebrand Hall, Berkeley, CA 94720, USA. [email protected]. (11)QB3 Genetic Epidemiology and Genomics Lab, School of Public Health, University of California Berkeley, 209 Hildebrand Hall, Berkeley, CA 94720, USA. [email protected]. Blacks have different dominant polymorphisms in the vitamin D-binding protein (DBP) gene that result in higher bioavailable vitamin D than whites. This study tested whether the lack of association between 25-hydroxyvitamin D (25OHD) and multiple sclerosis (MS) risk in blacks and Hispanics is due to differences in these common polymorphisms (rs7041, rs4588). We recruited incident MS cases and controls (blacks 116 cases/131 controls; Hispanics 183/197; whites 247/267) from Kaiser Permanente Southern California. AA is the dominant rs7041 genotype in blacks (70.0%) whereas C is the dominant allele in whites (79.0% AC/CC) and Hispanics (77.1%). Higher 25OHD levels were associated with a lower risk of MS in whites who carried at least one copy of the C allele but not AA carriers. No association was found in Hispanics or blacks regardless of genotype. Higher ultraviolet radiation exposure was associated with a lower risk of MS in blacks (OR = 0.06), Hispanics and whites who carried at least one copy of the C allele but not in others. Racial/ethnic variations in bioavailable vitamin D do not explain the lack of association between 25OHD and MS in blacks and Hispanics. These findings further challenge the biological plausibility of vitamin D deficiency as causal for MS. DOI: 10.3390/nu10020184 PMID: 29414925
Conflict of interest statement: Annette Langer-Gould is site principal investigator for two industry- sponsored phase 3 clinical trials (Biogen Idec; Hoffman-LaRoche) and was site PI for one industry- sponsored observation study (Biogen Idec). She receives grant support from the National Institutes of Health, NINDS, PCORI and the National MS Society. Robyn M. Lucas receives grant support from Cancer Australia and the National Health and Medical Research Council of Australia. Lie H. Chen declares no conflict of interest. Jun Wu, Edlin Gonzales, Samantha Haraszti, Jessica B. Smith, Anny H. Xiang, Hong Quach and Lisa F. Barcellos declares no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
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326. Oncotarget. 2018 Jan 2;9(4):5287-5300. doi: 10.18632/oncotarget.23866. eCollection 2018 Jan 12. Identifying characteristic miRNAs-genes and risk pathways of multiple sclerosis based on bioinformatics analysis. Luo D(1), Fu J(1). Author information: (1)Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Nangang District, Harbin 150086, China. Multiple sclerosis is a chronic autoimmune disorder of the central nervous system. In MS, the genetic susceptibility is high and currently there is no effective treatment. MicroRNA, a small non-coding RNA, plays a vital role in immune responses. Aberrant or dysfunctional miRNAs may cause several diseases, including MS, thus miRNAs and miRNA related genes may be therapeutic weapons against MS. Here, we identified 21 miRNAs in peripheral blood mono-nuclear cells from over 600 persons, including healthy controls. By using informatics databases, 1637 susceptibility genes were evaluated and Cytoscape was used to integrate and visualize the relation between the miRNA identified and susceptibility genes. By using the cluster Profile package, a total of 10 risk pathways were discovered. Top pathways included: hsa05200 (pathway in cancer), hsa04010 (MAPK signaling pathway), and hsa04060 (cytokine-cytokine receptor interaction). By using the STRING database, a protein-protein interaction network was conducted to identify highly susceptibility genes. Moreover, the GSE21942 dataset was used to indicate the gene expression profiles and to correct prediction results, thereby identifying the most pivotal genes. The MiRSystem database provided information on both pivotal miRNAs and genes. In conclusion, miR-199a and miR-142-3p may be crucial for MS by targeting pivotal susceptibility genes, in particular KRAS and IL7R. DOI: 10.18632/oncotarget.23866 PMCID: PMC5797050 PMID: 29435179
Conflict of interest statement: CONFLICTS OF INTEREST All the authors declared no conflict of interest.
327. Oxf Med Case Reports. 2018 Jan 25;2018(1):omx085. doi: 10.1093/omcr/omx085. eCollection 2018 Jan. Case report of a patient with 'one-and-a-half plus syndrome: nine syndrome'. Uthman M(1), Kamran M(1). Author information: (1)Internal Medicine, Shaikh Zayed Medical Complex, Lahore, Pakistan. This case talks about 'One-and-a-half plus syndrome', a clinical syndrome affecting binocular vision and facial nerve. One-and-a-half plus syndrome is a less known clinical syndrome which constitutes of a conjugate horizontal gaze palsy in one direction and an internuclear ophthalmoplegia in the other direction. Despite the known association between ischemia, autoimmune disorders, multiple sclerosis, with mono neuritis multiplex resulting in extra ocular movement disorder, one-and-a-half plus syndrome is rarely considered in the differential diagnosis of eye ball movement disorders, as many clinicians are not able to diagnose such a case as ' the eyes don't see what the mind doesn't know'. Our report aims to raise awareness about connective tissue disorders presenting as neuro- ophthalmological syndrome, as early recognition can accelerate diagnosis and decrease the morbidity. DOI: 10.1093/omcr/omx085 PMCID: PMC5786233 PMID: 29383261
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328. Palliat Support Care. 2018 Feb 5:1-7. doi: 10.1017/S1478951517001213. [Epub ahead of print] Support needs of caregivers of patients with amyotrophic lateral sclerosis: A qualitative study. de Wit J(1), Schröder CD(1), El Mecky J(2), Beelen A(3), van den Berg LH(4), Visser-Meily JMA(1). Author information: (1)Center of Excellence in Rehabilitation Medicine,Brain Center Rudolf Magnus,University Medical Center Utrecht, andDe Hoogstraat Rehabilitation,Utrecht,The Netherlands. (2)Department of Clinical Genetics,University Medical Center Groningen,Groningen,The Netherlands. (3)Department of Rehabilitation,Academic Medical Center,University of Amsterdam,Amsterdam,The Netherlands. (4)Department of Neurology,Brain Center Rudolf Magnus,University Medical Center Utrecht,Utrecht,The Netherlands. OBJECTIVE: The aim of this study was to explore the support needs of Dutch informal caregivers of patients with amyotrophic lateral sclerosis (ALS). METHOD: Individual semi-structured interviews were conducted with 21 caregivers of ALS patients. Audio-taped interviews were transcribed and data were analyzed thematically. Result A total of four global support needs emerged: "more personal time", "assistance in applying for resources", "counseling", and "peer contact". Despite their needs, caregivers are reluctant to apply for and accept support. They saw their own needs as secondary to the needs of the patients. Significance of results ALS seems to lead to an intensive caregiving situation with multiple needs emerging in a short period. This study offers targets for the development of supportive interventions. A proactive approach seems essential, acknowledging the importance of the role of the caregivers in the care process at an early stage, informing them about the risk of burden, monitoring their wellbeing, and repeatedly offering support opportunities. Using e-health may help tailor interventions to the caregivers' support needs. DOI: 10.1017/S1478951517001213 PMID: 29397051
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329. Pediatr Hematol Oncol. 2018 Feb 8:1-4. doi: 10.1080/08880018.2018.1427818. [Epub ahead of print] Syncytial variant of nodular sclerosing Hodgkin lymphoma in children: A prognostic factor? Granot N(1), Ben-Barak A(2), Fisher Y(3), Golan H(4), Weyl Ben-Arush M(1)(2). Author information: (1)a The Bruce Rappaport Faculty of Medicine , Technion-Israel Institute of Technology , Haifa , Israel. (2)b The Joan and Sanford Weill Pediatric Hematology Oncology and Bone Marrow Transplantation Division , Ruth Rappaport Children's Hospital, Rambam Health Care Campus , Haifa , Israel. (3)c Pathology Institute, Rambam Health Care Campus , Haifa , Israel. (4)d Department of Pediatric Hematology Oncology , Safra Children's Hospital, Sheba Medical Center , Tel Aviv , Israel. Nodular sclerosing Hodgkin lymphoma (HL) has an excellent prognosis in children. The syncytial variant (SV) of HL in adults represents a clinic pathologic entity with a worse outcome. We report the clinical features and the course of the disease of three children with refractory HL. The three patients with SV were analyzed in a retrospective multi-institutional study conducted in Israel in 51 children diagnosed with refractory or recurrent HL between 1997 and 2014. All the three children developed multiple recurrences soon after diagnosis. All three received at least three different chemotherapy combinations with autologous bone marrow transplantation for two patients, allogenic bone marrow transplantation in one, and immunotherapy in one. One patient died of disease, one is in complete response of the disease but developed a second metastatic malignancy, and one is alive without disease. This retrospective study shows that SV histology may be a prognostic factor for poor outcome in children diagnosed with HL. DOI: 10.1080/08880018.2018.1427818 PMID: 29420106
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330. Pharmacoecon Open. 2018 Mar;2(1):31-41. doi: 10.1007/s41669-017-0035-2. Comparison of Disease-Modifying Therapies for the Management of Multiple Sclerosis: Analysis of Healthcare Resource Utilization and Relapse Rates from US Insurance Claims Data. Nicholas J(1), Boster A(1), Wu N(2), Yeh WS(2), Fay M(2), Kendter J(2), Huang MY(2), Lee A(3). Author information: (1)OhioHealth Multiple Sclerosis Center, Riverside Methodist Hospital, Columbus, OH, USA. (2)Biogen, 225 Binney Street, Cambridge, MA, 02142, USA. (3)Biogen, 225 Binney Street, Cambridge, MA, 02142, USA. [email protected]. BACKGROUND: Data on comparative healthcare resource utilization and costs associated with the newer oral disease-modifying therapies (DMTs) for managing relapsing-remitting multiple sclerosis (MS) in routine clinical practice are limited. The purpose of this study was to estimate healthcare resource utilization, costs, and relapse rates in the year after initiating treatment with dimethyl fumarate (DMF), interferon (IFN)-β, glatiramer acetate (GA), teriflunomide, or fingolimod in routine clinical practice for patients with MS who did not receive a DMT in the previous year. METHODS: Patients initiating DMF, IFNβ, GA, teriflunomide, or fingolimod were identified based on claims data from 2012 to 2015 in the Truven MarketScan Commercial Claims Databases (n = 4194). Healthcare resource utilization assessment included the proportion of patients who were hospitalized, or had emergency room (ER) or urgent care (UC) visits. Healthcare costs were estimated for 1 year before and 1 year after DMT initiation. Relapse episodes were identified based on a published claims-based algorithm and clinical input from the research investigators. RESULTS: After DMT initiation, significant reductions in the proportions of patients who were hospitalized or requiring ER/UC visits were observed in all patient cohorts (p < 0.001 and p < 0.05, respectively). Non-prescription medical costs decreased after DMT initiation, with the largest decrease observed in the DMF cohort (US$5761 reduction, p < 0.0001). Reductions in non-prescription medical costs were associated with decreased use of outpatient services and inpatient hospital stays, and have the potential to partially offset DMT costs. CONCLUSIONS: DMT initiation is associated with reductions in healthcare resource utilization and non-prescription medical costs in routine clinical practice. DOI: 10.1007/s41669-017-0035-2 PMID: 29464673
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331. Pilot Feasibility Stud. 2018 Jan 23;4:35. doi: 10.1186/s40814-018-0230-7. eCollection 2018. A protocol for a randomised double-blind placebo-controlled feasibility study to determine whether the daily consumption of flavonoid-rich pure cocoa has the potential to reduce fatigue in people with relapsing and remitting multiple sclerosis (RRMS). Coe S(1), Collett J(1), Izadi H(2), Wade DT(1), Clegg M(1), Harrison JM(1), Buckingham E(1), Cavey A(3), DeLuca GC(3), Palace J(3), Dawes H(1)(3). Author information: (1)1Centre for Movement and Occupational Rehabilitation Sciences, Oxford Institute of Midwifery, Nursing and Allied Health Research, and Oxford Brookes Centre for Nutrition and Health, Oxford Brookes University, Oxford, OX30BP UK. (2)3School of Engineering, Computing and Mathematics, Faculty of Technology, Design and Environment, Oxford Brookes University, Wheatley Campus, Room R2.32, Oxford, OX33 1HX UK. (3)2Department of Neurology, Nuffield Department of Clinical Neuroscienes, University of Oxford, Oxford, OX3 9DU UK. Background: Dietary interventions including consumption of flavonoids, plant compounds found in certain foods, may have the ability to improve fatigue. However, to date, no well-designed intervention studies assessing the role of flavonoid consumption for fatigue management in people with MS (pwMS) have been performed. The hypothesis is that the consumption of a flavonoid-rich pure cocoa beverage will reduce fatigue in pwMS. The aim of this study is to determine the feasibility and potential outcome of running a trial to evaluate this hypothesis. Methods: Using a randomised (1:1) double-blind placebo-controlled feasibility study, 40 men and women (20 in each trial arm) with a recent diagnosis (< 10 years) of relapsing and remitting MS (RRMS) and who are over 18 years of age will be recruited from neurology clinics and throughout the Thames Valley community. During a 6-week nutrition intervention period, participants will consume the cocoa beverage, high flavonoid or low flavonoid content, at breakfast daily. At baseline, demographic factors and disease-related factors will be assessed. Fatigue, activity and quality of life, in addition to other measures, will be taken at three visits (baseline, week 3 and week 6) in a university setting by a researcher blinded to group membership. Feasibility and fidelity will be assessed through recruitment and retention, adherence and a quantitative process evaluation at the end of the trial.We will describe demographic factors (age, gender, level of education) as well as disease-related factors (disease burden scores, length of time diagnosed with MS) and cognitive assessment, depression and quality of life and general physical activity in order to characterise participants and determine possible mediators to identify the processes by which the intervention may bring about change. Feasibility (recruitment, safety, feasibility of implementation of the intervention and evaluation, protocol adherence and data completion) and potential for benefit (estimates of effect size and variability) will be determined to inform future planned studies. Results will be presented using point estimates, 95% confidence intervals and p values. Primary statistical analysis will be on an intention-to-treat basis and will use the complete case data set. Discussion: We propose that a flavonoid-enriched cocoa beverage for the management of fatigue will be well received by participants. Further, if it is implemented early in the disease course of people diagnosed with RRMS, it will improve mobility and functioning by modifying fatigue. Trial registration: Registered with ISRCTN Registry. Trial registration No: ISRCTN69897291; Date April 2016. DOI: 10.1186/s40814-018-0230-7 PMCID: PMC5778802 PMID: 29403649
