Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 1 – Multiple Sklerose: Veröffentlichungen Mai 2018
Literatur-Dauerrecherche Multiple Sklerose Ausgabe April 2019
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1 lhe IFNB MS Stuijy Group, Neurology1993; 43:655-661. 1 BayerPharma AG, Data on file. 'KapposLe t al.; Neurol�y2016;87:978-987. 'GoodinD et al., Neurology 2012; 78: 1315-1322 Betaferon"250 Mlkrogramn\lmlPu lver und Lösungsmittelzur Herstellung ei ner lnjektionslösung. Wirkstoff:Interferon beta-1 b ('M\lerschreibungbi tte dieF achinformationb �;,,amnnensetz\llg:A1meikdi ,wksiiTJerBestancteil' 1 ml der gebrauchsferrigen lnjektionslösung emhält 150 Mikrogramm (8,0 Mio. l.E.) rekombinan1eslnlerferon beta-1 I1 1 Durch Inhaltsverzeichnis Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Oct. CADTH Common Drug Reviews...... 17 Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Oct. CADTH Common Drug Reviews...... 17 Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Oct. CADTH Common Drug Reviews...... 17 Codelivery of Plasmid and Curcumin with Mesoporous Silica Nanoparticles for Promoting Neurite Outgrowth...... 18 O-GlcNAc Modification Protects against Protein Misfolding and Aggregation in Neurodegenerative Disease...... 18 Cerebral abscess in a multiple sclerosis patient during treatment with natalizumab.19 Mental imagery training for treatment of central neuropathic pain: a narrative review...... 19 Real-life use of oral disease-modifying treatments in Austria...... 20 ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD...... 21 Vitamin D increases glucocorticoid efficacy via inhibition of mTORC1 in experimental models of multiple sclerosis...... 22 Blood vessels guide Schwann cell migration in the adult demyelinated CNS through Eph/ephrin signaling...... 23 FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy...... 24 Unique RNA signature of different lesion types in the brain white matter in progressive multiple sclerosis...... 25 Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis...... 26 The effectiveness of whole-body cryotherapy and physical exercises on the psychological well-being of patients with multiple sclerosis: A comparative analysis.26 Novel Insights on Systemic and Brain Aging, Stroke, Amyotrophic Lateral Sclerosis, and Alzheimer's Disease...... 27 The Central Vein Sign in Radiologically Isolated Syndrome...... 28 A Controlled Clinical Trial On The Effects Of Exercise On Lower Urinary Tract Symptoms In Women With Multiple Sclerosis...... 28 Bioluminescent aptamer-based sandwich-type assay of anti-myelin basic protein autoantibodies associated with multiple sclerosis...... 29 Association of corneal nerve fiber measures with cognitive function in dementia. . 29 Investigation of white matter PiB uptake as a marker of white matter integrity. ... 30 Can We Treat Secondary Progressive Multiple Sclerosis Now? ...... 30 Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex...... 31 Reliability, validity, and normative investigation of Persian version of a High-Level Language Test (BESS)...... 31 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 2 – Multiple Sklerose: Veröffentlichungen April 2019 Montreal Cognitive Assessment in a Greek sample of patients with multiple sclerosis: A validation study...... 32 Oxygen cost during mobility tasks and its relationship to fatigue in progressive Multiple Sclerosis...... 32 The prevalence of bruxism and related factors in patients with multiple sclerosis: a comparative study...... 33 Polymorphisms in the CIITA -168A/G (rs3087456) and CIITA +1614G/C (rs4774) may influence severity in multiple sclerosis patients...... 33 Study of MRI brain findings and carotid US features in systemic sclerosis patients, relationship with disease parameters...... 34 Association of Delta-6-Desaturase Expression with Aggressiveness of Cancer, Diabetes Mellitus, and Multiple Sclerosis: A Narrative Review ...... 35 Emerging role of air pollution in autoimmune diseases...... 36 Myeloid disorders after autoimmune disease...... 37 Perspectives on gender parity in bioanalysis: an interview with Lauren Stevenson.37 Dimethyl Fumarate Attenuates Oxaliplatin-Induced Peripheral Neuropathy without Affecting the Anti-tumor Activity of Oxaliplatin in Rodents...... 38 Stem Cell-Based Therapies for Multiple Sclerosis: Current Perspectives...... 38 Women's Health: Contemporary Management of MS in Pregnancy and Post-Partum.39 Synthesis and characterization of hydrogen peroxide activated estrogen receptor beta ligands...... 39 Synthesis and SAR development of quinoline analogs as novel P2X7 receptor antagonists...... 39 Effects of Oenothera biennis L. and Hypericum perforatum L. extracts on some central nervous system myelin proteins, brain histopathology and oxidative stress in mice with experimental autoimmune encephalomyelitis...... 40 Alternative or complementary attitudes toward alternative and complementary medicines...... 41 The agreement between chronic diseases reported by patients and derived from administrative data in patients undergoing joint arthroplasty...... 42 Harding's disease: an important MS mimic...... 42 Impact of red meat, processed meat and fibre intake on risk of late-onset chronic inflammatory diseases: prospective cohort study on lifestyle factors using the Danish 'Diet, Cancer and Health' cohort (PROCID-DCH): protocol...... 43 Management of multiple sclerosis symptoms through reductions in sedentary behaviour: protocol for a feasibility study...... 44 DPP-4 inhibitors lower the risk of autoimmune disease in patients with type 2 diabetes mellitus: A nationwide population-based cohort study...... 44 Towards a standard MRI protocol for multiple sclerosis across the UK...... 45 Survival: the ultimate long-term outcome in multiple sclerosis...... 45 Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders...... 46 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 3 – Multiple Sklerose: Veröffentlichungen April 2019 Reactivation of nonsense-mediated mRNA decay protects against C9orf72 dipeptide-repeat neurotoxicity...... 47 Secondary progressive multiple sclerosis and the gut-brain axis...... 47 TRPM4 channel and cancer...... 48 Deceased Donor Renal Transplantation Combined with Bilateral Nephrectomy in a Patient with Tuberous Sclerosis and Renal Failure...... 48 Small Molecules with Big Promises for Curing Demyelinating Diseases...... 49 Transplantation of clinical-grade human neural stem cells reduces neuroinflammation, prolongs survival and delays disease progression in the SOD1 rats...... 50 Advances in the pathogenesis and treatment of autoimmunity...... 51 PAD2-Mediated Citrullination Contributes to Efficient Oligodendrocyte Differentiation and Myelination...... 51 Distillation of Posterior Fossa Demyelination in Acute Vestibular Syndrome: the Eyes Have It...... 52 Immune and autonomic nervous system interactions in multiple sclerosis: clinical implications...... 52 Epstein-Barr Virus and Monoclonal Gammopathy of Clinical Significance in Autologous Stem Cell Transplantation for Multiple Sclerosis...... 53 A pilot study on the efficacy of transcranial direct current stimulation applied to the pharyngeal motor cortex for dysphagia associated with brainstem involvement in multiple sclerosis...... 54 The incremental value of neuropsychological assessment: a critical review...... 55 Limb apraxia profiles in different clinical samples...... 55 Novel Multiple Sclerosis Drugs in the Pipeline...... 56 Impairment of Quality of Life Associated With Lifetime Diagnosis of Post-traumatic Stress Disorder in Women - A National Survey in Italy...... 56 The clinical- and cost-effectiveness of functional electrical stimulation and ankle- foot orthoses for foot drop in Multiple Sclerosis: a multicentre randomized trial. ... 57 A cohort study of functional electrical stimulation in people with multiple sclerosis demonstrating improvements in quality of life and cost-effectiveness...... 57 Analysis of serum interleukin(IL)-1α, IL-1β and IL-18 in patients with systemic sclerosis...... 58 A non-randomized clinical trial to evaluate the effect of fingolimod on expanded disability status scale score and number of relapses in relapsing-remitting multiple sclerosis patients...... 58 Determine safety of outpatient chemotherapy and autotransplants using refrigerated, non-frozen grafts in persons with multiple sclerosis...... 59 Herbal medicinal products or preparations for neuropathic pain...... 60 Weight control and physical exercise in people with multiple sclerosis: Current knowledge and future perspectives...... 62 The effect of exercise, yoga and physiotherapy on the quality of life of people with multiple sclerosis: Systematic review and meta-analysis...... 62 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 4 – Multiple Sklerose: Veröffentlichungen April 2019 Effect of coenzyme Q10 supplementation on fatigue: A systematic review of interventional studies...... 63 Effects of osteopathic manipulative treatment on patients with multiple sclerosis: A pilot study...... 63 Rationale and design of the STEP for MS Trial: Comparative effectiveness of Supervised versus Telerehabilitation Exercise Programs for Multiple Sclerosis...... 64 Emotional disturbances in multiple sclerosis: A neuropsychological and fMRI study.65 Cumulative administrations of gadolinium-based contrast agents: risks of accumulation and toxicity of linear vs macrocyclic agents...... 65 Correction to: Autologous Haematopoietic Stem Cell Transplantation in Multiple Sclerosis: a Review of Current Literature and Future Directions for Transplant Haematologists and Oncologists...... 66 Serum IL-33 level and IL-33, IL1RL1 gene polymorphisms in asthma and multiple sclerosis patients...... 66 Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. .. 67 Current therapeutic landscape in multiple sclerosis: an evolving treatment paradigm...... 67 Diagnosis of multiple sclerosis: revisions of the McDonald criteria 2017 - continuity and change...... 68 Imaging the multiple sclerosis lesion: insights into pathogenesis, progression and repair...... 68 Multiple sclerosis: clinical trial design 2019...... 69 Targeting P2X4 and P2X7 receptors in multiple sclerosis...... 69 ABC transporters in neurological disorders: an important gateway for botanical compounds mediated neuro-therapeutics...... 70 IL-23 and dendritic cells: What are the roles of their mutual attachment in immune response and immunotherapy? ...... 70 Case report of a recalcitrant allergic contact eczema successfully treated with Teriflunomide...... 71 Body mass index trajectories in pediatric multiple sclerosis...... 71 Konuskan B(1), Anlar B(1)...... 72 Fatigue, depression, and quality of life in children with multiple sclerosis: a comparative study with other demyelinating diseases...... 72 Paediatric multiple sclerosis: a new era in diagnosis and treatment...... 73 An emerging role of dysfunctional axon-oligodendrocyte coupling in neurodegenerative diseases...... 75 Quality of life in patients with multiple sclerosis: A study with patients and caregivers...... 76 How people with multiple sclerosis experience the influence of nutrition and lifestyle factors on the disease...... 76 The multiple faces of pain in motor neuron disease: a qualitative study to inform pain assessment and pain management...... 77 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 5 – Multiple Sklerose: Veröffentlichungen April 2019 A qualitative exploration of physiotherapists' perceptions about exercise and physical activity: reflections on the results from a Delphi Study...... 77 Comparison of sedentary behaviour questionnaires in people with multiple sclerosis.78 Social capital components and social support of persons with multiple sclerosis: a systematic review of the literature from 2000 to 2018...... 78 Curcumin ameliorates experimental autoimmune encephalomyelitis in a C57BL/6 mouse model...... 79 Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course...... 80 OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes...... 81 Sensory Neurons of the Dorsal Root Ganglia Become Hyperexcitable in a T-Cell- Mediated MOG-EAE Model of Multiple Sclerosis...... 81 Melanoma during fingolimod treatment for multiple sclerosis...... 82 Self-Limited Cytomegalovirus Infection During Natalizumab Treatment for Multiple Sclerosis...... 82 InCl3 mediated heteroarylation of indoles and their derivatization via CH activation strategy: Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis...... 83 Depression in multiple sclerosis: effect of brain derived neurotrophic factor Val66Met polymorphism and disease perception...... 83 The cerebrospinal fluid CD4/CD8 ratio and interleukin-6 and -10 levels in neurosarcoidosis: a multicenter, pragmatic, comparative study...... 84 Neurofilament light chain levels in pregnant multiple sclerosis patients: a prospective cohort study...... 85 Alpinia oxyphylla Fruit Extract Ameliorates Experimental Autoimmune Encephalomyelitis through the Regulation of Th1/Th17 Cells...... 86 CD20 monoclonal antibodies for the treatment of multiple sclerosis: up-to-date. .. 86 Vascular Aspects of Multiple Sclerosis: Emphasis on Perfusion and Cardiovascular Comorbidities...... 87 CD28 null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection...... 87 The S1P mimetic fingolimod phosphate regulates mitochondrial oxidative stress in neuronal cells...... 88 Protective function of autophagy during VLCFA-induced cytotoxicity in a neurodegenerative cell model...... 89 The Fine Tuning of Drp1-Dependent Mitochondrial Remodeling and Autophagy Controls Neuronal Differentiation...... 89 Pericytes Favor Oligodendrocyte Fate Choice in Adult Neural Stem Cells...... 90 Antiphospholipid Antibodies Overlapping in Isolated Neurological Syndrome and Multiple Sclerosis: Neurobiological Insights and Diagnostic Challenges...... 90 Galectin-3 (MAC-2) Controls Microglia Phenotype Whether Amoeboid and Phagocytic or Branched and Non-phagocytic by Regulating the Cytoskeleton...... 91 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 6 – Multiple Sklerose: Veröffentlichungen April 2019 Genome-Wide DNA Methylation Profiles Reveal Common Epigenetic Patterns of Interferon-Related Genes in Multiple Autoimmune Diseases...... 91 Circulating Cytokines Could Not Be Good Prognostic Biomarkers in a Mouse Model of Amyotrophic Lateral Sclerosis...... 92 The Cerebrospinal Fluid in Multiple Sclerosis...... 92 PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation...... 93 Brain Citrullination Patterns and T Cell Reactivity of Cerebrospinal Fluid-Derived CD4+ T Cells in Multiple Sclerosis...... 93 The iNOS Activity During an Immune Response Controls the CNS Pathology in Experimental Autoimmune Encephalomyelitis...... 94 Epstein-Barr Virus and miRNAs: Partners in Crime in the Pathogenesis of Multiple Sclerosis? ...... 94 CSF Free Light Chains as a Marker of Intrathecal Immunoglobulin Synthesis in Multiple Sclerosis: A Blood-CSF Barrier Related Evaluation in a Large Cohort...... 95 A Sentinel in the Crosstalk Between the Nervous and Immune System: The (Immuno)-Proteasome...... 95 Immune Cell Profiling of the Cerebrospinal Fluid Provides Pathogenetic Insights Into Inflammatory Neuropathies...... 96 Prevotella histicola, A Human Gut Commensal, Is as Potent as COPAXONE® in an Animal Model of Multiple Sclerosis...... 97 NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms...... 97 Bioinformatics Analyses Determined the Distinct CNS and Peripheral Surrogate Biomarker Candidates Between Two Mouse Models for Progressive Multiple Sclerosis...... 98 The MRZ-Reaction and Specific Autoantibody Detection for Differentiation of ANA- Positive Multiple Sclerosis From Rheumatic Diseases With Cerebral Involvement. . 99 The Association Between Vitamin D and Multiple Sclerosis Risk: 1,25(OH)2D3 Induces Super-Enhancers Bound by VDR...... 99 Abrogation of Endogenous Glycolipid Antigen Presentation on Myelin-Laden Macrophages by D-Sphingosine Ameliorates the Pathogenesis of Experimental Autoimmune Encephalomyelitis...... 100 CSF Cytokines in Aging, Multiple Sclerosis, and Dementia...... 101 Cognitive Impairment in Multiple Sclerosis Is Reflected by Increased Susceptibility to the Sound-Induced Flash Illusion...... 101 Anti-IL-6 Receptor Antibody Inhibits Spontaneous Pain at the Pre-onset of Experimental Autoimmune Encephalomyelitis in Mice...... 102 Fatigue in Multiple Sclerosis: General and Perceived Fatigue Does Not Depend on Corticospinal Tract Dysfunction...... 102 Neurofilament Light Chain as a Biomarker in Multiple Sclerosis...... 103 Cancer Risk and Multiple Sclerosis: Evidence From a Large Italian Cohort...... 103 Standardization of T1w/T2w Ratio Improves Detection of Tissue Damage in Multiple Sclerosis...... 104 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 7 – Multiple Sklerose: Veröffentlichungen April 2019 Three-Dimensional In vivo Magnetic Resonance Imaging (MRI) of Mouse Facial Nerve Regeneration...... 104 Glial Activation Markers in CSF and Serum From Patients With Primary Progressive Multiple Sclerosis: Potential of Serum GFAP as Disease Severity Marker? ...... 105 Best Practices for Long-Term Monitoring and Follow-Up of Alemtuzumab-Treated MS Patients in Real-World Clinical Settings...... 106 Functional Connectivity Changes After Initial Treatment With Fingolimod in Multiple Sclerosis...... 107 A Longitudinally Extensive Spinal Cord Lesion Restricted to Gray Matter in an Adolescent Male...... 108 Cognitive Impairment in Multiple Sclerosis With Regards to Disease Duration and Clinical Phenotypes...... 108 Corrigendum: A Perspective of Coagulation Dysfunction in Multiple Sclerosis and in Experimental Allergic Encephalomyelitis...... 109 Impact of the McDonald Criteria 2017 on Early Diagnosis of Relapsing-Remitting Multiple Sclerosis...... 109 Focus on 1,25-Dihydroxyvitamin D3 in the Peripheral Nervous System...... 110 Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review...... 110 Venlafaxine Improves the Cognitive Impairment and Depression-Like Behaviors in a Cuprizone Mouse Model by Alleviating Demyelination and Neuroinflammation in the Brain...... 111 Targeting Microglia and Macrophages: A Potential Treatment Strategy for Multiple Sclerosis...... 111 Depression in Somatic Disorders: Is There a Beneficial Effect of Exercise? ...... 112 Autoimmune Diseases and Psychotic Disorders...... 112 Glutamate versus GABA in neuron-oligodendroglia communication...... 113 Uncovering the biology of myelin with optical imaging of the live brain...... 113 Low-intensity transcranial magnetic stimulation promotes the survival and maturation of newborn oligodendrocytes in the adult mouse brain...... 114 Diversity in the oligodendrocyte lineage: Plasticity or heterogeneity? ...... 114 Venoarterial extracorporeal membrane oxygenation and implantable cardioverter- defibrillator implantation in a hemodynamically unstable infant with ventricular tachycardia from multiple cardiac rhabdomyomas...... 114 Continuous cuprizone intoxication allows active experimental autoimmune encephalomyelitis induction in C57BL/6 mice...... 115 High-grade Oncocytic Tumor (HOT) of Kidney in a Patient with Tuberous Sclerosis Complex...... 115 Clinical assessment of balance using BBS and SARAbal in cerebellar ataxia: Synthesis of findings of a psychometric property analysis...... 116 Precentral degeneration and cerebellar compensation in amyotrophic lateral sclerosis: A multimodal MRI analysis...... 116 [Symptomatic trigeminal autonomic cephalalgia without headache]...... 117 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 8 – Multiple Sklerose: Veröffentlichungen April 2019 GAS8 and its naturally occurring antisense RNA as biomarkers in multiple sclerosis.117 Blood-brain barrier dysfunction in immuno-mediated neurological diseases...... 118 Commentary: Ganglion cell complex of retinal layer thickness by optical coherence tomography in cases of multiple sclerosis without optic neuritis compared to healthy eyes...... 118 Macular ganglion cell complex parameters by optical coherence tomography in cases of multiple sclerosis without optic neuritis compared to healthy eyes...... 118 Autoimmune thyroid disease following treatment with alemtuzumab for multiple sclerosis...... 119 Dulaglutide Modulates the Development of Tissue-Infiltrating Th1/Th17 Cells and the Pathogenicity of Encephalitogenic Th1 Cells in the Central Nervous System. . 120 Delayed Astrogliosis Associated with Reduced M1 Microglia Activation in Matrix Metalloproteinase 12 Knockout Mice during Theiler's Murine Encephalomyelitis. . 121 Interferon-Stimulated Genes-Mediators of the Innate Immune Response during Canine Distemper Virus Infection...... 122 The Association between Vitamin D Deficiency and variants of Vitamin D Binding protein gene among Healthy Iranian Adults...... 122 Differences in the Level of Electronic Health Literacy Between Users and Nonusers of Digital Health Services: An Exploratory Survey of a Group of Medical Outpatients.123 Quantification of Visual Fixation in Multiple Sclerosis...... 124 Gold Nanoparticles and Polyethylene Glycol Alleviate Clinical Symptoms and Alter Cytokine Secretion in a Mouse Model of Experimental Autoimmune Encephalomyelitis...... 125 Modeling and Prediction of Multiple Correlated Functional Outcomes...... 125 Data linkages between patient-powered research networks and health plans: a foundation for collaborative research...... 126 Doming the Diaphragm in a Patient With Multiple Sclerosis...... 126 Small non-coding RNAs as important players, biomarkers and therapeutic targets in multiple sclerosis: A comprehensive overview...... 127 Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation...... 128 Mesenchymal stem cell mediated effects on microglial phenotype in cuprizone- induced demyelination model...... 129 Survivin modulatory role in autoimmune and autoinflammatory diseases...... 129 Altered expression patterns of complement factor H and miR-146a genes in acute- chronic phases in experimental autoimmune encephalomyelitis mouse...... 130 Insights and Recommendations From Parents Receiving a Diagnosis of Pediatric Multiple Sclerosis for Their Child...... 130 K Index is a Reliable Marker of Intrathecal Synthesis, and an Alternative to IgG Index in Multiple Sclerosis Diagnostic Work-Up...... 131 Illuminating an Invisible Epidemic: A Systemic Review of the Clinical and Economic Benefits of Early Diagnosis and Treatment in Inflammatory Disease and Related Syndromes...... 132 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 9 – Multiple Sklerose: Veröffentlichungen April 2019 White matter lesion loads associated with dynamic functional connectivity within attention network in patients with relapsing-remitting multiple sclerosis...... 132 Surgical management of patients with coexistent multiple sclerosis and cervical stenosis: A systematic review and meta-analysis...... 133 Challenges in the Diagnosis of Euglycemic Diabetic Ketoacidosis in a Patient With Multiple Sclerosis Taking a Sodium-Glucose Cotransporter 2 Inhibitor...... 133 The burden of headache disorders in the Eastern Mediterranean Region, 1990- 2016: findings from the Global Burden of Disease study 2016...... 134 Dysregulation of Inflammasome Priming and Activation by MicroRNAs in Human Immune-Mediated Diseases...... 135 Does cognitive dysfunction correlate with neurofilament light polypeptide levels in the CSF of patients with multiple sclerosis? ...... 135 Neural stimulations regulate the infiltration of immune cells into the CNS...... 136 Probing demyelination and remyelination of the cuprizone mouse model using multimodality MRI...... 136 Fetal heart rhabdomyomatosis: a single-center experience...... 137 Discovery and Lead-optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase...... 137 Oligoprotective effect of metformin through the AMPK-dependent on restoration of mitochondrial hemostasis in the cuprizone-induced multiple sclerosis model...... 138 Functional Neurosonology Reveals Impaired Cerebrovascular Reactivity in Multiple Sclerosis...... 138 Dopaminergic Therapeutics in Multiple Sclerosis: Focus on Th17-Cell Functions. . 139 Resveratrol (3, 5, 4'-Trihydroxy-trans-Stilbene) Attenuates a Mouse Model of Multiple Sclerosis by Altering the miR-124/Sphingosine Kinase 1 Axis in Encephalitogenic T Cells in the Brain...... 139 Toll-like receptors in the pathogenesis of neuroinflammation...... 140 IL-17A is associated with the breakdown of the blood-brain barrier in relapsing- remitting multiple sclerosis...... 140 Regenerative neuroimmunology: The impact of immune and neural stem cell interactions for translation in neurodegeneration and repair...... 141 The PD-1/PD-Ls pathway is up-regulated during the suppression of experimental autoimmune encephalomyelitis treated by Astragalus polysaccharides...... 141 Pathologic and MRI analysis in acute atypical inflammatory demyelinating lesions.142 In search of distinct MS-related fatigue subtypes: results from a multi-cohort analysis in 1.403 MS patients...... 143 Neurofilament light chain as a biomarker in neurological disorders...... 144 Neurofilament light chain serum levels reflect disease severity in MOG-Ab associated disorders...... 145 Cortical grey matter sodium accumulation is associated with disability and secondary progressive disease course in relapse-onset multiple sclerosis...... 146 The real p(atient) value...... 146 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 10 – Multiple Sklerose: Veröffentlichungen April 2019 Induction of apoptosis in CD4(+) T-cells is linked with optimal treatment response in patients with relapsing-remitting multiple sclerosis treated with Glatiramer acetate...... 147 Literature Commentary...... 147 A Highly Sensitive Sandwich ELISA to Detect CSF Progranulin: A Potential Biomarker for CNS Disorders...... 148 Neuroprotective Benefits of Antidepressants in Multiple Sclerosis: Are We Missing the Mark? ...... 148 Percutaneous glycerol rhizotomy for trigeminal neuralgia in patients with multiple sclerosis: a long-term retrospective cohort study...... 149 Chemoenzymatic Synthesis of a Chiral Ozanimod Key Intermediate Starting from Naphthalene as Cheap Petrochemical Feedstock...... 149 A Pharmacological Review on Portulaca oleracea L.: Focusing on Anti-Inflammatory, Anti- Oxidant, Immuno-Modulatory and Antitumor Activities...... 150 Prevalence and Psychopathological Determinants of Sexual Dysfunction and Related Distress in Women With and Without Multiple Sclerosis...... 151 Visualizing Impairment of the Endothelial and Glial Barriers of the Neurovascular Unit during Experimental Autoimmune Encephalomyelitis In Vivo...... 152 Fulminant Hepatitis Associated With Echovirus 25 During Treatment With Ocrelizumab for Multiple Sclerosis...... 152 Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis...... 153 Deficiency of Socs3 leads to brain-targeted EAE via enhanced neutrophil activation and ROS production...... 154 Myelin repair stimulated by CNS-selective thyroid hormone action...... 155 The Effect of Vitamin D Supplements on Clinical and Para-Clinical Outcomes in Patients With Multiple Sclerosis: Protocol for a Systematic Review...... 155 Estimating the Change in Renal Function During the First Year of Therapy in ANCA- Associated Vasculitis...... 156 Normal Visual Recovery after Optic Neuritis Despite Significant Loss of Retinal Ganglion Cells in Patients with Multiple Sclerosis...... 157 [Susac Syndrome: A Diagnostic Chameleon]...... 159 Patient characteristics and outcomes of a home mechanical ventilation program in a developing country...... 159 Clinical feasibility of brain quantitative susceptibility mapping...... 160 Magnetic resonance elastography of brain: Comparison between anisotropic and isotropic stiffness and its correlation to age...... 160 How Cost-of-Illness (COI) Study Provides Direct and Indirect Costs of Multiple Sclerosis (MS) in Bosnia and Herzegovina ? ...... 161 Turning Feed-forward and Feedback Processes on Patient-reported Data into Intelligent Action and Informed Decision-making: Case Studies and Principles. .. 161 Acute exacerbation of Hashimoto's thyroiditis in a patient treated with dimethyl fumarate for multiple sclerosis: A case report...... 162 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 11 – Multiple Sklerose: Veröffentlichungen April 2019 Functional connectivity in multiple sclerosis after robotic rehabilitative treatment: A case report...... 162 An FTLD-associated SQSTM1 variant impacts Nrf2 and NF-κB signalling and is associated with reduced phosphorylation of p62...... 163 Influence of genetic copy number variants of the human GLUT3 glucose transporter gene SLC2A3 on protein expression, glycolysis and rheumatoid arthritis risk: A genetic replication study...... 163 Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing...... 164 PI3K activity in dendritic cells exerts paradoxical effects during autoimmune inflammation...... 165 Brain Activation Changes During Balance- and Attention-Demanding Tasks in Middle- and Older-Aged Adults With Multiple Sclerosis...... 165 Immune profiling of a patient with alemtuzumab-associated progressive multifocal leukoencephalopathy...... 166 Magnetisation transfer ratio abnormalities in primary and secondary progressive multiple sclerosis...... 167 Are children with multiple sclerosis really "old" adults...... 167 Childhood multiple sclerosis is associated with reduced brain volumes at first clinical presentation and brain growth failure...... 168 Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis...... 169 Evidence of diffuse cerebellar neuroinflammation in multiple sclerosis by 11C-PBR28 MR-PET...... 170 Pregnancy outcomes in patients with multiple sclerosis treated with teriflunomide: Clinical study data and 5 years of post-marketing experience...... 171 MOG-related disorders: A new cause of imaging-negative myelitis? ...... 171 Occupational Therapy in Fatigue Management in Multiple Sclerosis: An Umbrella Review...... 172 Predictors of hospital-based multidisciplinary rehabilitation effects in persons with multiple sclerosis: a large-scale, single-centre study...... 172 Three suggestions to decrease the financial burden of MS treatments...... 172 Corrigendum to "Changes in patient-reported outcomes between continuers and discontinuers of disease modifying therapy in patients with multiple sclerosis over age 60" [Multiple Sclerosis and Related Disorders 30 (2019) 252-256]...... 173 Corrigendum to: "A case of Takotsubo syndrome during a multiple sclerosis brainstem relapse" [Mult. Scler. Relat. Disord. 24 (2018) 1-2]...... 173 Corrigendum to "Foxp3+ regulatory T cells expression in Neuromyelitis optica spectrum disorders" [Multiple Sclerosis and Related Disorders 30 (2019) 114-118].173 Teriflunomide real-world evidence: Global differences in the phase 4 Teri-PRO study...... 174 Resting-state functional connectivity networks associated with fatigue in multiple sclerosis with early age onset...... 175 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 12 – Multiple Sklerose: Veröffentlichungen April 2019 Characterization of gray-matter multiple sclerosis lesions using double inversion recovery, diffusion, contrast-enhanced, and volumetric MRI...... 176 Seeing function in structure: "incidental" eye findings on OCT in a patient with multiple sclerosis...... 176 Evaluation of natalizumab pharmacokinetics and pharmacodynamics with standard and extended interval dosing...... 177 A case of ADEM-like presentation with anti-MOG antibody following tumefactive demyelinating lesion...... 177 Management strategies for female patients of reproductive potential with multiple sclerosis: An evidence-based review...... 178 The association between dietary sugar intake and neuromyelitis optica spectrum disorder: A case-control study...... 179 Racial differences in retinal neurodegeneration as a surrogate marker for cortical atrophy in multiple sclerosis...... 180 Whole-body vibration impedes the deterioration of postural control in patients with multiple sclerosis...... 180 Cervical spondylotic myelopathy mimicking transverse myelitis...... 181 Recurrent atrial fibrillation after pulse corticosteroid treatment for a relapse of multiple sclerosis...... 181 The relationship between cognitive function and body mass index in multiple sclerosis patients...... 182 CSF oligoclonal bands and normal appearing white matter periventricular damage in patients with clinically isolated syndrome suggestive of MS...... 183 Tumefactive multiple sclerosis which initially presented with brainstem encephalitis with a long-term follow-up...... 183 Perceived fatigue and cognitive performance change in multiple sclerosis: Uncovering predictors beyond baseline fatigue...... 184 Callosal lesions on magnetic resonance imaging with multiple sclerosis, neuromyelitis optica spectrum disorder and acute disseminated encephalomyelitis.185 Successful intravenous immunoglobulin treatment in relapsing MOG-antibody- associated disease...... 185 Worsening of disability caused by relapses in multiple sclerosis: A different approach...... 186 Capturing fatigue parameters: The impact of vagal processing in multiple sclerosis related cognitive fatigue...... 187 Evaluation of a web-based fall prevention program among people with multiple sclerosis...... 188 A SCA7 premutation may be a novel Mendelian modifier of MS course: A case report...... 189 Cognitive and physical fatigue are associated with distinct problems in daily functioning, role fulfilment, and quality of life in multiple sclerosis...... 189 Plasma brain-derived neurotrophic factor (BDNF) and sphingosine-1-phosphat (S1P) are NOT the main mediators of neuroprotection induced by resistance training in persons with multiple sclerosis-A randomized controlled trial...... 190 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 13 – Multiple Sklerose: Veröffentlichungen April 2019 Relationship of High-mobility group box 1 levels and multiple sclerosis: A systematic review and meta-analysis...... 191 Acute effects of aerobic intensities on the cytokine response in women with mild multiple sclerosis...... 192 Aberrant oligodendroglial-vascular interactions disrupt the blood-brain barrier, triggering CNS inflammation...... 192 Bassoon proteinopathy drives neurodegeneration in multiple sclerosis...... 193 Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis...... 193 Epidemiology and treatment of multiple sclerosis in elderly populations...... 194 Immunoneuropsychiatry - novel perspectives on brain disorders...... 194 Author Correction: Progress in multiple sclerosis - from diagnosis to therapy. .... 195 Involvement of the myeloid cell compartment in fibrogenesis and systemic sclerosis...... 195 Galectin-3 prospects as a therapeutic agent for multiple sclerosis...... 195 Pathological changes in mice with long term cuprizone administration...... 196 Abdominal functional electrical stimulation for bowel management in multiple sclerosis...... 196 Bowel symptoms predate the diagnosis among many patients with multiple sclerosis: A 14-year cohort study...... 197 DeepQSM - using deep learning to solve the dipole inversion for quantitative susceptibility mapping...... 197 Multi-branch convolutional neural network for multiple sclerosis lesion segmentation...... 198 Usefulness of [11C] Methionine PET in the Differentiation of Tumefactive Multiple Sclerosis from High Grade Astrocytoma...... 198 Cognitive and physical disability in Egyptian patients with multiple sclerosis: genetic and optical coherence tomography study...... 199 Correction to: Normative values of the Rao's Brief Repeatable Battery in an Italian young adolescent population: the influence of age, gender, and education...... 199 Aging with multiple sclerosis: prevalence and profile of cognitive impairment. ... 200 Long-term disability outcomes in relapsing-remitting multiple sclerosis: a 10-year follow-up study...... 201 A complex relation between depression and multiple sclerosis: a descriptive review.201 Exercise in Multiple Sclerosis: Knowing is Not Enough-The Crucial Role of Intention Formation and Intention Realization...... 202 Restless legs syndrome in patients with multiple sclerosis: evaluation of risk factors and clinical impact...... 202 Natalizumab-associated progressive multifocal leukoencephalopathy in Germany.203 Total intake of different minerals and the risk of multiple sclerosis...... 204 Severe transient myopathy in a progressive multiple sclerosis patient with high- dose biotin...... 204 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 14 – Multiple Sklerose: Veröffentlichungen April 2019 Temporal lobe epilepsy: Hippocampal pathology modulates connectome topology and controllability...... 205 Diagnosing and quantifying a common deficit in multiple sclerosis: Internuclear ophthalmoplegia...... 206 Damage of the lateral geniculate nucleus in MS: Assessing the missing node of the visual pathway...... 207 Longer Duration of Downslope Treadmill Walking Induces Depression of H-Reflexes Measured during Standing and Walking...... 208 Effect of mesenchymal stem cells on glial cells population in cuprizone induced demyelination model...... 208 Impact of sex differences and gender specificity on behavioral characteristics and pathophysiology of neurodegenerative disorders...... 209 Regulation of sirtuin expression in autoimmune neuroinflammation: Induction of SIRT1 in oligodendrocyte progenitor cells...... 209 Rapamycin relieves inflammation of experimental autoimmune encephalomyelitis by altering the balance of Treg/Th17 in a mouse model...... 210 The Effectiveness of Percutaneous Balloon Compression, Thermocoagulation, and Glycerol Rhizolysis for Trigeminal Neuralgia in Multiple Sclerosis...... 210 Effects of Curcumin on Microglial Cells...... 211 MicroRNAs in Neuroinflammation: Implications in Disease Pathogenesis, Biomarker Discovery and Therapeutic Applications...... 211 Glycated Hemoglobin, but not Insulin Sensitivity, is Associated with Memory in Subjects with Obesity...... 212 Gadolinium Deposition in Neurology Clinical Practice...... 212 [Optical coherence tomography angiography in neuronal diseases : Preliminary findings]...... 213 Distal radius and tibia bone microarchitecture impairment in female patients with diffuse systemic sclerosis. Sampaio-Barros MM(1), Alvarenga JC(1), Takayama L(1), Assad APL(1), Sampaio-Barros PD(1), Pereira RMR(2)...... 213 Gender differences in information needs and preferences regarding depression among individuals with multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis...... 214 Tuberous Sclerosis Complex Genotypes and Developmental Phenotype...... 215 HERVs, immunity, and autoimmunity: understanding the connection...... 216 Telemedicine in Rehabilitation...... 216 A qualitative study of active participation in sport and exercise for individuals with multiple sclerosis...... 217 Activation of aryl hydrocarbon receptor signaling by a novel agonist ameliorates autoimmune encephalomyelitis...... 218 The clinical significance of single or double bands in cerebrospinal fluid isoelectric focusing. A retrospective study and systematic review...... 219 PP2A activation alone and in combination with cisplatin decreases cell growth and tumor formation in human HuH6 hepatoblastoma cells...... 219 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 15 – Multiple Sklerose: Veröffentlichungen April 2019 Epidemiology of multiple sclerosis in Iran: A systematic review and meta-analysis.220 A computer-aided diagnosis of multiple sclerosis based on mfVEP recordings. .... 220 Symptoms of fatigue and depression is reflected in altered default mode network connectivity in multiple sclerosis...... 221 Anesthetic management for cesarean section and tubal ligation in a patient with Marfan syndrome, multiple sclerosis, and multiple postdural puncture headaches.221 Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease...... 222 Structural basis for ligand modulation of the CCR2 conformational landscape. .... 223 Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide- loaded tolerogenic dendritic cells in a phase 1b trial...... 224 New age for progressive multiple sclerosis...... 225 MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis...... 226 DNA threads released by activated CD4+ T lymphocytes provide autocrine costimulation...... 227 Oligodendrocyte precursor cells as a therapeutic target for demyelinating diseases.227 Retinal oximetry: Metabolic imaging for diseases of the retina and brain...... 228 Quality of life and health of patients in early stages of Multiple sclerosis...... 229 Factors associated with disease self-efficacy in individuals aging with a disability.229 Cortical Lesions on 7-T MRI in Multiple Sclerosis: A Window into Pathogenetic Mechanisms? ...... 229 Longitudinal Characterization of Cortical Lesion Development and Evolution in Multiple Sclerosis with 7.0-T MRI...... 230 Regulatory effects of hemp seed/evening primrose oil supplement in comparison with rapamycin on the expression of the mammalian target of rapamycin-complex 2 and interleukin-10 genes in experimental autoimmune encephalomyelitis...... 231 Design and molecular dynamic simulation of a new double-epitope tolerogenic protein as a potential vaccine for multiple sclerosis disease...... 231 [Extended optic neuropathy with myelin oligodendrocyte glycoprotein antibodies].232 [Epilepsy surgery for refractory neurocysticercosis-related epilepsy]...... 232 [Efficacy of virtual reality on balance and gait in multiple sclerosis. Systematic review of randomized controlled trials]...... 233 Impact of astrocyte and lymphocyte interactions on the blood-brain barrier in multiple sclerosis...... 234 Dronabinol use in France between 2004 and 2017...... 235 The potentials of umbilical cord-derived mesenchymal stem cells in the treatment of multiple sclerosis...... 236 Association of acute stress with multiple sclerosis onset and relapse in Saudi Arabia.236 Luring T cells into a gray area...... 237 An ecological measure to screen executive functioning in MS: the Picture Interpretation Test (PIT) 360°...... 237 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 16 – Multiple Sklerose: Veröffentlichungen April 2019 Siponimod (BAF312) Treatment Reduces Brain Infiltration but Not Lesion Volume in Middle-Aged Mice in Experimental Stroke...... 238 Risks and risk management in modern multiple sclerosis immunotherapeutic treatment...... 239 Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis...... 240 Prediction of conversion to multiple sclerosis using the 2017 McDonald and 2016 MAGNIMS criteria in patients with clinically isolated syndrome: a retrospective single-centre study...... 241 Pulsed immune reconstitution therapy in multiple sclerosis...... 241 Real-life outcomes of teriflunomide treatment in patients with relapsing multiple sclerosis: TAURUS-MS observational study...... 