Conflict of interest statement: This study was approved by the Solihull NRES Committee, West Midlands NHS ethics committee: 199515Not applicable.The gait measurement system and the smart watch software were developed by the research team (Dawes, Esser and Wade, and James and Amor, respectively), and both systems are in the process of being commercialised by the universities concerned.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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332. PLoS One. 2018 Feb 27;13(2):e0193302. doi: 10.1371/journal.pone.0193302. eCollection 2018. The cellular uptake of angiogenin, an angiogenic and neurotrophic factor is through multiple pathways and largely dynamin independent. Ferguson R(1), Subramanian V(1). Author information: (1)Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom. Angiogenin (ANG), a member of the RNase superfamily (also known as RNase 5) has neurotrophic, neuroprotective and angiogenic activities. Recently it has also been shown to be important in stem cell homeostasis. Mutations in ANG are associated with neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Fronto-temporal dementia (FTD). ANG is a secreted protein which is taken up by cells and translocated to the nucleus. However, the import pathway/s through which ANG is taken up is/are still largely unclear. We have characterised the uptake of ANG in neuronal, astrocytic and microglial cell lines as well as primary neurons and astrocytes using pharmacological agents as well as dominant negative dynamin and Rab5 to perturb uptake and intracellular trafficking. We find that uptake of ANG is largely clathrin/dynamin independent and microtubule depolymerisation has a marginal effect. Perturbation of membrane ruffling and macropinocytosis significantly inhibited ANG uptake suggesting an uptake mechanism similar to RNase A. Our findings shed light on why mutations which do not overtly affect RNase activity but cause impaired localization are associated with neurodegenerative disease. DOI: 10.1371/journal.pone.0193302 PMID: 29486010
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 303 – Multiple Sklerose: Veröffentlichungen Oktober 2013
333. PLoS One. 2018 Feb 27;13(2):e0193381. doi: 10.1371/journal.pone.0193381. eCollection 2018. Sexual dysfunctions in MS in relation to neuropsychiatric aspects and its psychological treatment: A scoping review. Pöttgen J(1)(2), Rose A(3), van de Vis W(4), Engelbrecht J(5), Pirard M(6), Lau S(1)(2), Heesen C(1)(2), Köpke S(7); RiMS Special Interest Group Psychology and Neuropsychology. Author information: (1)Institut für Neuroimmunologie und Multiple Sklerose, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. (2)Klinik und Poliklinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. (3)The Raphael Medical Centre, Tonbridge, United Kingdom. (4)Revalidatie Centre Roessingh, Enschede, Netherlands. (5)Sclerose Hospital Erne, Ry, Denmark. (6)National MS Centre, Melsbroek, Belgium. (7)University of Lübeck, Nursing Research Unit, Institute for Social Medicine and Epidemiology, Lübeck, Germany. OBJECTIVE: Sexual dysfunction in multiple sclerosis (MS) is a significant, but often underestimated and overlooked suffering. Interventions to treat sexual dysfunction in MS are rare. The relation between sexual dysfunction in MS and psychological as well as neuropsychological aspects is evident. However, this field of research remains markedly underdeveloped in this severe chronic illness. The aim of this scoping review is to describe the relevant knowledge in this area and to identify psychological interventions to treat sexual dysfunctions in MS. METHODS: A scoping review was conducted to answer the following questions: (1) Which psychological and neuropsychological factors impact on sexual dysfunction in MS and vice versa? (2) What kind of psychological interventions aiming to improve sexual dysfunctions in MS are available? A comprehensive search and review of MEDLINE, PsycINFO, and CINAHL was completed by using a recent methodological framework for scoping reviews. RESULTS: 23 publications covering a total of 13,259 people with MS and 532 healthy controls were identified. Sexual dysfunction was found to be very common in MS and there is an obvious relation to psychological disorders as e.g. depression and anxiety and also to psychological aspects as partner relationship and quality of life. The relation between sexual dysfunction in MS and neuropsychological impairment has only rarely been studied and no clear results were found. Only two studies were identified, assessing the effectiveness of psychological intervention studies on sexual dysfunction in people with MS, and a third study presenting a secondary analysis of a study targeting depression. All three studies reported significant improvements in sexual dysfunction as well as partly in psychological variables. CONCLUSIONS: There is a pressing need for the development and adequate evaluation of psychological interventions for sexual dysfunctions in MS. In addition, sexual dysfunction and its impact on psychological wellbeing should be more focussed in clinical care. REGISTRATION: This review is registered with PROSPERO; Registration number: CRD42016033066. DOI: 10.1371/journal.pone.0193381 PMID: 29486006
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334. PLoS One. 2018 Feb 23;13(2):e0192911. doi: 10.1371/journal.pone.0192911. eCollection 2018. Support service utilization and out-of-pocket payments for health services in a population-based sample of adults with neurological conditions. Obembe AO(1)(2), Goldsmith CH(3)(4), Simpson LA(2)(5), Sakakibara BM(1)(2), Eng JJ(1)(2). Author information: (1)Department of Physical Therapy, The University of British Columbia, Vancouver, Canada. (2)Rehabilitation Research Program, GF Strong Rehab Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada. (3)Adjunct Professor, Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada. (4)Adjunct Professor, Department of Occupational Science and Occupational Therapy, The University of British Columbia, Vancouver, Canada. (5)Graduate Program in Rehabilitation Sciences, The University of British Columbia, Vancouver, Canada. BACKGROUND: Social support can help to deal with the consequences of neurological conditions and promote functional independence and quality of life. Our aim was to evaluate the impact of neurological conditions on the use of support and health-care services in a population-based sample of community-dwelling adults with neurological conditions. METHODS: Data were from the Survey of Living with Neurological Conditions in Canada, which was derived from a representative sample of household residents. Formal and informal support received and out-of-pocket payments were assessed by personal interviews. Logistic regression was used to explore the association between support service utilization and six common neurological conditions (Stroke, Parkinson's disease, Alzheimer's disease/dementias, traumatic brain injury, spinal cord injury and multiple sclerosis) with stroke as the reference category. RESULTS: The sample contained 2,410 respondents and equate to an estimated 459,770 when sample weights were used. A larger proportion of people within each of the neurological conditions received informal support than formal support (at least twice as much). Samples with the non-stroke conditions were more likely to receive formal assistance for personal (odds ratios 2.7 to 5.6; P < 0.05) and medical (odds ratios 2.4 to 4.4; P < 0.05) care compared to the stroke group. Also, the non-stroke conditions were more likely to receive informal assistance (odds ratios 2.7 to 17.9; P < 0.05) and less likely to make out-of-pocket payments for rehabilitation therapy (odds ratios 0.2 to 0.3; P < 0.05) than the stroke group. The Alzheimer's disease/dementia group had the highest proportion who received formal and informal support services. CONCLUSIONS: Our findings suggest that Canadians with neurological conditions receive more informal assistance than formal assistance. Furthermore, it appears that stroke survivors receive less support services, while those with Alzheimer's disease/dementia receive the most compared to other adult neurological conditions. Such data can help inform the development of support services in the community. DOI: 10.1371/journal.pone.0192911 PMID: 29474391
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335. PLoS One. 2018 Feb 13;13(2):e0190043. doi: 10.1371/journal.pone.0190043. eCollection 2018. Highly conserved extended haplotypes of the major histocompatibility complex and their relationship to multiple sclerosis susceptibility. Goodin DS(1), Khankhanian P(2), Gourraud PA(1)(3)(4), Vince N(3)(4). Author information: (1)Department of Neurology, University of California, San Francisco, CA, United States of America. (2)Center for Neuro-engineering and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States of America. (3)Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France. (4)Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France. OBJECTIVE: To determine the relationship between highly-conserved extended-haplotypes (CEHs) in the major histocompatibility complex (MHC) and MS-susceptibility. BACKGROUND: Among the ~200 MS-susceptibility regions, which are known from genome-wide analyses of single nucleotide polymorphisms (SNPs), the MHC accounts for roughly a third of the currently explained variance and the strongest MS-associations are for certain Class II alleles (e.g., HLA-DRB1*15:01; HLA- DRB1*03:01; and HLA-DRB1*13:03), which frequently reside on CEHs within the MHC. DESIGN/METHODS: Autosomal SNPs (441,547) from 11,376 MS cases and 18,872 controls in the WTCCC dataset were phased. The most significant MS associated SNP haplotype was composed of 11 SNPs in the MHC Class II region surrounding the HLA-DRB1 gene. We also phased alleles at the HLA-A, HLA-C, HLA-B, HLA-DRB1, and HLA-DQB1 loci. This data was used to probe the relationship between CEHs and MS susceptibility. RESULTS: We phased a total of 59,884 extended haplotypes (HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DQB1 and SNP haplotypes) from 29,942 individuals. Of these, 10,078 unique extended haplotypes were identified. The 10 most common CEHs accounted for 22% (13,302) of the total. By contrast, the 8,446 least common extended haplotypes also accounted for approximately 20% (12,298) of the total. This extreme frequency-disparity among extended haplotypes necessarily complicates interpretation of reported disease-associations with specific HLA alleles. In particular, the HLA motif HLA-DRB1*15:01~HLA-DQB1*06:02 is strongly associated with MS risk. Nevertheless, although this motif is almost always found on the a1 SNP haplotype, it can rarely be found on others (e.g., a27 and a36), and, in these cases, it seems to have no apparent disease-association (OR = 0.7; CI = 0.3-1.3 and OR = 0.7; CI = 0.2-2.2, respectively). Furthermore, single copy carriers of the a1 SNP-haplotype without this HLA motif still have an increased disease risk (OR = 2.2; CI = 1.2-3.8). In addition, even among the set of CEHs, which carry the Class II motif of HLA-DRB1*15:01~HLA-DQB1*06:02~a1, different CEHs have differing strengths in their MS- associations. CONCLUSIONS: The MHC in diverse human populations consists, primarily, of a very small collection of very highly-selected CEHs. Our findings suggest that the MS-association with the HLA-DRB1*15:01~HLA-DQB1*06:02 haplotype may be due primarily to the combined attributes of the CEHs on which this particular HLA-motif often resides. DOI: 10.1371/journal.pone.0190043 PMID: 29438392
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336. PLoS One. 2018 Feb 8;13(2):e0192516. doi: 10.1371/journal.pone.0192516. eCollection 2018. Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls. de Flon P(1), Söderström L(2), Laurell K(1), Dring A(1), Sundström P(1), Gunnarsson M(3), Svenningsson A(1)(4). Author information: (1)Dept of Pharmacology and Clinical Neuroscience, Neurology, Umeå University, Umeå, Sweden. (2)Unit of Research, Education and Development, Östersund Hospital, Region Jämtland Härjedalen, Östersund, Sweden. (3)Dept of Neurology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden. (4)Dept of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden. OBJECTIVE: To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to compare the profile in MS patients with healthy controls (HC). METHOD: Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis. RESULTS: Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab. CONCLUSION: We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS. DOI: 10.1371/journal.pone.0192516 PMCID: PMC5805315 PMID: 29420590
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337. PLoS One. 2018 Feb 2;13(2):e0192109. doi: 10.1371/journal.pone.0192109. eCollection 2018. Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells. Hassani A(1), Corboy JR(2), Al-Salam S(3), Khan G(1). Author information: (1)Department of Microbiology and Immunology, College of Medicine and Health Sciences, Tawam Hospital Campus, United Arab Emirates University, Al Ain, UAE. (2)Department of Neurology, University of Colorado School of Medicine, Rocky Mountain MS Center at University of Colorado, Aurora, United States of America. (3)Department of Pathology, College of Medicine and Health Sciences, Tawam Hospital Campus, United Arab Emirates University, Al Ain, UAE. Multiple sclerosis (MS) is a chronic neuroinflammatory condition of the central nervous system (CNS). It is a major cause of neurological disability in young adults, particularly women. What triggers the destruction of myelin sheaths covering nerve fibres is unknown. Both genetic and infectious agents have been implicated. Of the infectious agents, Epstein-Barr virus (EBV), a common herpesvirus, has the strongest epidemiological and serological evidence. However, the presence of EBV in the CNS and demonstration of the underlying mechanism(s) linking EBV to the pathogenesis of MS remain to be elucidated. We aimed at understanding the contribution of EBV infection in the pathology of MS. We examined 1055 specimens (440 DNA samples and 615 brain tissues) from 101 MS and 21 non- MS cases for the presence of EBV using PCR and EBER-in situ hybridization (EBER-ISH). EBV was detected by PCR and/or EBER-ISH in 91/101 (90%) of MS cases compared to only 5/21 (24%) of non- MS cases with other neuropathologies. None of the samples were PCR positive for other common herpesviruses (HSV-1, CMV, HHV-6). By quantitative PCR, EBV viral load in MS brain was mainly low to moderate in most cases. However, in 18/101 (18%) of MS cases, widespread but scattered presence of EBV infected cells was noted in the affected tissues by EBER-ISH. Immunohistochemical analysis of EBV gene expression in the 18 heavily infected cases, revealed that the EBV latent protein EBNA1, and to a lesser extent the early lytic protein BZLF1 were expressed. Furthermore, using double-staining we show for the first time that astrocytes and microglia, in addition to B-cells can also be infected. To the best of our knowledge, this is the most comprehensive study demonstrating that EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis. Further studies are required to address the mechanism of EBV involvement in MS pathology. DOI: 10.1371/journal.pone.0192109 PMCID: PMC5796799 PMID: 29394264
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338. PLoS One. 2018 Feb 1;13(2):e0191646. doi: 10.1371/journal.pone.0191646. eCollection 2018. Socio-economic status influences access to second-line disease modifying treatment in Relapsing Remitting Multiple Sclerosis patients. Calocer F(1)(2), Dejardin O(3)(4), Droulon K(5), Launoy G(3)(4), Defer G(1)(2). Author information: (1)CHU de Caen, Department of Neurology, Caen, FR. (2)Normandie Université, UNICAEN, INSERM 1237, Physiopathology and Imaging of Neurological Disorders, Caen, FR. (3)CHU de Caen, Pôle de Recherche, Caen, FR. (4)Normandie Université, UNICAEN, INSERM 1086, ANTICIPE « Cancers et Préventions » Caen, FR. (5)Réseau Bas-Normand pour la SEP, Caen, FR. OBJECTIVE: In MS, Socio-Economic status (SES) may influence healthcare and access to disease- modifying treatments (DMTs). Optimising delays to switch patients to a second-line DMT may hamper disease progression most effectively and achieve long term disease control. The objective of this study is to identify the influence of SES on the delay between first and second line DMT in RRMS patients, in Western-Normandy, France. METHODS: The association between SES and the delay to access a second-line DMT were studied using data from the MS registry of Western-Normandy including 733 patients with a diagnosis of RRMS during the period in question [1982-2011]. We used the European Deprivation Index (EDI), a score with a rank level inversely related to SES. We performed multivariate adjusted Cox models for studying EDI effect on the delay between first and second line DMT. RESULTS: No significant influence of SES was observed on delay to access a second-line DMT if first-line DMT exposure time was less than 5 years. After 5 years from initiation of first-line treatment the risk of accessing a second-line DMT is 3 times higher for patients with lower deprivation indices (1st quintile of EDI) ([HR] 3.14 95%CI [1.72-5.72], p-value<0.001) compared to patients with higher values (EDI quintiles 2 to 5). INTERPRETATION: In RRMS, a high SES may facilitate access to a second-line DMT a few years after first-line DMT exposure. Greater consideration should also be given to the SES of MS patients as a risk factor in therapeutic healthcare issues throughout medical follow-up. DOI: 10.1371/journal.pone.0191646 PMCID: PMC5794112 PMID: 29390025
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339. PM R. 2018 Feb 22. pii: S1934-1482(18)30101-1. doi: 10.1016/j.pmrj.2018.02.010. [Epub ahead of print] Safety, Tolerability, and Effectiveness of Dextromethorphan/Quinidine for Pseudobulbar Affect Among Study Participants With Traumatic Brain Injury: Results From the PRISM-II Open Label Study. Hammond FM(1), Sauve W(2), Ledon F(3), Davis C(4), Formella AE(3). Author information: (1)Indiana University School of Medicine, Indianapolis, IN, US. Electronic address: [email protected]. (2)TMS NeuroHealth Centers, Richmond, VA, US. (3)Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, US. (4)CSD Biostatistics, Inc. Tucson, AZ, US. BACKGROUND: Dextromethorphan 20mg /quinidine 10mg (DM/Q) was approved to treat pseudobulbar affect (PBA) based upon phase 3 trials conducted in participants with amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness, safety and tolerability for PBA following stroke, dementia or traumatic brain injury (TBI). OBJECTIVE: To report results from the TBI cohort of PRISM II, including a TBI-specific functional scale. DESIGN: Open-label trial evaluating twice daily DM/Q over 90 days. STUDY PARTICIPANTS: Adults (n=120) with a clinical diagnosis of PBA secondary to non-penetrating TBI; stable psychiatric medications were allowed. METHODS: PRISM II was an open-label, 12-week trial enrolling adults with PBA secondary to dementia, stroke, or TBI. All study participants received DM/Q 20/10 mg twice daily. Study visits occurred at baseline and at day 30 and day 90. SETTING: 150 US centers. MAIN OUTCOME MEASUREMENTS: Primary endpoint was change in Center for Neurologic Study-Lability Scale (CNS- LS) score from baseline to day 90. Secondary outcomes included PBA episode count, Clinical and Patient Global Impression of Change (CGI-C; PGI-C), Quality of Life-Visual Analog Scale (QOL-VAS), treatment satisfaction, Neurobehavioral Functioning Inventory (NFI), Patient Health Questionnaire (PHQ-9), and Mini Mental State Examination (MMSE). RESULTS: DM/Q-treated participants showed significant mean (SD) reductions in CNS-LS from baseline (day 30, -5.6 [5.2]; day 90, -8.5 [5.2]; both, P<.001). Compared with baseline, PBA episodes were reduced by 61.3% and 78.5% at days 30 and 90 (both, P<.001). At day 90, 78% and 73% of study participants had "much improved" or "very much improved" on the CGI-C and PGI-C. QOL-VAS scores were significantly reduced from baseline (-3.7 [3.3]; P<.001). Mean (SD) PHQ-9 scores improved compared to baseline at day 30 (-3.2 [5.3], P<.001) and 90 (-5.2 [6.4], P<.001). NFI T-scores were significantly improved (P<.001), while MMSE scores were unchanged. Adverse events (AEs) were consistent with the known DM/Q safety profile; the most common AE was diarrhea (8.3%). CONCLUSIONS: DM/Q was well tolerated and significantly reduced PBA episodes in study participants with TBI. Changes in CNS-LS and PBA episode count were similar to changes with DM/Q in phase 3 trials. Copyright © 2018 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.pmrj.2018.02.010 PMID: 29477412
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340. Pract Neurol. 2018 Feb 22. pii: practneurol-2017-001743. doi: 10.1136/practneurol-2017- 001743. [Epub ahead of print] Neuropsychological testing. Zucchella C(1), Federico A(1)(2), Martini A(3), Tinazzi M(1)(2), Bartolo M(4), Tamburin S(1)(2). Author information: (1)Neurology Unit, Verona University Hospital, Verona, Italy. (2)Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy. (3)School of Psychology, Keele University, Staffordshire, UK. (4)Department of Rehabilitation, Neurorehabilitation Unit, Habilita, Zingonia, Italy. Neuropsychological testing is a key diagnostic tool for assessing people with dementia and mild cognitive impairment, but can also help in other neurological conditions such as Parkinson's disease, stroke, multiple sclerosis, traumatic brain injury and epilepsy. While cognitive screening tests offer gross information, detailed neuropsychological evaluation can provide data on different cognitive domains (visuospatial function, memory, attention, executive function, language and praxis) as well as neuropsychiatric and behavioural features. We should regard neuropsychological testing as an extension of the neurological examination applied to higher order cortical function, since each cognitive domain has an anatomical substrate. Ideally, neurologists should discuss the indications and results of neuropsychological assessment with a clinical neuropsychologist. This paper summarises the rationale, indications, main features, most common tests and pitfalls in neuropsychological evaluation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. DOI: 10.1136/practneurol-2017-001743 PMID: 29472384
Conflict of interest statement: Competing interests: None declared.
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 311 – Multiple Sklerose: Veröffentlichungen Oktober 2013
341. Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2186-2191. doi: 10.1073/pnas.1719902115. Epub 2018 Feb 12. Bryostatin-1 alleviates experimental multiple sclerosis. Kornberg MD(1), Smith MD(1), Shirazi HA(2), Calabresi PA(1)(3), Snyder SH(4)(3)(5), Kim PM(4). Author information: (1)Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287. (2)Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287. (3)Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205. (4)Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287; [email protected] [email protected]. (5)Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205. Multiple sclerosis (MS) is an inflammatory disorder targeting the central nervous system (CNS). The relapsing-remitting phase of MS is largely driven by peripheral activation of autoreactive T-helper (Th) 1 and Th17 lymphocytes. In contrast, compartmentalized inflammation within the CNS, including diffuse activation of innate myeloid cells, characterizes the progressive phase of MS, the most debilitating phase that currently lacks satisfactory treatments. Recently, bryostatin-1 (bryo-1), a naturally occurring, CNS-permeable compound with a favorable safety profile in humans, has been shown to act on antigen-presenting cells to promote differentiation of lymphocytes into Th2 cells, an action that might benefit Th1-driven inflammatory conditions such as MS. In the present study, we show that bryo-1 provides marked benefit in mice with experimental autoimmune encephalomyelitis (EAE), an experimental MS animal model. Preventive treatment with bryo-1 abolishes the onset of neurologic deficits in EAE. More strikingly, bryo-1 reverses neurologic deficits after EAE onset, even when treatment is initiated at a late stage of disease when peak adaptive immunity has subsided. Treatment with bryo-1 in vitro promotes an anti-inflammatory phenotype in antigen-presenting dendritic cells, macrophages, and to a lesser extent, lymphocytes. These findings suggest the potential for bryo-1 as a therapeutic agent in MS, particularly given its established clinical safety. Furthermore, the benefit of bryo-1, even in late treatment of EAE, combined with its targeting of innate myeloid cells suggests therapeutic potential in progressive forms of MS. DOI: 10.1073/pnas.1719902115 PMID: 29440425
Conflict of interest statement: The authors declare no conflict of interest.
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342. Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2168-2173. doi: 10.1073/pnas.1716146115. Epub 2018 Feb 12. Sex bias in MHC I-associated shaping of the adaptive immune system. Schneider-Hohendorf T(1), Görlich D(2), Savola P(3), Kelkka T(3), Mustjoki S(3), Gross CC(1), Owens GC(4), Klotz L(1), Dornmair K(5), Wiendl H(1), Schwab N(6). Author information: (1)Department of Neurology, University of Muenster, 48149 Muenster, Germany. (2)Institute of Biostatistics and Clinical Research, University of Muenster, 48149 Muenster, Germany. (3)Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, 00029 Helsinki, Finland. (4)Department of Neurosurgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095. (5)Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, 80539 Munich, Germany. (6)Department of Neurology, University of Muenster, 48149 Muenster, Germany; [email protected]. HLA associations, T cell receptor (TCR) repertoire bias, and sex bias have independently been shown for many diseases. While some immunological differences between the sexes have been described, they do not fully explain bias in men toward many infections/cancers, and toward women in autoimmunity. Next-generation TCR variable beta chain (TCRBV) immunosequencing of 824 individuals was evaluated in a multiparametric analysis including HLA-A -B/MHC class I background, TCRBV usage, sex, age, ethnicity, and TCRBV selection/expansion dynamics. We found that HLA- associated shaping of TCRBV usage differed between the sexes. Furthermore, certain TCRBVs were selected and expanded in unison. Correlations between these TCRBV relationships and biochemical similarities in HLA-binding positions were different in CD8 T cells of patients with autoimmune diseases (multiple sclerosis and rheumatoid arthritis) compared with healthy controls. Within patients, men showed higher TCRBV relationship Spearman's rhos in relation to HLA-binding position similarities compared with women. In line with this, CD8 T cells of men with autoimmune diseases also showed higher degrees of TCRBV perturbation compared with women. Concerted selection and expansion of CD8 T cells in patients with autoimmune diseases, but especially in men, appears to be less dependent on high HLA-binding similarity than in CD4 T cells. These findings are consistent with studies attributing autoimmunity to processes of epitope spreading and expansion of low-avidity T cell clones and may have further implications for the interpretation of pathogenic mechanisms of infectious and autoimmune diseases with known HLA associations. Reanalysis of some HLA association studies, separating the data by sex, could be informative. DOI: 10.1073/pnas.1716146115 PMID: 29440397
Conflict of interest statement: The authors declare no conflict of interest.