242 Nox2-dependent Neuroinflammation in An EAE Model of Multiple Sclerosis...... 243 Fifty Shades of Microglia...... 243 Uro-Vaxom® versus placebo for the prevention of recurrent symptomatic urinary tract infections in participants with chronic neurogenic bladder dysfunction: a randomised controlled feasibility study...... 244 Validation and reliability study of the Turkish version of the Neuroquality of Life (Neuro-QoL)-Stigma Scale for neurological disorders ...... 245 Development and Validation of the FSIQ-RMS: A New Patient-Reported Questionnaire to Assess Symptoms and Impacts of Fatigue in Relapsing Multiple Sclerosis...... 245 The Saffold Virus-Penang 2B and 3C Proteins, but not the L Protein, Induce Apoptosis in HEp-2 and Vero Cells...... 246 Influence of Cognitive and Motor Abilities on the Level of Current Functioning in People with Multiple Sclerosis...... 247 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Sicherheit durch Erfahrung 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 | L.DE.MKT.SM.02.2017.5323 – 17 – Multiple Sklerose: Veröffentlichungen April 2019 1. Clinical Review Report: Cladribine (Mavenclad): (EMD Serono): Indication: As monotherapy for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) to reduce the frequency of clinical exacerbations and delay the progression of disability. Cladribine is generally recommended in RRMS patients who have had an inadequate response to, or are unable to tolerate, one or more therapies for RRMS [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Oct. CADTH Common Drug Reviews. The objective of this report is to perform a systematic review of the beneficial and harmful effects of cladribine for the treatment of relapsing-remitting multiple sclerosis. 2. Pharmacoeconomic Review Report: Cladribine (Mavenclad): (EMD Serono): Indication: As monotherapy for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) to reduce the frequency of clinical exacerbations and delay the progression of disability. Cladribine is generally recommended in RRMS patients who have had an inadequate response to, or are unable to tolerate, one or more therapies for RRMS [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Oct. CADTH Common Drug Reviews. Cladribine (Mavenclad) is indicated as monotherapy for the treatment of adult patients with relapsing- remitting multiple sclerosis (RRMS) to reduce the frequency of clinical exacerbations and delay the progression of disability. It is administered orally and is available as a 10 mg tablet at a price of $3,082.70 per tablet. The recommended cumulative dose is 3.5 mg/kg over the course of two years, with one treatment course of 1.75 mg/kg per year. The treatment course is spread over two weeks each year, one week at the beginning of the first month of that year, and the other at the beginning of the second month. During each week, patients receive one or two 10 mg tablets, based on body weight, over the course of four to five days. The average annual cost is $43,158 based on patient weight of 70 kg. The manufacturer submitted a cost- utility analysis based on a Markov state-transition model comparing cladribine with other available disease- modifying therapies (DMTs). 3. CADTH Canadian Drug Expert Committee Recommendation: Cladribine (Mavenclad — EMD Serono): Indication: Relapsing-Remitting Multiple Sclerosis [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018 Oct. CADTH Common Drug Reviews. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 18 – Multiple Sklerose: Veröffentlichungen April 2019 4. ACS Appl Mater Interfaces. 2019 Apr 19. doi: 10.1021/acsami.9b02797. [Epub ahead of print] Codelivery of Plasmid and Curcumin with Mesoporous Silica Nanoparticles for Promoting Neurite Outgrowth. Cheng CS(1), Liu TP(2)(3), Chien FC(4), Mou CY(1), Wu SH, Chen YP. Author information: (1)Department of Chemistry , National Taiwan University , Taipei 106 , Taiwan. (2)Mackay Junior College of Medicine, Nursing and Management , Taipei 112 , Taiwan. (3)Department of Surgery , Mackay Memorial Hospital , Taipei 104 , Taiwan. (4)Department of Optics and Photonics , National Central University , Chung-Li 320 , Taiwan. Reactive oxygen species (ROS)-induced oxidative stress leads to neuron damage and is involved in the pathogenesis of chronic inflammation in neurodegenerative diseases (NDs), such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Researchers, therefore, are looking for antiinflammatory drugs and gene therapy approaches to slow down or even prevent neurological disorders. Combining therapeutics has shown a synergistic effect in the treatment of human diseases. Many nanocarriers could be designed for the simultaneous codelivery of drugs with genes to fight diseases. However, only a few researches have been performed in NDs. In this study, we developed a mesoporous silica nanoparticle (MSN)-based approach for neurodegenerative therapy. This MSN-based platform involved multiple designs in the targeted codelivery of (1) curcumin, a natural antioxidant product, to protect ROS-induced cell damage and (2) plasmid RhoG-DsRed, which is associated with the formation of lamellipodia and filopodia for promoting neurite outgrowth. At the same time, TAT peptide was introduced to the plasmid RhoG-DsRed via electrostatic interaction to elevate the efficiency of nonendocytic pathways and the nuclear plasmid delivery of RhoG-DsRed in cells for enhanced gene expression. Besides, such a plasmid RhoG-DsRed/TAT complex could work as a noncovalent gatekeeper. The release of curcumin inside the channel of the MSN could be triggered when the complex was dissociated from the MSN surface. Taken together, this MSN-based platform combining genetic and pharmacological manipulations of an actin cytoskeleton as well as oxidative stress provides an attractive way for ND therapy. DOI: 10.1021/acsami.9b02797 5. ACS Chem Neurosci. 2019 Apr 26. doi: 10.1021/acschemneuro.9b00143. [Epub ahead of print] O-GlcNAc Modification Protects against Protein Misfolding and Aggregation in Neurodegenerative Disease. Ryan P(1)(2)(3), Xu M(4), Davey AK(1)(2)(3), Danon JJ(5), Mellick GD(3), Kassiou M(5), Rudrawar S(1)(2)(3)(4)(5). Author information: (1)Menzies Health Institute Queensland , Griffith University , Gold Coast 4222 , Australia. (2)School of Pharmacy and Pharmacology , Griffith University , Gold Coast , 4222 , Australia. (3)Quality Use of Medicines Network , Griffith University , Gold Coast , 4222 , Australia. (4)Griffith Institute for Drug Discovery , Griffith University , Nathan , 4111 , Australia. (5)School of Chemistry , The University of Sydney , NSW 2006 , Australia. Post-translational modifications (PTMs) of proteins are becoming the focus of intense research due to their implications in a broad spectrum of neurodegenerative diseases. Various PTMs have been identified to alter the toxic profiles of proteins which play critical roles in disease etiology. In Alzheimer's disease (AD), dysregulated phosphorylation is reported to promote pathogenic processing of the microtubule-associated tau protein. Among the PTMs, the enzymatic addition of N-acetyl-d-glucosamine (GlcNAc) residues to Ser/Thr residues is reported to deliver protective effects against the pathogenic processing of both amyloid precursor protein (APP) and tau. Modification of tau with as few as one single O-GlcNAc residue inhibits its toxic self-assembly. This modification also has the same effect on the assembly of the Parkinson's disease (PD) associated α-synuclein (ASyn) protein. In fact, O-GlcNAcylation ( O-linked GlcNAc modification) affects the processing of numerous proteins implicated in AD, PD, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) in a similar manner. As such, manipulation of a protein's O-GlcNAcylation status has been proposed to offer therapeutic routes toward addressing multiple neurodegenerative pathologies. Here we review the various effects that O-GlcNAc modification, and its modulated expression, have on pathogenically significant proteins involved in neurodegenerative disease. DOI: 10.1021/acschemneuro.9b00143 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 19 – Multiple Sklerose: Veröffentlichungen April 2019 6. Acta Neurol Belg. 2019 Apr 5. doi: 10.1007/s13760-019-01131-5. [Epub ahead of print] Cerebral abscess in a multiple sclerosis patient during treatment with natalizumab. Durmus B(1), Van Goethem J(2)(3), Vercruyssen A(4), De la Meilleure G(4), Jadoul C(4), Willekens B(5)(6). Author information: (1)Department of Neurology, AZ Nikolaas, Moerlandstraat 1, 9100, Sint-Niklaas, Belgium. [email protected]. (2)Department of Radiology, AZ Nikolaas, Moerlandstraat 1, 9100, Sint- Niklaas, Belgium. (3)Department of Radiology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium. (4)Department of Neurology, AZ Nikolaas, Moerlandstraat 1, 9100, Sint-Niklaas, Belgium. (5)Department of Neurology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. (6)Laboratory of Experimental Hematology, University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium. DOI: 10.1007/s13760-019-01131-5 7. Acta Neurol Belg. 2019 Apr 15. doi: 10.1007/s13760-019-01139-x. [Epub ahead of print] Mental imagery training for treatment of central neuropathic pain: a narrative review. Kaur J(1)(2), Ghosh S(3), Sahani AK(2), Sinha JK(4). Author information: (1)Amity Institute of Neuropsychology and Neurosciences (AINN), Amity University UP, Room No. 222A, J1 Block, Sector 125, Noida, 201303, India. (2)Indian Spinal Injuries Centre (ISIC), Sector C, Vasant Kunj, New Delhi, 110070, India. (3)Indian Council of Medical Research-National Institute of Nutrition, Tarnaka, Hyderabad, 500007, India. (4)Amity Institute of Neuropsychology and Neurosciences (AINN), Amity University UP, Room No. 222A, J1 Block, Sector 125, Noida, 201303, India. [email protected]. Mental imagery is a quasi-perceptual experience in the absence of external stimuli. This concept has intrigued psychologists, sportspersons, neurologists and other scientists for over a decade now. Imagery has been used in rehabilitation and the results have been promising. Researchers refer to this as healing the body through the mind. However, the challenge is lack of standardized protocols, homogeneity and consistency in application of mental imagery in different populations. The purpose of this review is to discuss and understand the role of mental imagery in the treatment of central neuropathic pain (CNP). Treatment options of CNP are inadequate and their benefits are short lived. We conducted an extensive search on various databases using combinations of different keywords and reviewed the available literature in this area. We were able to finalize twelve studies where mental imagery was used for treating CNP in spinal cord injury (SCI), stroke and multiple sclerosis. However, the methodology and techniques of mental imagery training used in these studies were non-homogeneous and inconsistent. This review provides a guiding framework to further explore the different techniques of mental imagery and their roles in treating CNP. DOI: 10.1007/s13760-019-01139-x Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 20 – Multiple Sklerose: Veröffentlichungen April 2019 8. Acta Neurol Scand. 2019 Apr 8. doi: 10.1111/ane.13097. [Epub ahead of print] Real-life use of oral disease-modifying treatments in Austria. Guger M(1), Enzinger C(2), Leutmezer F(3), Kraus J(4)(5), Kalcher S(6), Kvas E(7), Berger T(3); Austrian MS Treatment Registry (AMSTR). Author information: (1)Clinic for Neurology 2, Kepler University Clinic, Linz, Austria. (2)Department of Neurology, Medical University of Graz, Graz, Austria. (3)Department of Neurology, Medical University of Vienna, Vienna, Austria. (4)Department of Laboratory Medicine, Paracelsus Medical University and Salzburger Landeskliniken, Salzburg, Austria. (5)Department of Neurology, Medical Faculty, Heinrich-Heine- University, Düsseldorf, Germany. (6)Hermesoft, Data management, Graz, Austria. (7)Hermesoft, Statistics, Graz, Austria. OBJECTIVES: To compare the efficacy, frequencies and reasons for treatment interruption of fingolimod, dimethyl fumarate (DMF) or teriflunomide in a nationwide observational cohort using prospectively collected data. MATERIALS AND METHODS: Two cohorts of patients with relapsing-remitting multiple sclerosis (RRMS) starting treatment with fingolimod, dimethyl fumarate or teriflunomide documented in the Austrian MS Treatment Registry (AMSTR) since 2014 and either staying on therapy for at least 12 months (12m cohort) or having at least one follow-up visit (total cohort). The 12m cohort included 664 RRMS patients: 315 in the fingolimod, 232 in the DMF and 117 in the teriflunomide group. Multinomial propensity scores were used for inverse probability weighting to correct for the bias of this non-randomised registry study. RESULTS: Estimated mean annualized relapse rates (ARR) over 12 months were 0.21 for fingolimod, 0.20 for DMF and 0.19 for teriflunomide treatment, causing an incidence rate ratio (IRR) of 1.01 for fingolimod vs DMF (P = 0.96) and 0.92 for teriflunomide vs DMF (P = 0.84). No differences were found regarding the probability for experiencing a relapse, EDSS change, EDSS progression and EDSS regression, except regarding less sustained EDSS progression for 12 weeks concerning DMF vs fingolimod (P = 0.02). The hazard ratio for treatment interruption comparing fingolimod vs DMF was 1.03 (P = 0.86) and 1.07 comparing teriflunomide vs DMF (P = 0.77). CONCLUSIONS: In the AMSTR, there was no difference concerning ARR, probability for a relapse, EDSS change, treatment interruption, EDSS progression or regression between oral DMTs, except regarding less sustained EDSS progression for 12 weeks concerning DMF vs fingolimod. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. DOI: 10.1111/ane.13097 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 21 – Multiple Sklerose: Veröffentlichungen April 2019 9. Acta Neuropathol. 2019 Apr 3. doi: 10.1007/s00401-019-01999-w. [Epub ahead of print] ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72- mediated ALS/FTD. Moore S(1)(2), Alsop E(3), Lorenzini I(1), Starr A(1), Rabichow BE(1), Mendez E(1), Levy JL(1), Burciu C(1), Reiman R(3), Chew J(4), Belzil VV(4), W Dickson D(4), Robertson J(5), Staats KA(6), Ichida JK(6), Petrucelli L(4), Van Keuren-Jensen K(3), Sattler R(7). Author information: (1)Department of Neurobiology, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA. (2)School of Life Sciences, Arizona State University, Tempe, AZ, USA. (3)Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA. (4)Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA. (5)Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada. (6)Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. (7)Department of Neurobiology, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA. [email protected]. The hexanucleotide repeat expansion GGGGCC (G4C2)n in the C9orf72 gene is the most common genetic abnormality associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent findings suggest that dysfunction of nuclear-cytoplasmic trafficking could affect the transport of RNA binding proteins in C9orf72 ALS/FTD. Here, we provide evidence that the RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is mislocalized in C9orf72 repeat expansion mediated ALS/FTD. ADAR2 is responsible for adenosine (A) to inosine (I) editing of double-stranded RNA, and its function has been shown to be essential for survival. Here we show the mislocalization of ADAR2 in human induced pluripotent stem cell-derived motor neurons (hiPSC-MNs) from C9orf72 patients, in mice expressing (G4C2)149, and in C9orf72 ALS/FTD patient postmortem tissue. As a consequence of this mislocalization we observe alterations in RNA editing in our model systems and across multiple brain regions. Analysis of editing at 408,580 known RNA editing sites indicates that there are vast RNA A to I editing aberrations in C9orf72-mediated ALS/FTD. These RNA editing aberrations are found in many cellular pathways, such as the ALS pathway and the crucial EIF2 signaling pathway. Our findings suggest that the mislocalization of ADAR2 in C9orf72 mediated ALS/FTD is responsible for the alteration of RNA processing events that may impact vast cellular functions, including the integrated stress response (ISR) and protein translation. DOI: 10.1007/s00401-019-01999-w Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 22 – Multiple Sklerose: Veröffentlichungen April 2019 10. Acta Neuropathol. 2019 Apr 27. doi: 10.1007/s00401-019-02018-8. [Epub ahead of print] Vitamin D increases glucocorticoid efficacy via inhibition of mTORC1 in experimental models of multiple sclerosis. Hoepner R(1), Bagnoud M(2), Pistor M(2)(3), Salmen A(2), Briner M(2), Synn H(4), Schrewe L(2), Guse K(2), Ahmadi F(2), Demir S(3), Laverick L(5), Gresle M(5), Worley P(6), Reichardt HM(7), Butzkueven H(8), Gold R(3), Metz I(4), Lühder F(9), Chan A(10). Author information: (1)Department of Neurology, Inselspital Bern, University Hospital, University of Bern, Bern, Switzerland. [email protected]. (2)Department of Neurology, Inselspital Bern, University Hospital, University of Bern, Bern, Switzerland. (3)Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany. (4)Institute of Neuropathology, University Medical Center Goettingen, Goettingen, Germany. (5)Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia. (6)The Solomon H. Snyder Department of Neuroscience, School of Medicine, John Hopkins University, Baltimore, USA. (7)Institute for Cellular and Molecular Immunology, University Medical Center Goettingen, Georg-August-University Goettingen, Goettingen, Germany. (8)Department of Neuroscience, Central Clinical School, Alfred Campus, Monash University, Melbourne, Australia. (9)Institute of Neuroimmunology and Multiple Sclerosis Research, University Medical Center Goettingen, Georg-August-University Goettingen, Goettingen, Germany. (10)Department of Neurology, Inselspital Bern, University Hospital, University of Bern, Bern, Switzerland. [email protected]. The limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH)2D3 (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG35-55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in two independent cohorts of MS patients with stable disease or relapses either responsive or resistant to GC treatment (initial cohort: n = 110; validation cohort: n = 85). Gene expression of human CD8+ T cells was analyzed by microarray (n = 112) and correlated with 25D serum levels. In vitro, 1,25D upregulated GR protein levels, leading to increased GC-induced T cell apoptosis. 1,25D/GC combination therapy ameliorated clinical EAE course more efficiently than respective monotherapies, which was dependent on GR expression in T cells. In MS patients from two independent cohorts, 25D deficiency was associated with GC-resistant relapses. Mechanistic studies revealed that synergistic 1,25D/GC effects on apoptosis induction were mediated by the mTOR but not JNK pathway. In line, 1,25D inhibited mTORc1 activity in murine T cells, and low 25D levels in humans were associated with a reduced expression of mTORc1 inhibiting tuberous sclerosis complex 1 in CD8+ T cells. GR upregulation by 1,25D and 1,25D/GC synergism in vitro and therapeutic efficacy in vivo were abolished in animals with a T cell-specific mTORc1 deficiency. Specific inhibition of mTORc1 by everolimus increased the efficacy of GC in EAE. 1,25D augments GC-mediated effects in vitro and in vivo in a T cell-specific, GR-dependent manner via mTORc1 inhibition. These data may have implications for improvement of anti-inflammatory GC therapy. DOI: 10.1007/s00401-019-02018-8 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 23 – Multiple Sklerose: Veröffentlichungen April 2019 11. Acta Neuropathol. 2019 Apr 22. doi: 10.1007/s00401-019-02011-1. [Epub ahead of print] Blood vessels guide Schwann cell migration in the adult demyelinated CNS through Eph/ephrin signaling. Garcia-Diaz B(1)(2), Bachelin C(3), Coulpier F(4), Gerschenfeld G(4), Deboux C(3), Zujovic V(3), Charnay P(4), Topilko P(4), Evercooren AB(5). Author information: (1)Institut du Cerveau et de la Moelle Epinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM, U1127; CNRS, UMR 7225; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UM- 75, Paris, France. [email protected]. (2)Unidad de Gestión Clínica de Neurociencias, IBIMA, Hospital Regional Universitario de Málaga, Malaga, 29009, Spain. [email protected]. (3)Institut du Cerveau et de la Moelle Epinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM, U1127; CNRS, UMR 7225; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UM-75, Paris, France. (4)Ecole normale supérieure, PSL Research University, CNRS, Inserm, Institut de Biologie de l'Ecole normale supérieure (IBENS), 75005, Paris, France. (5)Institut du Cerveau et de la Moelle Epinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM, U1127; CNRS, UMR 7225; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, UM-75, Paris, France. [email protected]. Schwann cells (SC) enter the central nervous system (CNS) in pathophysiological conditions. However, how SC invade the CNS to remyelinate central axons remains undetermined. We studied SC migratory behavior ex vivo and in vivo after exogenous transplantation in the demyelinated spinal cord. The data highlight for the first time that SC migrate preferentially along blood vessels in perivascular extracellular matrix (ECM), avoiding CNS myelin. We demonstrate in vitro and in vivo that this migration route occurs by virtue of a dual mode of action of Eph/ephrin signaling. Indeed, EphrinB3, enriched in myelin, interacts with SC Eph receptors, to drive SC away from CNS myelin, and triggers their preferential adhesion to ECM components, such as fibronectin via integrinβ1 interactions. This complex interplay enhances SC migration along the blood vessel network and together with lesion-induced vascular remodeling facilitates their timely invasion of the lesion site. These novel findings elucidate the mechanism by which SC invade and contribute to spinal cord repair. DOI: 10.1007/s00401-019-02011-1 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 24 – Multiple Sklerose: Veröffentlichungen April 2019 12. Acta Neuropathol. 2019 Apr 1. doi: 10.1007/s00401-019-01998-x. [Epub ahead of print] FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy. Marrone L(1), Drexler HCA(2), Wang J(3), Tripathi P(4), Distler T(1), Heisterkamp P(1), Anderson EN(5)(6), Kour S(5)(6), Moraiti A(1), Maharana S(3), Bhatnagar R(7), Belgard TG(7)(8), Tripathy V(1), Kalmbach N(9), Hosseinzadeh Z(1), Crippa V(10), Abo-Rady M(1), Wegner F(9), Poletti A(10), Troost D(11), Aronica E(11), Busskamp V(1), Weis J(4), Pandey UB(5)(6)(12), Hyman AA(3), Alberti S(3), Goswami A(4), Sterneckert J(13). Author information: (1)Technische Universität Dresden, Center for Regenerative Therapies Dresden, Fetscherstr. 105, 01307, Dresden, Germany. (2)Max Planck Institute for Molecular Biomedicine, Bioanalytical Mass Spectrometry, Röntgenstr. 20, 48149, Münster, Germany. (3)Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307, Dresden, Germany. (4)Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany. (5)Division of Child Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (6)Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA. (7)Verge Genomics, San Francisco, CA, USA. (8)The Bioinformatics CRO, Niceville, FL, USA. (9)Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. (10)Dipartimento di Scienze Farmacologiche e Biomolecolari, Centre of Excellence on Neurodegenerative Diseases Università degli studi di Milano, Milan, 20133, Italy. (11)Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. (12)Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (13)Technische Universität Dresden, Center for Regenerative Therapies Dresden, Fetscherstr. 105, 01307, Dresden, Germany. [email protected]. Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. We show that FUS' tendency to aggregate is normally buffered by interacting RBPs, but this buffering is lost when FUS mislocalizes to the cytoplasm due to ALS mutations. The presence of aggregation-prone FUS in the cytoplasm causes imbalances in RBP homeostasis that exacerbate neurodegeneration. However, enhancing autophagy using small molecules reduces cytoplasmic FUS, restores RBP homeostasis and rescues motor function in vivo. We conclude that disruption of RBP homeostasis plays a critical role in FUS-ALS and can be treated by stimulating autophagy. DOI: 10.1007/s00401-019-01998-x Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 25 – Multiple Sklerose: Veröffentlichungen April 2019 13. Acta Neuropathol Commun. 2019 Apr 25;7(1):58. doi: 10.1186/s40478-019-0709-3. Unique RNA signature of different lesion types in the brain white matter in progressive multiple sclerosis. Elkjaer ML(1)(2)(3), Frisch T(4), Reynolds R(5), Kacprowski T(4)(6), Burton M(7), Kruse TA(3)(7), Thomassen M(3)(7), Baumbach J(4)(8), Illes Z(9)(10)(11). Author information: (1)Department of Neurology, Odense University Hospital, J.B. Winslowsvej 4, DK-5000, Odense, Denmark. (2)Institute of Clinical Research, BRIDGE, University of Southern Denmark, Odense, Denmark. (3)Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. (4)Department of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark. (5)Division of Brain Science, Imperial College, London, UK. (6)Research Group Computational Systems Medicine, Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany. (7)Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. (8)Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany. (9)Department of Neurology, Odense University Hospital, J.B. Winslowsvej 4, DK-5000, Odense, Denmark. [email protected]. (10)Institute of Clinical Research, BRIDGE, University of Southern Denmark, Odense, Denmark. [email protected]. (11)Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. [email protected]. The heterogeneity of multiple sclerosis is reflected by dynamic changes of different lesion types in the brain white matter (WM). To identify potential drivers of this process, we RNA-sequenced 73 WM areas from patients with progressive MS (PMS) and 25 control WM. Lesion endophenotypes were described by a computational systems medicine analysis combined with RNAscope, immunohistochemistry, and immunofluorescence. The signature of the normal-appearing WM (NAWM) was more similar to control WM than to lesions: one of the six upregulated genes in NAWM was CD26/DPP4 expressed by microglia. Chronic active lesions that become prominent in PMS had a signature that were different from all other lesion types, and were differentiated from them by two clusters of 62 differentially expressed genes (DEGs). An upcoming MS biomarker, CHI3L1 was among the top ten upregulated genes in chronic active lesions expressed by astrocytes in the rim. TGFβ-R2 was the central hub in a remyelination-related protein interaction network, and was expressed there by astrocytes. We used de novo networks enriched by unique DEGs to determine lesion-specific pathway regulation, i.e. cellular trafficking and activation in active lesions; healing and immune responses in remyelinating lesions characterized by the most heterogeneous immunoglobulin gene expression; coagulation and ion balance in inactive lesions; and metabolic changes in chronic active lesions. Because we found inverse differential regulation of particular genes among different lesion types, our data emphasize that omics related to MS lesions should be interpreted in the context of lesion pathology. Our data indicate that the impact of molecular pathways is substantially changing as different lesions develop. This was also reflected by the high number of unique DEGs that were more common than shared signatures. A special microglia subset characterized by CD26 may play a role in early lesion development, while astrocyte-derived TGFβ-R2 and TGFβ pathways may be drivers of repair in contrast to chronic tissue damage. The highly specific mechanistic signature of chronic active lesions indicates that as these lesions develop in PMS, the molecular changes are substantially skewed: the unique mitochondrial/metabolic changes and specific downregulation of molecules involved in tissue repair may reflect a stage of exhaustion. DOI: 10.1186/s40478-019-0709-3 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 26 – Multiple Sklerose: Veröffentlichungen April 2019 14. Acta Neuropathol Commun. 2019 Apr 25;7(1):60. doi: 10.1186/s40478-019-0705-7. Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis. Melief J(1), Orre M(2), Bossers K(3), van Eden CG(1), Schuurman KG(1), Mason MRJ(1)(3), Verhaagen J(3), Hamann J(1)(4), Huitinga I(5). Author information: (1)Department of Neuroimmunology, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. (2)Department of Astrocyte Biology and Neurodegeneration, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. (3)Department of Neuroregeneration, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. (4)Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. (5)Department of Neuroimmunology, Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. [email protected]. Inter-individual differences in cortisol production by the hypothalamus-pituitary-adrenal (HPA) axis are thought to contribute to clinical and pathological heterogeneity of multiple sclerosis (MS). At the same time, accumulating evidence indicates that MS pathogenesis may originate in the normal-appearing white matter (NAWM). Therefore, we performed a genome-wide transcriptional analysis, by Agilent microarray, of post- mortem NAWM of 9 control subjects and 18 MS patients to investigate to what extent gene expression reflects disease heterogeneity and HPA-axis activity. Activity of the HPA axis was determined by cortisol levels in cerebrospinal fluid and by numbers of corticotropin-releasing neurons in the hypothalamus, while duration of MS and time to EDSS6 served as indicator of disease severity. Applying weighted gene co- expression network analysis led to the identification of a range of gene modules with highly similar co- expression patterns that strongly correlated with various indicators of HPA-axis activity and/or severity of MS. Interestingly, molecular profiles associated with relatively mild MS and high HPA-axis activity were characterized by increased expression of genes that actively regulate inflammation and by molecules involved in myelination, anti-oxidative mechanism, and neuroprotection. Additionally, group-wise comparisons of gene expression in white matter from control subjects and NAWM from (subpopulations of) MS patients uncovered disease-associated gene expression as well as strongly up- or downregulated genes in patients with relatively benign MS and/or high HPA-axis activity, with many differentially expressed genes being previously undescribed in the context of MS. Overall, the data suggest that HPA-axis activity strongly impacts on molecular mechanisms in NAWM of MS patients, but partly also independently of disease severity. DOI: 10.1186/s40478-019-0705-7 15. Adv Clin Exp Med. 2019 Apr 5. doi: 10.17219/acem/104529. [Epub ahead of print] The effectiveness of whole-body cryotherapy and physical exercises on the psychological well-being of patients with multiple sclerosis: A comparative analysis. Pawik M(1), Kowalska J(1), Rymaszewska J(2). Author information: (1)Department of Physiotherapy, University School of Physical Education, Wrocław, Poland. (2)Department of Psychiatry, Wroclaw Medical University, Poland. BACKGROUND: Due to the chronic character of multiple sclerosis (MS), non-pharmacological treatment can be applied. These therapies can be a good complementation to standard pharmacological treatment. OBJECTIVES: The aim of the study was to evaluate the effectiveness of whole-body cryotherapy (WBC) and physical exercise training on the psychological and general well-being of patients with MS. MATERIAL AND METHODS: The study was carried out on 60 patients, who were divided into 3 groups: cryotherapy (Cryo), physical exercise training (Gym) and cryotherapy with physical exercise training (CryoGym). The Psychological General Well-Being Index, the Hospital Anxiety and Depression Scale and the Rivermead Mobility Index were used at 2 points in time: T1 - before the first therapy session and T2 - after 14 days of therapy. RESULTS: Statistically significant differences in the psychosocial well-being were found in the Gym and CryoGym group. Reduction of depressive symptoms and improved functional status was noted in Cryo group. The most significant improvement was observed in the group using WBC with exercise training (CryoGym). CONCLUSIONS: Whole-body cryotherapy with physical exercise training was an effective therapy for patients with MS. The introduction of WBC into the standard physiotherapy protocol for patients with MS is fully justified. DOI: 10.17219/acem/104529 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 27 – Multiple Sklerose: Veröffentlichungen April 2019 16. Aging Dis. 2019 Apr 1;10(2):470-482. doi: 10.14336/AD.2019.0330. eCollection 2019 Apr. Novel Insights on Systemic and Brain Aging, Stroke, Amyotrophic Lateral Sclerosis, and Alzheimer's Disease. Shetty AK(1), Upadhya R(1), Madhu LN(1), Kodali M(1). Author information: (1)Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center College of Medicine, College Station, Texas, USA. The mechanisms that underlie the pathophysiology of aging, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and stroke are not fully understood and have been the focus of intense and constant investigation worldwide. Studies that provide insights on aging and age-related disease mechanisms are critical for advancing novel therapies that promote successful aging and prevent or cure multiple age-related diseases. The April 2019 issue of the journal, "Aging & Disease" published a series of articles that confer fresh insights on numerous age-related conditions and diseases. The age-related topics include the detrimental effect of overweight on energy metabolism and muscle integrity, senoinflammation as the cause of neuroinflammation, the link between systemic C-reactive protein and brain white matter loss, the role of miR-34a in promoting healthy heart and brain, the potential of sirtuin 3 for reducing cardiac and pulmonary fibrosis, and the promise of statin therapy for ameliorating asymptomatic intracranial atherosclerotic stenosis. Additional aging-related articles highlighted the involvement of miR-181b-5p and high mobility group box-1 in hypertension, Yes-associated protein in cataract formation, multiple miRs and long noncoding RNAs in coronary artery disease development, the role of higher meat consumption on sleep problems, and the link between glycated hemoglobin and depression. The topics related to ALS suggested that individuals with higher education and living in a rural environment have a higher risk for developing ALS, and collagen XIX alpha 1 is a prognostic biomarker of ALS. The topics discussed on AD implied that extracellular amyloid β42 is likely the cause of intraneuronal neurofibrillary tangle accumulation in familial AD and traditional oriental concoctions may be useful for slowing down the progression of AD. The article on stroke suggested that inhibition of the complement system is likely helpful in promoting brain repair after ischemic stroke. The significance of the above findings for understanding the pathogenesis in aging, ALS, AD, and stroke, slowing down the progression of aging, ALS and AD, and promoting brain repair after stroke are discussed. DOI: 10.14336/AD.2019.0330 PMCID: PMC6457051 Conflict of interest statement: Disclosure Statement The authors declared no conflicts of interest. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 28 – Multiple Sklerose: Veröffentlichungen April 2019 17. AJNR Am J Neuroradiol. 2019 Apr 18. doi: 10.3174/ajnr.A6045. [Epub ahead of print] The Central Vein Sign in Radiologically Isolated Syndrome. Suthiphosuwan S(1)(2), Sati P(3), Guenette M(2), Montalban X(2), Reich DS(3)(4), Bharatha A(1)(5), Oh J(6)(4). Author information: (1)From the Division of Neuroradiology (S.S., A.B.). (2)Division of Neurology (S.S., M.G., X.M., J.O.), Department of Medicine. (3)Translational Neuroradiology Section (P.S., D.S.R.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. (4)Department of Neurology (D.S.R., J.O.), Johns Hopkins University, Baltimore, Maryland. (5)Division of Neurosurgery (A.B.), Department of Surgery, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. (6)Division of Neurology (S.S., M.G., X.M., J.O.), Department of Medicine [email protected]. BACKGROUND AND PURPOSE: Radiologically isolated syndrome describes asymptomatic individuals with incidental radiologic abnormalities suggestive of multiple sclerosis. Recent studies have demonstrated that >40% of white matter lesions in MS (and often substantially more) have visible central veins on MR imaging. This "central vein sign" reflects perivenous inflammatory demyelination and can assist in differentiating MS from other white matter disorders. We therefore hypothesized that >40% of white matter lesions in cases of radiologically isolated syndrome would show the central vein sign. MATERIALS AND METHODS: We recruited 20 participants diagnosed with radiologically isolated syndrome after evaluation by a neurologist. We performed 3T MR imaging of the brain and cervical spinal cord. White matter lesions were analyzed for the central vein sign. RESULTS: Of 391 total white matter lesions, 292 (75%) demonstrated the central vein sign (central vein sign+). The median proportion of central vein sign+ lesions per case was 87% (range, 29%-100%). When the "40% rule" that has been proposed to distinguish MS from other disorders was applied, of 20 participants, 18 cases of radiologically isolated syndrome (90%) had ≥40% central vein sign+ lesions (range, 55%-100%). Two participants (10%) had <40% central vein sign+ lesions (29% and 31%). When the simpler "rule of 6" was applied, 19 participants (95%) met these criteria. In multivariable models, the number of spinal cord and infratentorial lesions was associated with a higher proportion of central vein sign+ lesions (P = .002; P = .06, respectively). CONCLUSIONS: Most cases of radiologically isolated syndrome had a high proportion of central vein sign+ lesions, suggesting that lesions in these individuals reflect perivenous inflammatory demyelination. Moreover, we found correlations between the proportion of central vein sign+ lesions and spinal cord lesions, a known risk factor for radiologically isolated syndrome progressing to MS. These findings raise the possibility, testable prospectively, that the central vein sign may have prognostic value in distinguishing patients with radiologically isolated syndrome at risk of developing clinical MS from those with white matter lesions of other etiologies. © 2019 by American Journal of Neuroradiology. DOI: 10.3174/ajnr.A6045 18. Am J Phys Med Rehabil. 2019 Mar 29. doi: 10.1097/PHM.0000000000001189. [Epub ahead of print] A Controlled Clinical Trial On The Effects Of Exercise On Lower Urinary Tract Symptoms In Women With Multiple Sclerosis. Ferreira APS(1), de Souza Pegorare ABG, Junior AM, Salgado PR, Medola FO, Christofoletti G. Author information: (1)From the Faculty of Medicine, Universidade Federal de Mato Grosso do Sul, Brazil (APSF, GC); Institute of Health, Universidade Federal de Mato Grosso do Sul, Brazil (ABP, GC); UroVida Medical Outpatient Clinic, Brazil (AM); Multiple Sclerosis Outpatient Center, Hospital Universitário Maria Aparecida Pedrossian, Universidade Federal de Mato Grosso do Sul, Brazil (PRS); and Department of Design, Universidade Estadual Paulista, Brazil (FOM). OBJECTIVE: To investigate the effects of two pelvic floor exercise programs on lower urinary tract symptoms and quality of life in participants with multiple sclerosis. DESIGN: Prospective, single blind, clinical trial. SETTINGS: A community rehabilitation program within a large metropolitan health service. PARTICIPANTS: Thirty women in moderate stage of multiple sclerosis, referred for outpatient rehabilitation. INTERVENTIONS: In a period of six months, participants underwent a pelvic floor exercise program, associated or not with vaginal electrotherapy. MAIN OUTCOMES: Overactive bladder, perineal contraction and quality of life. RESULTS: The findings showed benefits of both programs on overactive bladder and quality of life. Participants undergoing exercise plus electrotherapy presented greater improvement on contraction of the perineal musculature and quality of life. CONCLUSION: Six months of exercise provided benefits on lower urinary tract symptoms and quality of life in women with multiple sclerosis. Electrical stimulation potentiated the improvement on perineal musculature and quality of life. This trial was registered prospectively with the Clinical Trials Register, ID: BR-287q65 (http://www.ensaiosclinicos.gov.br/rg/RBR- 287q65/). DOI: 10.1097/PHM.0000000000001189 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 29 – Multiple Sklerose: Veröffentlichungen April 2019 19. Anal Chim Acta. 2019 Aug 8;1064:112-118. doi: 10.1016/j.aca.2019.03.015. Epub 2019 Mar 12. Bioluminescent aptamer-based sandwich-type assay of anti-myelin basic protein autoantibodies associated with multiple sclerosis. Krasitskaya VV(1), Chaukina VV(2), Abroskina MV(3), Vorobyeva MA(2), Ilminskaya AA(3), Kabilov MR(2), Prokopenko SV(3), Nevinsky GA(2), Venyaminova AG(2), Frank LA(4). Author information: (1)Institute of Biophysics SB RAS, Federal Research Center "Krasnoyarsk Science Center SB RAS", Krasnoyarsk, 660036, Russia. Electronic address: [email protected]. (2)Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, 630090, Russia. (3)State Medical University named after V.F. Voino-Yasenetsky, Krasnoyarsk, 660022, Russia. (4)Institute of Biophysics SB RAS, Federal Research Center "Krasnoyarsk Science Center SB RAS", Krasnoyarsk, 660036, Russia. Bioluminescent solid-phase sandwich-type microassay was developed to detect multiple sclerosis (MS)- associated autoantibodies in human sera. The assay is based on two different 2'-F-Py RNA aptamers against the target autoantibodies as biospecific elements, and Ca2+-regulated photoprotein obelin as a reporter. The paper describes elaboration of the assay and its application to 91 serum samples from patients with clinically definite MS and 86 ones from individuals healthy in terms of MS. Based on the receiver-operator curve (ROC) analysis, the chosen threshold value as clinical decision limit offers sensitivity of 63.7% and specificity of 94.2%. The area under the ROC curve (AUC) value of 0.87 shows a good difference between the groups under investigation. The likelihood ratio of 10.97 proves the diagnostic value of the assay and its potential as one of the laboratory MS-tests. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.aca.2019.03.015 20. Ann Clin Transl Neurol. 2019 Mar 2;6(4):689-697. doi: 10.1002/acn3.746. eCollection 2019 Apr. Association of corneal nerve fiber measures with cognitive function in dementia. Ponirakis G(1), Al Hamad H(2), Sankaranarayanan A(3), Khan A(1), Chandran M(2), Ramadan M(2), Tosino R(2), Gawhale PV(2), Alobaidi M(2), AlSulaiti E(2), Elsotouhy A(4), Elorrabi M(2), Khan S(2), Nadukkandiyil N(2), Osman S(2), Thodi N(5), Almuhannadi H(1), Gad H(1), Mahfoud ZR(1), Al-Shibani F(1), Petropoulos IN(1), Own A(4), Al Kuwari M(2), Shuaib A(6)(7), Malik RA(1). Author information: (1)Weill Cornell Medicine-Qatar Qatar Foundation Education City Doha Qatar. (2)Geriatric & Memory Clinic Rumailah Hospital Hamad Medical Corporation Doha Qatar. (3)School of Medicine Western Sydney University Campbelltown New South Wales Australia. (4)Neuroradiology Hamad General Hospital Hamad Medical Corporation Doha Qatar. (5)MRI Unit Rumailah Hospital Hamad Medical Corporation Doha Qatar. (6)Neuroscience Institute Hamad General Hospital Hamad Medical Corporation Doha Qatar. (7)Department of Medicine University of Alberta Edmonton Canada. Objectives: Corneal confocal microscopy (CCM) is a noninvasive ophthalmic technique that identifies corneal nerve degeneration in a range of peripheral neuropathies and in patients with multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. We sought to determine whether there is any association of corneal nerve fiber measures with cognitive function and functional independence in patients with MCI and dementia. Methods: In this study, 76 nondiabetic participants with MCI (n = 30), dementia (n = 26), and healthy age-matched controls (n = 20) underwent assessment of cognitive and physical function and CCM. Results: There was a progressive reduction in corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P < 0.0001) in patients with MCI and dementia compared to healthy controls. Adjusted for confounders, all three corneal nerve fiber measures were significantly associated with cognitive function (P < 0.05) and functional independence (P < 0.01) in MCI and dementia. The area under the ROC curve to distinguish MCI with CNFD, CNBD, and CNFL was 69.1%, 73.2%, and 73.0% and for dementia it was 84.8%, 84.2%, and 86.2%, respectively. Interpretation: CCM demonstrates corneal nerve fiber loss, which is associated with a decline in cognitive function and functional independence in patients with MCI and dementia. DOI: 10.1002/acn3.746 PMCID: PMC6469344 Conflict of interest statement: We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship and are not listed. We confirm that the order of authors listed in the manuscript has been approved by all authors. None of the authors have received or anticipate receiving income, goods or benefit from a company that will influence the design, conduct, or reporting of the study. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 30 – Multiple Sklerose: Veröffentlichungen April 2019 21. Ann Clin Transl Neurol. 2019 Mar 3;6(4):678-688. doi: 10.1002/acn3.741. eCollection 2019 Apr. Investigation of white matter PiB uptake as a marker of white matter integrity. Zeydan B(1)(2)(3), Schwarz CG(1), Lowe VJ(1), Reid RI(4), Przybelski SA(5), Lesnick TG(5), Kremers WK(5), Senjem ML(1)(4), Gunter JL(1)(4), Min HK(1), Vemuri P(1), Knopman DS(2), Petersen RC(2), Jack CR Jr(1), Kantarci OH(2)(3), Kantarci K(1). Author information: (1)Department of Radiology Mayo Clinic Rochester Minnesota. (2)Department of Neurology Mayo Clinic Rochester Minnesota. (3)Center for Multiple Sclerosis and Autoimmune Neurology Mayo Clinic Rochester Minnesota. (4)Department of Information Technology Mayo Clinic Rochester Minnesota. (5)Department of Health Sciences Research Mayo Clinic Rochester Minnesota. Objective: To investigate the associations of Pittsburgh compound-B (PiB) uptake in white matter hyperintensities (WMH) and normal appearing white matter (NAWM) with white matter (WM) integrity measured with DTI and cognitive function in cognitively unimpaired older adults. Methods: Cognitively unimpaired older adults from the population-based Mayo Clinic Study of Aging (n = 537, age 65-95) who underwent both PiB PET and DTI were included. The associations of WM PiB standard uptake value ratio (SUVr) with fractional anisotropy (FA) and mean diffusivity (MD) in the WMH and NAWM were tested after adjusting for age. The associations of PiB SUVr with cognitive function z-scores were tested after adjusting for age and global cortical PiB SUVr. Results: The WMH PiB SUVr was lower than NAWM PiB SUVr (P < 0.001). In the WMH, lower PiB SUVr correlated with lower FA (r = 0.21, P < 0.001), and higher MD (r = - 0.31, P < 0.001). In the NAWM, lower PiB SUVr only correlated with higher MD (r = -0.10, P = 0.02). Both in the WMH and NAWM, lower PiB SUVr was associated with lower memory, language, and global cognitive function z-scores after adjusting for age and global cortical PiB SUVr. Interpretation: Reduced PiB uptake in the WMH is associated with a loss of WM integrity and cognitive function after accounting for the global cortical PiB uptake, suggesting that WM PiB uptake may be an early biomarker of WM integrity that precedes cognitive impairment in older adults. When using WM as a reference region in cross-sectional analysis of PiB SUVr, individual variability in WMH volume as well as age should be considered. DOI: 10.1002/acn3.741 PMCID: PMC6469255 Conflict of interest statement: B Zeydan has nothing to disclose. CG Schwarz receives funding from the NIH. VJ Lowe consults for Bayer Schering Pharma, Piramal Life Sciences and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH (NIA, NCI). RI Reid, SA Przybelski, TG Lesnick and WK Kremers have nothing to disclose. ML Senjem discloses equity/options ownership in medical companies: Gilead Sciences Inc., Inovio Pharmaceuticals, Medtronic, and PAREXEL International Corporation. JL Gunter has nothing to disclose. H Min has nothing to disclose. P Vemuri receives funding from the NIH (NIA and NINDS). DS Knopman serves on a Data Safety Monitoring Board for the DIAN study; is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California; and receives research support from the NIH. RC Petersen receives funding from the NIH, has served on the National Advisory Council on Aging and on the scientific advisory boards of Pfizer, GE Healthcare, Elan Pharmaceuticals, and Janssen Alzheimer Immunotherapy, has received publishing royalties from Oxford University Press, and has been a consultant for Roche Incorporated, Merck, Genentech, Biogen, and Eli Lily. CR Jack consults for Lily and serves on an independent data monitoring board for Roche but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. OH Kantarci receives grant support from Biogen Inc. K Kantarci serves on data safety monitoring board for Takeda Global Research and Development Center, Inc, receives research support from Avid Radiopharmaceuticals and Eli Lilly, and receives funding from the NIH and Alzheimer's Drug Discovery Foundation. 22. Ann Indian Acad Neurol. 2019 Apr-Jun;22(2):131-136. doi: 10.4103/aian.AIAN_345_18. Can We Treat Secondary Progressive Multiple Sclerosis Now? Bhatia R(1), Singh N(1). Author information: (1)Department of Neurology, All India Institute of Medical Sciences, New Delhi, India. Secondary progressive multiple sclerosis (SPMS) is characterized by progressive accumulation of disability without intermittent recovery. Treatment of these patients is challenging due to limited understanding of pathogenesis and fewer therapeutic options. This article summarizes difficulties in defining and conducting trials in SPMS, review major clinical trials on therapies approved and unapproved in SPMS and lastly, therapies in pipeline for use in SPMS. DOI: 10.4103/aian.AIAN_345_18 PMCID: PMC6472227 Conflict of interest statement: There are no conflicts of interest. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 31 – Multiple Sklerose: Veröffentlichungen April 2019 23. Annu Rev Genomics Hum Genet. 2019 Apr 24. doi: 10.1146/annurev-genom-083118-015354. [Epub ahead of print] Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex. Salussolia CL(1), Klonowska K(2), Kwiatkowski DJ(2), Sahin M(1). Author information: (1)F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; email: [email protected]. (2)Division of Pulmonary and Critical Care Medicine and Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems due to an inactivating variant in either TSC1 or TSC2, resulting in the hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. Dysregulated mTOR signaling results in increased cell growth and proliferation. Clinically, TSC patients exhibit great phenotypic variability, but the neurologic and neuropsychiatric manifestations of the disease have the greatest morbidity and mortality. TSC-associated epilepsy occurs in nearly all patients and is often difficult to treat because it is refractory to multiple antiseizure medications. The advent of mTOR inhibitors offers great promise in the treatment of TSC- associated epilepsy and other neurodevelopmental manifestations of the disease; however, the optimal timing of therapeutic intervention is not yet fully understood. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 30, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. DOI: 10.1146/annurev-genom-083118-015354 24. Appl Neuropsychol Adult. 2019 Apr 5:1-9. doi: 10.1080/23279095.2019.1575221. [Epub ahead of print] Reliability, validity, and normative investigation of Persian version of a High-Level Language Test (BESS). Rahimifar P(1), Soltani M(1), Mahmood Latifi S(2), Madjdinasab N(3), Moradi N(1). Author information: (1)a Musculoskeletal Rehabilitation Research Center , Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran. (2)b Health Research Institute, Diabetes Research Center , Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran. (3)c Department of Neurology, Golestan Hospital , Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran. Our study aimed at reliability, validity, and normative investigation of the Persian version of the High-Level Language Test (BESS). This study was conducted on 60 multiple sclerosis (MS) patients as well as 60 healthy individuals. After translating the BESS into Persian, its content validity was determined based on 10 experts working in the same field. The reliability of the test was determined using techniques such as the test-retest method, Cronbach's alpha, and clinical validity. The content validity ratio (CVR) was higher than 0.62 for every subtest, and the content validity index (CVI) was between 0.1 and 0.8 for all subtests. Cronbach's alpha coefficient was between 0.70 and 0.93, and intraclass correlation coefficient (ICC) was between 0.80 and 0.96. Clinical validity results showed a significant difference between means of patients' scores and healthy subjects scores (p ≤ 0.005). The Persian version of BESS benefits from high reliability and validity values. Speech therapists can use the test to examine high-level language disorders in MS patients. DOI: 10.1080/23279095.2019.1575221 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 32 – Multiple Sklerose: Veröffentlichungen April 2019 25. Appl Neuropsychol Adult. 2019 Apr 2:1-5. doi: 10.1080/23279095.2019.1588123. [Epub ahead of print] Montreal Cognitive Assessment in a Greek sample of patients with multiple sclerosis: A validation study. Konstantopoulos K(1)(2), Vogazianos P(3). Author information: (1)a Department of Health sciences , European University Cyprus , Engomi, Nicosia , Cyprus. (2)b Cyprus Institute for Neurology and Genetics , Nicosia , Cyprus. (3)c School of Humanities, Social & Education Sciences , European University Cyprus , Engomi, Nicosia , Cyprus. The Montreal Cognitive Assessment (MoCA) is a brief cognitive instrument for the measurement of dementia. The aim of the present study was to measure the sensitivity of this test in a group of Greek speaking participants diagnosed with multiple sclerosis. 40 MS participants complaining for cognitive dysfunction were matched in age and education to 490 healthy participants. The MoCA test and a neuropsychological test battery were administered to both groups. The MoCA test was found to differentiate the MS from the controls (U = 3761.00, p < .001) and it was correlated with all neuropsychological tests (digit span: r = 0.454, p < .0001; phonemic verbal fluency: r = 0.390, p < .0001; semantic verbal fluency: r = 0.319, p < .0001; Color Trails Test 1 (CTT1): r = -.256, p < .0001; Color Trails Test 2 (CTT2): r = -.321, p < .0001). Multiple regression analysis showed that 10.3% of the variation in the MoCA score was accounted for by the Expanded Disability Status Scale (EDSS) total score. Also, the test showed high discriminant validity (optimal screening cut off point 25, sensitivity 0.68, specificity 0.89). MoCA is a sensitive test to differentiate cognitive impairment in Greek speaking MS participants from healthy controls. Further research is needed to use it in larger clinical samples and in different subtypes of the disease. DOI: 10.1080/23279095.2019.1588123 26. Arch Phys Med Rehabil. 2019 Apr 23. pii: S0003-9993(19)30257-6. doi: 10.1016/j.apmr.2019.03.017. [Epub ahead of print] Oxygen cost during mobility tasks and its relationship to fatigue in progressive Multiple Sclerosis. Devasahayam AJ(1), Kelly LP(1), Wallack EM(1), Ploughman M(2). Author information: (1)Recovery & Performance Laboratory, Faculty of Medicine, Memorial University of Newfoundland, Rm 400, L.A. Miller Centre, 100 Forest Road, St. John's NL Canada A1A 1E5. (2)Recovery & Performance Laboratory, Faculty of Medicine, Memorial University of Newfoundland, Rm 400, L.A. Miller Centre, 100 Forest Road, St. John's NL Canada A1A 1E5. Electronic address: [email protected]. OBJECTIVE: To compare the oxygen costs of mobility tasks between individuals with progressive MS using walking aids and matched controls and to determine whether oxygen cost predicted fatigue. DESIGN: Cross- sectional descriptive. SETTING: A rehabilitation research laboratory. PARTICIPANTS: 14 adults with progressive MS (54.07+8.46 years of mean age) using walking aids and 8 age/sex-matched controls without MS. INTERVENTIONS: Participants performed five mobility tasks (rolling in bed, lying to sitting, sitting to standing, walking and climbing steps) wearing a portable metabolic cart. OUT E E SU E(S) ygen consumption ( ) during mobility tas s, ma imal 2 during graded maximal exercise test, perceived exertion and task-induced fatigue measured on a visual analogue scale before and after mobility tasks. RESULTS: People with progressive MS had significantly higher oxygen cost in all tasks compared to controls (p<0.05): climbing steps (3.60 times more in MS), rolling in bed (3.53), walking (3.10), lying to sitting (2.50), and sitting to standing (1.82). There was a strong, positive correlation between task-induced fatigue and oxygen cost of walking, (rs(13)=0.626, p=0.022). CONCLUSIONS: People with progressive MS used 2.81 times more energy on average for mobility tasks compared to controls. People with progressive MS experienced accumulation of oxygen cost, fatigue and exertion when repeating tasks and higher oxygen cost during walking was related to greater perception of fatigue. Our findings suggest that rehabilitation interventions that increase endurance during functional tasks could help reduce fatigue in people with progressive MS who use walking aids. Copyright © 2019. Published by Elsevier Inc. DOI: 10.1016/j.apmr.2019.03.017 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 33 – Multiple Sklerose: Veröffentlichungen April 2019 27. Arq Neuropsiquiatr. 2019 Mar;77(3):179-183. doi: 10.1590/0004-282X20190017. The prevalence of bruxism and related factors in patients with multiple sclerosis: a comparative study. Odabas FÖ(1), Uca AU(2). Author information: (1)University of Health Sciences, Konya Health Application and Research Center, Department of Neurology, Konya, Turkey. (2)Necmettin Erbakan University, Meram Faculty of Medicine, Department of Neurology, Konya, Turkey. OBJECTIVE: To determine the prevalence of bruxism and related factors in patients with multiple sclerosis (MS). METHODS: Diagnosed with relapsing-remitting MS under the 2010-revised McDonald diagnostic criteria, 182 patients without MS exacerbations during the previous three months were included in the patient group, and 145 healthy individuals made up the control group in the study. Demographic data of the participants in both groups were determined. In the patient and control groups, the diagnosis of definite bruxism was made using the International Classification of Sleep Disorders (Diagnosis and Coding Manual, Second Edition). RESULTS: Bruxism was found in 29.7% (n = 54) of the patients and in 12.4% (n = 18) of the controls, and the difference was statistically significant (p < 0.001). Of all patients, the onset of bruxism was found in 70.4% (n = 38) after the diagnosis and in 29.6% (n = 169) prior to the diagnosis of MS. Compared with those without bruxism, the mean age (p = 0.031) and the score of the Expanded Disability Status Scale (p = 0.001) were also significantly higher among MS patients with bruxism. Between MS patients with and without bruxism, no significant differences were found in terms of sex, marital status, educational status, employment, cigarette smoking, total number of exacerbations, number of exacerbations within the previous year, and drugs used. CONCLUSIONS: The frequency of bruxism was found to be higher in the patients with MS than in the controls. Bruxism is associated with age and the Expanded Disability Status Scale score in MS patients. DOI: 10.1590/0004-282X20190017 28. Arq Neuropsiquiatr. 2019 Mar;77(3):166-173. doi: 10.1590/0004-282X20190026. Polymorphisms in the CIITA -168A/G (rs3087456) and CIITA +1614G/C (rs4774) may influence severity in multiple sclerosis patients. Pereira VCSR(1), Fontes-Dantas FL(2), Paradela ER(2), Malfetano FR(1), Scherpenhuijzen SSB(1), Mansur LF(2), Luiz RR(1), Oliveira AP(2), Farinhas JGD(2), Maiolino Â(1), Alves-Leon SV(1)(2). Author information: (1)Universidade Federal do Rio de Janeiro, Departamento de Neurologia, Rio de Janeiro RJ, Brasil. (2)Universidade Federal do Estado do Rio de Janeiro, Laboratório de Neurociências Translacional, Programa de Pós-Graduação em Neurologia, Rio de Janeiro RJ, Brasil. It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS).OBJECTIVE: We examined the impact of CIITA polymorphisms -168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments. METHODS: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS). RESULTS: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA -168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA -168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA -168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS. CONCLUSION: These data suggest that CIITA -168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management. DOI: 10.1590/0004-282X20190026 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 34 – Multiple Sklerose: Veröffentlichungen April 2019 29. Arthritis Res Ther. 2019 Apr 15;21(1):95. doi: 10.1186/s13075-019-1877-z. Study of MRI brain findings and carotid US features in systemic sclerosis patients, relationship with disease parameters. Gamal RM(1), Abozaid HSM(2), Zidan M(3), Abdelmegid MAF(4), Abdel-Razek MR(1), Alsayed SA(5), Mourad AF(6), Azoz NMA(7), Mohram LA(7), Furst DE(8)(9)(10). Author information: (1)Rheumatology and Rehabilitation Department, Assiut University Hospital, Assiut, 71515, Egypt. (2)Rheumatology and Rehabilitation Department, Sohag University Hospital, Sohag university, Sohag, 82524, Egypt. [email protected]. (3)Diagnostic Radiology Department, Assiut University Hospital, Assiut, Egypt. (4)Cardiovascular Medicine Department, Assiut University Heart Hospital, Assiut, Egypt. (5)Rheumatology and Rehabilitation Department, Sohag University Hospital, Sohag university, Sohag, 82524, Egypt. (6)Diagnostic Radiology Department, South Egypt Cancer Institute, Assiut, Egypt. (7)Internal Medicine Department, Assiut University Hospital, Assiut, Egypt. (8)Division of Rheumatology, University of California in Los Angeles (Emeritus), Los Angeles, USA. (9)Department of Medicine, University of Washington, Seattle, WA, USA. (10)Division of Rheumatology and Experimental Medicine, University of Florence, Florence, Italy. BACKGROUND/OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease associated with immune abnormalities and widespread vascular lesions, including increased intimal and medial thickness. These changes may be reflected in early atherosclerosis and cardiovascular risks. We aimed in this study to examine the carotid artery intima-media thickness and MRI brain findings in SSc patients and compared them to a group of normal controls. A relationship between these parameters and clinical measures in SSc was also sought. METHODS: Seventy-two SSc patients with no central nervous system (CNS) symptoms and 42 healthy controls were included. Clinical and laboratory measures, Medsger's severity scale, and Doppler ultrasound common carotid artery intima-media thickness (CCA-IMT) were measured. Brain fluid- attenuated inversion recovery (FLAIR)-MRI and diffusion-weighted MRI (DWI) were also done. RESULTS: SSc patients had more CCA-IMT, higher CRP, and more brain MRI hyperintense lesions than controls (P < 0.05). Significant positive correlations existed between CCA-IMT and Medsger vascular (r = 0.7, P = 0.02). The FLAIR-MRI showed multiple hyperintense lesions in 24 patients (33%), ranging 0-36 lesions. SSc patients with more lesions (positive MRI) had longer disease duration (P = 0.001) and left and right carotid artery atheromata (P = 0.001, and 0.013, respectively) than SSc patients with negative MRIs; Medsger vascular score did not separate the SSc groups (P = 0.08). CONCLUSIONS: In systemic sclerosis patients without central nervous system symptoms, MRI lesion numbers correlated with CCA-IMT. MRI abnormalities were found more frequently if CRP was elevated, if the Medsger SSc Severity Scale was increased, or if there was thickened carotid IMT. DOI: 10.1186/s13075-019-1877-z PMCID: PMC6466742 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 35 – Multiple Sklerose: Veröffentlichungen April 2019 30. Asian Pac J Cancer Prev. 2019 Apr 29;20(4):1005-1018. Association of Delta-6-Desaturase Expression with Aggressiveness of Cancer, Diabetes Mellitus, and Multiple Sclerosis: A Narrative Review Arshad Z(1), Rezapour-Firouzi S(2), Ebrahimifar M(3), Mosavi Jarrahi A(4), Mohammadian M(5). Author information: (1)Department of Pathology of Anatomy, School of medicine, Baku University of Medical Sciences, Baku, Azerbaijan. (2)Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran. Email: [email protected], [email protected] (3)Department of Toxicology, Faculty of Pharmacy, Islamic Azad University, Shahreza Branch, Shahreza, Iran. (4)Department of Social Medicine, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (5)Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran. Background: The phosphatidylinositol 3-kinase/ protein kinase B /mammalian target of rapamycin (PI3K/Akt/ mTOR) signaling regulates multiple cellular processes and organizes cell proliferation, survival, and differentiation with the available nutrients, in particular, fatty acids. Polyunsaturated fatty acids (PUFAs) are cytotoxic to cancer cells and play a critical role in the treatment of multiple sclerosis (MS) and diabetes mellitus (DM). PUFAs are produced in the body by desaturases and elongases from dietary essential fatty acids (EFAs), primarily involving delta-6-desaturase (D6D). D6D is a rate-limiting enzyme for maintaining many aspects of lipid homeostasis and normal health. D6D is important to recognize the mechanisms that regulate the expression of this enzyme in humans. A lower level of D6D was seen in breast tumors compared to normal tissues. Interestingly, the elevated serum level of D6D was seen in MS and DM, which explains the critical role of D6D in inflammatory diseases. Methods: We searched databases of PubMed, Web of Science (WOS), Google Scholar, Scopus and related studies by predefined eligibility criteria. We assessed their quality and extracted data. Results: Regarding the mTOR signaling pathway, there is remarkable contributions of many inflammatory diseases to attention to common metabolic pathways are depicted. Of course, we need to have the insights into each disorder and their pathological process. The first step in balancing the intake of EFAs is to prevent the disruption of metabolism and expression of the D6D enzyme. Conclusions: The ω6 and ω3 pathways are two major pathways in the biosynthesis of PUFAs. In both of these, D6D is a vital bifunctional enzyme desaturating linoleic acid or alpha-linolenic acid. Therefore, if ω6 and ω3 EFAs are given together in a ratio of 2: 1, the D6D expression will be down-regulated and normalized. Creative Commons Attribution License DOI: 10.31557/APJCP.2019.20.4.1005 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 36 – Multiple Sklerose: Veröffentlichungen April 2019 31. Autoimmun Rev. 2019 Apr 5. pii: S1568-9972(19)30088-6. doi: 10.1016/j.autrev.2018.12.010. [Epub ahead of print] Emerging role of air pollution in autoimmune diseases. Zhao CN(1), Xu Z(2), Wu GC(3), Mao YM(1), Liu LN(1), Qian-Wu(1), Dan YL(1), Tao SS(1), Zhang Q(1), Sam NB(1), Fan YG(1), Zou YF(1), Ye DQ(1), Pan HF(4). Author information: (1)Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, China. (2)School of Public Health and Social Work & Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia. (3)School of Nursing, Anhui Medical University, 15 Feicui Road, Hefei, Anhui, China. (4)Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, China. Electronic address: [email protected]. Autoimmune diseases (ADs) are a broad spectrum of disorders featured by the body's immune responses being directed against its own tissues, resulting in prolonged inflammation and subsequent tissue damage. Recently, the exposure to ambient air pollution has been implicated in the occurrence and development of ADs. Mechanisms linking air pollution exposures and ADs mainly include systemic inflammation, increased oxidative stress, epigenetic modifications induced by exposures and immune response caused by airway damage. The lung may be an autoimmunity initiation site in autoimmune diseases (ADs). Air pollutants can bind to the Aryl hydrocarbon receptor (AHR) to regulate Th17 and Treg cells. Oxidative stress and inducible bronchus associated lymphoid tissue caused by the pollutants can influence T, B cells, resulting in the production of proinflammatory cytokines. These cytokines stimulate B cell and dendritic cells, resulting in a lot of antibodies and self-reactive T lymphocytes. Moreover, air pollutants may induce epigenetic changes to contribute to ADs. In this review, we will concern the associations between air pollution and immune- inflammatory responses, as well as mechanisms linking air pollution exposure and autoimmunity. In addition, we focus on the potential roles of air pollution in major autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), and type 1 diabetes mellitus (T1DM). Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.autrev.2018.12.010 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 37 – Multiple Sklerose: Veröffentlichungen April 2019 32. Best Pract Res Clin Haematol. 2019 Mar;32(1):74-88. doi: 10.1016/j.beha.2019.02.002. Epub 2019 Feb 7. Myeloid disorders after autoimmune disease. Boddu PC(1), Zeidan AM(2). Author information: (1)Yale University School of Medicine, Department of Medicine, Section of Hematology, New Haven, CT, USA. (2)Yale University School of Medicine, Department of Medicine, Section of Hematology, New Haven, CT, USA. Electronic address: [email protected]. Autoimmune diseases (ADs) are associated with an increased risk not only of lymphoproliferative disorders but also of myeloid malignancies. The excess risk of myelodysplastic syndromes and/or acute myeloid leukemia is observed across several AD types, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disorders, multiple sclerosis, among others. The risk of developing myeloid neoplasms (MNs) is dependent on several variables, including the specific AD type, chronicity and severity of the AD, type and duration of exposure of disease modifying anti-rheumatic drugs or cytotoxics/immunosuppressives, and genetic predisposition risk. Putative triggering factors linking AD to elevated MN risk include AD-directed medications, shared genetic susceptibilities between the two disease entities, and chronic immune stimulation or bone marrow infiltration by the AD. Molecular mechanisms underpinning leukemogenesis remain largely speculative and warrant further investigation. Leukemias arising in patients with AD are not always 'therapy-related' in that MNs may develop in certain AD subtypes even among patients with no prior therapy exposure. Only a few studies have attempted to determine factors associated with MN development in AD but failed to demonstrate consistent characteristic clinical or paraclinical features. These reports have failed to demonstrate a clear correlation between individual agent exposure and subsequent leukemia development due to the low rates of therapy exposure compounded by the rarity of MN occurrence. Notwithstanding, the leukemogenic potential is best documented with agents such as azathioprine, cyclophosphamide, and mitoxantrone; this risk of MN development does not appear to be shared by biologic approaches such as anti-tumor necrosis factors-alpha inhibitors. In this article, we discuss plausible biologic mechanisms underlying MN pathogenesis in AD and review the data available on the development of MNs in patients with AD. Copyright © 2019. Published by Elsevier Ltd. DOI: 10.1016/j.beha.2019.02.002 33. Bioanalysis. 2019 Apr 18. doi: 10.4155/bio-2019-0060. [Epub ahead of print] Perspectives on gender parity in bioanalysis: an interview with Lauren Stevenson. Stevenson LF(1). Author information: (1)Development Biomarkers and Bioanalytical Sciences, Biogen, Cambridge, MA 02142, USA. Biography Lauren is Senior Director, Development Biomarkers & Bioanalytical Sciences at Biogen, Cambridge, MA, USA where she leads a team of talented scientists, setting bioanalytical and biomarker strategies and developing pharmacokinetics (PK), immunogenicity and biomarker assays in support of programs at all stages of development, from discovery to post-marketing. Lauren's team currently supports over 40 therapeutic programs, delivering PK and immunogenicity strategy and execution for Biogen's large molecule, antisense oligonucleotide (ASO0 and gene therapy portfolio as well as developing biomarkers in support of multiple sclerosis, immunology, fibrosis, rare and neurodegenerative disease indications. Externally, Lauren engages the broader industry and regulatory agencies as an invited speaker and course instructor at multiple conferences and workshops each year. In concert with her scientific role, Lauren is passionate about people development, has received certification as a Strengths coach and is active in mentorship and career development programs. DOI: 10.4155/bio-2019-0060 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 38 – Multiple Sklerose: Veröffentlichungen April 2019 34. Biol Pharm Bull. 2019;42(4):638-644. doi: 10.1248/bpb.b18-00855. Dimethyl Fumarate Attenuates Oxaliplatin-Induced Peripheral Neuropathy without Affecting the Anti-tumor Activity of Oxaliplatin in Rodents. Miyagi A(1), Kawashiri T(1), Shimizu S(1), Shigematsu N(1), Kobayashi D(1), Shimazoe T(1). Author information: (1)Department of Clinical Pharmacy and Pharmaceutical Care, Graduate School of Pharmaceutical Sciences, Kyushu University. Oxaliplatin has been used as a first choice for colorectal, gastric and pancreatic cancer, but it induces peripheral neuropathies. Dimethyl fumarate (DMF) is an oral drug for multiple sclerosis with neuroprotective effects on oxidative stress. Using both in vivo and in vitro models, we investigated the effects of DMF on oxaliplatin-induced peripheral neuropathy and other side effects, as well as on the anti-tumor activity of oxaliplatin. Repeated intraperitoneal injection of 4 mg/kg oxaliplatin (twice per week for 4 weeks) caused mechanical allodynia (as revealed by the von Frey tests), cold hyperalgesia (as revealed by the acetone tests), and axonal degeneration in the sciatic nerve of rats. Co-administration of oral DMF (200 mg/kg, five times per week for 4 weeks) relieved oxaliplatin-induced mechanical allodynia but not cold hyperalgesia, and ameliorated axonal degeneration. In addition, DMF did not exacerbate oxaliplatin-induced body weight loss or bone marrow suppression, such as reduction in red blood cells, white blood cells, neutrophils and lymphocytes. Furthermore, DMF did not inhibit the anti-tumor activity of oxaliplatin in any cultured cancer cell line (C26, mouse colon carcinoma; HCT116, human colon carcinoma; MKN45, human gastric adenocarcinoma; MIA PaCa-2, human pancreatic carcinoma) or C26-bearing mice. These results suggest that DMF prevents oxaliplatin-induced mechanical allodynia and axonal degeneration without affecting the anti-tumor activity of oxaliplatin. Therefore, DMF may be useful for managing oxaliplatin-induced chronic peripheral neuropathy. DOI: 10.1248/bpb.b18-00855 35. Biomedicines. 2019 Mar 30;7(2). pii: E26. doi: 10.3390/biomedicines7020026. Stem Cell-Based Therapies for Multiple Sclerosis: Current Perspectives. Cuascut FX(1), Hutton GJ(2). Author information: (1)Baylor College of Medicine, Maxine Mesigner Multiple Sclerosis Center, Houston, TX 77030, USA. [email protected]. (2)Baylor College of Medicine, Maxine Mesigner Multiple Sclerosis Center, Houston, TX 77030, USA. [email protected]. Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS). Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce disease activity in patients with relapsing⁻remitting MS (RRMS). The current therapeutic challenge is to find an effective treatment to halt disease progression and reverse established neural damage. Stem cell- based therapies have emerged to address this dilemma. Several types of stem cells have been considered for clinical use, such as autologous hematopoietic (aHSC), mesenchymal (MSC), neuronal (NSC), human embryonic (hESC), and induced pluripotent (iPSC) stem cells. There is convincing evidence that immunoablation followed by hematopoietic therapy (aHSCT) has a high efficacy for suppressing inflammatory MS activity and improving neurological disability in patients with RRMS. In addition, MSC therapy may be a safe and tolerable treatment, but its clinical value is still under evaluation. Various studies have shown early promising results with other cellular therapies for CNS repair and decreasing inflammation. In this review, we discuss the current knowledge and limitations of different stem cell-based therapies for the treatment of patients with MS. DOI: 10.3390/biomedicines7020026 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 39 – Multiple Sklerose: Veröffentlichungen April 2019 36. Biomedicines. 2019 Apr 19;7(2). pii: E32. doi: 10.3390/biomedicines7020032. Women's Health: Contemporary Management of MS in Pregnancy and Post-Partum. Tisovic K(1), Amezcua L(2). Author information: (1)Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. [email protected]. (2)Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. [email protected]. Multiple sclerosis (MS) primarily affects women in childbearing age and is associated with an increased risk of adverse post-partum outcomes. Relapses and now fetal exposure to disease modifying treatments in the early phase of pregnancy and thereafter are of concern. Safe and effective contraception is required for women who wish to delay or avoid pregnancy while on disease-modifying treatments. Counseling and planning is essential to assess the risk of both fetal and maternal complications, particularly now in the era of highly efficient and riskier therapies. The purpose of this review is to provide a practical framework using the available data surrounding pregnancy in MS with the goal of optimizing outcomes during this phase in MS. DOI: 10.3390/biomedicines7020032 37. Bioorg Med Chem. 2019 May 15;27(10):2075-2082. doi: 10.1016/j.bmc.2019.04.003. Epub 2019 Apr 3. Synthesis and characterization of hydrogen peroxide activated estrogen receptor beta ligands. Park H(1), McEachon JD 2nd(1), Pollock JA(2). Author information: (1)Department of Chemistry, University of Richmond, 138 UR Drive, Richmond, VA 23173, USA. (2)Department of Chemistry, University of Richmond, 138 UR Drive, Richmond, VA 23173, USA. Electronic address: [email protected]. The development and evaluation of selective estrogen receptor modulators (SERMs) is of interest because of the complex and significant role of estrogen receptors in normal tissues as well as disease states. In neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, estrogen receptor beta (ERβ) seems to provide a protective anti-inflammatory response. Due to the increase in reactive oxygen species (ROS) in these diseases, we have masked ERβ ligands, including diarylpropionitrile (DPN), as boronate esters that release the active estrogen in the presence of H2O2. Here we demonstrate their synthesis, decreased binding affinities, kinetics of release, and selectivity toward ROS. The most promising ligand can be unmasked in the presence of pathological H2O2 to modulate ERβ transcription in cells. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.bmc.2019.04.003 38. Bioorg Med Chem Lett. 2019 Apr 24. pii: S0960-894X(19)30253-7. doi: 10.1016/j.bmcl.2019.04.033. [Epub ahead of print] Synthesis and SAR development of quinoline analogs as novel P2X7 receptor antagonists. Xiao Y(1), Karra S(2), Goutopoulos A(3), Morse NT(2), Zhang S(2), Dhanabal M(2), Tian H(2), Seenisamy J(4), Jayaadevan J(4), Caldwell R(2), Potnick J(2), Bleich M(2), Chekler E(2), Sherer B(2). Author information: (1)EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States. Electronic address: [email protected]. (2)EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States. (3)EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, United States. Electronic address: [email protected]. (4)Syngene International Ltd, Biocon Park, SEZ, Bommasandra Industrial Area - Phase-IV Bommasandra-Jigani Link Road, Bangalore 560 099, India. The P2X7 receptor (P2X7R) plays an important role in diverse conditions associated with tissue damage and inflammation, suggesting that the human P2X7R (hP2X7R) is an attractive therapeutic target. In the present study, the synthesis and structure-activity relationship (SAR) of a novel series of quinoline derivatives as P2X7R antagonists are described herein. These compounds exhibited mechanistic activity (YO PRO) in an engineered HEK293 expressing hP2X7R as well as a functional response (IL-1β) in human THP-1 (hTHP-1) cellular assays. Compound 19 was identified as the most promising compound in this series with excellent cellular potency, low liver microsomal clearance, good permeability and low efflux ratio. In addition, this compound also displayed good pharmacokinetic properties and acceptable brain permeability (Kp,uu of 0.37). Copyright © 2019. Published by Elsevier Ltd. DOI: 10.1016/j.bmcl.2019.04.033 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 40 – Multiple Sklerose: Veröffentlichungen April 2019 39. Biotech Histochem. 2019 Apr 8:1-9. doi: 10.1080/10520295.2018.1482001. [Epub ahead of print] Effects of Oenothera biennis L. and Hypericum perforatum L. extracts on some central nervous system myelin proteins, brain histopathology and oxidative stress in mice with experimental autoimmune encephalomyelitis. Selek S(1), Esrefoglu M(2), Meral I(3), Bulut H(1), Caglar HG(1), Sonuc G(4), Yildiz C(4), Teloglu ES(4), Dogan N(4), Yuce B(4), Tiftik E(4), Bayindir N(2). Author information: (1)a Departments of Medical Biochemistry , Bezmialem Vakif University , Istanbul , Turkey. (2)b Histology and Embryology , Bezmialem Vakif University , Istanbul , Turkey. (3)c Physiology Faculty of Medicine , Bezmialem Vakif University , Istanbul , Turkey. (4)d School of Medicine , Bezmialem Vakif University , Istanbul , Turkey. We investigated the effects of Oenothera biennis L. and Hypericum perforatum L. extracts on brain tissue histopathology, myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) in mice with experimental autoimmune encephalomyelitis (EAE). Forty-seven C57BL/6J mice were divided into the following groups: multiple sclerosis (MS), control (healthy mice), MS + H. perforatum treated (MS + HP), MS + O. biennis treated (MS + OB). All groups except the control group were immunized by EAE methods. Two weeks after the immunization, the mice in the MS + HP group were fed normal food containing 18 - 21 g/kg H. perforatum extract, the mice in MS + OB group were fed normal food containing 18 - 21 g/kg O. biennis extract, and the mice in control and MS groups were fed normal food for six weeks. Brain tissue samples were collected from all mice for histopathological and biochemical analysis. Clinical signs of the disease were scored using functional systems scores (FSS) daily. The H. perforatum and O. biennis extracts ameliorated the increased brain tissue MOG and MBP values for animals with MS. H. perforatum and O. biennis extract decreased the TOS and OSI values for brain tissue and increased TAS levels in brain tissue of animals with MS. In addition, H. perforatum and O. biennis extracts decreased the clinical signs at the end of the experiment compared to the beginning of extract administration. We found that myelin was lost in MS group vs. control group. H. perforatum and O. biennis extract treatments decreased the amount of myelin loss in the MS + HP and MS + OB groups. We also observed amyloid deposition on vascular walls, in the cytoplasm of the neurons and in the intercellular space in the MS group. O. biennis and H. perforatum treated groups exhibited neither abnormal amyloid deposition nor obvious cell infiltration. The beneficial effects of O. biennis and H. perforatum for attenuating myelin loss and amyloid deposition suggest their therapeutic utility for treatment of MS. DOI: 10.1080/10520295.2018.1482001 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 41 – Multiple Sklerose: Veröffentlichungen April 2019 40. BMC Complement Altern Med. 2019 Apr 8;19(1):83. doi: 10.1186/s12906-019-2490-z. Alternative or complementary attitudes toward alternative and complementary medicines. Berna F(1)(2)(3)(4), Göritz AS(5), Mengin A(6), Evrard R(7), Kopferschmitt J(6)(8)(9), Moritz S(10). Author information: (1)Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, Clinique Psychiatrique, F- 67091, Strasbourg Cedex, France. [email protected]. (2)Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France. fabrice.berna@chru- strasbourg.fr. (3)Inserm U1114, Strasbourg France ; Fondation FondaMental, Créteil, France. [email protected]. (4)CUMIC, Collège Universitaire des Médecines Intégratives et Complémentaires, Nantes, France. [email protected]. (5)Occupational and Consumer Psychology, Freiburg University, Engelbergerstraße 41, D-79085, Freiburg, Germany. (6)Hôpitaux Universitaires de Strasbourg, 1 place de l'Hôpital, Clinique Psychiatrique, F-67091, Strasbourg Cedex, France. (7)INTERPSY (EA 4432), Université de Lorraine, 23 Boulevard Albert 1er, F-54000, Nancy, France. (8)Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France. (9)CUMIC, Collège Universitaire des Médecines Intégratives et Complémentaires, Nantes, France. (10)University Medical Center Hamburg-Eppendorf, Department of Psychiatry and Psychotherapy, Martinistr. 52, D-20246, Hamburg, Germany. BACKGROUND: Integrative and complementary health approaches (ICHA) are often pursued by patients facing chronic illnesses. Most of the studies that investigated the factors associated with ICHA consumption have considered that the propensity to use ICHA is a stable or fixed characteristic of an individual. However, people may prefer using ICHA in some situations and not in others, depending on the characteristics of the illness to face. Moreover, the attitude toward ICHA may differ within a single individual and between individuals so that ICHA can be used either in addition to (i.e., complementary attitude) or in place of (i.e., alternative attitude). The present study aimed at examining distinct patterns of attitudes toward ICHA in people hypothetically facing chronic illnesses that differed according to severity and clinical expression. METHODS: We conducted a web-based study including 1807 participants who were asked to imagine that they had a particular chronic illness based on clinical vignettes (mental illnesses: depression, schizophrenia; somatic illnesses: rheumatoid arthritis, multiple sclerosis). Participants were invited to rate their perceived distress and social stigma associated with each illness as well as its perceived treatability. They also rated their belief in treatment effectiveness, and their treatment preference. Four patterns of treatment choice were determined: strictly conventional, weak or strong complementary, and alternative. Bayesian methods were used for statistical analyses. RESULTS: ICHA were selected as complementary treatment option by more than 95% of people who hypothetically faced chronic illness. The complementary attitude towards ICHA (in addition to conventional treatment) was more frequent than the alternative one (in place of conventional treatment). Factors driving this preference included employment status, severity of illness, age and perceived distress, social stigma and treatability of the illness. When the label of illnesses was included in the vignettes, patterns of treatment preference were altered. CONCLUSIONS: This study provides evidence that "medical pluralism" (i.e., the integration of ICHA with conventional treatment) is likely the norm for people facing both mental or somatic illness. However, our result must be interpreted with caution due to the virtual nature of this study. We suggest that taking attitudes toward ICHA into account is crucial for a better understanding of patients' motivation to use ICHA. DOI: 10.1186/s12906-019-2490-z PMCID: PMC6454683 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 42 – Multiple Sklerose: Veröffentlichungen April 2019 41. BMC Med Res Methodol. 2019 Apr 24;19(1):87. doi: 10.1186/s12874-019-0729-5. The agreement between chronic diseases reported by patients and derived from administrative data in patients undergoing joint arthroplasty. Podmore B(1), Hutchings A(2), Konan S(3), van der Meulen J(2). Author information: (1)Department of Health Services Research & Policy, London School of Hygiene & Tropical Medicine, UK, Clinical Effectiveness Unit, The Royal College of Surgeons of England, 15-17 Tavistock Place, London, WC1H 9SH, UK. [email protected]. (2)Department of Health Services Research & Policy, London School of Hygiene & Tropical Medicine, UK, Clinical Effectiveness Unit, The Royal College of Surgeons of England, 15-17 Tavistock Place, London, WC1H 9SH, UK. (3)Consultant Orthopaedic Surgeon, University College London Hospitals NHS Foundation Trust, London, UK. BACKGROUND: This study examined the agreement between patient-reported chronic diseases and hospital administrative records in hip or knee arthroplasty patients in England. METHODS: Survey data reported by 676,428 patients for the English Patient Reported Outcome Measures (PROMs) programme was linked to hospital administrative data. Sensitivity and specificity of 11 patient-reported chronic diseases were estimated with hospital administrative data as reference standard. RESULTS: Specificity was high (> 90%) for all 11 chronic diseases. However, sensitivity varied by disease with the highest found for 'diabetes' (87.5%) and 'high blood pressure' (74.3%) and lowest for 'kidney disease' (18.8%) and 'leg pain due to poor circulation' (26.1%). Sensitivity was increased for diseases that were given as specific examples in the questionnaire (e.g. 'parkinson's disease' (65.6%) and 'multiple sclerosis' (69.5%), compared to 'diseases of the nervous system' (20.9%)). CONCLUSIONS: Patients can give information about the presence of chronic diseases that is consistent with chronic diseases derived from hospital administrative data if the description in the patient questionnaire is precise and if the disease is familiar to most patients and has significant impact on their life. Such patient questionnaires need to be validated before they are used for research and service evaluation projects. DOI: 10.1186/s12874-019-0729-5 42. BMJ Case Rep. 2019 Mar 31;12(3). pii: e228337. doi: 10.1136/bcr-2018-228337. Harding's disease: an important MS mimic. Joshi S(1), Kermode AG(2)(3). Author information: (1)Department of Neurology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. (2)The Perron Institute for Neurological and Translational Science, Nedlands, Western Australia, Australia. (3)Murdoch University, Institute for Immunology and Infectious Diseases, Murdoch, Western Australia, Australia. Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited disorder characterised by bilateral, painless visual loss which leads to severe optic atrophy. It can be associated with other conditions including multiple sclerosis (MS), movement disorders, epilepsy and cardiac arrhythmias. The association of LHON with an MS-like illness is often referred to as Harding's disease (or Harding's syndrome). We report two siblings, who both harbour the 11 778 mitochondrial DNA (mtDNA) mutation, but who manifest markedly different clinical phenotypes; a male with classical LHON and a female with an MS-like illness. LHON affects males four to five times more often than females. By contrast, Harding's disease is seen predominantly in females, in a pattern comparable to that seen in MS. The pathogenic basis behind the variation in penetrance and phenotype between genders and individual family members remains unclear. © BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/bcr-2018-228337 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 | L.DE.MKT.SM.02.2017.5323 – 43 – Multiple Sklerose: Veröffentlichungen April 2019 43. BMJ Open. 2019 Mar 30;9(3):e024555. doi: 10.1136/bmjopen-2018-024555. Impact of red meat, processed meat and fibre intake on risk of late-onset chronic inflammatory diseases: prospective cohort study on lifestyle factors using the Danish 'Diet, Cancer and Health' cohort (PROCID-DCH): protocol. Rasmussen NF(1)(2), Rubin KH(3), Stougaard M(3), Tjønneland A(4), Stenager E(5)(6), Lund Hetland M(7), Glintborg B(7)(8), Bygum A(9), Andersen V(10)(11). Author information: (1)Faculty of Health Sciences, Aarhus University, Aarhus, Denmark. (2)Focused Research Unit for Molecular Diagnostic and Clinical Research, IRS-Center Sonderjylland, Hospital of Southern Jutland, Aabenraa, Denmark. (3)OPEN - Odense Patient Data Explorative Network, Department of Clinical Research, University of Southern Denmark, and Odense University Hospital, Odense, Denmark. (4)Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen Ø, Denmark/Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. (5)Department of Regional Health Research, University of Southern Denmark, Odense, Denmark. (6)The Multiple Sclerosis Clinic of Southern Jutland (Sonderborg, Kolding, Esbjerg), Department of Neurology, Hospital of Southern Jutland, Sonderborg, Denmark. (7)DANBIO Registry/Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet Glostrup, Glostrup, Denmark. (8)Department of Rheumatology, Gentofte Hospital, Hellerup, Hovedstaden, Denmark. (9)Department of Dermatology and Allergy Centre, Odense Universitetshospital, Odense, Denmark. (10)Focused Research Unit for Molecular Diagnostic and Clinical Research, Hospital of Southern Jutland, Aabenraa, Denmark. (11)institute og molecular medicine, Syddansk Universitet Det Sundhedsvidenskabelige Fakultet, Odense, Denmark. INTRODUCTION: Chronic inflammatory diseases (CIDs) (Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, rheumatoid arthritis and multiple sclerosis) are diseases of the immune system that have some shared genetic and environmental predisposing factors, but still few studies have investigated the effects of lifestyle on disease risk of several CIDs. The primary aim of this prospective cohort study is to investigate the impact of fibre, red meat and processed meat on risk of late-onset CID, with the perspective that results of this study can contribute in supporting future diet recommendations for effective personalised prevention. METHODS AND ANALYSIS: The study will use data from 57 053 persons from the prospective Danish cohort study 'Diet, Cancer and Health' together with National Health Registry data. The follow-up period is from December 1993 to December 2018. Questionnaire data on diet and lifestyle were collected at entry to the Diet, Cancer and Health study. The outcome CID is defined as having a diagnosis of one of the CIDs registered in the National Patient Registry or, for multiple sclerosis, in the Danish Multiple Sclerosis Registry during follow-up and being treated with a drug used for the specific disease. The major outcome of the analyses will be to detect variability in risk of late onset of any CID and, if power allows, disease risk of late onset of each CID diagnosis between persons with different fibre and red meat, and processed meat intake. The outcome will be adjusted for age, sex, body mass index, physical activity, energy, alcohol, fermented dairy products, education, smoking status, hormone replacement therapy and comorbidity. ETHICS AND DISSEMINATION: The study is approved by the Danish Data Protection Agency (2012-58- 0018). The core study is an open register-based cohort study. The study does not need approval from the Ethics committee or Institutional Review Board by Danish law. Study findings will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences. TRIAL REGISTRATION NUMBER: NCT03456206; Post-results. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/bmjopen-2018-024555 Conflict of interest statement: Competing interests: BG declares to have received research funding from Abbvie, Biogen, Pfizer. MLH declares to have received research funding from BMS, MSD, Pfizer, Biogen, Samsung, CellTrion, Lilly and Novartis. AB has participated in the development of educational material for Biogen. All other 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 | L.DE.MKT.SM.02.2017.5323 – 44 – Multiple Sklerose: Veröffentlichungen April 2019 44. BMJ Open. 2019 Apr 1;9(4):e026622. doi: 10.1136/bmjopen-2018-026622. Management of multiple sclerosis symptoms through reductions in sedentary behaviour: protocol for a feasibility study. Aminian S(1), Motl RW(2), Rowley J(1), Manns PJ(1). Author information: (1)Department of Physical Therapy, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada. (2)Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, Alabama, USA. INTRODUCTION: People with multiple sclerosis (MS) are less physically active, and more sedentary than their peers despite evidence that activity helps to manage MS-related symptoms. Traditional approaches to increasing physical activity, such as exercise programmes, can be challenging for people with MS, especially those with walking disability. Focusing on decreasing prolonged sitting, and increasing light-intensity activities may be more feasible and result in more sustainable behaviour change in persons with MS. This paper describes the rationale and development of a sedentary behaviour intervention targeting persons with MS. METHODS AND ANALYSIS: The feasibility and preliminary efficacy of a sedentary behaviour intervention will be tested using a prepost intervention design in 40 adults with MS. The 22-week programme includes a 15-week intervention and a 7-week follow-up. The intervention itself is divided into two stages: Sit- Less and Move-More. The Sit-Less stage is designed to encourage participants to break up prolonged sitting bouts, while the Move-More stage promotes increasing steps per day, in addition to interrupting sitting. The intervention is delivered through individual coaching sessions between an interventionist and a participant, and an accompanying newsletter based on social cognitive theory. A Fitbit is used to monitor activity throughout the programme. Process, resource and management metrics will be recorded (eg, retention, time required for communication during the trial). Sedentary and physical activities and MS-related symptoms are measured before and after the intervention and again during follow-up. Experiences with the programme are explored through an online survey and one-on-one interviews. ETHICS AND DISSEMINATION: The Health Research Ethics Board at the University of Alberta granted permission to conduct this study. Results will be disseminated in scientific journals and conferences, and the MS Society of Alberta. Physical therapists and kinesiologists are important stakeholders and will be targeted during dissemination. TRIAL REGISTRATION NUMBER: NCT03136744. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/bmjopen-2018-026622 Conflict of interest statement: Competing interests: None declared. 45. Br J Clin Pharmacol. 2019 Apr 9. doi: 10.1111/bcp.13955. [Epub ahead of print] DPP-4 inhibitors lower the risk of autoimmune disease in patients with type 2 diabetes mellitus: A nationwide population-based cohort study. Seong JM(1), Yee J(1), Gwak HS(1). Author information: (1)College of Pharmacy and Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea. AIMS: To evaluate the real-world effect of DPP-4 inhibitor (DPP4i) on the incidence of autoimmune diseases (AD), including rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). METHODS: We identified new users of DPP4i (N=497 619) or non- DPP4i (N=643 165) oral combination therapy between 1 January 2011 and 30 June 2015 among patients with type 2 diabetes mellitus in the Korean national health insurance claims database. Patients were followed from the date of initiation of combination therapy until AD outcome, censoring for treatment discontinuation or switching, death or end of study (31 August 2016). Hazard ratios (HR) and 95% confidence intervals (CI) for RA, IBD, other AD (MS and SLE), and the composite of all outcomes were estimated using propensity score (PS)-adjusted Cox model. RESULTS: In the PS-weighted and PS-matched analysis, the risk of incident RA was decreased for DPP4i initiators compared with non-DPP4i initiators (adjusted HR (aHR), 0.67 [95% CI 0.49-0.92] and aHR, 0.72 [95% CI 0.51-1.01], respectively). In both analyses, the risk of incident composite AD was also decreased for DPP4i initiators compared with non- DPP4i initiators (aHR, 0.82 [95% CI 0.68-0.99] and aHR, 0.76 [95% CI 0.62-0.93], respectively). CONCLUSIONS: In this large population-based cohort study, upfront DPP4i combination therapy was associated with a lower risk of composite AD compared with initial non-DPP4i combination therapy. This article is protected by copyright. All rights reserved. DOI: 10.1111/bcp.13955 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 45 – Multiple Sklerose: Veröffentlichungen April 2019 46. Br J Radiol. 2019 Apr 17:20180926. doi: 10.1259/bjr.20180926. [Epub ahead of print] Towards a standard MRI protocol for multiple sclerosis across the UK. Schmierer K(1)(2), Campion T(3), Sinclair A(4), van Hecke W(5), Matthews PM(6), Wattjes MP(7)(8). Author information: (1)1 Blizard Institute (Neuroscience) Queen Mary University of London , London , UK. (2)2 Barts Health NHS Trust, Clinical Board Medicine (Neuroscience), The Royal London Hospital , London , UK. (3)3 Department of Neuroradiology, University College London Hospitals NHS Foundation Trust, The National Hospital, Queen Square, Lysholm , London , UK. (4)4 Department of Neuroradiology, St George's Hospital , London , UK. (5)5 Icometrix , Leuven , Belgium. (6)6 Imperical College London, Division of Brain Sciences & UK Dementia Research Institute , London , UK. (7)7 Department of Diagnostic and Interventional Neuroradiology, Hannover Medical School , Hannover , Germany. (8)8 Department of Radiology & Nuclear Medicine, VU University Medical Center , Amsterdam , NL. Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disease of the central nervous system. It is the most common non-traumatic cause of chronic disability in young adults. An early and accurate diagnosis, and effective disease modifying treatment (DMT) are key elements of optimum care for people with MS (pwMS). Magnetic resonance imaging (MRI) has become a critical tool to confirm the presence of dissemination in space and time of lesions characteristic of inflammatory demyelination, a cornerstone of MS diagnosis, over and above exclusion of numerous differential diagnoses. In the modern era of early and highly effective DMT, follow-up of pwMS also relies heavily on MRI, to both confirm efficacy and for pharmacovigilance. Since criteria for MS rely heavily on MRI, an agreed standardized acquisition and reporting protocol enabling efficient and equitable application across the UK is desirable. Following a recent meeting of MS experts in London (UK), we make recommendations for a standardized UK MRI protocol that captures the diagnostic phase as well as monitoring for safety and treatment efficacy once the diagnosis is established. Our views take into account issues arising from the (repeated) use of contrast agents as well as the advent of (semi-) automated tools to further optimise disease monitoring in pwMS. DOI: 10.1259/bjr.20180926 47. Brain. 2019 May 1;142(5):1166-1167. doi: 10.1093/brain/awz101. Survival: the ultimate long-term outcome in multiple sclerosis. Giovannoni G(1). Author information: (1)Blizard Institute, Queen Mary University London, Barts and The London School of Medicine. DOI: 10.1093/brain/awz101 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 46 – Multiple Sklerose: Veröffentlichungen April 2019 48. Brain. 2019 May 1;142(5):1310-1323. doi: 10.1093/brain/awz054. Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders. Palace J(1), Lin DY(2), Zeng D(2), Majed M(3)(4), Elsone L(5), Hamid S(5), Messina S(1), Misu T(6), Sagen J(7), Whittam D(5), Takai Y(6), Leite MI(1), Weinshenker B(3), Cabre P(8), Jacob A(5), Nakashima I(6), Fujihara K(6)(9), Pittock SJ(3)(4). Author information: (1)Nuffield Department of Clinical Neurosciences, Oxford, UK. (2)Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA. (3)Department of Neurology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, Minnesota, USA. (4)Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, Minnesota, USA. (5)The Walton Centre, NHS Foundation Trust, Liverpool, UK. (6)Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan. (7)Clinical Research Unit, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, Minnesota, USA. (8)Department of Neurology, Fort-de-France University Hospital Center, Pierre Zobda Quitman Hospital, Fort-de-France, Martinique, France. (9)Department of Multiple Sclerosis Therapeutics, Fukushima Medical University School of Medicine and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for NeuroScience, Koriyama, Japan. Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success. © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. DOI: 10.1093/brain/awz054 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 47 – Multiple Sklerose: Veröffentlichungen April 2019 49. Brain. 2019 May 1;142(5):1349-1364. doi: 10.1093/brain/awz070. Reactivation of nonsense-mediated mRNA decay protects against C9orf72 dipeptide-repeat neurotoxicity. Xu W(1)(2), Bao P(1), Jiang X(1)(2), Wang H(1), Qin M(1), Wang R(1), Wang T(1), Yang Y(1)(2), Lorenzini I(3), Liao L(4), Sattler R(3), Xu J(1). Author information: (1)Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. (2)University of Chinese Academy of Sciences, Shanghai, China. (3)Barrow Neurological Institute, Dignity Health, St. Joseph's Hospital and Medical Center, Phoenix AZ, USA. (4)Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China. Amyotrophic lateral sclerosis is a deleterious neurodegenerative disease without effective treatment options. Recent studies have indicated the involvement of the dysregulation of RNA metabolism in the pathogenesis of amyotrophic lateral sclerosis. Among the various RNA regulatory machineries, nonsense-mediated mRNA decay (NMD) is a stress responsive cellular surveillance system that degrades selected mRNA substrates to prevent the translation of defective or harmful proteins. Whether this pathway is affected in neurodegenerative diseases is unclear. Here we report the inhibition of NMD by arginine-rich dipeptide repeats derived from C9orf72 hexanucleotide repeat expansion, the most common cause of familial amyotrophic lateral sclerosis. Bioinformatic analysis of multiple transcriptome profiles revealed significant overlap of upregulated genes in NMD-defective cells with those in the brain tissues, micro-dissected motor neurons, or induced pluripotent stem cell-derived motor neurons specifically from amyotrophic lateral sclerosis patients carrying C9orf72 hexanucleotide repeat expansion, suggesting the suppression of NMD pathway in these patients. Using Drosophila as a model, we have validated that the C9orf72 hexanucleotide repeat expansion products could lead to the accumulation of the NMD substrates and identified arginine-rich dipeptide repeats, including poly glycine-arginine and poly proline-arginine, as the main culprits of NMD inhibition. Furthermore, in human SH-SY5Y neuroblastoma cells and in mouse brains, expression of glycine- arginine with 36 repeats (GR36) was sufficient to cause NMD inhibition. In cells expressing GR36, stress granule accumulation was accompanied by decreased processing body formation, which contributed to the inhibition of NMD. Remarkably, expression of UPF1, a core gene in the NMD pathway, efficiently blocked neurotoxicity caused by arginine-rich dipeptide repeats in both cellular and Drosophila models. Although not as effective as UPF1, expression of another NMD gene UPF2 also ameliorated the degenerative phenotypes in dipeptide repeat-expressing flies, indicating that genetically reactivating the NMD pathway could suppress dipeptide repeat toxicity. Finally, after validating tranilast as an NMD-activating drug, we demonstrated the therapeutic potential of this asthma drug in cellular and Drosophila models of C9orf72 dipeptide repeat neurotoxicity. Therefore, our study has revealed a cellular mechanism whereby arginine-rich C9orf72 dipeptide repeats could inhibit NMD activities by reducing the abundance of processing bodies. Furthermore, our results suggested that activation of the NMD pathway could be a potential therapeutic strategy for amyotrophic lateral sclerosis with defective RNA metabolism. © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. DOI: 10.1093/brain/awz070 50. Brain. 2019 Apr 1;142(4):838-840. doi: 10.1093/brain/awz068. Secondary progressive multiple sclerosis and the gut-brain axis. Wekerle H(1). Author information: (1)Max-Planck Institute of Neurobiology, and Biomedical Center, LMU Munich. DOI: 10.1093/brain/awz068 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 48 – Multiple Sklerose: Veröffentlichungen April 2019 51. Cancer Lett. 2019 Apr 10;454:66-69. doi: 10.1016/j.canlet.2019.04.012. [Epub ahead of print] TRPM4 channel and cancer. Gao Y(1), Liao P(2). Author information: (1)Calcium Signalling Laboratory, National Neuroscience Institute, Singapore. (2)Calcium Signalling Laboratory, National Neuroscience Institute, Singapore; Duke-NUS Medical School, Singapore; Health and Social Sciences, Singapore Institute of Technology, Singapore. Electronic address: [email protected]. The TRPM4 channel has been extensively studied in cerebral diseases such as stroke, head injury and multiple sclerosis. In the heart, gain-of-function mutations of TRPM4 are a cause of familial cardiac block. Recently, evidence has emerged to support the role of TRPM4 in certain types of cancer, such as prostate cancer and large B cell lymphoma. The expression of TRPM4 could mediate certain behaviors of cancer cells such as migration and invasion. However, the mechanisms are largely unknown. As a nonselective monovalent cation channel, TRPM4 upregulation and activation enhance sodium entry, which leads to depolarization of the membrane potential. The membrane potential is critical in regulating calcium influx, and a disturbed calcium homeostasis is always associated with cancer cell behaviors. Research on TRPM4 channels in cancer is at a very early stage. In this review, we summarize the expression of TRPM4 in various cancers as well as our current understanding of TRPM4 in cancer. The potential mechanisms of the TRPM4 channel in regulating calcium homeostasis in cancer cells are further discussed in detail. Targeting the TRPM4 channel can be a novel way of managing cancer metastasis via disrupting calcium signaling pathways. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.canlet.2019.04.012 52. Case Rep Transplant. 2019 Mar 6;2019:2172163. doi: 10.1155/2019/2172163. eCollection 2019. Deceased Donor Renal Transplantation Combined with Bilateral Nephrectomy in a Patient with Tuberous Sclerosis and Renal Failure. Novotny R(1), Chlupac J(1)(2), Marada T(1), Bloudickova-Rajnochova S(3), Vavrinova H(3), Janousek L(1)(2), Fronek J(1)(2)(4). Author information: (1)Transplant Surgery Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. (2)First Faculty of Medicine, Charles University, Prague, Czech Republic. (3)Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. (4)Second Faculty of Medicine, Charles University, Prague, Czech Republic. Introduction: A 27-year-old female patient with known tuberous sclerosis complex (TSC), polycystic kidneys with multiple large bilateral angiomyolipomas, and failing renal functions with prehemodialysis values (urea: 19 mmol/L; creatinine: 317 μmol/L; CKD-EPI 0,27) was admitted to our department for pre-renal transplant evaluation. The patient was placed on the transplant waiting list as the living donor did not pass pretransplant workup and was subsequently contraindicated. Patient was placed on the "cadaverous kidney transplant waiting list". Method: Computed tomography angiography revealed symptomatic PSA in the right kidney angiomyolipoma (AML). The patient underwent urgent transarterial embolisation of the PSA's feeding vessel in the right kidney AML. Based on the "kidney transplant waiting list" order patient underwent a bilateral nephrectomy combined with transperitoneal renal allotransplantation of a cadaverous kidney graft through midline laparotomy, appendectomy, and cholecystectomy. Results: Postoperative period was complicated by delayed graft function caused by acute tubular necrosis requiring postoperative hemodialysis. The patient was discharged on the 17th postoperative day with a good renal graft function. Patient's follow-up is currently 23 months with good graft function (urea: 9 mmol/L; creatinine: 100 μmol/L). Conclusion: Renal transplantation combined with radical nephrectomy provides a definitive treatment for TSC renal manifestations. DOI: 10.1155/2019/2172163 PMCID: PMC6431358 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 49 – Multiple Sklerose: Veröffentlichungen April 2019 53. Cell Chem Biol. 2019 Apr 18;26(4):468-470. doi: 10.1016/j.chembiol.2019.04.006. Small Molecules with Big Promises for Curing Demyelinating Diseases. Han F(1), Zhou MM(2). Author information: (1)Bethune Institute of Epigenetic Medicine, The First Hospital, Jilin University, Changchun 130021, China. (2)Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected]. Myelin regeneration by myelinating oligodendrocytes is key to neuronal damage repair for treatment of neurological disorders such as multiple sclerosis. In this issue of Cell Chemical Biology, Allimuthu et al. (2019) report new small molecule inhibitors of cholesterol biosynthesis enzymes that enhance oligodendrocyte formation and subsequent remyelination. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.chembiol.2019.04.006 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 50 – Multiple Sklerose: Veröffentlichungen April 2019 54. Cell Death Dis. 2019 Apr 25;10(5):345. doi: 10.1038/s41419-019-1582-5. Transplantation of clinical-grade human neural stem cells reduces neuroinflammation, prolongs survival and delays disease progression in the SOD1 rats. Zalfa C(1), Rota Nodari L(1), Vacchi E(1), Gelati M(2), Profico D(2), Boido M(3), Binda E(4), De Filippis L(5), Copetti M(6), Garlatti V(1), Daniele P(7), Rosati J(8), De Luca A(7), Pinos F(1), Cajola L(1), Visioli A(9), Mazzini L(10), Vercelli A(3), Svelto M(11), Vescovi AL(12)(13)(14), Ferrari D(15). Author information: (1)Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126, Milan, Italy. (2)Fondazione IRCCS Casa Sollievo della Sofferenza, Production Unit of Advanced Therapies (UPTA), Institute for Stem-Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), 71013, San Giovanni Rotondo, Foggia, Italy. (3)Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy. (4)Fondazione IRCCS Casa Sollievo della Sofferenza, Cancer Stem Cells Unit, Institute for Stem-Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), 71013, San Giovanni Rotondo, (FG), Italy. (5)Fondazione IRCCS Casa Sollievo della Sofferenza, Regenerative Medicine and Innovative Therapies (ISBReMIT), 71013, San Giovanni Rotondo, (FG), Italy. (6)Fondazione IRCCS Casa Sollievo della Sofferenza, Bioinformatics Unit, Viale dei Cappuccini, 71013, San Giovanni Rotondo, (FG), Italy. (7)Fondazione IRCCS Casa Sollievo della Sofferenza, Molecular Genetics Unit, Viale dei Cappuccini, 71013, San Giovanni Rotondo, (FG), Italy. (8)Fondazione IRCCS Casa Sollievo della Sofferenza, Cellular Reprogramming Unit, San Giovanni Rotondo, (FG), Italy. (9)StemGen S.p.a, Milan, Italy. (10)Centro Regionale Esperto SLA Azienda Ospedaliero-Universitaria "Maggiore della Carità", Novara, Italy. (11)Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy. (12)Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126, Milan, Italy. [email protected]. (13)Fondazione IRCCS Casa Sollievo della Sofferenza, Production Unit of Advanced Therapies (UPTA), Institute for Stem-Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), 71013, San Giovanni Rotondo, Foggia, Italy. [email protected]. (14)Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, Bari, Italy. [email protected]. (15)Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126, Milan, Italy. [email protected]. Stem cells are emerging as a therapeutic option for incurable diseases, such as Amyotrophic Lateral Sclerosis (ALS). However, critical issues are related to their origin as well as to the need to deepen our knowledge of the therapeutic actions exerted by these cells. Here, we investigate the therapeutic potential of clinical-grade human neural stem cells (hNSCs) that have been successfully used in a recently concluded phase I clinical trial for ALS patients (NCT01640067). The hNSCs were transplanted bilaterally into the anterior horns of the lumbar spinal cord (four grafts each, segments L3-L4) of superoxide dismutase 1 G93A transgenic rats (SOD1 rats) at the symptomatic stage. Controls included untreated SOD1 rats (CTRL) and those treated with HBSS (HBSS). Motor symptoms and histological hallmarks of the disease were evaluated at three progressive time points: 15 and 40 days after transplant (DAT), and end stage. Animals were treated by transient immunosuppression (for 15 days, starting at time of transplantation). Under these conditions, hNSCs integrated extensively within the cord, differentiated into neural phenotypes and migrated rostro- caudally, up to 3.77 ± 0.63 cm from the injection site. The transplanted cells delayed decreases in body weight and deterioration of motor performance in the SOD1 rats. At 40DAT, the anterior horns at L3-L4 revealed a higher density of motoneurons and fewer activated astroglial and microglial cells. Accordingly, the overall survival of transplanted rats was significantly enhanced with no rejection of hNSCs observed. We demonstrated that the beneficial effects observed after stem cell transplantation arises from multiple events that counteract several aspects of the disease, a crucial feature for multifactorial diseases, such as ALS. The combination of therapeutic approaches that target different pathogenic mechanisms of the disorder, including pharmacology, molecular therapy and cell transplantation, will increase the chances of a clinically successful therapy for ALS. DOI: 10.1038/s41419-019-1582-5 PMCID: PMC6484011 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 51 – Multiple Sklerose: Veröffentlichungen April 2019 55. Cell Immunol. 2019 Apr 8. pii: S0008-8749(19)30134-0. doi: 10.1016/j.cellimm.2019.04.005. [Epub ahead of print] Advances in the pathogenesis and treatment of autoimmunity. Moudgil KD(1). Author information: (1)Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Department of Medicine, Division of Rheumatology, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Baltimore VA Medical Center, Baltimore, MD 21201, United States. Electronic address: [email protected]. DOI: 10.1016/j.cellimm.2019.04.005 56. Cell Rep. 2019 Apr 23;27(4):1090-1102.e10. doi: 10.1016/j.celrep.2019.03.108. PAD2-Mediated Citrullination Contributes to Efficient Oligodendrocyte Differentiation and Myelination. Falcão AM(1), Meijer M(1), Scaglione A(2), Rinwa P(1), Agirre E(1), Liang J(3), Larsen SC(4), Heskol A(5), Frawley R(2), Klingener M(2), Varas-Godoy M(6), Raposo AASF(7), Ernfors P(1), Castro DS(7), Nielsen ML(4), Casaccia P(2), Castelo-Branco G(8). Author information: (1)Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden. (2)Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York, New York, NY, USA. (3)Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029. (4)Department of Proteomics, the Novo Nordisk Foundation Center for Protein Research, Faculty of Heath Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. (5)Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal. (6)Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Cancer Cell Biology Lab, Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510157, Chile. (7)Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal. (8)Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Ming Wai Lau Centre for Reparative Medicine, Stockholm Node, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: [email protected]. Citrullination, the deimination of peptidylarginine residues into peptidylcitrulline, has been implicated in the etiology of several diseases. In multiple sclerosis, citrullination is thought to be a major driver of pathology through hypercitrullination and destabilization of myelin. As such, inhibition of citrullination has been suggested as a therapeutic strategy for MS. Here, in contrast, we show that citrullination by peptidylarginine deiminase 2 (PAD2) contributes to normal oligodendrocyte differentiation, myelination, and motor function. We identify several targets for PAD2, including myelin and chromatin-related proteins, implicating PAD2 in epigenomic regulation. Accordingly, we observe that PAD2 inhibition and its knockdown affect chromatin accessibility and prevent the upregulation of oligodendrocyte differentiation genes. Moreover, mice lacking PAD2 display motor dysfunction and a decreased number of myelinated axons in the corpus callosum. We conclude that citrullination contributes to proper oligodendrocyte lineage progression and myelination. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.celrep.2019.03.108 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 52 – Multiple Sklerose: Veröffentlichungen April 2019 57. Cerebellum. 2019 Apr 27. doi: 10.1007/s12311-019-01032-6. [Epub ahead of print] Distillation of Posterior Fossa Demyelination in Acute Vestibular Syndrome: the Eyes Have It. Shaikh AG(1), Manto M(2). Author information: (1)University Hospitals and Cleveland VA Medical Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, 44110, USA. [email protected]. (2)Chef du Service de Neurologie, CHU-Charleroi, Charleroi, Belgium. Separating the etiologies of an acute vestibular syndrome (AVS) of central origin is a clinical challenge; the common causes include (1) stroke of the brainstem/cerebellum and (2) demyelinating disorders such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Overshadowed by the vascular etiologies, the literature describing AVS due to demyelinating disorders has been growing through the last decade. The discovery of IgG-NMO, a specific pathogenic antibody directed against the astrocytic water channel aquaporin-4 (AQP4), has improved the differential diagnoses between MS and NMOSD. AQP4 is particularly expressed in ependymal/subependymal astrocytes and glia limitans astrocyte processes, including around the fourth ventricle. Adding a clinical biomarker to distinguish MS and NMOSD in AVS patients, as reported in this issue, will be of great clinical value. DOI: 10.1007/s12311-019-01032-6 58. Clin Auton Res. 2019 Apr 8. doi: 10.1007/s10286-019-00605-z. [Epub ahead of print] Immune and autonomic nervous system interactions in multiple sclerosis: clinical implications. Habek M(1)(2). Author information: (1)Department of Neurology, Referral Center for Autonomic Nervous System Disorders, University Hospital Center Zagreb, Kišpatićeva 1 , 10000, Zagreb, Croatia. [email protected]. (2)School of Medicine, University of Zagreb, Zagreb, Croatia. [email protected]. Multiple sclerosis is characterized by a wide spectrum of clinical manifestations, among which dysfunction of the autonomic nervous system represents an important cause of multiple sclerosis-related disability. The aim of this review is to provide an overview of autonomic dysfunction in people with multiple sclerosis, and to discuss the interactions between the immune and autonomic nervous systems and the effects of these interactions on various aspects of multiple sclerosis. Autonomic dysfunction in people with multiple sclerosis can be demonstrated clinically and on a molecular level. Clinically, it can be demonstrated by measuring autonomic symptoms with the Composite Autonomic Symptom Score (COMPASS-31), and neurophysiologically, with different autonomic nervous system tests. Both symptomatic and objectively determined autonomic dysfunction can be associated with increased risk of multiple sclerosis disease activity. Further supporting these clinical observations are molecular changes in immune cells. Changes in the sympathetic autonomic system, such as different expression of dopaminergic and adrenergic receptors on immune cells, or modulation of the cholinergic anti-inflammatory pathway over different subunits of the nicotinic acetylcholine receptor in the peripheral immune system, may mediate different effects on multiple sclerosis disease activity. DOI: 10.1007/s10286-019-00605-z Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 53 – Multiple Sklerose: Veröffentlichungen April 2019 59. Clin Infect Dis. 2019 Jan 15. pii: ciz047. doi: 10.1093/cid/ciz047. [Epub ahead of print] Epstein-Barr Virus and Monoclonal Gammopathy of Clinical Significance in Autologous Stem Cell Transplantation for Multiple Sclerosis. Mehra V(1), Rhone E(2), Widya S(3), Zuckerman M(4), Potter V(1), Raj K(1)(5), Kulasekararaj A(1), McLornan D(1)(5), de Lavallade H(1), Benson-Quarm N(1), Lim C(1), Ware S(1), Sudhanva M(4), Malik O(6), Nicholas R(6), Muraro PA(6)(7), Marsh J(1), Mufti GJ(1), Silber E(2), Pagliuca A(1), Kazmi MA(1)(5). Author information: (1)Department of Hematology, King's College Hospital NHS Foundation Trust, Denmark Hill. (2)Department of Neurology, King's College Hospital NHS Foundation Trust, Denmark Hill. (3)GKT School of Medical Education, Kings College London University. (4)Department of Virology, King's College Hospital NHS Foundation Trust, Denmark Hill. (5)Department of Hematology, Guy's and St. Thomas' NHS Foundation Trust. (6)Department of Neurology, Imperial College Healthcare, United Kingdom. (7)Department of Neuroimmunology, Imperial College London, United Kingdom. INTRODUCTION: Autologous hematopoietic stem cell transplantation (AHSCT) with anti-thymocyte globulin (ATG) conditioning as treatment of active multiple sclerosis (MS) is rapidly increasing across Europe (EBMT registry data 2017). Clinically significant Epstein-Barr virus reactivation (EBV-R) following AHSCT with ATG for severe autoimmune conditions is an underrecognized complication relative to T-cell deplete transplants performed for hematological diseases. This retrospective study reports EBV-R associated significant clinical sequelae in MS patients undergoing AHSCT with rabbit ATG. METHODS: Retrospective data were analyzed for 36 consecutive MS-AHSCT patients at Kings College Hospital, London. All patients routinely underwent weekly EBV DNA polymerase chain reaction monitoring and serum electrophoresis for monoclonal gammopathy (MG or M-protein). EBV-R with rising Epstein-Barr viral load, M-protein, and associated clinical sequelae were captured from clinical records. RESULTS: All patients had evidence of rising EBV DNA-emia, including 7 who were lost to long-term follow-up, with a number of them developing high EBV viral load and associated lymphoproliferative disorder (LPD). Nearly 72% (n = 18/29) developed de novo MG, some with significant neurological consequences with high M-protein and EBV-R. Six patients required anti-CD20 therapy (rituximab) with complete resolution of EBV related symptoms. Receiver operating characteristics estimated a peak EBV viremia of >500 000 DNA copies/mL correlated with high sensitivity (85.5%) and specificity (82.5%) (area under the curve: 0.87; P = .004) in predicting EBV-R related significant clinical events. CONCLUSION: Symptomatic EBV reactivation increases risk of neurological sequelae and LPD in MS-AHSCT. We recommend regular monitoring for EBV and serum electrophoresis for MG in MS patients in the first 3 months post-AHSCT. © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected]. DOI: 10.1093/cid/ciz047 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 54 – Multiple Sklerose: Veröffentlichungen April 2019 60. Clin Neurophysiol. 