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343. Psychol Health Med. 2018 Feb 7:1-6. doi: 10.1080/13548506.2018.1437277. [Epub ahead of print] Management of multiple sclerosis: the role of coping self-efficacy and self-esteem. Mikula P(1), Nagyova I(1), Vitkova M(2), Szilasiova J(2). Author information: (1)a Faculty of Medicine, Department of Social and Behavioural Medicine , PJ Safarik University , Kosice , Slovakia. (2)b Faculty of Medicine, Department of Neurology , PJ Safarik University , Kosice , Slovakia. Patients with multiple sclerosis (MS) engage in various coping behaviours in order to manage their disease. The aim of this study is to find out if the self-esteem of patients is associated with coping strategies - problem-focused (e.g. making a plan of action when confronted with a problem); emotion focused (e.g. get emotional support from community); and focused on stopping unpleasant emotions and thoughts (e.g. keeping oneself from feeling sad), and if it can enhance or hinder coping efforts in the disease management. We collected data from 155 consecutive MS patients who completed the Coping Self-Efficacy Scale (CSE) and the Rosenberg Self-esteem Scale (RSE). Explained variance for problem-focused coping, emotion-focused coping, and coping focused on stopping unpleasant emotions and thoughts was 33, 24, and 31%, respectively. Self-esteem seems to be associated with coping strategies indicating that feelings of self-worth are linked with the ability to handle difficult life situations and can be helpful in chronic disease management. DOI: 10.1080/13548506.2018.1437277 PMID: 29409337
344. Qual Health Res. 2018 Feb 1:1049732317753584. doi: 10.1177/1049732317753584. [Epub ahead of print] The Experience of Persons With Multiple Sclerosis Using MS INFoRm: An Interactive Fatigue Management Resource. Pétrin J(1), Akbar N(1), Turpin K(2), Smyth P(2), Finlayson M(1). Author information: (1)1 Queen's University, Kingston, Ontario, Canada. (2)2 University of Alberta, Edmonton, Alberta, Canada. We aimed to understand participants' experiences with a self-guided fatigue management resource, Multiple Sclerosis: An Interactive Fatigue Management Resource ( MS INFoRm), and the extent to which they found its contents relevant and useful to their daily lives. We recruited 35 persons with MS experiencing mild to moderate fatigue, provided them with MS INFoRm, and then conducted semistructured interviews 3 weeks and 3 months after they received the resource. Interpretive description guided the analysis process. Findings indicate that participants' experience of using MS INFoRm could be understood as a process of change, influenced by their initial reactions to the resource. They reported experiencing a shift in knowledge, expectations, and behaviors with respect to fatigue self-management. These shifts led to multiple positive outcomes, including increased levels of self-confidence and improved quality of life. These findings suggest that MS INFoRm may have a place in the continuum of fatigue management interventions for people with MS. DOI: 10.1177/1049732317753584 PMID: 29411682
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345. Radiol Med. 2018 Feb 23. doi: 10.1007/s11547-018-0864-9. [Epub ahead of print] Re: Effects of serial macrocyclic-based contrast materials gadoterate meglumine and gadobutrol administrations on gadolinium-related dentate nuclei signal increases in unenhanced T1-weighted brain: a retrospective study in 158 multiple sclerosis (MS) patients. Raynaud JS(1), Darmon-Kern E(2), Lancelot E(2), Laurent AC(2), Desché P(2). Author information: (1)Guerbet, BP 57400, 95943, Roissy CDG Cedex, France. jean- [email protected]. (2)Guerbet, BP 57400, 95943, Roissy CDG Cedex, France. DOI: 10.1007/s11547-018-0864-9 PMID: 29476438
346. Recent Pat Anticancer Drug Discov. 2018 Feb 19. doi: 10.2174/1574892813666180220105958. [Epub ahead of print] Novel Patents Targeting Interleukin-17A; Implications in Cancer and Inflammation. Bjelica S(1), Santibanez JF(1). Author information: (1)Group for Molecular Oncology, Institute for Medical Research, University of Belgrade, Dr. Subotica 4, 11129 Belgrade. Serbia. BACKGROUND: IL-17A is a founding member of the IL-17 family that has been implicated in the pathogenesis of inflammatory-associated diseases such as cancer and autoimmune disease. In cancer, IL-17A participates in many key events for tumor development, in part by affecting innate and adaptive immune system and also by direct modulation of many pro-tumor events. Moreover, IL-17A dysregulation at the site of inflammation is associated with rheumatoid arthritis, multiple sclerosis, psoriasis, among others. IL-17A has emerged as a topic of interest and is under profound investigation for its involvement in several types of inflammatory-associated diseases. OBJECTIVE: This review aims to present an overview of the state of the art of IL-17A role in cancer and inflammation, as well as to describe recent patents targeting IL-17A with relevant clinical and biological properties for the prevention and treatment of cancer and inflammatory diseases. METHODS: Relevant information was obtained by searching in PubMed using IL-17A or IL-17, cancer and inflammation as keywords, while relevant patents were obtained mainly from Google Patents. RESULTS: Literature data indicated IL- 17A as important biomolecule in the physiopathology of cancer and inflammatory diseases. Whereas, novel patents (2010 to 2017) targeting IL-17A are focused mainly on describing strategies to modulate IL-17A per se, co-modulation by bispecific antibodies to blocking IL-17A and important cytokines for IL-17A functions, upstream mechanisms and compounds to regulate IL-17A expression. CONCLUSION: The promising effects of patented agents against IL-17A may open new opportunities to therapeutic intervention targeting at different levels of involvement in the pathogenesis of cancer and inflammatory diseases. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]. DOI: 10.2174/1574892813666180220105958 PMID: 29468982
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347. Sci Rep. 2018 Jan 31;8(1):1933. doi: 10.1038/s41598-018-20390-5. Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-κB pathway. Li G(1), Yamasaki R(2), Fang M(1), Masaki K(1), Ochi H(3), Matsushita T(1), Kira JI(4). Author information: (1)Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. (2)Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. [email protected]. (3)Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Matsuyama, 791-0295, Japan. (4)Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. [email protected]. We aimed to elucidate the effects of iguratimod, a widely used anti-rheumatic drug with no severe side effects, on chronic experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Iguratimod was orally administered to mice immunised with myelin oligodendrocyte glycoprotein peptide 35-55. Preventive administration of iguratimod from the time of immunisation was found to markedly reduce the clinical severity of acute and chronic EAE. Pathologically, iguratimod treatment significantly reduced demyelination and infiltration of CD3+ T, F4/80+, and CD169+ cells into the spinal cord, and suppressed macrophage/microglia activation in the parenchyma at the acute and chronic stages compared with vehicle treatment. Therapeutic administration of iguratimod after the onset of clinical symptoms significantly ameliorated the clinical severity of chronic EAE and reduced demyelination, T helper (Th)1/Th17 cell infiltration, macrophage/microglia activation, and nuclear factor (NF)-κB p65 and cyclooxygenase-2 expression in the spinal cord. In vitro, iguratimod treatment inhibited nuclear translocation of NF-κB p65 and down-regulated pro-inflammatory responses in macrophages and microglia. Our results suggest that iguratimod ameliorates acute and chronic EAE by suppressing inflammatory cell infiltration and immune cell activation, partly through inhibition of NF-κB p65, supporting the therapeutic potential of this drug for not only acute, but also chronic MS. DOI: 10.1038/s41598-018-20390-5 PMCID: PMC5792543 PMID: 29386552
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348. Sci Rep. 2018 Feb 22;8(1):3472. doi: 10.1038/s41598-018-21645-x. Whole genome diversity of inherited chromosomally integrated HHV-6 derived from healthy individuals of diverse geographic origin. Telford M(1), Navarro A(2)(3)(4)(5), Santpere G(6)(7). Author information: (1)Institute of Evolutionary Biology (UPF-CSIC), Departament de Ciències Experimentals i la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Catalonia, Spain. (2)Institute of Evolutionary Biology (UPF-CSIC), Departament de Ciències Experimentals i la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Catalonia, Spain. [email protected]. (3)National Institute for Bioinformatics (INB), PRBB, Barcelona, Catalonia, Spain. [email protected]. (4)Institució Catalana de Recerca i Estudis Avançats (ICREA), PRBB, Barcelona, Catalonia, Spain. [email protected]. (5)Center for Genomic Regulation (CRG), PRBB, Barcelona, Catalonia, Spain. [email protected]. (6)Institute of Evolutionary Biology (UPF-CSIC), Departament de Ciències Experimentals i la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Catalonia, Spain. [email protected]. (7)Department of Neuroscience, Yale School of Medicine, New Haven, CT, 06510, USA. [email protected]. Human herpesviruses 6-A and -B (HHV-6A, HHV-6B) are ubiquitous in human populations worldwide. These viruses have been associated with several diseases such as multiple sclerosis, Hodgkin's lymphoma or encephalitis. Despite of the need to understand the genetic diversity and geographic stratification of these viruses, the availability of complete viral sequences from different populations is still limited. Here, we present nine new inherited chromosomally integrated HHV-6 sequences from diverse geographical origin which were generated through target DNA enrichment on lymphoblastoid cell lines derived from healthy individuals. Integration with available HHV-6 sequences allowed the assessment of HHV-6A and -6B phylogeny, patterns of recombination and signatures of natural selection. Analysis of the intra-species variability showed differences between A and B diversity levels and revealed that the HHV-6B reference (Z29) is an uncommon sequence, suggesting the need for an alternative reference sequence. Signs of geographical variation are present and more defined in HHV- 6A, while they appear partly masked by recombination in HHV-6B. Finally, we conducted a scan for signatures of selection in protein coding genes that yielded at least 6 genes (4 and 2 respectively for the A and B species) showing significant evidence for accelerated evolution, and 1 gene showing evidence of positive selection in HHV-6A. DOI: 10.1038/s41598-018-21645-x PMCID: PMC5823862 PMID: 29472617
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349. Sci Rep. 2018 Feb 19;8(1):3300. doi: 10.1038/s41598-018-21599-0. Impaired Cardiac Function in Patients with Multiple Sclerosis by Comparison with Normal Subjects. Mincu RI(1)(2), Magda SL(2), Mihaila S(1)(2), Florescu M(1)(2), Mihalcea DJ(1), Velcea A(1), Chiru A(3), Tiu C(1)(2), Popescu BO(1)(3), Cinteza M(1)(2), Vinereanu D(4)(5). Author information: (1)University of Medicine and Pharmacy Carol Davila, Bucharest, Romania. (2)University and Emergency Hospital, Bucharest, Romania. (3)Colentina Clinical Hospital, Bucharest, Romania. (4)University of Medicine and Pharmacy Carol Davila, Bucharest, Romania. [email protected]. (5)University and Emergency Hospital, Bucharest, Romania. [email protected]. Multiple sclerosis (MS), neurologic disease affecting young population, may cause cardiovascular dysfunction, due to autonomous nervous dysfunction, physical invalidity, increased oxidative stress, and systemic inflammatory status. However, cardiovascular function is rarely evaluated in these patients. We assessed left and right ventricular (LV and RV) function by 2D, 3D, tissue Doppler, and speckle tracking echocardiography, and vascular function by remodeling, stiffness, and endothelial dysfunction parameters in patients with MS, compared to control subjects. 103 subjects (35 ± 10 years,70 women) were studied: 67 patients with MS and 36 control subjects. Patients with MS had decreased LV systolic function, confirmed by lower 2D and 3D ejection fraction, mitral annular plane systolic excursion, longitudinal myocardial systolic velocities, and 2D and 3D global longitudinal strain. The RV function was also decreased, as demonstrated by lower fractional area change, tricuspid annular plane systolic excursion, longitudinal systolic velocities, and longitudinal strain. Additionally, LV diastolic and left atrial (LA) function were decreased compared to controls. The parameters of arterial and endothelial function were similar between groups. Patients with MS have impaired biventricular function by comparison with normal subjects, with reduced LA function, but normal arterial and endothelial function. The noninvasive echocardiographic techniques might help to determine patients with MS at risk of developing cardiovascular dysfunction. DOI: 10.1038/s41598-018-21599-0 PMCID: PMC5818507 PMID: 29459794
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350. Sci Rep. 2018 Feb 15;8(1):3071. doi: 10.1038/s41598-018-21497-5. Enhanced release of acid sphingomyelinase-enriched exosomes generates a lipidomics signature in CSF of Multiple Sclerosis patients. Pieragostino D(1)(2), Cicalini I(2)(3), Lanuti P(2)(4), Ercolino E(2)(4), di Ioia M(5), Zucchelli M(2), Zappacosta R(3), Miscia S(2)(4), Marchisio M(2)(4), Sacchetta P(1)(2), Onofrj M(2)(5), Del Boccio P(6)(7). Author information: (1)Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy. (2)Centre on Aging Sciences and Translational Medicine (Ce.S.I-MeT), University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy. (3)Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy. (4)Department of Medicine and Aging Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy. (5)Department of Neuroscience, Imaging and Clinical Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy. (6)Centre on Aging Sciences and Translational Medicine (Ce.S.I-MeT), University "G. d'Annunzio" of Chieti- Pescara, Chieti, Italy. [email protected]. (7)Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy. [email protected]. Multiple Sclerosis (MuS) is a complex multifactorial neuropathology, resulting in heterogeneous clinical presentation. A very active MuS research field concerns the discovery of biomarkers helpful to make an early and definite diagnosis. The sphingomyelin pathway has emerged as a molecular mechanism involved in MuS, since high levels of ceramides in cerebrospinal fluid (CSF) were related to axonal damage and neuronal dysfunction. Ceramides are the hydrolysis products of sphingomyelins through a reaction catalyzed by a family of enzymes named sphingomyelinases, which were recently related to myelin repair in MuS. Here, using a lipidomic approach, we observed low levels of several sphingomyelins in CSF of MuS patients compared to other inflammatory and non-inflammatory, central or peripheral neurological diseases. Starting by this result, we investigated the sphingomyelinase activity in CSF, showing a significantly higher enzyme activity in MuS. In support of these results we found high number of total exosomes in CSF of MuS patients and a high number of acid sphingomyelinase-enriched exosomes correlated to enzymatic activity and to disease severity. These data are of diagnostic relevance and show, for the first time, high number of acid sphingomyelinase- enriched exosomes in MuS, opening a new window for therapeutic approaches/targets in the treatment of MuS. DOI: 10.1038/s41598-018-21497-5 PMCID: PMC5814401 PMID: 29449691