2019 Apr 11;130(6):1017-1024. doi: 10.1016/j.clinph.2019.04.003. [Epub ahead of print] A pilot study on the efficacy of transcranial direct current stimulation applied to the pharyngeal motor cortex for dysphagia associated with brainstem involvement in multiple sclerosis. Restivo DA(1), Alfonsi E(2), Casabona A(3), Hamdy S(4), Tassorelli C(2), Panebianco M(5), Marchese- Ragona R(6), Quartarone A(7), Centonze D(8), Pavone A(9), Stampanoni Bassi M(10). Author information: (1)Neurological Unit, "Garibaldi" Hospital, Catania, Italy. Electronic address: [email protected]. (2)Neurophysiological Unit, IRCCS "Fondazione Casimiro Mondino", Pavia, Italy. (3)Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy. (4)School of Translational Medicine-Inflammation Sciences, Faculty of Medical and Human Sciences, University of Manchester (part of the Manchester Academic Health Sciences Centre MAHSC), Salford Royal Hospital, Eccles Old Road, Salford M6 8HD, UK. (5)Neurological Unit, "Garibaldi" Hospital, Catania, Italy; Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Clinical Sciences Centre for Research and Education, Lower Lane, L9 7LJ Liverpool, UK. (6)ENT Department, University of Padua, Padua, Italy. (7)IRCCS Centro Neurolesi "Bonibo-Pulejo", via Provinciale Palermo, Contrada Casazza 95124, Messina, Italy. (8)Laboratory of Synaptic Immunopathology, Department of Systems Medicine, Tor Vergata University, Via Montpellier 1, 00133 Rome, Italy; Unit of Neurology and Neurorehabilitation, IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, IS, Italy. (9)Neurological Unit, "Garibaldi" Hospital, Catania, Italy. (10)Unit of Neurology and Neurorehabilitation, IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, IS, Italy. OBJECTIVE: we investigated the effect of anodal transcranial direct current stimulation (tDCS) applied over the pharyngeal motor area in dysphagia associated with multiple sclerosis (MS). METHODS: Eighteen MS patients with dysphagia associated with brainstem involvement were randomized to receive either "real" or "sham" tDCS. PRIMARY OUTCOME: The Penetration/Aspiration Scale (PAS). SECONDARY OUTCOMES: changes in electromyographic (EMG) parameters and pharyngeal cortical motor evoked potentials (MEPs). Patients were evaluated at baseline (T0), at the end of 5-session cycle of tDCS stimulations (T1), after two (T2), and four (T3) weeks. RESULTS: the PAS values were significantly lower in the active group than in "sham" group at T1, and at T3. Over the post-stimulation periods, PAS significantly improved only in the "real" group. As regards the secondary outcomes, we observed a statistically significant difference between the 2 groups only in the MEPs amplitude at T1. The comparison between baseline and each of the post- stimulation times showed significant differences only of the "real" group across all the secondary parameters. CONCLUSIONS: Our findings support a beneficial effect of anodal tDCS applied to the pharyngeal motor cortex in MS-associated dysphagia. SIGNIFICANCE: Considering its safety and efficacy, tDCS may represent an important resource in MS-associated dysphagia. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.clinph.2019.04.003 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 55 – Multiple Sklerose: Veröffentlichungen April 2019 61. Clin Neuropsychol. 2019 Apr 23:1-32. doi: 10.1080/13854046.2019.1575471. [Epub ahead of print] The incremental value of neuropsychological assessment: a critical review. Donders J(1). Author information: (1)a Department of Psychology , Mary Free Bed Rehabilitation Hospital , Grand Rapids , MI , USA. OBJECTIVE: The purpose of this critical review was to evaluate the current state of research regarding the incremental value of neuropsychological assessment in clinical practice, above and beyond what can be accounted for on the basis of demographic, medical, and other diagnostic variables. The focus was on neurological and other medical conditions across the lifespan where there is known risk for presence or future development of cognitive impairment. METHOD: Eligible investigations were group studies that had been published after 01/01/2000 in English in peer-reviewed journals and that had used standardized neuropsychological measures and reported on objective outcome criterion variables. They were identified through PubMed and PsychInfo electronic databases on the basis of predefined specific selection criteria. Reference lists of identified articles were also reviewed to identify potential additional sources. The Grades of Recommendation, Assessment, Development and Evaluation Working Group's (GRADE) criteria were used to evaluate quality of studies. RESULTS: Fifty-six studies met the final selection criteria, including 2 randomized-controlled trials, 9 prospective cohort studies, 12 retrospective cohort studies, 21 inception cohort studies, 2 case control studies, and 10 case series studies. The preponderance of the evidence was strongly supportive with regard to the incremental value of neuropsychological assessment in the care of persons with mild cognitive impairment/dementia and traumatic brain injury. Evidence was moderately supportive with regard to stroke, epilepsy, multiple sclerosis, and attention-deficit/hyperactivity disorder. Participation in neuropsychological evaluations was also associated with cost savings. CONCLUSIONS: Neuropsychological assessment can improve both diagnostic classification and prediction of long-term daily- life outcomes in patients across the lifespan. Future high-quality prospective cohort studies and randomized- controlled trials are necessary to demonstrate more definitively the incremental value of neuropsychological assessment in the management of patients with various neurological and other medical conditions. DOI: 10.1080/13854046.2019.1575471 62. Clin Neuropsychol. 2019 Apr 19:1-26. doi: 10.1080/13854046.2019.1585575. [Epub ahead of print] Limb apraxia profiles in different clinical samples. Buchmann I(1)(2), Dangel M(1), Finkel L(1)(2), Jung R(1), Makhkamova I(1)(3), Binder A(4), Dettmers C(2)(5), Herrmann L(6), Liepert J(2)(7), Möller JC(4)(8), Richter G(6), Vogler T(6), Wolf C(6), Randerath J(1)(2). Author information: (1)a University of Konstanz , Konstanz , Germany. (2)b Lurija Institute for Rehabilitation Sciences and Health Research at the University of Konstanz , Konstanz , Germany. (3)c Graduate School of Systemic Neurosciences , Ludwig-Maximilians-University Munich , Munich , Germany. (4)d Center for Neurological Rehabilitation , Rehaklinik Zihlschlacht , Zihlschlacht , Switzerland. (5)e Kliniken Schmieder , Konstanz , Germany. (6)h Klinik für Alterspsychiatrie , Zentrum für Psychiatrie Reichenau , Reichenau , Germany. (7)f Kliniken Schmieder , Allensbach , Germany. (8)g Department of Neurology , Philipps University , Marburg , Germany. OBJECTIVE: Limb apraxia is a motor cognitive disorder that has been mainly studied in patients with dementia or left hemisphere stroke (LHS). However, limb apraxia has also been reported in patients with right hemisphere stroke (RHS), multiple sclerosis (MS) or traumatic brain injury (TBI). This study's aim was to report detailed praxis performance profiles in samples suffering from these different neurological disorders by use of the Diagnostic Instrument for Limb Apraxia (DILA-S). METHOD: 44 LHS patients, 36 RHS patients, 27 patients with dementia, 26 MS and 44 TBI patients participated. The diagnostics included the imitation of meaningless and meaningful hand gestures, pantomime of tool-use, single real tool-use as well as a multistep naturalistic action task (preparing breakfast). RESULTS: Apraxia occurred in all tested samples but to a varying degree and with dissimilar profiles. LHS patients demonstrated most severe deficits in pantomime, but they were also vulnerable to deficits in real tool-use. Dementia patients showed high incidence rates of apraxia in almost all subscales of the DILA-S. RHS patients demonstrated difficulties in imitation and pantomime of tool-use, but they did not show severe difficulties with real tool-use. TBI patients appeared challenged by multistep naturalistic actions. The tested MS sample did not show clinically relevant symptoms in the DILA-S. CONCLUSION: Different types of patients display varying limb apraxic symptoms detectable by the DILA-S. In these limb apraxia susceptible populations, testing should be warranted as standard. Prospectively, individual error profiles may be helpful for shaping motor cognitive training. DOI: 10.1080/13854046.2019.1585575 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 56 – Multiple Sklerose: Veröffentlichungen April 2019 63. Clin Pharmacol Ther. 2019 May;105(5):1082-1090. doi: 10.1002/cpt.1412. Novel Multiple Sclerosis Drugs in the Pipeline. De Angelis F(1), Chataway J(1). Author information: (1)1Queen Square MS Centre, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK. DOI: 10.1002/cpt.1412 64. Clin Pract Epidemiol Ment Health. 2019 Feb 28;15:38-43. doi: 10.2174/1745017901915010038. eCollection 2019. Impairment of Quality of Life Associated With Lifetime Diagnosis of Post-traumatic Stress Disorder in Women - A National Survey in Italy. Sancassiani F(1), Carmassi C(2), Romano F(3), Balestrieri M(4), Caraci F(5), Di Sciascio G(6), Drago F(5), Faravelli C(7), Hardoy MC(1), Moro MF(1)(8), Roncone R(9), Preti A(1), Dell'Osso L(2). Author information: (1)Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy. (2)University of Pisa ,Pisa, Italy. (3)University of Roma "La Sapienza", Rome, Italy. (4)University of Udine,Udine, Italy. (5)University of Catania, Catania, Italy. (6)University of Bari, Bari, Italy. (7)University of Florence, Florence, Italy. (8)Mailman School of Public Health Columbia University, New York, NY 10027, USA. (9)University of L'Aquila, L'Aquila, Italy. Introduction: The aim of the study was to measure the lifetime prevalence of Post-Traumatic Stress Disorder (PTSD) among women of an Italian community sample, the comorbidity of PTSD with mood and anxiety disorders and the burden attributable to PTSD in worsening the Quality of Life (QoL). Methods: Community survey on a sample of 1961 adult women randomly selected. Tools: psychiatric clinical interview ANTAS partially derived from the SCID-DSM-IV, administered by psychologists or medical doctors; Short Form Health Survey (SF-12); Mood Disorder Questionnaire (MDQ). Results: Lifetime prevalence of PTSD in women was 1.3%, (1.4% in<45 years aged, 1.3% in >44 years aged; p=0.8). In order of risk of comorbidity, PTSD was associated with: Bipolar Spectrum Disorders (MDQ+), Panic Disorders (PD) and Major Depressive Disorder (MDD). People with PTSD showed an SF-12 mean score lower than women of the same sample without PTSD (standardized by gender and age), with a mean difference (attributable burden) of 3.9±0.9 similarly to MDD and Eating Disorders and higher than PD. Among the analyzed nonpsychiatric diseases, Multiple Sclerosis and Carotid Atherosclerosis showed a higher burden in impairing QoL than PTSD; Wilson's Disease showed a similar burden and Celiac Disease was found less impairing on QoL than PTSD. Conclusion: The attributable burden in worsening women' perceived QoL due to a lifetime diagnosis of PTSD was found comparable to those caused by MDD, Eating Disorders or by neurological condition such as Wilson's Disease. The comorbidity of PTSD with Bipolar Spectrum Disorders was remarkable, even further studies are needed to clarify the direction of causality. DOI: 10.2174/1745017901915010038 PMCID: PMC6416466 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 57 – Multiple Sklerose: Veröffentlichungen April 2019 65. Clin Rehabil. 2019 Apr 11:269215519842254. doi: 10.1177/0269215519842254. [Epub ahead of print] The clinical- and cost-effectiveness of functional electrical stimulation and ankle- foot orthoses for foot drop in Multiple Sclerosis: a multicentre randomized trial. Renfrew LM(1), Paul L(2), McFadyen A(3), Rafferty D(2), Moseley O(4), Lord AC(1), Bowers R(5), Mattison P(1). Author information: (1)1 Douglas Grant Rehabilitation Centre, Ayrshire Central Hospital, NHS Ayrshire & Arran, Irvine, UK. (2)2 School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK. (3)3 AKM Statistics, Glasgow, UK. (4)4 Independent Consultant, Ayrshire, UK. (5)5 Department of Biomedical Engineering, University of Strathclyde, Glasgow, UK. OBJECTIVE: To compare the clinical- and cost-effectiveness of ankle-foot orthoses (AFOs) and functional electrical stimulation (FES) over 12 months in people with Multiple Sclerosis with foot drop. DESIGN: Multicentre, powered, non-blinded, randomized trial. SETTING: Seven Multiple Sclerosis outpatient centres across Scotland. SUBJECTS: Eighty-five treatment-naïve people with Multiple Sclerosis with persistent (>three months) foot drop. INTERVENTIONS: Participants randomized to receive a custom-made, AFO ( n = 43) or FES device ( n = 42). OUTCOME MEASURES: Assessed at 0, 3, 6 and 12 months; 5-minute self- selected walk test (primary), Timed 25 Foot Walk, oxygen cost of walking, Multiple Sclerosis Impact Scale- 29, Multiple Sclerosis Walking Scale-12, Modified Fatigue Impact Scale, Euroqol five-dimension five-level questionnaire, Activities-specific Balance and Confidence Scale, Psychological Impact of Assistive Devices Score, and equipment and National Health Service staff time costs of interventions. RESULTS: Groups were similar for age (AFO, 51.4 (11.2); FES, 50.4(10.4) years) and baseline walking speed (AFO, 0.62 (0.21); FES 0.73 (0.27) m/s). In all, 38% dropped out by 12 months (AFO, n = 21; FES, n = 11). Both groups walked faster at 12 months with device ( P < 0.001; AFO, 0.73 (0.24); FES, 0.79 (0.24) m/s) but no difference between groups. Significantly higher Psychological Impact of Assistive Devices Scores were found for FES for Competence ( P = 0.016; AFO, 0.85(1.05); FES, 1.53(1.05)), Adaptability ( P = 0.001; AFO, 0.38(0.97); FES 1.53 (0.98)) and Self-Esteem ( P = 0.006; AFO, 0.45 (0.67); FES 1 (0.68)). Effects were comparable for other measures. FES may offer value for money alternative to usual care. CONCLUSION: AFOs and FES have comparable effects on walking performance and patient-reported outcomes; however, high drop-outs introduces uncertainty. DOI: 10.1177/0269215519842254 66. Clin Rehabil. 2019 Apr 10:269215519837326. doi: 10.1177/0269215519837326. [Epub ahead of print] A cohort study of functional electrical stimulation in people with multiple sclerosis demonstrating improvements in quality of life and cost-effectiveness. Juckes FM(1), Marceniuk G(2), Seary C(1), Stevenson VL(1). Author information: (1)1 The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK. (2)2 BMJ Technology Assessment Group (BMJ), London, UK. OBJECTIVE: The objective of this study was to determine the impact on health-related quality of life of functional electrical stimulation used to improve walking in people with multiple sclerosis and to explore cost- effectiveness. DESIGN: A retrospective analysis of patient records was conducted. SETTING: This study used outpatient therapy service as the study setting. SUBJECTS: Data from 82 consecutive patients with multiple sclerosis attending for set up with functional electrical stimulation were analysed. INTERVENTIONS: Patients were seen at baseline, three and six months for support in use of functional electrical stimulation, and data were collected at baseline and six months. MAIN MEASURES: The EQ-5D-5L and walking speed were collected at baseline and six months after using functional electrical stimulation. The Psychosocial Impact of Assistive Device Scale was collected at six months. EQ-5D-3L utilities were derived and cost- effectiveness analysis was completed utilizing a five-year time horizon and methodology published by National Institute for Health and Care Excellence. RESULTS: Significant differences ( P < 0.001) were seen in walking speed (baseline 0.670 m/s; with stimulation 0.768 m/s) and maintained over six months (0.772 m/s with stimulation). EQ-5D data significantly improved over six months (baseline 0.486, six months 0.596, P < 0.001) and meaningful mean scores were seen in all aspects of the Psychosocial Impact of Assistive Device Scale. However, there were no correlations between measures. In the cost utility analysis, compared to standard care, functional electrical stimulation was more expensive and more effective with an incremental cost-effectiveness ratio of £6137. CONCLUSION: Functional electrical stimulation is a cost-effective treatment to improve walking speed and health-related quality of life in people with multiple sclerosis. DOI: 10.1177/0269215519837326 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 58 – Multiple Sklerose: Veröffentlichungen April 2019 67. Clin Transl Immunology. 2019 Apr 6;8(4):e1045. doi: 10.1002/cti2.1045. eCollection 2019. Analysis of serum interleukin(IL)-1α, IL-1β and IL-18 in patients with systemic sclerosis. Lin E(1), Vincent FB(1), Sahhar J(2), Ngian GS(2), Kandane-Rathnayake R(1), Mende R(1), Morand EF(1)(2), Lang T(1)(3), Harris J(1). Author information: (1)Rheumatology Group Centre for Inflammatory Diseases School of Clinical Sciences at Monash Health Monash University Clayton VIC Australia. (2)Department of Rheumatology Monash Health & Monash University Clayton VIC Australia. (3)Present address: Tali Lang, The Szalmuk Family Department of Medical Oncology Cabrini Institute Malvern VIC 3144 Australia. Objectives: Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis, vascular dysfunction and immune dysregulation. The pathogenesis of SSc remains poorly understood, although studies have indicated a role for the innate immune response. Methods: Here, we measured serum interleukin (IL)-1α, IL-1β and IL-18 levels in 105 SSc patients and 47 healthy controls (HC) and analysed them with respect to multiple clinical parameters. Results: Serum IL-18 concentrations were significantly higher in SSc patients than in HC, while no significant differences in concentrations of IL-1α and IL-1β were observed between SSc and HC. In both SSc and HC serum, IL-1α and IL-1β were positively correlated, while in SSc, both cytokines negatively correlated with IL-18. Serum IL-18 was significantly negatively correlated with both carbon monoxide transfer coefficient (KCO) and diffusing capacity of the lungs for carbon monoxide (DLCO). Serum IL-1β was positively correlated with the modified Rodnan skin score (mRSS), particularly in patients with limited subtype. DLCO, KCO and tricuspid regurgitation (TR) velocity were significantly higher in patients with high serum IL-1β. Serum IL-1α was significantly lower in SSc patients with low KCO and positively correlated with KCO. SSc patients with high serum IL-1α concentrations were more likely to have digital ulcers. Conclusions: Our data suggest that these IL-1 family cytokines may have different roles in the pathogenesis of SSc fibrotic complications. DOI: 10.1002/cti2.1045 PMCID: PMC6451750 68. Clin Transl Med. 2019 Apr 8;8(1):11. doi: 10.1186/s40169-019-0228-7. A non-randomized clinical trial to evaluate the effect of fingolimod on expanded disability status scale score and number of relapses in relapsing-remitting multiple sclerosis patients. Mazdeh M(1)(2), Kargar Monhaser S(1), Taheri M(3), Ghafouri-Fard S(4). Author information: (1)Department of Neurology, Hamadan University of Medical Sciences, Hamadan, Iran. (2)Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran. (3)Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. [email protected]. (4)Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran. [email protected]. BACKGROUND: Multiple sclerosis (MS) is a chronic disease characterized by demyelination, glial activation and axonal degeneration in the central nervous system. At the present, there is no certain remedy for this disease. However, available therapies often attenuate disease progress. METHODS: This study aims at identification of the effect of fingolimod on expanded disability status scale (EDSS) score and number of relapses in relapsing-remitting MS (RRMS) patients in comparison with IFNβ. In the present 12-month non- randomized clinical trial, 55 RRMS patients aged between 18 and 45 with EDSS scores between 0 and 5.5 were divided into two groups. Twenty-five patients received 0.5 mg oral fingolimod once a day for 12 months and 30 patients were under treatment with IFNβ. EDSS scores and number of relapses were recorded for all study participants monthly. RESULTS: No significant difference was found in age and sex of patients recruited in two study groups. EDSS score was significantly lower in treatment group in month 10, 11 and 12 after treatment compared with control group (p values of 0.004, 0.006 and 0.007 respectively). CONCLUSION: Treated patients experienced no relapse during the study period. Fingolimod is effective in reduction of EDSS score and number of relapses in Iranian MS patients. DOI: 10.1186/s40169-019-0228-7 PMCID: PMC6451934 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 59 – Multiple Sklerose: Veröffentlichungen April 2019 69. Clin Transplant. 2019 Apr 20:e13567. doi: 10.1111/ctr.13567. [Epub ahead of print] Determine safety of outpatient chemotherapy and autotransplants using refrigerated, non-frozen grafts in persons with multiple sclerosis. Gale RP(1), Gómez-Cruz GB(2)(3), Olivares-Gazca JC(2)(4), León-Peña A(2)(3), Gómez-Almaguer D(5), Gómez-De-León A(5), González-López EE(4), Ruiz-Argüelles A(2)(4)(6), Soto-Vega E(7), Muñoz-Pérez MJ(7), Ruiz-Delgado GJ(2)(4)(6), Ruiz-Argüelles GJ(2)(4)(6). Author information: (1)Imperial College London, London, UK. (2)Centro de Hematología y Medicina Interna de Puebla, Puebla, México. (3)Benemérita Universidad Autónoma de Puebla, Puebla, México. (4)Universidad Popular Autónoma del Estado de Puebla, Puebla, México. (5)Hospital Universitario de la Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México. (6)Laboratorios Ruiz, Puebla, México. (7)Universidad Anáhuac, Puebla, México. Persons with multiple sclerosis (MS) are sometimes treated with intermediate- or high-dose chemotherapy and an autotransplant (1, 2). More than 1000 autotransplants are reported with MS (2-6) but use of autotransplants may be substantially more common as many cases are not reported. Recent data from a small randomized trial of less-intensive chemotherapy reported better outcomes with this approach compared with disease-modifying therapy in persons with advanced relapsing-remitting MS (7). As such, autotransplant frequency is likely to increase. As currently done autotransplants for MS are expensive and technically-demanding requiring hospitalization and programmed freezing of the graft. We previously reported autotransplants for several haematologic neoplasms can be done in an outpatient setting using refrigerated, non-frozen blood cells (2, 6). We wondered whether the same modifications could be used in persons with MS? We report data from 426 subjects with MS receiving autotransplants as outpatients setting using refrigerated, non-frozen, grafts. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/ctr.13567 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 60 – Multiple Sklerose: Veröffentlichungen April 2019 70. Cochrane Database Syst Rev. 2019 Apr 2;4:CD010528. doi: 10.1002/14651858.CD010528.pub4. [Epub ahead of print] Herbal medicinal products or preparations for neuropathic pain. Boyd A(1), Bleakley C, Hurley DA, Gill C, Hannon-Fletcher M, Bell P, McDonough S. Author information: (1)School of Health Sciences, Ulster University, Jordanstown campus, Shore Road, Newtownabbey, County Antrim, UK, BT37 0QB. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 61 – Multiple Sklerose: Veröffentlichungen April 2019 BACKGROUND: Neuropathic pain is a consequence of damage to the central nervous system (CNS), for example, cerebrovascular accident, multiple sclerosis or spinal cord injury, or peripheral nervous system (PNS), for example, painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN), or surgery. Evidence suggests that people suffering from neuropathic pain are likely to seek alternative modes of pain relief such as herbal medicinal products due to adverse events brought about by current pharmacological agents used to treat neuropathic pain. This review includes studies in which participants were treated with herbal medicinal products (topically or ingested) who had experienced neuropathic pain for at least three months. OBJECTIVES: To assess the analgesic efficacy and effectiveness of herbal medicinal products or preparations for neuropathic pain, and the adverse events associated with their use. SEARCH METHODS: We searched CENTRAL and the Cochrane Database of Systematic Reviews, MEDLINE, Embase, CINAHL and AMED to March 2018. We identified additional studies from the reference lists of the retrieved papers. We also searched trials registries for ongoing trials and we contacted experts in the field for relevant data in terms of published, unpublished or ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (including cross-over designs) of double-blind design, assessing efficacy of herbal treatments for neuropathic pain compared to placebo, no intervention or any other active comparator. Participants were 18 years and above and had been suffering from one or more neuropathic pain conditions, for three months or more.We applied no restrictions to language or gender. We excluded studies monitoring effects of isolated, single chemicals derived from the plant or synthetic chemicals based on constituents of the plant, if they were not administered at a concentration naturally present within the plant.We excluded studies monitoring the effects of traditional Asian medicine and Cannabinoids as well as studies looking at headache or migraine as these treatments and conditions are addressed in distinct reviews. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for inclusion, assessed risk of bias, and extracted data. We calculated the risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNTB). The primary outcomes were participant-reported pain relief of 30%, or 50%, or greater, and participant-reported global impression of clinical change (PGIC). We also collected information on adverse events. We assessed evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included two studies (128 participants). Both diabetic neuropathy and non-diabetic neuropathic pain conditions were investigated across these two studies.Two herbal medicinal products, namely nutmeg (applied topically as a 125 mL spray for four weeks, containing mace oil 2%, nutmeg oil 14%, methyl salicylate 6%, menthol 6%, coconut oil and alcohol) and St John's wort (taken in capsule form containing 900 μg total hypericin each, taken three times daily, giving a total concentration of 2700 mg for five weeks). Both studies allowed the use of concurrent analgesia.Both reported at least one pain-related outcome but we could not carry out meta- analysis of effectiveness due to heterogeneity between the primary outcomes and could not draw any conclusions of effect. Other outcomes included PGIC, adverse events and withdrawals. There were no data for participant-reported pain relief of 50% or greater or PGIC (moderate and substantial) outcomes.When looking at participant-reported pain relief of 30% or greater over baseline, we observed no evidence of a difference (P = 0.64) in response to nutmeg versus placebo (RR 1.12, 95% confidence interval (CI) 0.69 to 1.85; 48.6% vs 43.2%). We downgraded the evidence for this outcome to very low quality.We observed no change between placebo and nutmeg treatment when looking at secondary pain outcomes. Visual analogue scale (VAS) scores for pain reduction (0 to 100, where 0 = no pain reduction), were 44 for both nutmeg and placebo with standard deviations of 21.5 and 26.5 respectively. There was no evidence of a difference (P = 0.09 to 0.33) in total pain score in response to St John's wort compared to placebo, as there was only a reduction of 1 point when looking at median differences in change from baseline on a 0 to 10-point numeric rating scale.There was a total of five withdrawals out of 91 participants (5%) in the treatment groups compared to six of 91 (6.5%) in the placebo groups, whilst adverse events were the same for both the treatment and placebo groups.We judged neither study as having a low risk of bias. We attributed risk of bias to small study size and incomplete outcome data leading to attrition bias. We downgraded the evidence to very low quality for all primary and secondary outcomes reported in this review. We downgraded the quality of the evidence twice due to very serious limitations in study quality (due to small study size and attrition bias) and downgraded a further level due to indirectness as the included studies only measured outcomes at short-term time points. The results from this review should be treated with scepticism as we have very little confidence in the effect estimate. AUTHORS' CONCLUSIONS: There was insufficient evidence to determine whether nutmeg or St John's wort has any meaningful efficacy in neuropathic pain conditions.The quality of the current evidence raises serious uncertainties about the estimates of effect observed, therefore, we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. DOI: 10.1002/14651858.CD010528.pub4 PMCID: PMC6445324 [Available on 2020-04-02] Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 62 – Multiple Sklerose: Veröffentlichungen April 2019 71. Complement Ther Med. 2019 Apr;43:240-246. doi: 10.1016/j.ctim.2019.02.006. Epub 2019 Feb 8. Weight control and physical exercise in people with multiple sclerosis: Current knowledge and future perspectives. Mokhtarzade M(1), Agha-Alinejad H(1), Motl RW(2), Negaresh R(3), Baker JS(4), Zimmer P(5). Author information: (1)Department of Physical Education & Sport Sciences, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran. (2)Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, USA. (3)Department of Physical Education & Sport Sciences, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran. Electronic address: [email protected]. (4)Applied Physiology Research Laboratory, School of Health and Life Sciences, University of the West of Scotland, Lanarkshire Campus, Scotland, UK. (5)Department for Molecular and Cellular Sports Medicine, German Sport University Cologne, Cologne, Germany; Division of Physical Activity, Prevention and Cancer, German Cancer Research Center, Heidelberg, Germany. There is extensive data supporting a high prevalence of both overweight and obesity status in people with multiple sclerosis, and increases in body mass index has been associated with an increased risk of multiple sclerosis. Body composition may influence the course, treatment and management of multiple sclerosis. One proposed strategy for managing overweight and obesity status and associated secondary effects in people with multiple sclerosis involves increasing the levels of physical activity. In fact, increased levels of physical activity affect various physiological (endurance capacity, strength, balance) and biological processes (fat oxidation, insulin sensitivity, anti-inflammation, neurotrophic factors) which are known to be dysfunctional in multiple sclerosis and which may worsen with increases in obesity. When designing personalized exercise programs it should be kept in mind that current exercise recommendations for people with multiple sclerosis should exceed energy expenditure recommendations to efficiently counteract weight gain. Therefore, it is necessary to consider body composition as a primary endpoint in experimental studies. In addition, designing guidelines for weight control or weight loss in people MS is needed. The most comprehensive weight management guidelines are outlined in the American College of Sports Medicine Position Statement, which recommends between 150-250 min per week of moderate-intensity physical activity for preventing weight gain, and between 225-420 min per week of moderate-intensity physical activity for weight loss. These recommendations seem applicable for people with multiple sclerosis. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ctim.2019.02.006 72. Complement Ther Med. 2019 Apr;43:188-195. doi: 10.1016/j.ctim.2019.02.010. Epub 2019 Feb 10. The effect of exercise, yoga and physiotherapy on the quality of life of people with multiple sclerosis: Systematic review and meta-analysis. Alphonsus KB(1), Su Y(2), D'Arcy C(3). Author information: (1)University of Saskatchewan, School of Public Health, 104 Clinic Place, Saskatoon, SK, S7N 2Z4, Canada. Electronic address: [email protected]. (2)University of Saskatchewan, School of Public Health, 104 Clinic Place, Saskatoon, SK, S7N 2Z4, Canada. (3)University of Saskatchewan, School of Public Health, 104 Clinic Place, Saskatoon, SK, S7N 2Z4, Canada; Department of Psychiatry, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada. INTRODUCTION: Multiple sclerosis (MS) is a chronic autoimmune disease affecting the myelinated axons of the central nervous system causing neurological deterioration. People living with MS have a poor quality of life (QOL) because of the symptoms caused by the disease and there are various types of treatments to manage the symptoms aside from medication. OBJECTIVE: This meta-analysis examines the effect of exercise, yoga and physiotherapy on the physical, mental and social QOL among individuals living with MS. SETTING: A systematic review with meta-analysis was conducted using PubMed, Medline, and Scopus from 1990 to 2017. The standard mean difference scores were computed in each study for the domains of physical, mental and social functioning. RESULTS: Eighteen studies met the inclusion criteria for this meta- analysis. Aerobic exercise was effective in improving satisfaction with physical functioning,d = 0.35 (95% CI = 0.08 to 0.62), mental functioning d = 0.42 (95% CI = 0.11 to 0.72), and social functioning d = 0.42 (95% CI = 0.15 to 0.69). Physiotherapy was also found to be effective for physical functioning d = 0.50 (95% CI 0.19 to 0.80), mental functioning d = 0.44 (95% CI 0.14 to 0.75) and social functioning d = 0.60 (95% CI 0.21 to 0.90). However yoga and combination of exercises did not have a significant effect on any of the QOL domains. CONCLUSION: These findings suggest that aerobic exercise and physiotherapy improves the satisfaction of MS patients with their physical, mental and social functioning and may be included as normal practice in the treatment of MS. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ctim.2019.02.010 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 63 – Multiple Sklerose: Veröffentlichungen April 2019 73. Complement Ther Med. 2019 Apr;43:181-187. doi: 10.1016/j.ctim.2019.01.022. Epub 2019 Jan 23. Effect of coenzyme Q10 supplementation on fatigue: A systematic review of interventional studies. Mehrabani S(1), Askari G(2), Miraghajani M(3), Tavakoly R(4), Arab A(5). Author information: (1)Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran. (2)Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. (3)Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; The Early Life Research Unit, Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK. (4)Department of Nutrition, School of Health, Kerman University of Medical Sciences, Kerman, Iran. (5)Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: [email protected]. AIMS: A number of studies have examined the beneficial effects of Coenzyme Q10 (CoQ10) on fatigue in different population, but the findings have been inconclusive. Herein, we systematically reviewed available interventional studies to elucidate the overall effects of CoQ10 supplementation on fatigue among adolescent and adult population. METHODS: PubMed, Cochrane's library, Science direct, Scopus, Google scholar and ISI web of science databases were searched for all available literature until April 2018 for studies assessing the effects of CoQ10 supplementation on fatigue. The Cochrane bias assessment tool were used to assess the quality of studies. RESULTS: A total of 16 studies out of 1316 met our inclusion criteria and included in our systematic review. Among included studies 10 of them showed significant beneficial effects (p < 0.05) of CoQ10 supplementation on fatigue status among healthy, fibromyalgia, statin- related fatigue, multiple sclerosis and end-stage heart failure subjects. CoQ10 supplementation could alleviate fatigue, but differences between studies population should be taken into account. CONCLUSION: It seems CoQ10 has better therapeutic effects in statin-related fatigue and fibromyalgia patients compared with the other disease related fatigue. Finally, in order to draw a firm link between CoQ10 and fatigue, more clinical trials with adequate sample size and with sufficient follow-up periods are needed. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ctim.2019.01.022 74. Complement Ther Med. 2019 Apr;43:154-156. doi: 10.1016/j.ctim.2019.01.023. Epub 2019 Jan 30. Effects of osteopathic manipulative treatment on patients with multiple sclerosis: A pilot study. Porcari B(1), Russo M(2), Naro A(1), La Via C(1), Pullia M(1), Accorinti M(1), De Luca R(1), Calabrò RS(3). Author information: (1)IRCCS Centro Neurolesi "Bonino Pulejo", Messina, Italy. (2)Department of Medical and Surgical Sciences, "Magna Græcia" University of Catanzaro, Viale Europa, Germaneto, Catanzaro, Italy. (3)IRCCS Centro Neurolesi "Bonino Pulejo", Messina, Italy. Electronic address: [email protected]. OBJECTIVES: To describe the effects of osteopathic manipulative treatment in patients affected by Multiple Sclerosis (MS). DESIGN AND SETTING: This is a pilot study involving 20 MS patients attending the IRCCS Neurolesi "Bonino-Pulejo", Messina, Italy. INTERVENTION: The clinical evaluation was performed before starting rehabilitation treatment (T0) and after 8 weeks of treatment (T1). The CG sample undergo a conventional rehabilitation training (CRT), 5 times/week for 60 min (for a total of 40 sessions), the EG performed the same CRT (but with a different frequency, i.e. 3 times/week, for a total of 24 sessions) and a specific OMT 2 times/week for 60 min (for a total of 16 sessions). MAIN OUTCOME MEASURES: We analyzed the scores recorded in the following main scales: Expanded Disability Status Scale (EDSS), 10 m walking test (10mWT), Hamilton anxiety rating scale (HRS-A), and the Fatigue severity scale (FSS). RESULTS: Our data showed a reduction in the FSS score for the EG (40 ± 1,41 at T0 vs 37 ± 2,32 at T1; p = 0.04) but not in the CG (41 ± 2,41 at TO vs 39 ± 2,6 at T1) with an intergroup difference p < 0.00. An improvement of HRS-A and 10mWT was also detected in the EG. CONCLUSIONS: Our data raise idea that OMT might be useful in rehabilitative setting in MS patients, with particular regard to anxiety and fatigue. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ctim.2019.01.023 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 64 – Multiple Sklerose: Veröffentlichungen April 2019 75. Contemp Clin Trials. 2019 Apr 22. pii: S1551-7144(18)30772-9. doi: 10.1016/j.cct.2019.04.013. [Epub ahead of print] Rationale and design of the STEP for MS Trial: Comparative effectiveness of Supervised versus Telerehabilitation Exercise Programs for Multiple Sclerosis. Motl RW(1), Backus D(2), Neal WN(3), Cutter G(4), Palmer L(2), McBurney R(5), Schmidt H(5), Bethoux F(6), Hebert J(7), Ng A(8), McCully K(9), Plummer P(10). Author information: (1)Department of Physical Therapy, University of Alabama at Birmingham, United States of America. Electronic address: [email protected]. (2)Shepherd Center, United States of America. (3)Department of Physical Therapy, University of Alabama at Birmingham, United States of America. (4)Department of Biostatistics, University of Alabama at Birmingham, United States of America. (5)Accelerate Cure Project for Multiple Sclerosis, United States of America. (6)Mellen Center for MS, Neurological Institute, Cleveland Clinic, United States of America. (7)School of Medicine, University of Colorado Anschutz Medical Campus, United States of America. (8)Program in Exercise Science, Department of Physical Therapy, Marquette University, United States of America. (9)Department of Kinesiology, University of Georgia, United States of America. (10)Division of Physical Therapy, University of North Carolina at Chapel-Hill, United States of America. BACKGROUND: We propose a Phase III trial that compares the effectiveness of an exercise training program delivered in a facility-based setting with direct, in-person supervision or a home-based setting with remote supervision via telerehabilitation for improving walking performance in persons with multiple sclerosis(MS) who have walking dysfunction and mobility disability. METHODS/DESIGN: The study was developed with stakeholder engagement and is a multi-site trial that follows a 2-stage, randomized choice design. The trial compares the effectiveness of a 16-week evidence-based, individualized exercise program delivered in a supervised, facility-based setting versus a remotely coached/guided, home-based setting using telerehabilitation in physically inactive and cognitively intact people with MS who have walking dysfunction and mobility disability(N = 500). The primary outcome is walking speed. The secondary outcomes are walking endurance, disability status, and patient-reported outcomes of physical activity, walking impairment, fatigue, and quality of life. The components of the exercise program itself are similar between the groups and follow the Guidelines for Exercise in MS protocol. This includes a program manual, exercise prescription, exercise equipment, social-cognitive theory materials including newsletters, logs, and calendars, and one-on-one behavioral coaching by exercise specialists with background in MS. The main difference between groups is the coaching approach and setting for delivering the exercise training program. The outcomes will be collected by treatment-blinded assessors at baseline(week 0), mid-intervention(week 8), post-intervention(week 16), and follow-up(week 52). DISCUSSION: The proposed study will provide evidence for the effectiveness of a novel, widely-scalable program for delivering exercise training in persons with MS who have walking dysfunction and mobility disability. Copyright © 2019. Published by Elsevier Inc. DOI: 10.1016/j.cct.2019.04.013 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 65 – Multiple Sklerose: Veröffentlichungen April 2019 76. Cortex. 