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351. Sci Rep. 2018 Feb 15;8(1):3057. doi: 10.1038/s41598-018-21038-0. Human subarachnoid space width oscillations in the resting state. Gruszecki M(1), Lancaster G(2), Stefanovska A(2), Neary JP(3), Dech RT(3), Guminski W(4), Frydrychowski AF(5), Kot J(6), Winklewski PJ(5)(7). Author information: (1)Department of Radiology Informatics and Statistics, Medical University of Gdansk, Gdansk, Poland. [email protected]. (2)Department of Physics, Lancaster University, Lancaster, UK. (3)Faculty of Kinesiology and Health Studies, University of Regina, Regina, Canada. (4)Department of Computer Communications, Faculty of Electronics, Telecommunications and Informatics, Gdansk University of Technology, Gdansk, Poland. (5)Department of Human Physiology, Medical University of Gdansk, Gdansk, Poland. (6)National Centre for Hyperbaric Medicine, Institute of Maritime and Tropical Medicine, Medical University of Gdansk, Gdynia, Poland. (7)Department of Clinical Anatomy and Physiology, Pomeranian University of Slupsk, Slupsk, Poland. Abnormal cerebrospinal fluid (CSF) pulsatility has been implicated in patients suffering from various diseases, including multiple sclerosis and hypertension. CSF pulsatility results in subarachnoid space (SAS) width changes, which can be measured with near-infrared transillumination backscattering sounding (NIR-T/BSS). The aim of this study was to combine NIR-T/BSS and wavelet analysis methods to characterise the dynamics of the SAS width within a wide range of frequencies from 0.005 to 2 Hz, with low frequencies studied in detail for the first time. From recordings in the resting state, we also demonstrate the relationships between SAS width in both hemispheres of the brain, and investigate how the SAS width dynamics is related to the blood pressure (BP). These investigations also revealed influences of age and SAS correlation on the dynamics of SAS width and its similarity with the BP. Combination of NIR-T/BSS and time-frequency analysis may open up new frontiers in the understanding and diagnosis of various neurodegenerative and ageing related diseases to improve diagnostic procedures and patient prognosis. DOI: 10.1038/s41598-018-21038-0 PMCID: PMC5814422 PMID: 29449606
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352. Sci Rep. 2018 Feb 13;8(1):2935. doi: 10.1038/s41598-018-19749-5. Expression, Purification and Characterization of the Human Cannabinoid 1 Receptor. Mallipeddi S(1)(2), Zvonok N(1)(2), Makriyannis A(3)(4)(5). Author information: (1)Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA. (2)Center for Drug Discovery, Northeastern University, Boston, MA, 02115, USA. (3)Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA. [email protected]. (4)Center for Drug Discovery, Northeastern University, Boston, MA, 02115, USA. [email protected]. (5)Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115, USA. [email protected]. The human cannabinoid 1 receptor (hCB1) is involved in numerous physiological processes and therefore provides a wide scope of potential therapeutic opportunities to treat maladies such as obesity, cardio-metabolic disorders, substance abuse, neuropathic pain, and multiple sclerosis. Structure-based drug design using the current knowledge of the hCB1 receptor binding site is limited and requires purified active protein. Heterologous expression and purification of functional hCB1 has been the bottleneck for ligand binding structural studies using biophysical methods such as mass spectrometry, x-ray crystallography and NMR. We constructed several plasmids for in-cell or in vitro Escherichia coli (E. coli) based expression of truncated and stabilized hCB1 receptor (hΔCB1 and hΔCB1T4L) variants and evaluated their competency to bind the CP-55,940 ligand. MALDI-TOF MS analysis of in vitro expressed and purified hΔCB1T4Lhis6 variants, following trypsin digestion, generated ~80% of the receptor sequence coverage. Our data demonstrate the feasibility of a cell-free expression system as a promising part of the strategy for the elucidation of ligand binding sites of the hCB1 receptor using a "Ligand Assisted Protein Structure" (LAPS) approach. DOI: 10.1038/s41598-018-19749-5 PMCID: PMC5811539 PMID: 29440756
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 321 – Multiple Sklerose: Veröffentlichungen Oktober 2013
353. Sci Rep. 2018 Feb 12;8(1):2851. doi: 10.1038/s41598-018-21317-w. Expression and replication of virus-like circular DNA in human cells. Eilebrecht S(1), Hotz-Wagenblatt A(2), Sarachaga V(3)(4), Burk A(3)(4), Falida K(3), Chakraborty D(3), Nikitina E(3)(5)(6), Tessmer C(7), Whitley C(3), Sauerland C(3), Gunst K(3), Grewe I(3), Bund T(3). Author information: (1)German Cancer Research Center, Division of Episomal-Persistent DNA in Cancer and Chronic Diseases, Heidelberg, Germany. [email protected]. (2)German Cancer Research Center, Core Facility Genomics and Proteomics, Heidelberg, Germany. (3)German Cancer Research Center, Division of Episomal-Persistent DNA in Cancer and Chronic Diseases, Heidelberg, Germany. (4)Biosciences Faculty, University of Heidelberg, Heidelberg, Germany. (5)Department of Oncovirology, Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia. (6)Department of Translational Cell and Molecular Biomedicine, Tomsk State University, Tomsk, Russia. (7)German Cancer Research Center, Core Facility Genomics and Proteomics, Monoclonal Antibody Facility, Heidelberg, Germany. The consumption of bovine milk and meat is considered a risk factor for colon- and breast cancer formation, and milk consumption has also been implicated in an increased risk for developing Multiple Sclerosis (MS). A number of highly related virus-like DNAs have been recently isolated from bovine milk and sera and from a brain sample of a MS patient. As a genetic activity of these Acinetobacter- related bovine milk and meat factors (BMMFs) is unknown in eukaryotes, we analyzed their expression and replication potential in human HEK293TT cells. While all analyzed BMMFs show transcriptional activity, the MS brain isolate MSBI1.176, sharing homology with a transmissible spongiform encephalopathy-associated DNA molecule, is transcribed at highest levels. We show expression of a replication-associated protein (Rep), which is highly conserved among all BMMFs, and serological tests indicate a human anti-Rep immune response. While the cow milk isolate CMI1.252 is replication-competent in HEK293TT cells, replication of MSBI1.176 is complemented by CMI1.252, pointing at an interplay during the establishment of persistence in human cells. Transcriptome profiling upon BMMF expression identified host cellular gene expression changes related to cell cycle progression and cell viability control, indicating potential pathways for a pathogenic involvement of BMMFs. DOI: 10.1038/s41598-018-21317-w PMCID: PMC5809378 PMID: 29434270
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 322 – Multiple Sklerose: Veröffentlichungen Oktober 2013
354. Sci Rep. 2018 Feb 1;8(1):2110. doi: 10.1038/s41598-018-20343-y. Evaluating upper limb impairments in multiple sclerosis by exposure to different mechanical environments. Pellegrino L(1), Coscia M(2)(3), Muller M(4), Solaro C(5), Casadio M(4). Author information: (1)Department Informatics, Bioengineering, Robotics and Systems Engineering, University of Genoa, Genoa, Italy. [email protected]. (2)Bertarelli Foundation Chair in Translational Neuroengineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland. (3)Wyss Center for Bio- and Neuroengineering, Geneva, Switzerland. (4)Department Informatics, Bioengineering, Robotics and Systems Engineering, University of Genoa, Genoa, Italy. (5)Azienda Sanitaria Locale di Genova, ASL3, Genoa, Italy. Multiple sclerosis is a chronic, autoimmune and neurodegenerative disease affecting multiple functional systems and resulting in motor impairments associated with muscle weakness and lack of movement coordination. We quantified upper limb motor deficits with a robot-based assessment including behavioral and muscle synergy analysis in 11 multiple sclerosis subjects with mild to moderate upper limb impairment (9 female; 50 ± 10 years) compared to 11 age- and gender- matched controls (9 female; 50 ± 9 years). All subjects performed planar reaching tasks by moving their upper limb or applying force while grasping the handle of a robotic manipulandum that generated four different environments: free space, assistive or resistive forces, and rigid constraint. We recorded the activity of 15 upper body muscles. Multiple sclerosis subjects generated irregular trajectories. While activities in isolated arm muscles appeared generally normal, shoulder muscle coordination with arm motions was impaired and there was a marked co-activation of the biceps and triceps in extension movements. Systematic differences in timing and organization of muscle synergies have also been observed. This study supports the definition of new biomarkers and rehabilitative treatments for improving upper limb motor coordination in multiple sclerosis. DOI: 10.1038/s41598-018-20343-y PMCID: PMC5794735 PMID: 29391520
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 323 – Multiple Sklerose: Veröffentlichungen Oktober 2013
355. Sci Rep. 2018 Feb 1;8(1):2113. doi: 10.1038/s41598-018-19934-6. Grey matter OPCs are less mature and less sensitive to IFNγ than white matter OPCs: consequences for remyelination. Lentferink DH(1), Jongsma JM(1), Werkman I(1), Baron W(2). Author information: (1)Department of Cell Biology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands. (2)Department of Cell Biology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands. [email protected]. Multiple sclerosis (MS) is a chronic inflammatory disease characterized by the formation of demyelinated lesions in the central nervous system. At later stages of the disease repair in the form of remyelination often fails, which leads to axonal degeneration and neurological disability. For the regeneration of myelin, oligodendrocyte progenitor cells (OPCs) have to migrate, proliferate and differentiate into remyelinating oligodendrocytes. Remyelination occurs faster and is more extensive in grey matter (GM) lesions than in white matter (WM) lesions. Here, we examined differences in neonatal OPCs from GM (gmOPCs) and WM (wmOPCs), both intrinsically and in response to environmental (injury) signals. We show that gmOPCs are less mature than wmOPCs, both on morphological and on gene-expression level. Additionally, gmOPCs proliferate more and differentiate slower than wmOPCs. When exposed to astrocyte-secreted signals wmOPC, but not gmOPC, migration decreases. In addition, wmOPCs are more sensitive to the detrimental effects of IFNγ treatment on proliferation, differentiation, and process arborisation, which is potentiated by TNFα. Our results demonstrate that OPCs from GM and WM differ both intrinsically and in response to their environment, which may contribute to the difference in remyelination efficiency between GM and WM MS lesions. DOI: 10.1038/s41598-018-19934-6 PMCID: PMC5794790 PMID: 29391408
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 324 – Multiple Sklerose: Veröffentlichungen Oktober 2013
356. Soc Sci Med. 2018 Feb 2. pii: S0277-9536(18)30015-7. doi: 10.1016/j.socscimed.2018.01.015. [Epub ahead of print] Judgment hurts: The psychological consequences of experiencing stigma in multiple sclerosis. Cadden MH(1), Arnett PA(2), Tyry TM(3), Cook JE(2). Author information: (1)Department of Psychology, The Pennsylvania State University, University Park, PA, 16802, USA. Electronic address: [email protected]. (2)Department of Psychology, The Pennsylvania State University, University Park, PA, 16802, USA. (3)Dignity Health, St. Joseph's Hospital and Medical Center, AZ, 85013, USA. RATIONALE: People living with MS often report feeling stigmatized, but little research has examined the psychological impact of this, which is important considering the high prevalence of depression in this population. OBJECTIVES: The aim of this study was to assess, concurrently and prospectively, the association between stigma and depression in people living with MS. METHODS: Data were available from 5369 participants enrolled in the semi-annual survey conducted by the North American Research Committee on Multiple Sclerosis (NARCOMS). Participants reported their MS stigma and depression in the spring 2013 update survey (T1) and their depression again one year later (T2). Demographic and health-related covariates were also assessed. RESULTS: People experiencing higher levels of stigma reported more depression symptoms and were more likely to meet the threshold for clinical depression at both times, even controlling for covariates. Higher levels of stigma also predicted T2 depression, controlling for T1 depression (and covariates), suggesting a possible causal association. Greater psychosocial reserve, a composite of measures assessing participants' feelings of belonging, social support, and sense of control, attenuated the association between stigma and depression. CONCLUSIONS: Stigma is an important but understudied predictor of depression in people living with MS, but greater psychosocial reserve provides a buffer. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.socscimed.2018.01.015 PMID: 29439818
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 325 – Multiple Sklerose: Veröffentlichungen Oktober 2013
357. Spinal Cord Ser Cases. 2018 Jan 24;4:10. doi: 10.1038/s41394-018-0039-x. eCollection 2018. Temporal evolution of a patient with a spinal dural arteriovenous fistula on serial MRI. Kim MG(1), Jeong SW(2), Solli E(3), Amin AG(1), Ronecker JS(1), Bobra S(4). Author information: (1)1Department of Neurosurgery, Westchester Medical Center, Valhalla, NY USA. (2)2New York Medical College, Valhalla, NY USA. (3)3Department of Neurosurgery, Rutgers New Jersey Medical School, Newark, NJ USA. (4)4Department of Radiology, Westchester Medical Center, Valhalla, NY USA. Introduction: A spinal dural arteriovenous fistula is a rare type of vascular malformation. If left untreated, these fistulas can result in significant neurological deficits secondary to spinal cord infarct or hemorrhage. Case presentation: A 70-year-old female with a longstanding history of episodic progressive bilateral lower extremity weakness and sensory disturbances was previously misdiagnosed with multiple sclerosis. Imaging revealed a T2 signal change from T7 to the conus with associated signal change and she subsequently underwent a T10-L1 laminectomy for clip ligation of a spinal dural arteriovenous fistula. Here we present the clinical and radiographic progression of one patient with a spinal dural arteriovenous fistula. Discussion: Spinal dural arteriovenous fistulas are a rare but treatable cause of myelopathy, so it is important to understand its natural progression and radiologic findings as it is frequently misdiagnosed. DOI: 10.1038/s41394-018-0039-x PMCID: PMC5802505 [Available on 2019-01-24] PMID: 29423315
Conflict of interest statement: Compliance with ethical standardsThe authors declare that they have no conflict of interest.
358. Stem Cells Cloning. 2018 Feb 12;11:1-11. doi: 10.2147/SCCAA.S135415. eCollection 2018. A review on stem cell therapy for multiple sclerosis: special focus on human embryonic stem cells. Shroff G(1). Author information: (1)Department of Stem Cell Therapy, Nutech Mediworld, New Delhi, India. Multiple sclerosis (MS), a complex disorder of the central nervous system (CNS), is characterized with axonal loss underlying long-term progressive disability. Currently available therapies for its management are able to slow down the progression but fail to treat it completely. Moreover, these therapies are associated with major CNS and cardiovascular adverse events, and prolonged use of these treatments may cause life-threatening diseases. Recent research has shown that cellular therapies hold a potential for CNS repair and may be able to provide protection from inflammatory damage caused after injury. Human embryonic stem cell (hESC) transplantation is one of the promising cell therapies; hESCs play an important role in remyelination and help in preventing demylenation of the axons. In this study, an overview of the current knowledge about the unique properties of hESC and their comparison with other cell therapies has been presented for the treatment of patients with MS. DOI: 10.2147/SCCAA.S135415 PMCID: PMC5813951 PMID: 29483778
Conflict of interest statement: Disclosure The author reports no conflicts of interest in this work.
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 326 – Multiple Sklerose: Veröffentlichungen Oktober 2013
359. Stem Cells Int. 2017;2017:1606125. doi: 10.1155/2017/1606125. Epub 2017 Dec 14. Stemness Characteristics of Periodontal Ligament Stem Cells from Donors and Multiple Sclerosis Patients: A Comparative Study. Diomede F(1), Rajan TS(2), D'Aurora M(3), Bramanti P(2), Merciaro I(1), Marchisio M(4), Gatta V(3), Mazzon E(2), Trubiani O(1). Author information: (1)Stem Cells and Regenerative Medicine Laboratory, Department of Medical, Oral and Biotechnological Sciences, Università "G. d'Annunzio", Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy. (2)IRCCS Centro Neurolesi "Bonino-Pulejo", Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy. (3)Department of Psychological, Health and Territorial Sciences, School of Medicine, Università "G. d'Annunzio", Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy. (4)Department of Medicine and Aging Science, Università "G. d'Annunzio", Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy. Multiple sclerosis (MS) is the most prevalent and progressive autoimmune disease that affects the central nervous system, and currently, no drug is available for the treatment. Stem cell therapy has received substantial attention in MS treatment. Recently, we demonstrated the immunosuppressive effects of mesenchymal stem cells derived from neural crest-originated human periodontal ligament tissue (hPDLSCs) in an in vivo model of MS. In the present study, we comparatively investigated the stemness properties of hPDLSCs derived from healthy donors and relapsing-remitting MS patients. Stem cell marker expression, cell proliferation, and differentiation capacity were studied. We found that both donor- and MS patient-derived hPDLSCs at early passage 2 showed similar expression of surface antigen markers and cell proliferation rate. Significant level of osteogenic, adipogenic, chondrogenic, and neurogenic differentiation capacities was observed in both donor- and MS patient- derived hPDLSCs. Interestingly, these cells maintained the stemness properties even at late passage 15. Senescence markers p16 and p21 expression was considerably enhanced in passage 15. Our results propose that hPDLSCs may serve as simple and potential autologous stem cell niche, which may help in personalized stem cell therapy for MS patients. DOI: 10.1155/2017/1606125 PMCID: PMC5745749 PMID: 29387088
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 327 – Multiple Sklerose: Veröffentlichungen Oktober 2013
360. Ther Adv Neurol Disord. 2018 Jan 23;11:1756285617753365. doi: 10.1177/1756285617753365. eCollection 2018. Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY Extension study. Comi G(1), Cook S(2), Rammohan K(3), Soelberg Sorensen P(4), Vermersch P(5), Adeniji AK(6), Dangond F(6), Giovannoni G(7). Author information: (1)Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan 20132, Italy. (2)Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA. (3)Depatment of Neurology, University of Miami School of Medicine, Miami, FL, USA. (4)Department of Neurology, University of Copenhagen, Copenhagen, Denmark. (5)University of Lille, Lille, France. (6)EMD Serono, Inc., Billerica, MA, USA. (7)Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK. Background: The CLARITY and CLARITY Extension studies demonstrated that treatment of relapsing- remitting multiple sclerosis (RRMS) with cladribine tablets (CT) results in significant clinical improvements, compared with placebo. This paper presents the key magnetic resonance imaging (MRI) findings from the CLARITY Extension study. Methods: Patients who received a cumulative dose of either CT 3.5 or 5.25 mg/kg in CLARITY were rerandomized to either placebo or CT 3.5 mg/kg in CLARITY Extension. Patients from the arm that received placebo in CLARITY were assigned to CT 3.5 mg/kg. MRI assessments were carried out when patients entered CLARITY Extension and after Weeks 24, 48, 72 and 96, and in a supplemental follow-up period. Results: At CLARITY Extension baseline, patients who received placebo during CLARITY had more T1 gadolinium-enhanced (Gd+) lesions than patients who received CT during CLARITY. These patients, who were then exposed to cladribine 3.5 mg/kg during the extension, experienced a 90.4% relative reduction (median difference -0.33, 97.5% confidence interval -0.33-0.00; p < 0.001) in T1 Gd+ lesions at the end of the extension compared with the end of CLARITY. Overall, the majority of patients in each treatment group remained free from T1 Gd+ lesions throughout CLARITY Extension. However, a small proportion of patients who were treated with cladribine in CLARITY and received placebo in CLARITY Extension showed evidence of increased MRI activity, and this was associated with a prolonged treatment gap between CLARITY and CLARITY Extension. Conclusion: A 2-year treatment with CT 3.5 mg/kg has a durable effect on MRI outcomes in the majority of patients, an effect that was sustained in patients who were not retreated in the subsequent 2 years after initial treatment. ClinicalTrials.gov identifier: NCT00641537. DOI: 10.1177/1756285617753365 PMCID: PMC5788142 PMID: 29399054
Conflict of interest statement: Conflict of interest statement: GC has received consulting fees from Novartis, Teva Pharmaceutical Industries Ltd., Sanofi-Aventis, Merck, Receptos, Biogen Idec, Genentech-Roche, and Bayer Schering; lecture fees from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation; and trial grant support from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Receptos, Biogen Idec, Genentech-Roche, Merck, Biogen Dompè, and Bayer Schering. SC has received honoraria for lectures/consultations from Merck, Bayer HealthCare, Sanofi-Aventis, Neurology Reviews, Biogen Idec, Teva Pharmaceuticals and Actinobac Biomed Inc.; has served on advisory boards for Bayer HealthCare, Merck, Actinobac Biomed, Teva Pharmaceuticals, and Biogen Idec; and received grant support from Bayer HealthCare. KR has received honoraria for lectures and steering committee meetings from EMD Serono, Biogen Idec, Sanofi-Aventis, Genzyme, Novartis, Teva Neurosciences, Acorda and Roche/Genentech. PS-S has served on advisory boards for Biogen, Merck, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck, Teva, GSK, and Novartis; has received speaker honoraria from Biogen Idec, Merck, Teva, Sanofi-Aventis, Genzyme, and Novartis. His department has received research support from Biogen, Merck, Teva, Novartis, Roche, and Genzyme. PV has received honoraria or consulting fees from Biogen, Sanofi-Genzyme, Bayer, Novartis, Merck, Celgen, Roche and Almirall; and research support from Biogen, Sanofi-Genzyme, Bayer, and Merck. AA and FD are employees of EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany. GG has received speaker honoraria and consulting fees from Abbvie, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec FivePrime, GlaxoSmithKline, GW Pharma, Merck, Pfizer Inc., Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd., Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, Merck, Novartis and Ironwood. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 328 – Multiple Sklerose: Veröffentlichungen Oktober 2013
361. Ther Adv Neurol Disord. 2018 Jan 23;11:1756285617749802. doi: 10.1177/1756285617749802. eCollection 2018. An epidemiological study on the course of disease and therapeutic considerations in relapsing- remitting multiple sclerosis patients receiving injectable first-line disease-modifying therapies in Germany (EPIDEM). Schmidt S(1), Koehler J(2), Winterstein C(3), Schicklmaier P(3), Kallmann B(4). Author information: (1)Neurologische Gemeinschaftspraxis, Kölnstr. 54, 53111 Bonn, Germany. (2)Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke Gemeinnützige GmbH, Kempfenhausen, Germany. (3)Biogen, Medical Department, Munich, Germany. (4)Multiple Sklerose Zentrum Bamberg (MSZB), Bamberg, Germany. Background: In relapsing-remitting multiple sclerosis (RRMS), 'no evidence of disease activity' (NEDA) is regarded as a key treatment goal. The increasing number of treatments allows for individualized treatment optimization in patients with suboptimal response to first-line disease-modifying therapies (DMTs). Therefore, monitoring of clinical and subclinical disease activity on DMTs has been recognized as an important component of long-term patient management. Methods: EPIDEM was a multicenter non-interventional retrospective study in a large cohort of RRMS patients receiving injectable DMTs for at least 2 years in outpatient centers throughout Germany. It documented measures and ratings of disease activity on DMTs to characterize the factors that made the treating neurologists consider to switch therapy towards potentially more effective or better-tolerated drugs. Results: The cohort included predominantly female patients with a mean age of 45 years and a mean disease duration of 9.6 years, who had been continuously treated with an injectable DMT for a median duration of 54 months. Overall, 34.0% of the patients had experienced ⩾1 relapse on any DMT in the previous 2 years; 21.0% exhibited magnetic resonance imaging (MRI) activity, and the Kurtzke Expanded Disability Status Scale (EDSS) score increased by at least 0.5 points in 20.1%. Overall, 50.3% of the patients with EDSS progression and 70.6% of the patients with relapses were assessed as clinically stable by the neurologists. A change of treatment was considered in a fraction of patients with disease activity: in 22.8% of those with relapse activity, in 37.8% of those with MRI activity and in 20.1% of those with EDSS progression. Conclusion: The results of EPIDEM underline the importance of standardized evaluation and documentation of ongoing disease activity and disability deterioration. Judged from the present data, the current paradigm of low tolerance for disease activity and recommendations for early treatment optimization have not been turned fully into action as yet. More widespread implementation of current guideline recommendations may allow patients to more benefit from the growing panel of effective treatment options. DOI: 10.1177/1756285617749802 PMCID: PMC5788096 PMID: 29399053
Conflict of interest statement: Conflict of interest statement: B. Kallmann has received honoraria for serving on advisory boards and as speaker from Merck Serono, Biogen, Sanofi/Genzyme, TEVA and Novartis. J. Koehler has received honoraria for lecturing or travel expenses for attending meetings from Almirall, Bayer, Biogen, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis, and TEVA. He is a consultant for Allmiral, Bayer, Genzyme, Novartis and Roche. S. Schmidt has received speaking honoraria, travel compensations and fees for serving on advisory boards from BayerVital, Biogen, Merck Serono, Novartis and TEVA. P. Schicklmaier and C. Winterstein were employees of Biogen GmbH, Germany.