2019 Mar 1;117:205-216. doi: 10.1016/j.cortex.2019.02.017. [Epub ahead of print] Emotional disturbances in multiple sclerosis: A neuropsychological and fMRI study. Pfaff L(1), Lamy J(2), Noblet V(2), Gounot D(2), Chanson JB(3), de Seze J(3), Blanc F(4). Author information: (1)University of Strasbourg and CNRS, ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS/Neurocrypto, Strasbourg, France. Electronic address: [email protected]. (2)University of Strasbourg and CNRS, ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS/Neurocrypto, Strasbourg, France. (3)University Hospitals of Strasbourg, CIC (Clinical Investigation Centre) INSERM 1434 and Neurology Department, Strasbourg, France. (4)University of Strasbourg and CNRS, ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), Team IMIS/Neurocrypto, Strasbourg, France; University Hospitals of Strasbourg, CMRR (Memory Resources and Research Centre), Geriatric Day Hospital, Geriatrics Department, Strasbourg, France. BACKGROUND: Emotional disturbances in multiple sclerosis (MS) are often explored in terms of affect recognition, with controversial results that likely reflect the high lesional heterogeneity. Patients' emotional experience, however, has seldom been studied and has never been explored using fMRI. OBJECTIVES: To explore the emotional experience in MS and compare these data with fMRI measurements using for the first time real-life emotional scenes differing in valence and arousal. METHODS: Twenty-five right-handed women with relapsing-remitting MS and 27 right-handed age-, sex-, and education-matched healthy controls visualized during an fMRI session, emotional scenes taken from the international affect picture system (IAPS) and differing in valence (positive, negative, neutral) and arousal (ranging from calm to excited). During a post-scanning debriefing, participants were asked to look again at each image and score it in terms of valence and arousal sensation on a scale of 1-9. RESULTS: Cognitively well-preserved MS subjects presented a significantly more scattered emotional experience compared to controls in response to positive and negative pictures. In fMRI, MS patients also presented a higher variability of response when compared to controls in left inferior orbitofrontal cortex for positive stimulations. For negative condition, no significant results were observed between the two groups. However, a trend was detected in left amygdala, right fusiform gyrus, right caudate nucleus and right pallidum for negative stimulations. CONCLUSION: In response to emotional stimuli, MS subjects presented a scattered emotional experience subtended by a greater variability of brain response, highlighting an emotional pattern not previously reported in MS patients. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.cortex.2019.02.017 77. Crit Rev Toxicol. 2019 Apr 3:1-18. doi: 10.1080/10408444.2019.1592109. [Epub ahead of print] Cumulative administrations of gadolinium-based contrast agents: risks of accumulation and toxicity of linear vs macrocyclic agents. Chehabeddine L(1), Al Saleh T(2), Baalbaki M(3), Saleh E(3), Khoury SJ(3)(4), Hannoun S(3)(4). Author information: (1)a Department of Biology , American University of Beirut , Beirut , Lebanon. (2)b Department of Physics , American University of Beirut , Beirut , Lebanon. (3)c Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center , Beirut , Lebanon. (4)d Abu-Haidar Neuroscience Institute, Faculty of Medicine , American University of Beirut Medical Center , Beirut , Lebanon. Ever since gadolinium was found to deposit in the brain of patients with normal kidney function by Kanda et al. in 2014, several studies have been conducted to evaluate its effect on the patients' health. However, conflicting results were obtained regarding imaging in gadolinium retention. These finding were attributed to the chelating structure of the administered gadolinium-based contrast agent (GBCA): linear agents were found to accumulate in the dentate nucleus (DN) and the globus pallidus (GP) of subjects even after one dose. There are some contradictory results when assessing macrocyclic agents. In the following article, we review the basis of GBCAs characteristics and their side effects, as well as, the MRI studies that assessed the accumulation of gadolinium in the brain. Based on the results of several studies, in 2017, the European Medicine Agency requested the suspension of the marketing authorizations for three linear GBCAs: gadodiamide (Omniscan®), gadoversetamide (Optimark®) and gadopentate dimeglimine (Magnevist®) and limited the use of gadoxetate disodium (Primovist/Eovist®) and gadobenate dimeglumine (MultiHance®) to hepatic uptake for imaging poorly vascularized hepatic lesions. Accordingly, the FDA did not restrict GBCA use, but will continue to study their safety and urged clinicians to use these agents sparingly. All macrocyclic GBCAs continued however to be used as no available valid evidence linked them to brain gadolinium retention. Regardless of possible accumulation in the brain, there is no evidence to-date that gadolinium retention leads to any disease or disorders in subjects with normal renal function. Further investigations with long-term follow-up are needed. DOI: 10.1080/10408444.2019.1592109 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 66 – Multiple Sklerose: Veröffentlichungen April 2019 78. Curr Hematol Malig Rep. 2019 Apr 27. doi: 10.1007/s11899-019-00506-y. [Epub ahead of print] Correction to: Autologous Haematopoietic Stem Cell Transplantation in Multiple Sclerosis: a Review of Current Literature and Future Directions for Transplant Haematologists and Oncologists. Das J(1), Sharrack B(2), Snowden JA(3)(4). Author information: (1)Sheffield Institute for Translational Neuroscience, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK. [email protected]. (2)Clinical Neurology, Academic Department of Neuroscience, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. (3)Blood and Marrow Transplantation, Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. (4)Haemato-oncology and Stem Cell Transplantation, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK. Erratum for Curr Hematol Malig Rep. 2019 Mar 4;:. Modifications have been made to the 5th paragraph of the section "Efficacy", and in Table 3; Additional authors' information has also been added as an article note in the front matter. DOI: 10.1007/s11899-019-00506-y 79. Curr Mol Med. 2019 Apr 5. doi: 10.2174/1566524019666190405120137. [Epub ahead of print] Serum IL-33 level and IL-33, IL1RL1 gene polymorphisms in asthma and multiple sclerosis patients. Ahmadi M(1), Fathi F(1), Fouladi S(1), Alsahebfosul F(1), Manian M(2), Eskandari N(1). Author information: (1)Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan. Iran. (2)Department of Immunology, school of Medicine, Iran University of Medical Sciences, Tehran. Iran. BACKGROUND: Asthma is a chronic and complex inflammatory disease of the respiratory tract. Also multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Against this background, IL-33 and IL1RL1 play a critical part in autoimmune and inflammatory disorders. Here we explored the IL-33 serum level and 2 potential genetic variants in the IL33 gene and its receptor in Iranian asthma and MS patients. METHODS: This study consisted of asthma (n=140) and MS patients (n=140), and healthy subjects (n=72). Genotyping was carried out in 2 genetic polymorphisms, rs1342326 variant of IL-33 and rs10204137 SNP of IL-33 receptor genes, using High Resolution Melt Real Time PCR based method. The level of serum IL-33 also was measured using enzyme-linked immunosorbent assay method. RESULTS: The level of IL33 was significantly higher in asthma and MS patients compared to control group (P< 0.001- P<0.001). The frequency distribution of the genotype in rs1342326 in IL-33 gene in patients with asthma, MS and healthy subjects were not significantly different (P>0.05). The frequency distribution of the genotype in rs10204137 in IL-33 gene in patients MS and healthy subjects were significantly different (p = 0.013) Conclusion: Our findings demonstrated that asthma and MS patients had a higher level of IL-33, which IL-33 receptor genetic polymorphism was associated with MS. Further studies in a larger multicenter setting are needed to explore the value of this marker as a risk stratification biomarker. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]. DOI: 10.2174/1566524019666190405120137 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 67 – Multiple Sklerose: Veröffentlichungen April 2019 80. Curr Opin Neurol. 2019 Jun;32(3):305-312. doi: 10.1097/WCO.0000000000000701. Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Schweitzer F(1), Laurent S(1), Fink GR(1)(2), Barnett MH(3), Reddel S(4), Hartung HP(5), Warnke C(1). Author information: (1)Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne. (2)Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Jülich, Jülich, Germany. (3)Brain and Mind Centre. (4)Neuroimmunology Clinic, Concord Hospital, University of Sydney, Sydney, NSW, Australia. (5)Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. PURPOSE OF REVIEW: A variety of high-efficacy disease-modifying therapies (DMTs) are available for the treatment of multiple sclerosis (MS). After evaluation and approval by regulatory agencies, DMTs are likely to be administered to patients whose characteristics differ from those enrolled in clinical trials. This may contribute to the emergence of unexpected adverse events observed in the real-world setting. Higher age may be a relevant factor that could change the benefit-risk balance of DMTs, as it may associate with lower efficiency and higher frequency of adverse events. RECENT FINDINGS: The absolute and relative number of patients with MS who reach the age of 55 and higher increases. Growing evidence demonstrates lower efficacy of DMTs in older persons with MS. Specific risks during DMTs for MS, such as the risk of developing progressive multifocal leukoencephalopathy (PML) or the outcome following PML, have been associated with age. It is hypothesized that age-related and therapy-induced alterations to the immune system may have (super)additive effects, resulting in an acceleration of physiological immunosenescence and inflamm-aging. SUMMARY: In this article, we review the risks of high-efficacy DMTs in MS with a specific focus on age-related efficacy and risks, including opportunistic infections, malignancies, and autoimmune reactions. DOI: 10.1097/WCO.0000000000000701 81. Curr Opin Neurol. 2019 Jun;32(3):365-377. doi: 10.1097/WCO.0000000000000700. Current therapeutic landscape in multiple sclerosis: an evolving treatment paradigm. Cree BAC(1), Mares J(2), Hartung HP(3). Author information: (1)Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA. (2)Department of Neurology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. (3)Department of Neurology, Medical Faculty and Center for Neurology and Neuropsychiatry, LVR Klinikum, Heinrich-Heine- University Düsseldorf, Düsseldorf, Germany. PURPOSE OF REVIEW: To critically assess the current landscape of disease-modifying agents for multiple sclerosis (MS). Treatment algorithms will be discussed and studies for new agents in late development or recently approved are analyzed in terms of their impact on current treatment strategies. RECENT FINDINGS: A real-world study from Wales suggests that early initiation of highly effective therapy may provide more benefit that an escalation approach in relapsing MS. A study from the MSBase dataset found evidence that early treatment with highly effective therapies decreased the risk of developing secondary progressive MS. Ocrelizumab is highly efficacious in relapsing MS and in a group of patients with primary progressive MS. Another CD20 directed mAb, ofatumumab, is in phase 3. A large study examining extended interval dosing of natalizumab in an attempt to decrease the risk of developing progressive multifocal leukoencephalopathy is underway. Cladribine and alemtuzumab may work by immune reconstitution. Siponimod was recently approved by United States Federal Drug Administration for relapsing MS and active secondary progressive MS. Other S1P receptor modulators are being studied in phase 3 trials for relapsing MS. Cladribine received FDA approval as treatment for relapsing and active secondary progressive MS. Autologous hematopoetic stem-cell transplantation may be an option for treatment-refractory MS. SUMMARY: Development of disease-modifying agents in MS continues to be successful. Treatment algorithms need to take new developments into account. DOI: 10.1097/WCO.0000000000000700 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 68 – Multiple Sklerose: Veröffentlichungen April 2019 82. Curr Opin Neurol. 2019 Jun;32(3):327-337. doi: 10.1097/WCO.0000000000000699. Diagnosis of multiple sclerosis: revisions of the McDonald criteria 2017 - continuity and change. Hartung HP(1), Graf J(1), Aktas O(1), Mares J(2), Barnett MH(3)(4). Author information: (1)Department of Neurology, UKD and Center for Neurology and Neuropsychiatry, LVR Klinikum, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany. (2)Department of Neurology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. (3)Brain and Mind Centre, University of Sydney, Sydney. (4)Department of Neurology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. PURPOSE OF REVIEW: The purpose of this review is to describe the new 2017 revisions of the McDonald diagnostic criteria for multiple sclerosis and review first experiences in their application to different patient populations. RECENT FINDINGS: The 2017 revisions agreed on by an international expert panel, as the precursors, define criteria needed to fulfill dissemination in time and space in the clinically isolated syndrome after exclusion of alternative diagnoses. One major change is the inclusion of cerebrospinal fluid (CSF) oligoclonal bands as evidence of dissemination in time in a patient with dissemination in space gathered by clinical or magnetic resonance examination. The distinction between asymptomatic and symptomatic lesions in counting for evidence of dissemination in space or time in supra, infratentorial, and spinal cord syndrome has been abandoned. Finally, cortical lesions can be used to demonstrate dissemination in space. Major differential diagnoses, in particular, the still-evolving concept of neuromyelitis optica spectrum disorders and the myelin oligodendrocyte glycoprotein-IgG-related demyelinating central nervous system disorders. SUMMARY: The new 2017 revisions will simplify the application of the MRI criteria for dissemination in space and include CSF findings as evidence for dissemination in time in clinically isolated syndrome. DOI: 10.1097/WCO.0000000000000699 83. Curr Opin Neurol. 2019 Jun;32(3):338-345. doi: 10.1097/WCO.0000000000000698. Imaging the multiple sclerosis lesion: insights into pathogenesis, progression and repair. Wang CT(1)(2), Barnett M(1)(2), Barnett Y(2)(3)(4). Author information: (1)Brain and Mind Centre, The University of Sydney. (2)Sydney Neuroimaging Analysis Centre. (3)Department of Medical Imaging, St Vincent's Hospital. (4)The University of New South Wales, Sydney, Australia. PURPOSE OF REVIEW: Focal white matter lesions are the defining pathological and imaging hallmark of the multiple sclerosis. Until recently, elucidation of the pathophysiology of lesion formation, progression and repair has relied on point neuropathological observations. Here, we review current and emerging concepts of the MRI-defined multiple sclerosis lesion phenotype, advanced longitudinal imaging techniques that permit in-vivo exploration of dynamic microstructural change within lesions and emerging MRI measures of lesion repair. RECENT FINDINGS: Novel MRI techniques have elucidated dynamic features of the active multiple sclerosis lesion, defined imaging surrogates for chronic active lesions and revealed progressive microstructural change within chronic inactive lesions. Lesion-related anterograde, retrograde and trans- synaptic neurodegenerative mechanisms are being unravelled in vivo through MRI. An array of myelin- imaging techniques have emerged and in some cases have already been integrated into Phase 2 remyelination trials. SUMMARY: MRI has shed new light on dynamic processes that occur over the lifespan of the multiple sclerosis lesion, and reaffirms the critical role of focal pathology as a determinant of disease progression. The development of robust, longitudinal biomarkers of lesion microstructure, such as advanced diffusion imaging, will be especially important as the era of neurorepair trials in multiple sclerosis dawns. DOI: 10.1097/WCO.0000000000000698 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 69 – Multiple Sklerose: Veröffentlichungen April 2019 84. Curr Opin Neurol. 2019 Jun;32(3):358-364. doi: 10.1097/WCO.0000000000000697. Multiple sclerosis: clinical trial design 2019. Pardini M(1)(2), Cutter G(3), Sormani MP(2)(4). Author information: (1)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa. (2)IRCCS Ospedale Policlinico San Martino, Genoa, Italy. (3)Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA. (4)Department of Health Sciences, Biostatistics Unit, University of Genoa, Genoa, Italy. PURPOSE OF REVIEW: Recent years have seen the approval of more than 15 disease-modifying drugs for multiple sclerosis (MS), mainly for its relapsing-remitting form (RRMS). The focus of the MS clinical trials is moving toward clinical trials aimed at progressive patients or based on putatively neuroprotective compounds. Here we reviewed the challenges of this paradigm shift. RECENT FINDINGS: Progressive MS and neuroprotective drugs trials will both need a change in patients' enrollment criteria, outcome selection, and clinical trials design. Published ocrelizumab Primary Progressive MS data, as well as translational neuroimaging and clinical research suggest that MRI markers of inflammation could be used to enrich progressive MS trials population, albeit with the risk of overestimating the relevance of antiinflammatory therapeutic effects in this population and that conventional MRI-based metrics need to be complemented with volumetric and multiparametric approaches to disease severity quantification. Lastly, regarding statistical design, Bayesian approaches are at last making their way from oncology to neurology improving our ability to evaluate multiple treatments in the same trials' population. SUMMARY: Adequate clinical trials design was one of the key factors in the RRMS treatment success story. Multidisciplinary collaborations are needed to adequately plan the progressive MS and restorative therapies trials that lay ahead in the near future. DOI: 10.1097/WCO.0000000000000697 85. Curr Opin Pharmacol. 2019 Apr 20;47:119-125. doi: 10.1016/j.coph.2019.03.010. [Epub ahead of print] Targeting P2X4 and P2X7 receptors in multiple sclerosis. Domercq M(1), Matute C(2). Author information: (1)Department of Neurosciences, University of the Basque Country, Achucarro Basque Center for Neuroscience-UPV/EHU, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940 Leioa, Spain. (2)Department of Neurosciences, University of the Basque Country, Achucarro Basque Center for Neuroscience-UPV/EHU, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940 Leioa, Spain. Electronic address: [email protected]. Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by massive infiltration of immune cells, demyelination, and axonal loss. However, spontaneous myelin repair can occur during the course of the disease. A major component of this regenerative process is a robust innate immune response consisting of infiltrating macrophages and brain microgliosis. Therefore, specifically targeting myeloid cells could be an attractive therapeutic approach. Purinergic receptors control not only immune cell function together with the activation of microglia and astrocytes, but also neuronal and oligodendroglial survival in the pathology. Thus, targeting these receptors can modulate a whole variety of responses. In this review, we will summarize recent findings highlighting the potential of P2X4 and P2X7 as therapeutic targets for MS. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.coph.2019.03.010 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 70 – Multiple Sklerose: Veröffentlichungen April 2019 86. Curr Top Med Chem. 2019 Apr 12. doi: 10.2174/1568026619666190412121811. [Epub ahead of print] ABC transporters in neurological disorders: an important gateway for botanical compounds mediated neuro-therapeutics. Jha NK(1), Kar R(2), Niranjan R(3). Author information: (1)Department of Biotechnology, Noida Institute of Engineering amp; Technology (NIET). India. (2)Department of Biotechnology, Noida Institute of Engineering & Technology (NIET). India. (3)Unit of Microbiology and Molecular Biology, ICMR-Vector Control Research Center, Puducherry-605006. India. Neurodegeneration is a distinguishing feature of many age related disorders. There are a number of factors that can modulate the pathology of these disorders. ATP-binding cassette (ABC) transporters are primarily involved in the maintenance of normal brain homeostasis by eliminating toxic peptides and compounds from the brain. Also, ABC transporters protect the brain from the unwanted effects of endogenous and exogenous toxins that can enter the brain parenchyma. Therefore, these transporters have the ability to determine the pathological outcomes of several neurological disorders. For instance, ABC transporters like P-glycoprotein (ABCB1), and BCRP (ABCG2) have been reported to facilitate the clearance of peptides such as amyloid-β (Aβ) that accumulate in the brain during Alzheimer's disease (AD) progression. Other members such as ABCA1, ABCA2, ABCC8, ABCC9, ABCG1 and ABCG4 also have been reported to be involved in the progression of various brain metabolic disorders such as HIV-associated dementia, Multiple sclerosis (MS), Ischemic stroke, and Epilepsy. However, these defective transporters can be targeted by numerous botanical compounds such as Verapamil, Berberine and Fascalpsynas a therapeutic target to treat these neurological outcomes. These compounds are already reported to modulate ABC transporter activity in the CNS. Nonetheless, the exact mechanisms involving the ABC transporters role in normal brain functioning, their role in neuronal dysfunction and how these botanical compounds ensure and facilitate their therapeutic action in association with defective transporters still remain elusive. This review therefore, summarizes the role of ABC transporters in neurological disorders, with a special emphasis on its role in AD brains. The prospect of using botanical/natural compounds as modulators of ABC transporters in neurological disorders is discussed in the latter half of the article. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]. DOI: 10.2174/1568026619666190412121811 87. Cytokine. 2019 Apr 24;120:78-84. doi: 10.1016/j.cyto.2019.02.018. [Epub ahead of print] IL-23 and dendritic cells: What are the roles of their mutual attachment in immune response and immunotherapy? Hua S(1), Yu X(2), Ma Y(2), Li Y(2). Author information: (1)Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, 130 021 Jinlin, China. Electronic address: [email protected]. (2)Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, 130 021 Jinlin, China. Interleukin-23 (IL-23) is a cytokine that is composed of the subunits p19 and p40, while its receptor (IL-23R) consists of two subunits, that is, IL-23Rα and IL-12Rβ1. The interaction between IL-23 and IL-23R is necessary for exerting cardinal biological effects upon certain cell types, including promotion of memory T cell proliferation and Th17 cell-mediated IL-17 secretion. Accordingly, dendritic cells (DCs) are one of the main sources for IL-23 secretion. Interestingly, IL-23R is also present on the DC plasma membrane, suggesting that IL-23 potentially acts on DCs via an autocrine manner. In this review, we have summarized a variety of IL-23-mediated effects on the intracellular signaling pathways such as Janus kinase 2, tyrosine kinase 2, signal transducer and activator of transcription (STAT), mitogen-activated protein kinase signaling, and so forth, which may underlie numerous processes such as DC maturation, antigen presentation, T cell proliferation/activation, and cytokine secretion, which may be implicated in many immune-related diseases through IL-23/DC interactions. Accordingly, these signaling pathways are extensively involved in the pathogenesis and progression of numerous diseases, including autoimmune disease (e.g., atopic dermatitis, asthma, and multiple sclerosis) and infection (e.g., bacterial, fungal, and viral infections). Taken together, they are potentially applicable to novel but promising strategies for treating numerous diseases associated with the mutual attachment of IL-23 and DCs. Copyright © 2019. Published by Elsevier Ltd. DOI: 10.1016/j.cyto.2019.02.018 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 71 – Multiple Sklerose: Veröffentlichungen April 2019 88. Dermatol Ther. 2019 Apr 25:e12947. doi: 10.1111/dth.12947. [Epub ahead of print] Case report of a recalcitrant allergic contact eczema successfully treated with Teriflunomide. Reis J(1), Duarte S(2), Sardoeira A(2), Santos E(2), Sanches M(1), Lobo I(1), Selores M(1). Author information: (1)Department of Dermatology, Centro Hospitalar Universitário do Porto, Portugal. (2)Department of Neurology, Centro Hospitalar Universitário do Porto, Portugal. Allergic contact dermatitis (ACD) is a type IV, delayed-type reaction caused by skin contact with low- molecular-weight organic chemicals and metal ions that activate antigen-specific T cells, primarily T-helper 1 (Th1), in a sensitized individual, leading to skin eczema. First-line treatments are based on avoidance of causal agents and topical corticosteroids /immunomodulators. In recalcitrant cases, chronic oral immunosuppressive agents may be used, but they may have serious adverse effects and do not address the immunological disfunction. We report a case of severe ACD, unresponsive to topical or oral immunosuppressive therapy, which resolved itself after treatment with teriflunomide (TF) 14 mg/daily used for Multiple Sclerosis.TF is a once-daily oral selective and reversible dihydro-orotate dehydrogenase (DHODH) inhibitor, revealing a new treatment option for ACD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/dth.12947 89. Dev Med Child Neurol. 2019 Apr 5. doi: 10.1111/dmcn.14233. [Epub ahead of print] Body mass index trajectories in pediatric multiple sclerosis. Brenton JN(1), Woolbright E(2), Briscoe-Abath C(3), Qureshi A(4), Conaway M(5), Goldman MD(4). Author information: (1)Pediatric Neurology, Department of Neurology, University of Virginia, Charlottesville, VA, USA. (2)College of Arts and Sciences, University of Virginia, Charlottesville, VA, USA. (3)School of Medicine, University of Virginia, Charlottesville, VA, USA. (4)Department of Neurology, University of Virginia, Charlottesville, VA, USA. (5)Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA. AIM: To characterize growth trajectories of children who develop multiple sclerosis compared to typically developing, regional peers and Centers for Disease Control (CDC) normative values. METHOD: This case- control study collected weight, height, and body mass index (BMI) in 40 consecutive pediatric patients with multiple sclerosis (28 females, 12 males), in addition to 120 typically developing peers (84 females, 36 males), identified and matched for year of birth, sex, ethnicity, and socio-economic status. BMI values were converted to z-scores based on CDC reference values and were compared with respect to age between our two cohorts and by years relative to multiple sclerosis onset for cases. RESULTS: Median age for the clinical onset of multiple sclerosis was 15 years. BMI z-scores are significantly higher for patients with multiple sclerosis compared to typically developing, demographically-matched peers and CDC standards. These significant differences in BMI are noted from 4 years of age and onward. Height trajectories were similar among case and control individuals and CDC normative values. INTERPRETATION: BMI in pediatric multiple sclerosis is markedly higher, beginning in early childhood, years before the clinical-onset of the disease. WHAT THIS PAPER ADDS: Children with multiple sclerosis are significantly more overweight than typically developing peers at the time of diagnosis. Body mass index trajectories are significantly higher years before the clinical manifestation(s) of multiple sclerosis. © 2019 Mac Keith Press. DOI: 10.1111/dmcn.14233 90. Dev Med Child Neurol. 2019 Apr 16. doi: 10.1111/dmcn.14228. [Epub ahead of print] Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 72 – Multiple Sklerose: Veröffentlichungen April 2019 Treatment in childhood central nervous system demyelinating disorders. Konuskan B(1), Anlar B(1). Author information: (1)Department of Pediatric Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey. The last two decades witnessed significant advances in the treatment of acquired demyelinating disorders: thirteen new agents have been approved for the treatment of multiple sclerosis in adults by the European Medicines Agency and US Food and Drug Administration in the last twenty years. Although the long-term efficacy and safety profiles of some new drugs are still being assessed in paediatric MS, clinicians may have to use them in the management of paediatric onset MS resistant to first-line medications, based on results obtained in adult-onset disease. This review summarizes the current approach to treatment in children with demyelinating syndromes. WHAT THIS PAPER ADDS: Serological markers affect management in paediatric demyelinating diseases. Antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein should be tested in children with acute demyelinating disease. New therapeutic agents currently in trial for pediatric disease should be used with close follow-up. © 2019 Mac Keith Press. DOI: 10.1111/dmcn.14228 91. Dev Med Child Neurol. 2019 Apr 11. doi: 10.1111/dmcn.14242. [Epub ahead of print] Fatigue, depression, and quality of life in children with multiple sclerosis: a comparative study with other demyelinating diseases. Florea A(1), Maurey H(1), Le Sauter M(1), Bellesme C(1), Sevin C(1), Deiva K(1)(2)(3). Author information: (1)Pediatric Neurology Department, National Referral Center for Rare Inflammatory Brain and Spinal Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France. (2)Université Paris-Sud, Le Kremlin Bicêtre, France. (3)Center for Immunology of Viral Infections and Autoimmune Diseases, UMR 1184-CEA-IDMIT, Le Kremlin Bicêtre, France. AIM: To evaluate fatigue, depression, and quality of life (QoL) of children with multiple sclerosis and compare to other acute demyelinating syndromes (ADS). METHOD: Children followed in the National Referral Centre of rare inflammatory brain and spinal diseases were included in this study. The Expanded Disability Status Scale, the fatigue severity scale, the Multiscore Depression Inventory for Children, and the Pediatric Quality of Life Inventory were used for evaluation. RESULTS: Thirty-seven children (23 females, 14 males) were included in this study. Multiple sclerosis was diagnosed in 26 children and ADS in 11 children. Although not significant, severe fatigue was less frequently reported by patients with multiple sclerosis than children with ADS (44% vs 63%, p=0.2). Depression was reported more often in the multiple sclerosis group compared to the ADS group (24% vs 18%, p=0.6). Concerning the QoL in patients with multiple sclerosis, both parents and children reported poor emotional and school functioning. Physical and social functioning were rated as being good in both groups, and was significantly higher in the children's group (p=0.007). INTERPRETATION: This study highlights the importance of fatigue and depression in children with ADS and particularly in paediatric onset multiple sclerosis. Moreover, difficulties in school and emotional functioning were the main concerns for parents and children in the multiple sclerosis group which need to be taken in account during their care and treatment proposal. WHAT THIS PAPER ADDS: Invisible signs such as fatigue and depression affect all forms of acute demyelinating syndromes (ADS) in children. Depression seems to be higher in children with multiple sclerosis than with other forms of ADS. Fatigue seems to be lower in children with multiple sclerosis than with other forms of ADS. Children with multiple sclerosis and their parents are most concerned with emotional and academic functioning. © 2019 Mac Keith Press. DOI: 10.1111/dmcn.14242 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 73 – Multiple Sklerose: Veröffentlichungen April 2019 92. Dev Med Child Neurol. 2019 Apr 1. doi: 10.1111/dmcn.14212. [Epub ahead of print] Paediatric multiple sclerosis: a new era in diagnosis and treatment. Duignan S(1), Brownlee W(2), Wassmer E(3), Hemingway C(1), Lim M(4)(5), Ciccarelli O(2)(6), Hacohen Y(1)(2). Author information: (1)Department of Paediatric Neurology, Great Ormond Street Hospital for Children, London, UK. (2)Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK. (3)Department of Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK. (4)Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London, UK. (5)Faculty of Life Sciences and Medicine, Kings College London, London, UK. (6)National Institute for Health Research, Biomedical Research Centre, University College London Hospitals, London, UK. Multiple sclerosis is a chronic immune-mediated demyelinating disease of the central nervous system. The diagnosis of multiple sclerosis in children, as in adults, requires evidence of dissemination of inflammatory activity in more than one location in the central nervous system (dissemination in space) and recurrent disease over time (dissemination in time). The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) and aquaporin-A antibodies (AQP4-Ab), and the subsequent discovery of their pathogenic mechanisms, have led to a shift in the classification of relapsing demyelinating syndromes. This is reflected in the 2017 revised criteria for the diagnosis of multiple sclerosis, which emphasizes the exclusion of multiple sclerosis mimics and aims to enable earlier diagnosis and thus treatment initiation. The long-term efficacy of individual therapies initiated in children with multiple sclerosis is hard to evaluate, owing to the small numbers of patients who have the disease, the relatively high number of patients who switch therapy, and the need for long follow-up studies. Nevertheless, an improvement in prognosis with a globally reduced annual relapse rate in children with multiple sclerosis is now observed compared with the pretreatment era, indicating a possible long-term effect of therapies. Given the higher relapse rate in children compared with adults, and the impact multiple sclerosis has on cognition in the developing brain, there is a question whether rapid escalation or potent agents should be used in children, while the short- and long- term safety profiles of these drugs are being established. With the results of the first randomized controlled trial of fingolimod versus interferon-β1a in paediatric multiple sclerosis published in 2018 and several clinical trials underway, there is hope for further progress in the field of paediatric multiple sclerosis. WHAT THIS PAPER ADDS: Early and accurate diagnosis of multiple sclerosis is crucial. The discovery of antibody- mediated demyelination has changed the diagnosis and management of relapsing demyelination syndromes. Traditional escalation therapy is being challenged by induction therapy. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 74 – Multiple Sklerose: Veröffentlichungen April 2019 Publisher: ESCLEROSIS MÚLTIPLE PEDIÁTRICA: UNA NUEVA ERA EN EL DIAGNÓSTICO Y TRATAMIENTO: La esclerosis múltiple es una enfermedad desmielinizante crónica mediada por el sistema inmunitario del sistema nervioso central. El diagnóstico de esclerosis múltiple en niños, como en adultos, requiere evidencia de diseminación de actividad inflamatoria en más de un lugar en el sistema nervioso central (diseminación en el espacio) y enfermedad recurrente a lo largo del tiempo (diseminación en el tiempo). La identificación de los anticuerpos de la glicoproteína oligodendrocítica de la mielina (MOG-Ab) y los anticuerpos de la acuaporina-A (AQP4-Ab), y el posterior descubrimiento de sus mecanismos patógenos, han conducido a un cambio en la clasificación de los síndromes desmielinizantes recurrentes. Esto se refleja en los criterios revisados de 2017 para el diagnóstico de esclerosis múltiple, que enfatiza la exclusión de los imitadores de la esclerosis múltiple y tiene como objetivo permitir un diagnóstico más temprano y, por lo tanto, el inicio del tratamiento. La eficacia a largo plazo de las terapias individuales iniciadas en niños con esclerosis múltiple es difícil de evaluar, debido a la pequeña cantidad de pacientes que tienen la enfermedad, la cantidad relativamente alta de pacientes que cambian de terapia y la necesidad de estudios de seguimiento prolongados. Sin embargo, ahora se observa una mejora en el pronóstico con una tasa de recaída anual globalmente reducida en niños con esclerosis múltiple en comparación con la era anterior al tratamiento previo, lo que indica un posible efecto a largo plazo de las terapias. Debido a la mayor tasa de recaída en niños en comparación con los adultos, y el impacto que tiene la esclerosis múltiple en la cognición en el cerebro en desarrollo, existe la duda de si se deben usar agentes de aumento rápido o potentes en niños, mientras que los perfiles de seguridad a corto y largo plazo de estos medicamentos se están estableciendo. Con los resultados del primer ensayo controlado aleatorio de fingolimod versus interferón-β1a en esclerosis múltiple pediátrica publicado en 2018 y varios ensayos clínicos en curso, existe la esperanza de un mayor progreso en el campo de la esclerosis múltiple pediátrica.Publisher: ESCLEROSE MÚLTIPLA PEDIÁTRICA: UMA NOVA ERA NO DIAGNÓSTICO E TRATAMENTO: A esclerose múltipla é uma doença desmielinizante imunomediada crônica do sistema nervoso central. O diagnóstico de esclerose múltipla em crianças, como em adultos, exige evidência de disseminação da atividade inflamatória em mais de um local no sistema nervoso central (disseminação no espaço) e doença recorrente ao longo do tempo (disseminação no tempo). A identificação de anticorpos anti-glicoproteína de mielina do oligodendrócito (MOG-Ab) e anticorpos anti-aquaporina A (AQP4-Ab), e a subsequente descoberta de seus mecanismos patogênicos, levaram a uma mudança na classificação das síndromes desmielinizantes recidivantes. Isso se reflete nos critérios revisados de 2017 para o diagnóstico de esclerose múltipla, que enfatizam a exclusão de transtornos que mimetizam esclerose múltipla e visam permitir o diagnóstico precoce e, portanto, o início do tratamento. É difícil avaliar a eficácia a longo prazo de terapias individuais iniciadas em crianças com esclerose múltipla, devido ao pequeno número de pacientes que têm a doença, o número relativamente alto de pacientes que trocam de terapia e a necessidade de estudos de acompanhamento a longo prazo. No entanto, uma melhora no prognóstico com uma taxa de recaída anual globalmente reduzida em crianças com esclerose múltipla é agora observada em comparação com a era pré-tratamento, indicando um possível efeito a longo prazo das terapias. Dada a maior taxa de recaída em crianças em comparação com adultos, e o impacto da esclerose múltipla na cognição no cérebro em desenvolvimento, há uma questão se a escalada rápida ou agentes potentes devem ser usados em crianças, enquanto os perfis de segurança de curto e longo prazo destas drogas estão sendo estabelecidos. Com os resultados do primeiro estudo controlado randomizado de fingolimode versus interferon-β1a na esclerose múltipla pediátrica publicado em 2018 e vários ensaios clínicos em andamento, há esperança de mais progressos no campo da esclerose múltipla pediátrica. © 2019 Mac Keith Press. DOI: 10.1111/dmcn.14212 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 75 – Multiple Sklerose: Veröffentlichungen April 2019 93. Dialogues Clin Neurosci. 