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 329 – Multiple Sklerose: Veröffentlichungen Oktober 2013
362. Ther Adv Neurol Disord. 2018 Jan 23;11:1756285617748845. doi: 10.1177/1756285617748845. eCollection 2018. Patient satisfaction and healthcare services in specialized multiple sclerosis centres in Germany. Becker V(1), Heeschen V(2), Schuh K(2), Schieb H(2), Ziemssen T(3). Author information: (1)Neurologische Praxis Eppendorf, Hamburg, Germany. (2)Novartis Pharma GmbH, Nuremberg, Germany. (3)Center of Clinical Neuroscience, University Clinic Carl Gustav Carus Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Background: As patients with multiple sclerosis (MS) require lifelong treatment, optimization of therapy with respect to efficacy and safety is needed to limit long-term disease progression. Patients with MS also need a range of health-related services. Satisfaction with these as well as treatment is clinically relevant because satisfied patients are more likely to adhere to therapy. The aim of this study was to determine the status of patient satisfaction and of healthcare services in 70 specialized MS centres in Germany. Methods: In 2011, patients with MS responded to a questionnaire, which solicited clinical and demographic information, as well as patients' perceptions of their overall situation and their satisfaction with treatment. Results: Of 2791 patients surveyed, 81.9% had relapsing-remitting MS with mild disability [mean (standard deviation) Expanded Disability Status Scale score: 2.6 (1.8)]. Disease activity data were collected from 2205 patients, of whom 57.6% had remained relapse-free during the preceding 12 months. However, 38.9% had experienced one or more relapses, most of whom (67.3%) while receiving immunomodulatory treatment. About one-third of the patients indicated that they were more dissatisfied with their overall situation compared with the time before diagnosis. However, many patients (58.3%) were satisfied with their existing medication. Overall, 72.8% of patients would prefer oral to injectable treatments, assuming there was no difference in their efficacy. Conclusions: A substantial proportion of patients experienced breakthrough disease on treatment and may potentially benefit from a change of therapy. Although largely satisfied with treatment, most patients with MS would choose oral over injectable treatments. DOI: 10.1177/1756285617748845 PMCID: PMC5788086 PMID: 29399052
Conflict of interest statement: Conflict of interest statement: Veit Becker has received reimbursements for participation in scientific advisory boards and speaker honoraria from Merck, Biogen, Novartis Pharma AG, Genzyme, Sanofi. He received research support from Novartis Pharma AG, Merck and Teva. Volker Heeschen, Katrin Schuh and Heinke Schieb are employees of Novartis Pharma GmbH. Tjalf Ziemssen has received reimbursements for participation in scientific advisory boards from Bayer Healthcare, Biogen Idec, Novartis Pharma AG, Merck Serono, Teva, Genzyme, and Synthon. He has also received speaker honorarium from Bayer Healthcare, Biogen Idec, Genzyme, Merck Sharp & Dohme, GlaxoSmithKline, Novartis Pharma AG, Teva, Sanofi Aventis, and Almirall. He has also received research support from Bayer Healthcare, Biogen Idec, Genzyme, Novartis Pharma AG, Teva, and Sanofi Aventis.
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 330 – Multiple Sklerose: Veröffentlichungen Oktober 2013
363. Ther Adv Neurol Disord. 2017 Nov 29;11:1756285617741056. doi: 10.1177/1756285617741056. eCollection 2018. Decreased platelet number in multiple sclerosis during alemtuzumab infusion: a common, transient and clinically silent phenomenon. Puthenparampil M(1), Rinaldi F(2), Federle L(3), Cazzola C(3), Perini P(2), Gallo P(3). Author information: (1)Multiple Sclerosis Centre, Department of Neuroscience DNS, Università degli Studi di Padova, Via Giustiniani 2, 35128, Padova, Italy marco. (2)Multiple Sclerosis Centre, Azienda Ospedaliera di Padova, Padova, Italy. (3)Multiple Sclerosis Centre, Department of Neuroscience DNS, Università degli Studi di Padova, Padova, Italy. Background: The cause and clinical significance of the transient decrease in platelet (PLT) count observed in relapsing remitting multiple sclerosis (RRMS) during alemtuzumab administration remain undefined. The aim of this study was to analyse the kinetics and clinical relevance of early onset thrombocytopaenia in alemtuzumab-treated RRMS. Methods: A total of 26 patients with RRMS were included in a longitudinal study. Blood samples were collected immediately before the first alemtuzumab infusion (D0), and after 3 days (D3), 28 days (D28) and 49 days (D49). PLT, red blood cell (RC), leucocyte and lymphocyte counts, haemoglobin (Hb) concentration and haematocrit (Htc) were measured. Patients with MS were clinically evaluated every day of drug infusion and then at D28 and D49 to verify the presence of signs or symptoms suggestive of thrombocytopaenia. Results: PLT number significantly decreased at D3 (p < 0.005) and was associated with a decrease in RC count (r: 0.53, p < 0.01), Hb (r: 0.42, p = 0.05) and Htc (r: 0.53, p < 0.01). A progressive reversion of PLT number to normal values was observed at D28 and D49. A mild thrombocytopaenia was observed in 12 patients (46.2%), 8 of which (66.6%) had PLT nadir values at D3, and 4 (33.3%) at D28. No sign or symptom suggestive of thrombocytopaenia was observed. A strong correlation between pretreatment and nadir PTL counts (r: 0.59, p < 0.005) was observed; indeed, mild thrombocytopaenia was observed more frequently in these patients with a baseline PTL count lower than 230 × 109/L (83.3% versus 42.9%, p < 0.05). Conclusions: The early PLT decrease in alemtuzumab-treated patients is transient, mild, not associated with clinically relevant events and is probably related to the cytokine- released syndrome. Notwithstanding this, our findings suggest the opportunity for PLT monitoring during infusion and in the following 2 months, since a decrease in PLT count may occur. DOI: 10.1177/1756285617741056 PMCID: PMC5784536 PMID: 29399047
Conflict of interest statement: Conflict of interest statement: The authors declare no conflicts of interest in preparing this article.
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 331 – Multiple Sklerose: Veröffentlichungen Oktober 2013
364. Thromb Res. 2018 Jan 30;163:105-116. doi: 10.1016/j.thromres.2018.01.039. [Epub ahead of print] Endothelial cell functions impaired by interferon in vitro: Insights into the molecular mechanism of thrombotic microangiopathy associated with interferon therapy. Jia H(1), Thelwell C(2), Dilger P(3), Bird C(3), Daniels S(2), Wadhwa M(3). Author information: (1)Section of Cytokines and Growth Factors, Division of Biotherapeutics, National Institute for Biological Standards and Control, United Kingdom. Electronic address: [email protected]. (2)Section of Haemostasis, Division of Biotherapeutics, National Institute for Biological Standards and Control, United Kingdom. (3)Section of Cytokines and Growth Factors, Division of Biotherapeutics, National Institute for Biological Standards and Control, United Kingdom. INTRODUCTION: Interferon (IFN)-α and IFN-β approved for treatment of chronic hepatitis C viral infection and multiple sclerosis respectively have been linked to thrombotic microangiopathy (TMA) affecting renal function. Since the molecular mechanisms underlying this severe complication remain largely unclear, we aimed to investigate whether IFN affects directly in vitro endothelial cell functions associated with angiogenesis and blood haemostasis, as well as endothelial cell-derived vasodilators of nitric oxide (NO) and prostacyclin. METHODS: Proliferation and survival of human umbilical vein endothelial cells (HUVECs) were measured by BrdU incorporation and alamarBlue assays. Angiogenesis was evaluated in co-cultures of HUVECs and human dermal fibroblasts. Fibrinolysis molecules were measured with ELISA. NO and prostacyclin were measured using a fluorescent NO- specific probe and a competitive enzyme immunoassay, respectively. RESULTS: HUVEC proliferation was dose-dependently inhibited by IFN-β1a and IFN-β1b, but not by IFN-α2a and IFN-α2b. Consistently, IFN-β1a and IFN-β1b also reduced survival of HUVECs, but this again was not observed with IFN-α. However, both IFN subtypes inhibited VEGF-induced development of capillary-like structures, but the effect of IFN-α was less potent than IFN-β. In addition, both IFN subtypes upregulated interferon inducible protein 10 production from treated co-cultures while suppressing angiogenesis. Furthermore, intracellular NO generation was reduced by IFN-α2a and IFN-β1a, whereas prostacyclin release from HUVECs was not affected by IFN. Importantly, both IFN-β1a- and IFN-β1b-treated HUVECs showed a marked reduction in urokinase-type plasminogen activator release and a much greater secretion of plasminogen activator inhibitor-1 than tissue-type plasminogen activator compared with untreated cells, suggesting decreased fibrinolytic activity. IFN-α, however was less effective in modulating the fibrinolysis system. CONCLUSIONS: We demonstrate the detrimental effects of IFN on endothelial cell functions mediated with angiogenesis and fibrinolysis, which could potentially cause the loss of physiological endothelium thromboresistance and facilitate the development of vascular complications in a clinical setting. Mechanistically, our findings have implications for understanding how IFN therapy can foster the development of TMA. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved. DOI: 10.1016/j.thromres.2018.01.039 PMID: 29407621
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365. Toxicol Appl Pharmacol. 2018 Mar 1;342:86-98. doi: 10.1016/j.taap.2018.01.023. Epub 2018 Jan 31. Low, but not high, dose triptolide controls neuroinflammation and improves behavioral deficits in toxic model of multiple sclerosis by dampening of NF-κB activation and acceleration of intrinsic myelin repair. Sanadgol N(1), Golab F(2), Mostafaie A(3), Mehdizadeh M(4), Khalseh R(5), Mahmoudi M(6), Abdollahi M(7), Vakilzadeh G(8), Taghizadeh G(9), Sharifzadeh M(10). Author information: (1)Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. (2)Cellular and Molecular Research Center, Iran University of Medical Science, Tehran, Iran. (3)Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran. (4)Cellular and Molecular Research Center, Iran University of Medical Science, Tehran, Iran; Faculty of Advanced Technologies in Medicine, Department of Anatomical Sciences, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. (5)Department of Chemical Engineering, Babol Noshirvani University of Technology, Babol, Iran. (6)Department of Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA, USA. (7)Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran. (8)Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. (9)Department of Occupational Therapy, School of Rehabilitation Sciences, Iran University of Medical Sciences, Tehran, Iran; Rehabilitation Research Center, School of Rehabilitation Sciences, Iran University of Medical Sciences, Tehran, Iran. (10)Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: [email protected]. Cuprizone (Cup) is a copper chelating agent frequently used to study factors that affect oligodendrocytes (OLGs) death and acute demyelination. Triptolide (TP), a nuclear factor-kappaB (NF-κB) blocker, is a major bioactive component of Tripterygium wilfordii Hook f. (TWHf) with various therapeutic activities. In this study, we examined the effects of TP on neuroglia activation, inflammation, apoptosis, demyelination, and behavioral deficits in the Cup-induced toxic model of multiple sclerosis (MS). C57BL/6 J mice were fed with chow containing 0.2% Cup for 6 weeks to induce detectable neuroinflammation and myelin loss. TP was administered intraperitoneally at different doses (125, 250 or 500 μg/kg/day) during the last week of the Cup challenge. Although TP substantially decreased Cup-induced NF-κB extra activation, TNF-α and IL-1 over expression, and gliosis in a dose-dependent manner, only low dose of TP (TP-125) was able to raise the number of OLGs precursor cells (NG-2+/O4+), reduce Bax/Bcl-2 ratio and improve behavioral deficits. In addition, TP-125 decreased NF-κB activation on GFAP+ astrocytes more than MAC-3+ microglial and MOG+ oligodendrocytes which suggested the possibility of specific dampening of NF-κB signaling in reactive astrocytes. Behavioral assessments by open-field and rota-rod tests showed that only TP- 125 notably improved motor function and motor coordination compared to the Cup group. These findings highlight the pivotal role of NF-κB signaling in the oligodendrogenesis and lesion reduction in demyelination diseases such as MS. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.taap.2018.01.023 PMID: 29407366
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366. Toxicol Lett. 2018 Feb 3;287:131-141. doi: 10.1016/j.toxlet.2018.01.020. [Epub ahead of print] Protection by dimethyl fumarate against diabetic cardiomyopathy in type 1 diabetic mice likely via activation of nuclear factor erythroid-2 related factor 2. Hu X(1), Rajesh M(2), Zhang J(1), Zhou S(3), Wang S(3), Sun J(3), Tan Y(4), Zheng Y(5), Cai L(4). Author information: (1)Cardiovascular Center of the First Hospital of Jilin University, Chang Chun, Jilin, 130021, China; Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, 40202, United States. (2)Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Al Ain, 17666, United Arab Emirates. Electronic address: [email protected]. (3)Cardiovascular Center of the First Hospital of Jilin University, Chang Chun, Jilin, 130021, China. (4)Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, 40202, United States. (5)Cardiovascular Center of the First Hospital of Jilin University, Chang Chun, Jilin, 130021, China. Electronic address: [email protected]. Oxidative stress and inflammation play key roles in the development of diabetic cardiomyopathy (DCM). Dimethyl fumarate (DMF), an FDA approved medicine for relapsing multiple sclerosis, has manifested its antioxidant and anti-inflammatory function mostly in the central nervous system. In this study, we investigated whether DMF could attenuate the development of DCM. Type 1 diabetes mouse model was established using multiple low-dose streptozotocin, and the diabetic mice were treated with DMF (10 mg/kg body weight) for 3 months. Cardiac functions were determined using echocardiography. Oxidative stress, pro-inflammatory cytokines and pro-fibrotic markers were determined with commercially available kits, real-time quantitative PCR or western blot techniques. DCM was characterized by diminished cardiac function, accompanied by oxidative stress and enhanced expression of pro-inflammatory cytokines. Diabetic cardiac tissue exhibited marked fibrosis, revealed by extracellular matrix deposition as determined by Sirius red staining of the myocardial tissues. Furthermore, Nrf2 and its downstream effectors were repressed in diabetic myocardium. On the contrary, diabetic animals treated with DMF exhibited blunted oxidative stress, inflammation, fibrosis and this correlated with Nrf2 activation. Our findings suggest that DMF could potentially thwart diabetes-induced myocardial tissue injury, likely via activation of Nrf2 function, providing firm impetus for future repurposing of DMF in the management of DCM. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.toxlet.2018.01.020 PMID: 29408448
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 334 – Multiple Sklerose: Veröffentlichungen Oktober 2013
367. Toxicology. 2018 Feb 8;396-397:33-45. doi: 10.1016/j.tox.2018.02.003. [Epub ahead of print] Mitochondrial dysfunction induced by leflunomide and its active metabolite. Xuan J(1), Ren Z(1), Qing T(2), Couch L(1), Shi L(2), Tolleson WH(1), Guo L(3). Author information: (1)Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. (2)School of Pharmacy and School of Life Sciences, Fudan University, Shanghai 200438, China. (3)School of Pharmacy and School of Life Sciences, Fudan University, Shanghai 200438, China. Electronic address: [email protected]. Leflunomide, an anti-inflammatory drug used for the treatment of rheumatoid arthritis, has been marked with a black box warning regarding an increased risk of liver injury. The active metabolite of leflunomide, A771726, which also carries a boxed warning about potential hepatotoxicity, has been marketed as teriflunomide for the treatment of relapsing multiple sclerosis. Thus far, however, the mechanism of liver injury associated with the two drugs has remained elusive. In this study, cytotoxicity assays showed that ATP depletion and subsequent LDH release were induced in a time- and concentration-dependent manner by leflunomide in HepG2 cells, and to a lesser extent, by A77 1726. The decline of cellular ATP levels caused by leflunomide was dramatically exacerbated when galactose was substituted for glucose as the sugar source, indicating a potential mitochondrial liability of leflunomide. By measuring the activities of immuno-captured mitochondrial oxidative phosphorylation (OXPHOS) complexes, we found that leflunomide and A77 1726 preferentially targeted complex V (F1FO ATP synthase), with IC50 values of 35.0 and 63.7 μM, respectively. Bongkrekic acid, a mitochondrial permeability transition pore blocker that targets adenine nucleotide translocase, profoundly attenuated mitochondrial membrane depolarization, ATP depletion, and LDH leakage induced by leflunomide and A77 1726. Substantial alterations of mitochondrial function at the transcript level were observed in leflunomide-treated HepG2 cells, whereas the effects of A77 1726 on the cellular transcriptome were much less profound. Our results suggest that mitochondrial dysfunction may be implicated in the hepatotoxicity associated with leflunomide and A77 1726, with the former exhibiting higher toxicity potency. Published by Elsevier B.V. DOI: 10.1016/j.tox.2018.02.003 PMID: 29427785
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368. Toxins (Basel). 2018 Jan 27;10(2). pii: E55. doi: 10.3390/toxins10020055. Botulinum Toxin A for Sialorrhoea Associated with Neurological Disorders: Evaluation of the Relationship between Effect of Treatment and the Number of Glands Treated. Restivo DA(1), Panebianco M(2), Casabona A(3), Lanza S(4), Marchese-Ragona R(5), Patti F(6), Masiero S(7), Biondi A(8), Quartarone A(9). Author information: (1)Neurology Department, Garibaldi Hospital, 95100 Catania, Italy. [email protected]. (2)Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L271XF, UK. [email protected]. (3)Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95100 Catania, Italy. [email protected]. (4)UOC di Medicina Fisica e Riabilitazione, Comiso- Vittoria, ASP Ragusa, 97013 Ragusa, Italy. [email protected]. (5)ENT Department, University of Padova, 35121 Padova, Italy. [email protected]. (6)DANA Department, "GF Ingrassia", Neuroscience Section-Multiple Sclerosis Center, University of Catania, 95100 Catania, Italy. [email protected]. (7)School of Physical Medicine and Rehabilitation, University of Padua, 35121 Padua, Italy. [email protected]. (8)Department of Surgery, University of Catania, 95100 Catania, Italy. [email protected]. (9)IRCCS Centro Neurolesi "Bonibo-Pulejo", via Provinciale Palermo, Contrada Casazza, 95124 Messina, Italy. [email protected]. Background: Sialorrhoea and drooling are disabling manifestations of different neurological disorders. The aim of this study was to evaluate the effects of botulinum neurotoxin type A (BoNT/A) injection on hypersalivation in 90 patients with neurological diseases of different aetiologies, and to define the minimum number of injected salivary glands to reduce sialorrhoea. Determining the minimum number of glands that need to be engaged in order to have a significant reduction in drooling may be very useful for establishing the minimum total dosage of BoNT/A that may be considered effective in the treatment of hypersalivation. Methods: Twenty-five mouse units (MU) of BoNT/A (onabotulinumtoxin A, Botox; Allergan, Irvine, CA, USA; 100 MU/2 mL, 0.9% saline; or incobotulinumtoxin A, Xeomin; Merz Pharma, Germany; 100 MU/2 mL, 0.9% saline) were percutaneously injected into the parotid (p) glands and/or submandibular (s) glands under ultrasound control. On this basis, patients were divided into three groups. In group A (30 patients), BoNT/A injections were performed into four glands; in group B (30 patients), into three glands, and in group C (30 patients), into two glands. Patients treated in three glands (group B) were divided into two subgroups based on the treated glands (2 p + 1 s = 15 patients; 2 s + 1 p = 15 patients). Similarly, patients being injected in two glands (group C) were subdivided into three groups (2 p = 10 patients; 1 p + 1 s = 10 patients; 2 s = 10 patients). In patients who were injected in three and two salivary glands, saline solution was injected into the remaining one and two glands, respectively. Assessments were performed at baseline and at 2 weeks after the injections. Results: BoNT/A significantly reduced sialorrhoea in 82 out of 90 patients. The effect was more evident in patients who had four glands injected than when three or two glands were injected. The injections into three glands were more effective than injections into two glands. Conclusions: Our results have shown that BoNT/A injections induced a significant reduction in sialorrhoea in most patients (91%). In addition, we demonstrated that sialorrhoea associated with different neurological diseases was better controlled when the number of treated glands was higher. DOI: 10.3390/toxins10020055 PMID: 29382036
Conflict of interest statement: The authors declare no conflict of interest. We had no founding sponsor.
Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche – 336 – Multiple Sklerose: Veröffentlichungen Oktober 2013
369. Vaccine. 2018 Mar 14;36(12):1548-1555. doi: 10.1016/j.vaccine.2018.02.036. Epub 2018 Feb 15. Hepatitis B vaccination and the putative risk of central demyelinating diseases - A systematic review and meta-analysis. Mouchet J(1), Salvo F(2), Raschi E(3), Poluzzi E(3), Antonazzo IC(3), De Ponti F(3), Bégaud B(2). Author information: (1)Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France. Electronic address: julie.le-moal@u- bordeaux.fr. (2)Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France. (3)Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. BACKGROUND: The anti-hepatitis B immunization campaigns launched in the early 1990s were a major public health breakthrough and targeted various populations (at-risk adults, newborns, adolescents). However, debate is still active about a possible link between this vaccine and central demyelination. This study provides a pooled estimate of this risk based on a comprehensive review and meta-analysis of all available epidemiologic studies. METHODS: A systematic review was conducted in Medline, Embase, ISI Web of Science and the Cochrane Library from database inception to 10 May 2017. Grey literature was searched and snowballing was also undertaken. Only observational studies including a control group were retained. Primary outcome was multiple sclerosis diagnosed by recognized criteria. Study selection was performed by two independent reviewers with disagreements solved through discussion. This meta-analysis based on crude, adjusted estimates, or risks limited to the 3 months following immunization was performed using a generic inverse variance random-effect model. Heterogeneity was investigated; sensitivity and subgroup analyses were performed when necessary. This study followed the PRISMA statement and the MOOSE reporting guideline (Study protocol registered in PROSPERO: CRD42015020808). FINDINGS: Of the 2804 references reviewed, 13 studies with a control group were analysed. None of the pooled risk estimates for either multiple sclerosis or central demyelination following HB immunization reached statistical significance. When considering adjusted risk ratios, the following non-significant figures were obtained: 1.19 (95%CI: 0.93 - 1.52) and 1.25 (95%CI: 0.97 - 1.62), for multiple sclerosis and central demyelination, respectively. CONCLUSIONS: No evidence of an association between hepatitis B vaccination and central demyelination was found. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.vaccine.2018.02.036 PMID: 29454521
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370. Work. 2018 Jan 31. doi: 10.3233/WOR-182682. [Epub ahead of print] The impact of visible and invisible symptoms on employment status, work and social functioning in Multiple Sclerosis. Lorefice L(1), Fenu G(1), Frau J(1), Coghe GC(1), Marrosu MG(1), Cocco E(1). Author information: (1)Department of Medical Sciences and Public Health, Multiple Sclerosis Centre, University of Cagliari, Sardinia, Italy. BACKGROUND: Frequently diagnosed in young adulthood, multiple sclerosis (MS) and several MS- related factors can influence patients' unemployment status and negatively affect work productivity and daily functioning. OBJECTIVE: We examined MS patients' employment status and evaluated clinical features influencing it. Furthermore, we investigated patients' burdens due to visible and invisible MS symptoms through their worsening daily functioning. METHODS: The study included outpatients affected by MS according to the 2010 McDonald criteria. The co-occurrence of invisible symptoms (fatigue, depression and apathy) was stated using validated, self-administered tools: Fatigue Severity Scale (FSS); Beck Depression Inventory-Second Edition (BDI-II); Apathy Evaluation Scale (AES). Impairment in daily functioning due to MS was assessed using the Work and Social Adjustment Scale (WSAS). Descriptive statistics, hierarchical regression analyses, Pearson's correlation, and the t-test were conducted. RESULTS: Of the 123 participants, 52 (42.3%) were unemployed. Results showed employment to be positively associated with higher education levels (p 0.01); female gender (p 0.03) and higher disability (p 0.02) showed negative associations with employment. No associations were found between employment and fatigue or clinically relevant depressive and apathetic symptoms. High correlations were found between WSAS score and Expanded Disability Status Scale score (r = 565, p < 0.001), BDI-II score (r = 588, p < 0.001), and FSS score (r = 545, p < 0.001). CONCLUSION: Our study revealed physical disability's significance in determining MS patients' unemployment. Alternatively, invisible MS symptoms negatively affected principally patients' social lives. Therefore, programs should be designed to improve MS patients' work integration and daily activities. DOI: 10.3233/WOR-182682 PMID: 29400690
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