2018 Dec;20(4):283-292. An emerging role of dysfunctional axon-oligodendrocyte coupling in neurodegenerative diseases. Alexandra I M(1), Constanze D(1), Klaus-Armin N(1). Author information: (1)Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Gottingen, Germany. Myelin is made by highly specialized glial cells and enables fast axonal impulse propagation. Recent studies show that oligodendrocytes in the central nervous system are, in addition to myelination, required for the integrity and survival of axons, independent of the presence or absence of myelin itself. The underlying mechanism of this support is given by glycolytic oligodendrocytes which provide axons with energy-rich metabolites. These findings represent a paradigm shift for the physiological function of axon-associated glia, and open the intriguing possibility that oligodendrocytes are important contributors to neurodegenerative diseases in which myelinated axons are lost, such as in Alzheimer disease, amyotrophic lateral sclerosis, and multiple system atrophy. Understanding the role of axon-oligodendrocyte coupling in neurodegenerative diseases may pave the way for the development of metabolism-based therapeutic approaches. Publisher: La mielina es producida por células gliales altamente especializadas y permite la propagación rápida del impulso axonal. Estudios recientes muestran que los oligodendrocitos en el sistema nervioso central son, junto con la mielinización, necesarios para la integridad y sobrevida de los axones, independientemente de la presencia o ausencia de mielina. El mecanismo que subyace a este soporte está dado por oligodendrocitos glicolíticos que aportan a los axones metabolitos ricos en energía. Estos hallazgos representan un cambio de paradigma para la función fisiológica de la glía asociada a los axones, y abre la intrigante posibilidad que los oligodendrocitos sean importantes contribuyentes a las enfermedades neurodegenerativas en que se pierden los axones mielinizados, como la Enfermedad de Alzheimer, la esclerosis lateral amiotrófica y la atrofia de múltiples sistemas. La comprensión del papel del acoplamiento del oligodendrocito con el axón en las enfermedades neurodegenerativas puede abrir la vía para el desarrollo de aproximaciones terapéuticas basadas en el metabolismo.Publisher: Fabriquée par des cellules gliales très spécialisées, la myéline permet la propagation rapide de l'influx axonal. D'après des études récentes, les oligodendrocytes du système nerveux central sont nécessaires, outre à la myélinisation, à l'intégrité et à la survie des axones, indépendamment de la présence ou non de myéline. Les oligodendrocytes glycolytiques, apportant aux axones des métabolites riches en énergie, en forment le mécanisme sous-jacent. Ces résultats représentent un changement de paradigme pour la fonction physiologique de la glie associée aux axones. De manière très intéressante, les oligodendrocytes pourraient participer de façon importante aux maladies neurodégénératives dans lesquelles il y a une perte d'axones myélinisés comme la maladie d'Alzheimer, la sclérose latérale amyotrophique et les atrophies multiples de système. Comprendre le rôle du couplage axone-oligodendrocytes dans les maladies neurodégénératives peut ouvrir la voie du développement de traitements basés sur le métabolisme. PMCID: PMC6436955 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 76 – Multiple Sklerose: Veröffentlichungen April 2019 94. Disabil Health J. 2019 Mar 28. pii: S1936-6574(19)30052-4. doi: 10.1016/j.dhjo.2019.03.007. [Epub ahead of print] Quality of life in patients with multiple sclerosis: A study with patients and caregivers. Santos M(1), Sousa C(1), Pereira M(1), Pereira MG(2). Author information: (1)Department of Applied Psychology, School of Psychology, University of Minho, Braga, Portugal. (2)Department of Applied Psychology, School of Psychology, University of Minho, Braga, Portugal. Electronic address: [email protected]. BACKGROUND: Multiple Sclerosis (MS) is a chronic disease that affects patients' quality of life and requires long term demanding care. OBJECTIVE: The purpose of this study was to examine the relationships between patients and caregivers' variables regarding patients' quality of life, the moderating role of marital satisfaction between patients' psychological morbidity and quality of life, and the contribution of patient and caregiver variables towards patients' quality of life. METHODS: The sample included 100 patients with MS and 72 caregivers. Participants' variables were assessed using self-report measures. The design of this quantitative study was transversal. RESULTS: Marital satisfaction moderated the relationship between patients' anxiety and mental quality of life. Patients' perception of illness identity and consequences together with caregivers' depressive symptoms were mediators between patients' depression and quality of life. Burden also played a mediator role in the relationship between patients' depressive symptoms, disability level, and physical quality of life. CONCLUSION: Therefore, intervention in multiple sclerosis should be delivered in a dyadic context. Copyright © 2019 Elsevier Inc. All rights reserved. DOI: 10.1016/j.dhjo.2019.03.007 95. Disabil Rehabil. 2019 Apr 24:1-12. doi: 10.1080/09638288.2019.1602675. [Epub ahead of print] How people with multiple sclerosis experience the influence of nutrition and lifestyle factors on the disease. Karnoe A(1)(2), Pedersen LM(1), Karlsen S(1), Boesen F(3), Skovgaard L(2), Kayser L(1). Author information: (1)a Department of Public Health , University of Copenhagen , Copenhagen , Denmark. (2)b Section of Research and Development , Danish Multiple Sclerosis Society Valby , Denmark. (3)c Danish Multiple Sclerosis Hospital , Haslev , Denmark. PURPOSE: Increasing knowledge suggests that nutrition and lifestyle factors affect multiple sclerosis. This study explores how people with multiple sclerosis experience daily multiple sclerosis disease activity and the influence of nutrition and lifestyle factors (e.g., stress, sleep, and environmental temperature). METHODS: Four phases mix qualitative and quantitative elements in an exploratory study. The initial two phases consisted of an exploratory study with 14 participants followed by 15 semi-structured interviews. Results from the two first phases were substantiated in a survey completed by 425 respondents (response rate: 42.5%). Finally, findings and inconsistencies were elaborated in three focus group interviews. RESULTS: In the initial exploratory study, several of the participants linked nutrition and lifestyle factors to disease activity. Results from the semi-structured interviews showed that particularly stress, meat, fatty foods, and processed sugar were perceived to have a negative impact on disease activity, and some participants had experienced immediate effects of these factors on their disease activity. The survey supported these findings that were further elaborated in focus groups. CONCLUSION: People with multiple sclerosis perceive nutrition and lifestyle to affect daily disease activity. Individuals who have experienced links between their multiple sclerosis, and nutrition and lifestyle attribute some of these changes to e.g., stress, and the consumption of sugar, meat, and fatty food. Implications for rehabilitation A majority of the participants in this study perceived nutrition and lifestyle factors to have an effect on their multiple sclerosis, particularly stress, meat, fatty foods, and processed sugar. Some participants with multiple sclerosis experienced that nutrition, stress, environmental temperature, and physical activity had a direct effect on the severity of daily symptom manifestations. Nutrition and lifestyle factors that potentially influence multiple sclerosis disease activity should be considered when organizing rehabilitation and care to better meet the needs of the individual with multiple sclerosis. DOI: 10.1080/09638288.2019.1602675 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 77 – Multiple Sklerose: Veröffentlichungen April 2019 96. Disabil Rehabil. 2019 Apr 24:1-10. doi: 10.1080/09638288.2018.1555615. [Epub ahead of print] The multiple faces of pain in motor neuron disease: a qualitative study to inform pain assessment and pain management. Åkerblom Y(1), Jakobsson Larsson B(1), Zetterberg L(1), Åsenlöf P(1). Author information: (1)a Department of Neuroscience , Uppsala University , Uppsala , Sweden. PURPOSE: The aim was to explore personal experiences of pain in people with motor neuron disease. MATERIALS AND METHODS: Sixteen participants were individually interviewed on one occasion concerning their experiences of presentation, consequences, and management of pain. Qualitative content analysis with researcher triangulation was used to synthesize and interpret data. RESULTS: Four themes emerged as the result of the analysis: (1) The multiple faces of pain, (2) The thin line between experience of pain and no pain, (3) The negative effects of pain on role functioning (4) Successful coping with pain requiring personal effort and competent engagement. The important findings were the experiences of unpredictability of pain breakthroughs, the efforts required to manage pain, consequences for activity and quality of life, and the suffering induced by diminishment and neglect of pain from both patients and staff. CONCLUSIONS: Pain in motor neuron disease seems to have certain and multiple characteristics, which is why there is a need to develop and implement pain assessment methods adapted to this population. Such methods may help make pain more predictable, and increase the possibilities to provide effective and individually tailored pain treatment. IMPLICATIONS FOR REHABILITATION Pain is a common, but often neglected, ailment in motor neuro disease, which deserves more attention from health care. Staff should provide information about the pain being possible to treat successfully with medication, by contrast to the possibility of curing the disease itself. Pain assessments should be implemented during the entire course of the disease, covering a time frame long enough to cover characteristic fluctuations of pain. Whenever possible, facilitate the performance of painful activities of daily living as much as possible to make room for engagement in other personally valued activities of importance for individual quality of life. DOI: 10.1080/09638288.2018.1555615 97. Disabil Rehabil. 2019 Apr 23:1-10. doi: 10.1080/09638288.2019.1585969. [Epub ahead of print] A qualitative exploration of physiotherapists' perceptions about exercise and physical activity: reflections on the results from a Delphi Study. Stennett A(1), De Souza L(1), Norris M(1). Author information: (1)a Department of Clinical Sciences , Brunel University London , London , UK. PURPOSE: This study explored physiotherapists' interpretation of exercise and physical activity, examined physiotherapists' views and opinions about the prioritised physical activity practices of people with multiple sclerosis and its implication for clinical practice. METHOD: Fourteen physiotherapists (12 females, 2 males) with experience of working with people with multiple sclerosis in the community participated in three focus groups. Physiotherapists commented on the results of a previous Delphi study which highlighted the prioritised exercise and physical activity practices and reasons people with multiple sclerosis engage in exercise and physical activity. The focus groups were audio recorded and transcribed verbatim. Data were analysed using framework analysis. RESULTS: Four themes were developed from the analysis namely, Blurred terminologies, Influencing factors for the meaning of exercise and physical activity, When professional expertise meets experiential expertise and The resolve: resolving professional and experiential tensions. CONCLUSION: Physiotherapists described exercise and physical activity as movement with a focus on the physiological attributes. Nonetheless they valued and use exercise and physical activity as strategies to manage the symptoms associated with multiple sclerosis. Physiotherapists are strategically placed in the community to initiate discussions, assess, and create opportunities to enhance the physical activity practices of people with multiple sclerosis. However, there is greater scope for the application of physical activity to be embedded in routine clinical practice in the management of multiple sclerosis in the community. Implications for rehabilitation Physiotherapists should design flexible physical activity programmes which are meaningful, engaging and foster the necessary environment to sustain physical activity participation in people with multiple sclerosis. Health professionals should be aware of and understand the individuals' priorities as these are key drivers to engaging and sustaining physical activity in community dwelling people with multiple sclerosis. Physiotherapists should be aware of their own beliefs and theoretical principles that guide designs and treatment programmes as these might either enhance or restrict physical activity in people with multiple sclerosis. DOI: 10.1080/09638288.2019.1585969 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 78 – Multiple Sklerose: Veröffentlichungen April 2019 98. Disabil Rehabil. 2019 Apr 18:1-8. doi: 10.1080/09638288.2019.1597179. [Epub ahead of print] Comparison of sedentary behaviour questionnaires in people with multiple sclerosis. Hensman M(1)(2), Motl RW(3), Pilutti LA(4), Fenton SAM(1)(2), Duda JL(1)(2), Douglas M(5)(6), Veldhuijzen van Zanten JJCS(1)(2). Author information: (1)a School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham , Birmingham , UK. (2)b Dudley Group of Hospitals NHS Foundation Trust , Dudley , UK. (3)c Department of Physical Therapy , University of Alabama at Birmingham , Birmingham , AL , USA. (4)d Interdisciplinary School of Health Sciences, University of Ottawa , Ottawa , Canada. (5)e Department of Neurology , Dudley Group NHS Foundation Trust, Russells Hall Hospital , Birmingham , UK. (6)f School of Life and Health Sciences, Aston University , Birmingham , UK. BACKGROUND: People with multiple sclerosis are at risk of developing co-morbidities associated with sedentary behaviour. Despite an increase in studies examining sedentary behaviour in multiple sclerosis, researchers have not yet examined the appropriateness of the content or format of questionnaires assessing sedentary behaviour in multiple sclerosis. OBJECTIVE: Evaluate perceptions of sedentary behaviour questionnaires for people with multiple sclerosis. METHODS: Fifteen people with multiple sclerosis completed six validated sedentary behaviour questionnaires: Longitudinal Ageing Study Amsterdam, Marshall Sitting Questionnaire, International Physical Activity Questionnaire, Measure of Older Adults Sedentary Time, Sedentary Behaviour Questionnaire and SIT-Q. Participants' perceptions regarding questionnaire content and format were explored by interviews. RESULTS: Self-reported sedentary time ranged between a mean of 470 (standard deviation 260) (Measure of Older Adults Sedentary Time) and 782 (322) min (Longitudinal Ageing Study Amsterdam) per weekday. Analysis of variance revealed a significant effect of questionnaire on mean sitting time: Longitudinal Ageing Study Amsterdam and SIT-Q yielded higher mean estimates of weekday sitting time than other questionnaires. The questionnaires were viewed as being suitable for use in multiple sclerosis but failed to capture some sedentary activities. Variability of symptoms yielded difficulties in describing a "typical day". CONCLUSIONS: The questionnaires were considered suitable for multiple sclerosis but produced variation in estimated sedentary time. Future work might validate questionnaire data with device-based assessments of sedentary time. Implications for rehabilitation Self- reported sitting time ranged from 7.8 to 13.0 h per day in people with multiple sclerosis. Sedentary behaviour questionnaires are suitable for multiple sclerosis but yield variable estimates of sitting time. Watching television was the most prevalent sedentary activity and may have implications for interventions that break up sedentary time. DOI: 10.1080/09638288.2019.1597179 99. Disabil Rehabil. 2019 Apr 18:1-13. doi: 10.1080/09638288.2019.1597182. [Epub ahead of print] Social capital components and social support of persons with multiple sclerosis: a systematic review of the literature from 2000 to 2018. Koutsogeorgou E(1)(2), Chiesi AM(1), Leonardi M(3). Author information: (1)a Department of Social and Political Sciences (SPS) , Università degli Studi di Milano , Milan , Italy. (2)b Department of Cultures, Politics and Society (CPS) , Università degli Studi di Torino , Turin , Italy. (3)c Neurology, Public Health, Disability Unit and Coma Research Centre , Fondazione IRCCS Istituto Neurologico Carlo Besta , Milan , Italy. PURPOSE: To identify experiences of persons with multiple sclerosis (MS) in terms of social capital and its components (i.e., social networks, trust, and interpersonal relationships) and social support based on the current scientific knowledge. METHODS: Systematic literature review was conducted through PubMed, Scopus, Web of Science, ProQuest, and PsycINFO. Included articles were published from 2000 to 2018 and met specific selection criteria. Screening of records determined eligible studies for inclusion to data extraction and synthesis process. RESULTS: A total of 551 abstracts were screened, of which 34 studies met all selection criteria. The themes that emerged referred to the impact of physical and cognitive impairments on social functioning, stigma, psychosocial, emotional and mental challenges, association of quality of life with social capital components and social support, and contribution of social support to improvement of social functioning and health of persons with MS. Persons with MS face a series of issues regarding social support and social capital-related components, primarily facing psychological difficulties, difficulties with making and maintaining interpersonal relationships, and limitations for participating in social and daily activities due to the symptoms of MS, particularly fatigue. CONCLUSION: It appears that the ability to seek and maintain social relationships and to participate in social and daily activities is important for persons with MS. This has an impact on their quality of life, as well as on their health functioning, however issues around mobility and stigmatization of their condition hinder their social functioning. DOI: 10.1080/09638288.2019.1597182 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 79 – Multiple Sklerose: Veröffentlichungen April 2019 100. Drug Dev Res. 2019 Apr 29. doi: 10.1002/ddr.21540. [Epub ahead of print] Curcumin ameliorates experimental autoimmune encephalomyelitis in a C57BL/6 mouse model. Esmaeilzadeh E(1), Soleimani M(2), Zare-Abdollahi D(1), Jameie B(3), Khorram Kohrshid HR(1). Author information: (1)Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. (2)Department of basic science, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. (3)Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran. Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system. Although the exact etiology of the disease is largely unknown, it is identified that cytokines may play an important role in the pathogenesis of MS. In this study, the effects of curcumin has been investigated on the expression levels of selected cytokine coding genes as well as the extent of demyelination in the corpus callosum of C57BL/6 experimental autoimmune encephalomyelitis (EAE) model of MS. Gene expression analyses revealed that treatment with curcumin could lead to a significant reduction in the expression levels of pro-inflammatory cytokine coding genes including IL-6 (p = 0.001), IL-17 (p = 0.001), tumor necrosis factor (TNF)-α (p = 0.008), and interferon (IFN)-γ (p = 0.033) as well as a significant increase in the expression level of transforming growth factor (TGF)-β (p = 0.006) as an anti-inflammatory cytokine. Moreover, the expression of glutathione peroxidase (GPX)-1 gene and the activity of anti-oxidant enzymes were significantly higher (p < 0.001) in curcumin-treated mice. Luxol fast blue staining also confirmed a significant reduction in the extent of demyelination in the curcumin-treated group (p < 0.001). Our results have confirmed that curcumin is an effective therapeutic agent that could ameliorate the severity of EAE. © 2019 Wiley Periodicals, Inc. DOI: 10.1002/ddr.21540 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 80 – Multiple Sklerose: Veröffentlichungen April 2019 101. EBioMedicine. 2019 Apr 10. pii: S2352-3964(19)30232-4. doi: 10.1016/j.ebiom.2019.03.087. [Epub ahead of print] Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course. Castro K(1), Ntranos A(2), Amatruda M(3), Petracca M(2), Kosa P(4), Chen EY(5), Morstein J(6), Trauner D(6), Watson CT(7), Kiebish MA(5), Bielekova B(4), Inglese M(2), Katz Sand I(2), Casaccia P(8). Author information: (1)Department of Neuroscience, Icahn School of Medicine at Mount Sinai, NY, New York, United States of America. (2)Department of Neurology, Icahn School of Medicine at Mount Sinai, NY, New York, United States of America. (3)Advanced Science Research Center at The Graduate Center of The City University of New York and Inter-Institutional Center for Glial Biology at Icahn School of Medicine New York, New York, United States of America. (4)Neuroimmunological Disease Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America. (5)BERG, LLC. Framingham, MA, United States of America. (6)Department of Chemistry, New York University, NY, New York, United States of America. (7)Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, United States of America. (8)Department of Neuroscience, Icahn School of Medicine at Mount Sinai, NY, New York, United States of America; Advanced Science Research Center at The Graduate Center of The City University of New York and Inter-Institutional Center for Glial Biology at Icahn School of Medicine New York, New York, United States of America. Electronic address: [email protected]. BACKGROUND: Multiple Sclerosis (MS) results from genetic predisposition and environmental variables, including elevated Body Mass Index (BMI) in early life. This study addresses the effect of BMI on the epigenome of monocytes and disease course in MS. METHODS: Fifty-four therapy-naive Relapsing Remitting (RR) MS patients with high and normal BMI received clinical and MRI evaluation. Blood samples were immunophenotyped, and processed for unbiased plasma lipidomic profiling and genome-wide DNA methylation analysis of circulating monocytes. The main findings at baseline were validated in an independent cohort of 91 therapy-naïve RRMS patients. Disease course was evaluated by a two-year longitudinal follow up and mechanistic hypotheses tested in human cell cultures and in animal models of MS. FINDINGS: Higher monocytic counts and plasma ceramides, and hypermethylation of genes involved in negative regulation of cell proliferation were detected in the high BMI group of MS patients compared to normal BMI. Ceramide treatment of monocytic cell cultures increased proliferation in a dose-dependent manner and was prevented by DNA methylation inhibitors. The high BMI group of MS patients showed a negative correlation between monocytic counts and brain volume. Those subjects at a two-year follow-up showed increased T1 lesion load, increased disease activity, and worsened clinical disability. Lastly, the relationship between body weight, monocytic infiltration, DNA methylation and disease course was validated in mouse models of MS. INTERPRETATION: High BMI negatively impacts disease course in Multiple Sclerosis by modulating monocyte cell number through ceramide-induced DNA methylation of anti- proliferative genes. FUND: This work was supported by funds from the Friedman Brain Institute, NIH, and Multiple Sclerosis Society. Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.ebiom.2019.03.087 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 81 – Multiple Sklerose: Veröffentlichungen April 2019 102. EMBO J. 2019 Apr 3. pii: e100947. doi: 10.15252/embj.2018100947. [Epub ahead of print] OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes. Wang X(1)(2), Mulas F(3)(2), Yi W(3)(2), Brunn A(4), Nishanth G(3)(2), Just S(3)(2), Waisman A(5), Brück W(6), Deckert M(4), Schlüter D(1)(2)(7). Author information: (1)Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany [email protected] [email protected]. (2)Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany. (3)Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. (4)Department of Neuropathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. (5)Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. (6)Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany. (7)Organ-specific Immune Regulation, Helmholtz- Center for Infection Research, Braunschweig, Germany. Astrocytes are critical regulators of neuroinflammation in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Growing evidence indicates that ubiquitination of signaling molecules is an important cell-intrinsic mechanism governing astrocyte function during MS and EAE Here, we identified an upregulation of the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in astrocytes during MS and EAE Mice with astrocyte-specific OTUB1 ablation developed more severe EAE due to increased leukocyte accumulation, proinflammatory gene transcription, and demyelination in the spinal cord as compared to control mice. OTUB1-deficient astrocytes were hyperactivated in response to IFN-γ, a fingerprint cytokine of encephalitogenic T cells, and produced more proinflammatory cytokines and chemokines than control astrocytes. Mechanistically, OTUB1 inhibited IFN-γ- induced Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling by K48 deubiquitination and stabilization of the JAK2 inhibitor suppressor of cytokine signaling 1 (SOCS1). Thus, astrocyte-specific OTUB1 is a critical inhibitor of neuroinflammation in CNS autoimmunity. © 2019 The Authors. DOI: 10.15252/embj.2018100947 103. eNeuro. 2019 Apr 1;6(2). pii: ENEURO.0024-19.2019. doi: 10.1523/ENEURO.0024-19.2019. eCollection 2019 Mar-Apr. Sensory Neurons of the Dorsal Root Ganglia Become Hyperexcitable in a T-Cell- Mediated MOG-EAE Model of Multiple Sclerosis. Yousuf MS(1), Noh MC(2), Friedman TN(1), Zubkow K(1), Johnson JC(1), Tenorio G(3), Kurata HT(1)(2), Smith PA(1)(2), Kerr BJ(1)(2)(3). Author information: (1)Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada. (2)Department of Pharmacology, University of Alberta, Edmonton, Alberta T6E 2H7, Canada. (3)Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Alberta T6G 2G3, Canada. Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. Patients with MS typically present with visual, motor, and sensory deficits. However, an additional complication of MS in large subset of patients is neuropathic pain. To study the underlying immune-mediated pathophysiology of pain in MS we employed the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE) model in mice. Since sensory neurons are crucial for nociceptive transduction, we investigated the effect of this disease on sensory neurons of the lumbar dorsal root ganglia (DRG). Here, we report the disease was associated with activation of the complement system and the NLRP3 inflammasome in the DRG. We further observe a transient increase in the number of complement component 5a receptor 1- positive (C5aR1+) immune cells, CD4+ T-cells, and Iba1+ macrophages in the DRG. The absence of any significant change in the levels of mRNA for myelin proteins in the DRG and the sciatic nerve suggests that demyelination in the PNS is not a trigger for the immune response in the DRG. However, we did observe an induction of activating transcription factor 3 (ATF3) at disease onset and chronic disruption of cytoskeletal proteins in the DRG demonstrating neuronal injury in the PNS in response to the disease. Electrophysiological analysis revealed the emergence of hyperexcitability in medium-to-large (≥ 6 µm) diameter neurons, especially at the onset of MOG-EAE signs. These results provide conclusive evidence of immune activation, neuronal injury, and peripheral sensitization in MOG-EAE, a model classically considered to be centrally mediated. DOI: 10.1523/ENEURO.0024-19.2019 PMCID: PMC6449162 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 82 – Multiple Sklerose: Veröffentlichungen April 2019 104. Eur J Cancer. 2019 Apr 12;113:75-77. doi: 10.1016/j.ejca.2019.03.011. [Epub ahead of print] Melanoma during fingolimod treatment for multiple sclerosis. Velter C(1), Thomas M(2), Cavalcanti A(3), Bastien M(4), Chochon F(5), Lubetzki C(5), Routier E(2), Robert C(6). Author information: (1)Dermatology Unit, Oncology Department, Gustave Roussy, 94805 Villejuif, France. Electronic address: [email protected]. (2)Dermatology Unit, Oncology Department, Gustave Roussy, 94805 Villejuif, France. (3)Surgery Department, Gustave Roussy, 94805 Villejuif, France. (4)Dermatologue de ville, 1 square de La Mutualité, 75005 Paris, France. (5)Neurology Department, Pitié- Salpêtrière Hospital, APHP and Sorbonne University, 75013 Paris, France. (6)Dermatology Unit, Oncology Department, Gustave Roussy, 94805 Villejuif, France; Paris-Sud University, Kremlin-Bicêtre, France. DOI: 10.1016/j.ejca.2019.03.011 105. Eur J Case Rep Intern Med. 2019 Feb 1;6(2):001046. doi: 10.12890/2019_001046. eCollection 2019. Self-Limited Cytomegalovirus Infection During Natalizumab Treatment for Multiple Sclerosis. Lima MR(1), Farias LABG(2), da Ponte MF(3), de Arruda Furtado LET(3). Author information: (1)Faculty of Medicine, University Center UNINTA, Sobral, Ceará, Brazil. (2)Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil. (3)Internal Medicine Department, Hospital Regional Norte (HRN), Sobral, Ceará, Brazil. Natalizumab is indicated as monotherapy for the treatment of relapsing-remitting multiple sclerosis; it prevents outbreaks and delays the progression of physical disability. Here, we report the case of a 30-year- old patient with multiple sclerosis receiving natalizumab as monotherapy who subsequently developed self- limited cytomegalovirus disease. Cytomegalovirus infection has been reported during treatment with natalizumab, and in this study, we use new techniques to analyze the possible association of cytomegalovirus infection with natalizumab.LEARNING POINTS: Natalizumab is a humanized recombinant monoclonal antibody (IgG4k) against α4-integrin which promotes immunocompromise by blocking the adhesion interactions necessary for lymphocyte trafficking.Cytomegalovirus infection has been described during natalizumab treatment, although the pathogenesis and mechanisms are not complete understood.This case highlights the importance of awareness of this association and possible complications. DOI: 10.12890/2019_001046 PMCID: PMC6432828 Conflict of interest statement: Conflicts of Interests: The Authors declare that there are no competing interests. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 83 – Multiple Sklerose: Veröffentlichungen April 2019 106. Eur J Med Chem. 2019 Apr 16;174:198-215. doi: 10.1016/j.ejmech.2019.04.020. [Epub ahead of print] InCl3 mediated heteroarylation of indoles and their derivatization via CH activation strategy: Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis. Sunke R(1), Bankala R(1), Thirupataiah B(2), Ramarao EVVS(1), Kumar JS(1), Doss HM(3), Medishetti R(1), Kulkarni P(1), Kapavarapu RK(1), Rasool M(3), Mudgal J(4), Mathew JE(4), Shenoy GG(4), Parsa KVL(5), Pal M(6). Author information: (1)Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India. (2)Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India; Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, 576 104, Karnataka, India. (3)Immunopathology Lab, School of BioSciences and Technology, VIT University, Vellore, 632014, India. (4)Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, 576 104, Karnataka, India. (5)Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India. Electronic address: [email protected]. (6)Immunopathology Lab, School of BioSciences and Technology, VIT University, Vellore, 632014, India. Electronic address: [email protected]. A new class of PDE4 inhibitors were designed and synthesized via the InCl3 mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed CH activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC50 = 0.39 ± 0.13 μM with ∼27 and > 250 fold selectivity for PDE4B over PDE4D and C, respectively) showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis when dosed at 3, 10 and 30 mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30 mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) in Zebrafish. Copyright © 2019 Elsevier Masson SAS. All rights reserved. DOI: 10.1016/j.ejmech.2019.04.020 107. Eur J Neurol. 2019 May;26(5):830. doi: 10.1111/ene.13949. Depression in multiple sclerosis: effect of brain derived neurotrophic factor Val66Met polymorphism and disease perception. [No authors listed] Erratum for Eur J Neurol. 2016 Mar;23(3):630-40. DOI: 10.1111/ene.13949 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 84 – Multiple Sklerose: Veröffentlichungen April 2019 108. Eur J Neurol. 2019 Apr 25. doi: 10.1111/ene.13975. [Epub ahead of print] The cerebrospinal fluid CD4/CD8 ratio and interleukin-6 and -10 levels in neurosarcoidosis: a multicenter, pragmatic, comparative study. Chazal T(1), Costopoulos M(2), Maillart E(3), Fleury C(2), Psimaras D(4), Legendre P(1), Pineton de Chambrun M(1), Haroche J(1), Lubetzki C(3), Amoura Z(1), Legarff-Tavernier M(2), Cohen Aubart F(1). Author information: (1)Sorbonne Université, Assistance Publique Hôpitaux de Paris, Hôpital de la Pitié- Salpêtrière, Service de Médecine interne 2, Paris, 75013, France. (2)Assistance Publique Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Service d'Hématologie Biologique, Paris-75013, France et Centre de Recherche des Cordeliers, INSERM UMRS 1138, Cell Death and Drug Resistance in Lymphoproliferative Disorders, 15 rue de l'Ecole de Médecine, Paris, 75005, France. (3)Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Fédération des Maladies du Système Nerveux, Paris, 75013, France. (4)Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Service de Neurologie 1, Paris, 75013, France. OBJECTIVES: Neurosarcoidosis is a rare inflammatory disorder of unknown cause. The aim of this study was to evaluate the value of T/B lymphocyte population counts and the concentrations of the cytokines IL-6 and 10 in the cerebrospinal fluid (CSF) of neurosarcoidosis patients. METHODS: We conducted a retrospective study of CSF biomarkers in patients with neurosarcoidosis who underwent CSF analysis between 2012 and 2017 as well as various control populations. RESULTS: We analyzed 43 patients with neurosarcoidosis, 14 with multiple sclerosis (MS), and 48 with other inflammatory disorders. The IL-6 levels were higher in sarcoidosis patients than in MS patients (median 8 versus 3 pg/mL, p=0.006). The CD4/CD8 ratio was higher in sarcoidosis patients than in MS patients and in patients with other inflammatory disorders (median 3.18 versus 2.36 and 2.10, respectively, p=0.008). The IL-6 level was higher in patients with active neurosarcoidosis than in non-active neurosarcoidosis patients (median 13 versus 3 pg/mL, p=0.0005). In patients with neurosarcoidosis, a CSF IL-6 concentration >50 pg/ml was associated with a higher risk of relapse or progression-free survival (Hazard Ratio 3.60; 95% Confidence Interval 1.78-23.14). A refractory neurosarcoidosis patient was treated with an anti-IL-6 monoclonal antibody that produced a complete neurological response. CONCLUSIONS: The CSF CD4/CD8 ratio and IL-6 concentration are increased in neurosarcoidosis compared to MS and other inflammatory disorders. A CSF IL-6 concentration > 50 pg/mL is associated with relapse or progression of neurosarcoidosis. IL-10 levels may be elevated in neurosarcoidosis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/ene.13975 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 85 – Multiple Sklerose: Veröffentlichungen April 2019 109. Eur J Neurol. 2019 Apr 12. doi: 10.1111/ene.13965. [Epub ahead of print] Neurofilament light chain levels in pregnant multiple sclerosis patients: a prospective cohort study. Cuello JP(1), Martínez Ginés ML(1), Kuhle J(2), García Domínguez JM(1), Lozano Ros A(1), Romero Delgado F(1), Higueras Y(1), Meldaña Rivera A(1), Goicochea Briceño H(1), García-Tizon Larroca S(1), de- León Ruiz J(1), Michalak Z(2), Barro C(2), Álvarez Lafuente R(3), Medina Heras S(4), Fernández Velasco JI(4), Tejeda-Velarde A(4), Domínguez-Mozo MI(3), Muriel A(4), de Andrés C(1), Villar LM(4). Author information: (1)Hospital General Universitario Gregrorio Marañón. Madrid. España, C/ Dr. Esquerdo 46, Madrid, Spain. (2)Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland. (3)Grupo de Investigación de Esclerosis Múltiple, Instituto de investigación Sanitaria San Carlos (IdISSC) / Hospital Clínico San Carlos, Madrid, España. (4)Hospital Universitario Ramón y Cajal, Madrid, España. BACKGROUND: Neurofilament light chain (NfL) is a cytoskeletal protein of neurons. Its levels are increasingly recognized as measures of neuroaxonal damage. The aim of this study was to explore serum NfL (sNfL) levels in MS patients and healthy controls during pregnancy and puerperium. METHODS: Prospective, longitudinal, single-center study. sNfL concentration was assessed using a highly sensitive single-molecule array during pregnancy and in puerperium, in a cohort of 39 pregnant patients with relapsing multiple sclerosis (P-MS). Twenty-one healthy pregnant women (HPW) served as control groups. Eight R- MS patients suffered relapses during pregnancy (P-MS-R) in the first or second trimesters. RESULTS: No differences in pregnancy and delivery data were observed between P-MS and HPW. P-MS patients showed higher sNfL values than HPW in the first trimester, independently of the presence (p=0.002) or not (p=0.02) of relapses during pregnancy. However, in the third trimester, only P-MS-R showed higher sNfL values than HPW (p=0.001). These differences extended to the puerperium, where P-MS-R showed higher sNfL values than those with no relapses during gestation (p=0.02). CONCLUSION: These data strongly suggest that sNfL levels reflect MS activity during pregnancy. Additionally, the absence of relapses during pregnancy may have a beneficial effect on neurodegeneration during puerperium. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/ene.13965 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 86 – Multiple Sklerose: Veröffentlichungen April 2019 110. Evid Based Complement Alternat Med. 2019 Mar 14;2019:6797030. doi: 10.1155/2019/6797030. eCollection 2019. Alpinia oxyphylla Fruit Extract Ameliorates Experimental Autoimmune Encephalomyelitis through the Regulation of Th1/Th17 Cells. Huang KK(1)(2), Lin MN(2), Hsu YL(2), Lu IH(3), Pan IH(2), Yang JL(1). Author information: (1)Department of Life Science, Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan. (2)Department of Pharmacodynamics and Toxicology, Botanical Drug Technology Division, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 30011, Taiwan. (3)Department of Chemistry, Manufacturing and Controls Technology, Botanical Drug Technology Division, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 30011, Taiwan. Alpinia oxyphylla is a traditional Chinese medicine widely used for treating diarrhea, ulceration, and enuresis. Moreover, A. oxyphylla is effective for cognitive function improvement and nerve regeneration. Multiple sclerosis (MS) is a chronic neuronal inflammatory autoimmune disease that commonly affects young adults in high-latitude regions. The aim of this study was to evaluate the beneficial effects of A. oxyphylla in an experimental autoimmune encephalomyelitis (EAE) mouse model, which is an extensively used model for human MS. The ethanolic extract of A. oxyphylla fruit (AO-1) was orally administered to EAE mice. Our results showed AO-1 significantly reduced EAE symptoms. Histopathological analysis showed AO-1 reduced demyelination, inflammation, gliosis, and axonal swelling in the spinal cord. Furthermore, immunohistochemistry and quantitative polymerase chain reaction (qPCR) studies revealed that the infiltration of CD4+, CD8+ T cells, and CD11b+ monocytes into the spinal cord decreased in the AO-1- treated group. Mechanistically, the Th1 transcription factor T-bet, Th17 transcription factor retinoic acid receptor-related orphan receptor γ (RORγt), and inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17 were reduced in the spinal cords of mice treated with AO-1. The expression levels of T-bet and RORγt were also lowered in the spleens of those mice. Further in vitro study showed AO-1 inhibited production of IFN-γ, IL-2, and tumor necrosis factor-α from MOG35-55-peptide-stimulated splenocytes. One component isolated from AO-1, yakuchinone A, inhibited IL-17 production in vitro and reduced EAE symptoms in the mice. Collectively, our results indicate that AO-1 ameliorated the severity of EAE in mice and may involve the regulation of Th1/Th17 response. A. oxyphylla warrants further investigation, particularly regarding its clinical benefits for MS. DOI: 10.1155/2019/6797030 PMCID: PMC6437745 111. Expert Opin Biol Ther. 2019 Apr 26. doi: 10.1080/14712598.2019.1611778. [Epub ahead of print] CD20 monoclonal antibodies for the treatment of multiple sclerosis: up-to-date. Ancau M(1), Berthele A(1), Hemmer B(1)(2). Author information: (1)a Department of Neurology, Klinikum rechts der Isar , Technical University of Munich , Germany . (2)b Munich Cluster for Systems Neurology (SyNergy) , Germany . INTRODUCTION: Featuring demyelination and axonal degeneration, multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system representing a prominent cause of disability in young adults. The recently established therapeutic targeting of B cells in MS patients using CD20 monoclonal antibodies (CD20-mAbs) not only profoundly suppresses inflammatory disease activity, but also materializes as the first treatment approach against disability accumulation in a subset of patients with primary progressive MS. Areas covered: We will review current concepts regarding the immunopathology of B cells as well as results of clinical trials with CD20-mAbs in MS, from the murine-human chimeras rituximab and ublituximab to their increasingly humanized counterparts ocrelizumab and ofatumumab. We conducted a literature search using PubMed, clinicaltrials.gov and clinicaltrialsregister.eu. We will focus on studies emphasizing the effectiveness of these mAbs in reducing MS disease activity and progression, long-term safety, optimal dosage and maintenance regimens. Lastly, we will turn to outstanding questions regarding anti-CD20 therapy in MS. Expert opinion: CD20-mAbs could become first-line drugs in selected patients with highly active MS and already constitute an option for PPMS. Future studies could evaluate whether administration regimens currently in use can be optimized, while registry data could shed light on risk versus benefits on the long run, considering immunosenescence and a potentially increased risk of malignancies and infections in an ageing population. DOI: 10.1080/14712598.2019.1611778 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 87 – Multiple Sklerose: Veröffentlichungen April 2019 112. Expert Rev Neurother. 2019 Apr 19. doi: 10.1080/14737175.2019.1610394. [Epub ahead of print] Vascular Aspects of Multiple Sclerosis: Emphasis on Perfusion and Cardiovascular Comorbidities. Jakimovski D(1)(2), Topolski M(1), Genovese AV(1)(3), Weinstock-Guttman B(2), Zivadinov R(1)(2)(4). Author information: (1)a Buffalo Neuroimaging Analysis Center, Department of Neurology , Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York , Buffalo , NY , USA. (2)b Jacobs Multiple Sclerosis Center, Department of Neurology , Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York , Buffalo , NY , USA. (3)c Institute of Radiology, Department of Clinical Surgical Diagnostic and Pediatric Sciences , University of Pavia , Pavia , Italy. (4)d Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York , Buffalo , NY , USA. INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. Over the last two decades, more favorable MS long-term outcomes have contributed towards increase in prevalence of the aged MS population. Emergence of age-associated pathology, such as cardiovascular diseases, may interact with the MS pathophysiology and further contribute to disease progression. Areas covered: This review summarizes the cardiovascular involvement in MS pathology, its disease activity and progression. The cardiovascular health, the presence of various cardiovascular diseases, and their effect on MS cognitive performance are further explored. In similar fashion, the emerging evidence of a higher incidence of extracranial arterial pathology and its association with brain MS pathology are discussed. Finally, the authors outline the methodologies behind specific perfusion magnetic resonance imaging (MRI) and ultrasound Doppler techniques, which allow measurement of disease-specific and age-specific vascular changes in the aging population and MS patients. Expert opinion: Cardiovascular pathology significantly contributes to worse clinical and MRI-derived disease outcomes in MS. Global and regional cerebral hypoperfusion may be associated with poorer physical and cognitive performance. Prevention, improved detection, and treatment of the cardiovascular-based pathology may improve the overall long-term health of MS patients. DOI: 10.1080/14737175.2019.1610394 113. F1000Res. 2019 Mar 25;8. pii: F1000 Faculty Rev-327. doi: 10.12688/f1000research.17119.1. eCollection 2019. CD28 null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection. Bano A(1), Pera A(2), Almoukayed A(1), Clarke THS(1), Kirmani S(1), Davies KA(1), Kern F(1). Author information: (1)Department of Clinical and Experimental medicine, Brighton and Sussex Medical School, Brighton, Sussex, BN1 9PX, UK. (2)Department of Immunology, Maimonides Institute for Biomedical Research (IMIBIC), Reina Sofia Hospital, University of Cordoba, Av. Menendez Pidal, 14004, Cordoba, Spain. Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28 null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28 null CD4 T cells. DOI: 10.12688/f1000research.17119.1 PMCID: PMC6436193 Conflict of interest statement: No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 88 – Multiple Sklerose: Veröffentlichungen April 2019 114. Free Radic Biol Med. 2019 Apr 26. pii: S0891-5849(19)30240-0. doi: 10.1016/j.freeradbiomed.2019.04.022. [Epub ahead of print] The S1P mimetic fingolimod phosphate regulates mitochondrial oxidative stress in neuronal cells. Martín-Montañez E(1), Pavia J(2), Valverde N(3), Boraldi F(4), Lara E(3), Oliver B(5), Hurtado-Guerrero I(5), Fernandez O(6), Garcia-Fernandez M(7). Author information: (1)Department of Pharmacology and Paediatrics, Faculty of Medicine, Malaga University, Malaga, Spain. Electronic address: [email protected]. (2)Department of Pharmacology and Paediatrics, Faculty of Medicine, Malaga University, Malaga, Spain. Electronic address: [email protected]. (3)Department of Human Physiology, Faculty of Medicine, Malaga University, Malaga, Spain. (4)Department of Life Sciences, University of Modena e Reggio Emilia, Modena, Italy. (5)Neuroscience Unit, Biomedical Research Institute of Malaga (IBIMA), Malaga University Hospital, Malaga, Spain. (6)Department of Pharmacology and Paediatrics, Faculty of Medicine, Malaga University, Malaga, Spain. Electronic address: [email protected]. (7)Department of Human Physiology, Faculty of Medicine, Malaga University, Malaga, Spain. Electronic address: [email protected]. Fingolimod is one of the few oral drugs available for the treatment of multiple sclerosis (MS), a chronic, inflammatory, demyelinating and neurodegenerative disease. The mechanism of action proposed for this drug is based in the phosphorylation of the molecule to produce its active metabolite fingolimod phosphate (FP) which, in turns, through its interaction with S1P receptors, triggers the functional sequestration of T lymphocytes in lymphoid nodes. On the other hand, part if not most of the damage produced in MS and other neurological disorders seem to be mediated by reactive oxygen species (ROS), and mitochondria is one of the main sources of ROS. In the present work, we have evaluated the anti-oxidant profile of FP in a model of mitochondrial oxidative damage induced by menadione (Vitk3) on neuronal cultures. We provide evidence that incubation of neuronal cells with FP alleviates the Vitk3-induced toxicity, due to a decrease in mitochondrial ROS production. It also decreases regulated cell death triggered by imbalance in oxidative stress (restore values of advanced oxidation protein products and total thiol levels). Also restores mitochondrial function (cytochrome c oxidase activity, mitochondrial membrane potential and oxygen consumption rate) and morphology. Furthermore, increases the expression and activity of protective factors (increases Nrf2, HO1 and Trx2 expression and GST and NQO1 activity), being some of these effects modulated by its interaction with the S1P receptor. FP seems to increase mitochondrial stability and restore mitochondrial dynamics under conditions of oxidative stress, making this drug a potential candidate for the treatment of neurodegenerative diseases other than MS. Copyright © 2019. Published by Elsevier Inc. DOI: 10.1016/j.freeradbiomed.2019.04.022 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 89 – Multiple Sklerose: Veröffentlichungen April 2019 115. Free Radic Biol Med. 2019 Apr 17;137:46-58. doi: 10.1016/j.freeradbiomed.2019.04.016. [Epub ahead of print] Protective function of autophagy during VLCFA-induced cytotoxicity in a neurodegenerative cell model. Doria M(1), Nury T(1), Delmas D(2), Moreau T(3), Lizard G(1), Vejux A(4). Author information: (1)Université de Bourgogne Franche-Comté, Dijon, F-21000, France; Team 'Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism' EA 7270, Inserm, F-21000, Dijon, France. (2)Université de Bourgogne Franche-Comté, Dijon, F-21000, France; - Inserm Research Center LNC UMR U1231 - Team "Cancer and Adaptive Immune Response", Bioactive Molecules and Health Research Group, Dijon, F-21000, France. (3)Université de Bourgogne Franche-Comté, Dijon, F-21000, France; Team 'Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism' EA 7270, Inserm, F- 21000, Dijon, France; - Department of Neurology, University Hospital, F-2100, Dijon, France. (4)Université de Bourgogne Franche-Comté, Dijon, F-21000, France; Team 'Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism' EA 7270, Inserm, F-21000, Dijon, France. Electronic address: [email protected]. In recent years, a particular interest has focused on the accumulation of fatty acids with very long chains (VLCFA) in the occurrence of neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis or dementia. Indeed, it seems increasingly clear that this accumulation of VLCFA in the central nervous system is accompanied by a progressive demyelination resulting in death of neuronal cells. Nevertheless, molecular mechanisms by which VLCFA result in toxicity remain unclear. This study highlights for the first time in 3 different cellular models (oligodendrocytes 158 N, primary mouse brain culture, and patient fibroblasts) the types of cell death involved where VLCFA-induced ROS production leads to autophagy. The autophagic process protects the cell from this VLCFA-induced toxicity. Thus, autophagy in addition to oxidative stress can offer new therapeutic approaches. Copyright © 2019. Published by Elsevier Inc. DOI: 10.1016/j.freeradbiomed.2019.04.016 116. Front Cell Neurosci. 2019 Apr 4;13:120. doi: 10.3389/fncel.2019.00120. eCollection 2019. The Fine Tuning of Drp1-Dependent Mitochondrial Remodeling and Autophagy Controls Neuronal Differentiation. Vantaggiato C(1), Castelli M(1), Giovarelli M(2), Orso G(3), Bassi MT(1), Clementi E(1)(2), De Palma C(4). Author information: (1)Scientific Institute, IRCCS E. Medea, Laboratory of Molecular Biology, Lecco, Italy. (2)Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences "Luigi Sacco", "Luigi Sacco" University Hospital, Università di Milano, Milan, Italy. (3)Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Milan, Italy. (4)Unit of Clinical Pharmacology, "Luigi Sacco" University Hospital, ASST Fatebenefratelli Sacco, Milan, Italy. Mitochondria play a critical role in neuronal function and neurodegenerative disorders, including Alzheimer's, Parkinson's and Huntington diseases and amyotrophic lateral sclerosis, that show mitochondrial dysfunctions associated with excessive fission and increased levels of the fission protein dynamin-related protein 1 (Drp1). Our data demonstrate that Drp1 regulates the transcriptional program induced by retinoic acid (RA), leading to neuronal differentiation. When Drp1 was overexpressed, mitochondria underwent remodeling but failed to elongate and this enhanced autophagy and apoptosis. When Drp1 was blocked during differentiation by overexpressing the dominant negative form or was silenced, mitochondria maintained the same elongated shape, without remodeling and this increased cell death. The enhanced apoptosis, observed with both fragmented or elongated mitochondria, was associated with increased induction of unfolded protein response (UPR) and ER-associated degradation (ERAD) processes that finally affect neuronal differentiation. These findings suggest that physiological fission and mitochondrial remodeling, associated with early autophagy induction are essential for neuronal differentiation. We thus reveal the importance of mitochondrial changes to generate viable neurons and highlight that, rather than multiple parallel events, mitochondrial changes, autophagy and apoptosis proceed in a stepwise fashion during neuronal differentiation affecting the nuclear transcriptional program. DOI: 10.3389/fncel.2019.00120 PMCID: PMC6458285 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 90 – Multiple Sklerose: Veröffentlichungen April 2019 117. Front Cell Neurosci. 2019 Mar 27;13:85. doi: 10.3389/fncel.2019.00085. eCollection 2019. Pericytes Favor Oligodendrocyte Fate Choice in Adult Neural Stem Cells. Silva ME(1)(2)(3), Lange S(4)(5), Hinrichsen B(1)(2), Philp AR(1)(2), Reyes CR(1)(2), Halabi D(1)(2), Mansilla JB(1)(2), Rotheneichner P(5)(6), Guzman de la Fuente A(7), Couillard-Despres S(5)(6)(8), Bátiz LF(9), Franklin RJM(7), Aigner L(4)(5)(8), Rivera FJ(1)(2)(4)(5). Author information: (1)Laboratory of Stem Cells and Neuroregeneration, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile. (2)Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile. (3)Institute of Pharmacy, Faculty of Sciences, Universidad Austral de Chile, Valdivia, Chile. (4)Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria. (5)Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria. (6)Institute of Experimental Neuroregeneration, Paracelsus Medical University Salzburg, Salzburg, Austria. (7)Wellcome Trust and Medical Research Council (MRC) Cambridge Stem Cell Institute & Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom. (8)Austrian Cluster for Tissue Regeneration, Vienna, Austria. (9)Centro de Investigación Biomédica (CIB), Facultad de Medicina, Universidad de los Andes, Santiago, Chile. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Upon demyelination, oligodendrocyte progenitor cells (OPCs) are activated and they proliferate, migrate and differentiate into myelin-producing oligodendrocytes. Besides OPCs, neural stem cells (NSCs) may respond to demyelination and generate oligodendrocytes. We have recently shown that CNS-resident pericytes (PCs) respond to demyelination, proliferate and secrete Laminin alpha2 (Lama2) that, in turn, enhances OPC differentiation. Here, we aimed to evaluate whether PCs influence the fate choice of NSCs in vitro, towards the production of new myelin-producing cells. Indeed, upon exposure to conditioned medium derived from PCs (PC-CM), the majority of NSCs gave rise to GalC- and myelin basic protein (MBP)-expressing oligodendrocytes at the expense of the generation of GFAP-positive astrocytes. Consistent with these findings, PC-CM induces an increase in the expression of the oligodendrocyte fate determinant Olig2, while the expression level of the astrocyte determinant ID2 is decreased. Finally, pre-incubation of PC-CM with an anti-Lama2 antibody prevented the generation of oligodendrocytes. Our findings indicate that PCs-derived Lama2 instructs NSCs to an oligodendrocyte fate choice favoring the generation of myelin-producing cells at the expense of astrocytes in vitro. Further studies aiming to reveal the role of PCs during remyelination may pave the way for the development of new therapies for the treatment of MS. DOI: 10.3389/fncel.2019.00085 PMCID: PMC6446960 118. Front Cell Neurosci. 2019 Mar 19;13:107. doi: 10.3389/fncel.2019.00107. eCollection 2019. Antiphospholipid Antibodies Overlapping in Isolated Neurological Syndrome and Multiple Sclerosis: Neurobiological Insights and Diagnostic Challenges. D'Angelo C(1)(2)(3), Franch O(4), Fernández-Paredes L(1)(2), Oreja-Guevara C(5), Núñez-Beltrán M(1), Comins-Boo A(1)(2), Reale M(3), Sánchez-Ramón S(1)(2). Author information: (1)Department of Clinical Immunology and IdISSC, Hospital Clínico San Carlos, Madrid, Spain. (2)Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain. (3)Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. (4)Department of Neurology, Hospital Ruber Internacional, Madrid, Spain. (5)Department of Neurology, Hospital Clínico San Carlos, Madrid, Spain. Antiphospholipid syndrome (APS) is characterized by arterial and venous thrombosis, pregnancy morbidity and fetal loss caused by pathogenic autoantibodies directed against phospholipids (PL) and PL-cofactors. Isolated neurological APS may represent a significant diagnostic challenge, as epidemiological, clinical and neuroimaging features may overlap with those of multiple sclerosis (MS). In an open view, MS could be considered as an organ-specific anti-lipid (phospholipid and glycosphingolipid associated proteins) disease, in which autoreactive B cells and CD8+ T cells play a dominant role in its pathophysiology. In MS, diverse autoantibodies against the lipid-protein cofactors of the myelin sheath have been described, whose pathophysiologic role has not been fully elucidated. We carried out a review to select clinical studies addressing the prevalence of antiphospholipid (aPL) autoantibodies in the so-called MS-like syndrome. The reported prevalence ranged between 2% and 88%, particularly aCL and aβ2GPI, with predominant IgM isotype and suggesting worse MS prognosis. Secondarily, an updated summary of current knowledge on the pathophysiological mechanisms and events responsible for these conditions is presented. We draw attention to the clinical relevance of diagnosing isolated neurological APS. Prompt and accurate diagnosis and antiaggregant and anticoagulant treatment of APS could be vital to prevent or at least reduce APS-related morbidity and mortality. DOI: 10.3389/fncel.2019.00107 PMCID: PMC6433987 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 91 – Multiple Sklerose: Veröffentlichungen April 2019 119. Front Cell Neurosci. 2019 Mar 14;13:90. doi: 10.3389/fncel.2019.00090. eCollection 2019. Galectin-3 (MAC-2) Controls Microglia Phenotype Whether Amoeboid and Phagocytic or Branched and Non-phagocytic by Regulating the Cytoskeleton. Reichert F(1), Rotshenker S(1). Author information: (1)Department of Medical Neurobiology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Hebrew University, Jerusalem, Israel. Myelin surrounding central nervous system (CNS) axons breaks down in multiple sclerosis (MS) and following traumatic axonal injury. Myelin-debris so produced is harmful to repair since it impedes remyelination in MS and the regeneration of traumatized axons. These devastating outcomes are largely due to inefficient removal by phagocytosis of myelin-debris by microglia. Therefore, revealing mechanisms that control phagocytosis is vital. We previously showed that in phagocytosis, filopodia and lamellipodia extend/engulf and then retract/internalize myelin-debris. Moreover, cofilin activates phagocytosis by advancing the remodeling of actin filaments (i.e., existing filaments disassemble and new filaments assemble in a new configuration), causing filopodia/lamellipodia to protrude, and furthermore, Galectin-3 (formally named MAC-2) activates phagocytosis by enhancing K-Ras.GTP/PI3K signaling that leads to actin/myosin- based contraction, causing filopodia/lamellipodia to retract. To understand further how Galectin-3 controls phagocytosis we knocked-down (KD) Galectin-3 expression in cultured primary microglia using Galectin-3 small-hairpin RNA (Gal-3-shRNA). KD Galectin-3 protein levels reduced phagocytosis extensively. Further, inhibiting nucleolin (NCL) and nucleophosmin (NPM), which advance K-Ras signaling as does Galectin-3, also reduced phagocytosis. Strikingly and unexpectedly, knocking down Galectin-3 resulted in a dramatic transformation of microglia morphology from "amoeboid-like" to "branched-like," rearrangement of actin filaments and inactivation of cofilin. Thus, Galectin-3 may control microglia morphology and phagocytosis by regulating the activation state of cofilin, which, in turn, affects how actin filaments organize and how stable they are. Furthermore, our current and previous findings together suggest that Galectin-3 activates phagocytosis by targeting the cytoskeleton twice: first, by advancing cofilin activation, causing filopodia/lamellipodia to extend/engulf myelin-debris. Second, by advancing actin/myosin-based contraction through K-Ras.GTP/PI3K signaling, causing filopodia/lamellipodia to retract/internalize myelin-debris. DOI: 10.3389/fncel.2019.00090 PMCID: PMC6427835 120. Front Genet. 2019 Apr 5;10:223. doi: 10.3389/fgene.2019.00223. eCollection 2019. Genome-Wide DNA Methylation Profiles Reveal Common Epigenetic Patterns of Interferon-Related Genes in Multiple Autoimmune Diseases. Chen S(1)(2), Pu W(1)(2), Guo S(3), Jin L(1)(2), He D(4)(5), Wang J(1)(2)(6). Author information: (1)State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China. (2)Human Phenome Institute, Fudan University, Shanghai, China. (3)Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, United States. (4)Department of Rheumatology, Shanghai Guanghua Hospital of Integrated Traditional and Western Medicine, Shanghai, China. (5)Arthritis Institute of Integrated Traditional and Western Medicine, Shanghai Traditional Chinese Medicine Research Institute, Shanghai, China. (6)Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China. Graves' disease (GD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are complex autoimmune diseases sharing common clinical, genetic and pathogenetic features. However, the commonalities of the DNA methylation profiles for these diseases are still unknown. We conducted an integrative analysis of the multiple-autoimmune disease methylation dataset including GD, RA, SLE, and SSc samples, to identify the common methylation patterns of autoimmune diseases. We identified 15,289 differentially methylated sites between multiple-autoimmune disease patients and controls in CD4+ T cells. We found that the most significant differentially methylated sites had a remarkable enrichment in type I interferon (IFN) pathway genes. Similarly, we identified 9,295 differentially methylated sites between GD/SSc patients and controls in CD8+ T cells. The overall IFN-related gene panel annotated by gene ontology (GO) showed an excellent diagnostic capacity in CD4+ T cells (Sensitivity = 0.82, specificity = 0.82 and AUC = 0.90), while IFI44L, another IFN-related gene not annotated by GO, showed high prediction ability in both CD4+ (AUC = 0.86) and CD8+ (AUC = 0.75) T cells. In conclusion, our study demonstrated that hypomethylation of IFN-related genes is a common feature of GD/RA/SLE/SSc patients in CD4+ T cells, and the DNA methylation profile of IFN-related genes could be promising biomarkers for the diagnosis of GD, RA, SLE, and SSc. DOI: 10.3389/fgene.2019.00223 PMCID: PMC6459983 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 92 – Multiple Sklerose: Veröffentlichungen April 2019 121. Front Immunol. 2019 Apr 12;10:801. doi: 10.3389/fimmu.2019.00801. eCollection 2019. Circulating Cytokines Could Not Be Good Prognostic Biomarkers in a Mouse Model of Amyotrophic Lateral Sclerosis. Moreno-Martínez L(1), de la Torre M(1), Toivonen JM(1), Zaragoza P(1), García-Redondo A(2), Calvo AC(1), Osta R(1). Author information: (1)LAGENBIO, Faculty of Veterinary-IIS, IA2-CITA, CIBERNED, University of Zaragoza, Zaragoza, Spain. (2)ALS Unit, Neurology Department, CIBERER U-723, Health Research Institute, Madrid, Spain. Background: There is growing evidence of the role of inflammation in Amyotrophic Lateral Sclerosis (ALS) during the last decade. Although the origin of ALS remains unknown, multiple potential inflammatory biomarkers have been described in ALS patients and murine models of this disease to explain the progressive motor neuron loss and muscle atrophy. However, the results remain controversial. To shed light on this issue, we aimed to identify novel biomarkers of inflammation that can influence disease progression and survival in serial blood samples from transgenic SOD1G93A mice, a model of ALS. Methods: A cytokine array assay was performed to analyze protein expression of 97 cytokines in plasma samples from wildtype controls and transgenic SOD1G93A mice at asymptomatic stage. Subsequently, serial plasma samples were obtained from SOD1G93A mice at early symptomatic, symptomatic and terminal stages to monitor cytokine levels during disease progression through immunoassays. Comparisons of means of quantifiable cytokines between short-and long-lived mice were analyzed by unrelated t-test or Mann-Whitney U-test. Relationships between cytokines levels and survival time were assessed using Pearson's correlation analysis and Kaplan- Meier analysis. Results: A total of 16 cytokines (6Ckine, ALK-1, CD30 L, eotaxin-1, galectin-1, GITR, IL-2, IL- 6, IL-10, IL-13, IL-17B R, MIP-1α, MIP-3β, RANKL, TROY, and VEGF-D) were found dysregulated in transgenic SOD1G93A mice at asymptomatic stage compared with age-matched controls. Immunoassays of serial samples revealed positive expression of ALK-1, GITR and IL-17B R at P60 and P90 in mice with shorter survival. In addition, eotaxin-1 and galectin-1 levels were significantly increased at terminal stage in SOD1G93A mice that showed shorter survival time. Finally, levels of eotaxin-1, galectin-1, IL-2, IL-6, MIP-1α, and TROY at P90 or endpoint negatively correlated with the longevity of transgenic mice. Conclusions: We demonstrated in the SOD1G93A model of ALS that increased levels of several cytokines were associated with a shorter lifespan. However, their role as prognostic biomarkers is unclear as their expression was very variable depending on both the disease stage and the subject. Nevertheless, cytokines may be potential therapeutic targets. DOI: 10.3389/fimmu.2019.00801 PMCID: PMC6473074 122. Front Immunol. 2019 Apr 12;10:726. doi: 10.3389/fimmu.2019.00726. eCollection 2019. The Cerebrospinal Fluid in Multiple Sclerosis. Deisenhammer F(1), Zetterberg H(2)(3)(4)(5), Fitzner B(6), Zettl UK(6). Author information: (1)Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. (2)Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. (3)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. (4)Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom. (5)The Fluid Biomarker Laboratory, UK Dementia Research Institute at UCL, London, United Kingdom. (6)Division of Neuroimmunology, Department of Neurology, University Medicine Rostock, Rostock, Germany. Investigation of cerebrospinal fluid (CSF) in the diagnostic work-up in suspected multiple sclerosis (MS) patients has regained attention in the latest version of the diagnostic criteria due to its good diagnostic accuracy and increasing issues with misdiagnosis of MS based on over interpretation of neuroimaging results. The hallmark of MS-specific changes in CSF is the detection of oligoclonal bands (OCB) which occur in the vast majority of MS patients. Lack of OCB has a very high negative predictive value indicating a red flag during the diagnostic work-up, and alternative diagnoses should be considered in such patients. Additional molecules of CSF can help to support the diagnosis of MS, improve the differential diagnosis of MS subtypes and predict the course of the disease, thus selecting the optimal therapy for each patient. DOI: 10.3389/fimmu.2019.00726 PMCID: PMC6473053 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 93 – Multiple Sklerose: Veröffentlichungen April 2019 123. Front Immunol. 2019 Apr 5;10:711. doi: 10.3389/fimmu.2019.00711. eCollection 2019. PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation. Wimmer I(1)(2), Tietz S(1), Nishihara H(1), Deutsch U(1), Sallusto F(3)(4), Gosselet F(5), Lyck R(1), Muller WA(6), Lassmann H(2), Engelhardt B(1). Author information: (1)Theodor Kocher Institute, University of Bern, Bern, Switzerland. (2)Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria. (3)Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland. (4)Institute of Microbiology, ETH Zürich,, Zurich, Switzerland. (5)Blood-Brain Barrier Laboratory, Université d'Artois, Lens, France. (6)Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Breakdown of the blood-brain barrier (BBB) and increased immune cell trafficking into the central nervous system (CNS) are hallmarks of the pathogenesis of multiple sclerosis (MS). Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is expressed on cells of the vascular compartment and regulates vascular integrity and immune cell trafficking. Involvement of PECAM-1 in MS pathogenesis has been suggested by the detection of increased levels of soluble PECAM-1 (sPECAM-1) in the serum and CSF of MS patients. Here, we report profound upregulation of cell-bound PECAM-1 in initial (pre-phagocytic) white matter as well as active cortical gray matter MS lesions. Using a human in vitro BBB model we observed that PECAM-1 is not essential for the transmigration of human CD4+ T-cell subsets (Th1, Th1*, Th2, and Th17) across the BBB. Employing an additional in vitro BBB model based on primary mouse brain microvascular endothelial cells (pMBMECs) we show that the lack of endothelial PECAM-1 impairs BBB properties as shown by reduced transendothelial electrical resistance (TEER) and increases permeability for small molecular tracers. Investigating T-cell migration across the BBB under physiological flow by in vitro live cell imaging revealed that absence of PECAM-1 in pMBMECs did not influence arrest, polarization, and crawling of effector/memory CD4+ T cells on the pMBMECs. Absence of endothelial PECAM-1 also did not affect the number of T cells able to cross the pMBMEC monolayer under flow, but surprisingly favored transcellular over paracellular T-cell diapedesis. Taken together, our data demonstrate that PECAM-1 is critically involved in regulating BBB permeability and although not required for T-cell diapedesis itself, its presence or absence influences the cellular route of T-cell diapedesis across the BBB. Upregulated expression of cell-bound PECAM-1 in human MS lesions may thus reflect vascular repair mechanisms aiming to restore BBB integrity and paracellular T-cell migration across the BBB as it occurs during CNS immune surveillance. DOI: 10.3389/fimmu.2019.00711 PMCID: PMC6460670 124. Front Immunol. 2019 Apr 10;10:540. doi: 10.3389/fimmu.2019.00540. eCollection 2019. Brain Citrullination Patterns and T Cell Reactivity of Cerebrospinal Fluid-Derived CD4+ T Cells in Multiple Sclerosis. Faigle W(1), Cruciani C(1), Wolski W(2), Roschitzki B(2), Puthenparampil M(1), Tomas-Ojer P(1), Sellés- Moreno C(1), Zeis T(3), Jelcic I(1), Schaeren-Wiemers N(3), Sospedra M(1), Martin R(1). Author information: (1)Neuroimmunology and MS Research Section, Neurology Clinic, University Zurich, University Hospital Zurich, Zurich, Switzerland. (2)Functional Genomics Center Zurich, ETH Zurich & University of Zurich, Zurich, Switzerland. (3)Neurobiology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland. Immune responses to citrullinated peptides have been described in autoimmune diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). We investigated the post-translational modification (PTM), arginine to citrulline, in brain tissue of MS patients and controls (C) by proteomics and subsequently the cellular immune response of cerebrospinal fluid (CSF)-infiltrating T cells to citrullinated and unmodified peptides of myelin basic protein (MBP). Using specifically adapted tissue extraction- and combined data interpretation protocols we could establish a map of citrullinated proteins by identifying more than 80 proteins with two or more citrullinated peptides in human brain tissue. We report many of them for the first time. For the already described citrullinated proteins MBP, GFAP, and vimentin, we could identify additional citrullinated sites. The number of modified proteins in MS white matter was higher than control tissue. Citrullinated peptides are considered neoepitopes that may trigger autoreactivity. We used newly identified epitopes and previously reported immunodominant myelin peptides in their citrullinated and non-citrullinated form to address the recognition of CSF-infiltrating CD4+ T cells from 22 MS patients by measuring proliferation and IFN-γ secretion. We did not detect marked responses to citrullinated peptides, but slightly more strongly to the non-modified version. Based on these data, we conclude that citrullination does not appear to be an important activating factor of a T cell response, but could be the consequence of an immune- or inflammatory response. Our approach allowed us to perform a deep proteome analysis and opens new technical possibilities to analyze complex PTM patterns on minute quantities of rare tissue samples. DOI: 10.3389/fimmu.2019.00540 PMCID: PMC6467957 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 94 – Multiple Sklerose: Veröffentlichungen April 2019 125. Front Immunol. 2019 Apr 4;10:710. doi: 10.3389/fimmu.2019.00710. eCollection 2019. The iNOS Activity During an Immune Response Controls the CNS Pathology in Experimental Autoimmune Encephalomyelitis. Sonar SA(1), Lal G(1). Author information: (1)National Center for Cell Science, Pune, India. Inducible nitric oxide synthase (iNOS) plays a critical role in the regulation of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Previous studies have shown that iNOS plays pathogenic as well as regulatory roles in MS and EAE. However, how does iNOS alters the pathophysiology of the central nervous system (CNS) in neuronal autoimmunity is not clearly understood. In the present work, we show that treatment of mice with L-NAME, an iNOS inhibitor, during the antigen-priming phase primarily alters brain pathology, while in the subsequent effector phase of the immune response, the spinal cord is involved. Inhibition of iNOS during the priming phase of the immune response promotes the infiltration of pathogenic CD11b+F4/80-Gr-1+ cells, but there is low recruitment of regulatory CD11b+F4/80+ cells in the brain. Inhibition of iNOS during the effector phase shows similar pathogenic alterations in the spinal cord, instead of in the brain. Treatment of wild-type mice with L-NAME or mice having genetic deficiency of iNOS show lower MHC-II expression on the dendritic cells, but not on macrophages. Our data suggest that iNOS has a critical regulatory role during antigen-priming as well as in the effector phase of EAE, and inhibition iNOS at different stages of the immune response can differentially alter either the brain or spinal cord pathology. Understanding the cellular and molecular mechanisms through which iNOS functions could help to design a better strategies for the clinical management of neuroinflammation and neuronal autoimmunity. DOI: 10.3389/fimmu.2019.00710 PMCID: PMC6458273 126. Front Immunol. 2019 Apr 3;10:695. doi: 10.3389/fimmu.2019.00695. eCollection 2019. Epstein-Barr Virus and miRNAs: Partners in Crime in the Pathogenesis of Multiple Sclerosis? Hassani A(1), Khan G(1). Author information: (1)Department of Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression post transcriptionally. In healthy individuals, miRNAs contribute to maintaining gene expression homeostasis. However, the level of miRNAs expressed is markedly altered in different diseases, including multiple sclerosis (MS). The impact of such changes is being investigated, and thought to shape the immune system into the inflammatory autoimmune phenotype. Much is yet to be learned about the contribution of miRNAs in the molecular pathology of MS. Epstein-Barr virus (EBV) infection is a major risk factor for the development of MS. EBV encodes more than 40 miRNAs, most of which have been studied in the context of EBV associated cancers. These viral miRNAs regulate genes involved in cell apoptosis, antigen presentation and recognition, as well as B cell transformation. If EBV infection contributes to the pathology of MS, it is plausible that EBV miRNAs may be involved. Unfortunately, there are limited studies addressing how EBV miRNAs are involved in the pathogenesis of MS. This review summarizes what has been reported regarding cellular and viral miRNA profiles in MS and proposes possible interactions between the two in the development of MS. DOI: 10.3389/fimmu.2019.00695 PMCID: PMC6456696 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 95 – Multiple Sklerose: Veröffentlichungen April 2019 127. Front Immunol. 2019 Mar 29;10:641. doi: 10.3389/fimmu.2019.00641. eCollection 2019. CSF Free Light Chains as a Marker of Intrathecal Immunoglobulin Synthesis in Multiple Sclerosis: A Blood-CSF Barrier Related Evaluation in a Large Cohort. Senel M(1), Mojib-Yezdani F(1), Braisch U(2), Bachhuber F(1), Lewerenz J(1), Ludolph AC(1), Otto M(1), Tumani H(1)(3). Author information: (1)Department of Neurology, University of Ulm, Ulm, Germany. (2)Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany. (3)Specialty Hospital of Neurology Dietenbronn, Schwendi, Germany. Objectives: The importance of immunoglobulin G (IgG) oligoclonal bands (OCB) in the diagnosis of multiple sclerosis (MS) was reaffirmed again in the recently revised MS diagnostic criteria. Since OCB testing is based on non-quantitative techniques and demands considerable methodological experience, measurement of CSF immunoglobulin free light chains (FLC) has been suggested as quantitative alternative to OCB. We aimed to establish reference values for FLC measures and evaluate their diagnostic accuracy with regard to the diagnosis of MS. Methods: Immunoglobulin kappa (KFLC) and lambda (LFLC) free light chains were prospectively measured by nephelometry in CSF and serum sample pairs in 1,224 patients. The analyzed cohort included patients with MS, other autoimmune or infectious inflammatory diseases of the nervous system as well as 989 patients without signs for nervous system inflammation. Results: Regarding diagnosis of MS, the diagnostic sensitivity and specificity of intrathecal KFLC ratio were 93.3 and 93.7% using the CSF-serum albumin ratio-dependent reference values, 92.0 and 95.9% for intrathecal KFLC ratio applying the ROC-curve determined cut-off levels, 62.7 and 98.3% for IgG index, 64.0 and 98.8% for intrathecal IgG synthesis according to Reiber diagrams, and 94.7 and 93.3% for OCB. Diagnostic sensitivity and specificity of intrathecal LFLC were clearly lower than KFLC. Conclusions: Intrathecal KFLC and OCB showed the highest diagnostic sensitivities for MS. However, specificity was slightly lower compared to other quantitative IgG parameters. Consequently, CSF FLC may not replace OCB, but it may support diagnosis in MS as a quantitative parameter. DOI: 10.3389/fimmu.2019.00641 PMCID: PMC6449445 128. Front Immunol. 2019 Mar 29;10:628. doi: 10.3389/fimmu.2019.00628. eCollection 2019. A Sentinel in the Crosstalk Between the Nervous and Immune System: The (Immuno)-Proteasome. Limanaqi F(1), Biagioni F(2), Gaglione A(2), Busceti CL(2), Fornai F(1)(2). Author information: (1)Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. (2)I.R.C.C.S Neuromed, Pozzilli, Italy. The wealth of recent evidence about a bi-directional communication between nerve- and immune- cells revolutionized the traditional concept about the brain as an "immune-privileged" organ while opening novel avenues in the pathophysiology of CNS disorders. In fact, altered communication between the immune and nervous system is emerging as a common hallmark in neuro-developmental, neurodegenerative, and neuro- immunological diseases. At molecular level, the ubiquitin proteasome machinery operates as a sentinel at the crossroad between the immune system and brain. In fact, the standard proteasome and its alternative/inducible counterpart, the immunoproteasome, operate dynamically and coordinately in both nerve- and immune- cells to modulate neurotransmission, oxidative/inflammatory stress response, and immunity. When dysregulations of the proteasome system occur, altered amounts of standard- vs. immune- proteasome subtypes translate into altered communication between neurons, glia, and immune cells. This contributes to neuro-inflammatory pathology in a variety of neurological disorders encompassing Parkinson's, Alzheimer's, and Huntingtin's diseases, brain trauma, epilepsy, and Multiple Sclerosis. In the present review, we analyze those proteasome-dependent molecular interactions which sustain communication between neurons, glia, and brain circulating T-lymphocytes both in baseline and pathological conditions. The evidence here discussed converges in that upregulation of immunoproteasome to the detriment of the standard proteasome, is commonly implicated in the inflammatory- and immune- biology of neurodegeneration. These concepts may foster additional studies investigating the role of immunoproteasome as a potential target in neurodegenerative and neuro-immunological disorders. DOI: 10.3389/fimmu.2019.00628 PMCID: PMC6450179 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 96 – Multiple Sklerose: Veröffentlichungen April 2019 129. Front Immunol. 2019 Mar 21;10:515. doi: 10.3389/fimmu.2019.00515. eCollection 2019. Immune Cell Profiling of the Cerebrospinal Fluid Provides Pathogenetic Insights Into Inflammatory Neuropathies. Heming M(1), Schulte-Mecklenbeck A(1), Brix T(2), Wolbert J(1), Ruland T(3), Klotz L(1), Meuth SG(1), Gross CC(1), Wiendl H(1), Meyer Zu Hörste G(1). Author information: (1)Department of Neurology, Institute of Translational Neurology, University of Münster, Münster, Germany. (2)Institute of Medical Informatics, University of Münster, Münster, Germany. (3)Department of Psychiatry, University of Münster, Münster, Germany. Objective: Utilize immune cell profiles in the cerebrospinal fluid (CSF) to advance the understanding and potentially support the diagnosis of inflammatory neuropathies. Methods: We analyzed CSF cell flow cytometry data of patients with definite Guillain-Barré syndrome (GBS, n = 26) and chronic inflammatory demyelinating polyneuropathy (CIDP, n = 32) based on established diagnostic criteria in comparison to controls with relapsing-remitting multiple sclerosis (RRMS, n = 49) and idiopathic intracranial hypertension (IIH, n = 63). Results: Flow cytometry revealed disease-specific changes of CSF cell composition with a significant increase of NKT cells and CD8+ T cells in CIDP, NK cells in GBS, and B cells and plasma cells in MS in comparison to IIH controls. Principal component analysis demonstrated distinct CSF immune cells pattern in inflammatory neuropathies vs. RRMS. Systematic receiver operator curve (ROC) analysis identified NKT cells as the best parameter to distinguish GBS from CIDP. Composite scores combing several of the CSF parameters differentiated inflammatory neuropathies from IIH and GBS from CIDP with high confidence. Applying a novel dimension reduction technique, we observed an intra-disease heterogeneity of inflammatory neuropathies. Conclusion: Inflammatory neuropathies display disease- and subtype-specific alterations of CSF cell composition. The increase of NKT cells and CD8+ T cells in CIDP and NK cells in GBS, suggests a central role of cytotoxic cell types in inflammatory neuropathies varying between acute and chronic subtypes. Composite scores constructed from multi-dimensional CSF parameters establish potential novel diagnostic tools. Intra-disease heterogeneity suggests distinct disease mechanisms in subgroups of inflammatory neuropathies. DOI: 10.3389/fimmu.2019.00515 PMCID: PMC6448021 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 97 – Multiple Sklerose: Veröffentlichungen April 2019 130. Front Immunol. 2019 Mar 22;10:462. doi: 10.3389/fimmu.2019.00462. eCollection 2019. Prevotella histicola, A Human Gut Commensal, Is as Potent as COPAXONE® in an Animal Model of Multiple Sclerosis. Shahi SK(1), Freedman SN(2), Murra AC(1), Zarei K(3), Sompallae R(1), Gibson-Corley KN(1), Karandikar NJ(1)(2)(4), Murray JA(5)(6), Mangalam AK(1)(2)(3)(4). Author information: (1)Department of Pathology, University of Iowa, Iowa City, IA, United States. (2)Graduate Program in Immunology, University of Iowa, Iowa City, IA, United States. (3)Medical Scientist Training Program, University of Iowa, Iowa City, IA, United States. (4)Graduate Program in Molecular Cell Biology, University of Iowa, Iowa City, IA, United States. (5)Department of Immunology, Mayo Clinic, Rochester, MN, United States. (6)Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States. Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. We and others have shown that there is enrichment or depletion of some gut bacteria in MS patients compared to healthy controls (HC), suggesting an important role of the gut bacteria in disease pathogenesis. Thus, specific gut bacteria that are lower in abundance in MS patients could be used as a potential treatment option for this disease. In particular, we and others have shown that MS patients have a lower abundance of Prevotella compared to HC, whereas the abundance of Prevotella is increased in patients that receive disease-modifying therapies such as Copaxone® (Glatiramer acetate-GA). This inverse correlation between the severity of MS disease and the abundance of Prevotella suggests its potential for use as a therapeutic option to treat MS. Notably we have previously identified a specific strain, Prevotella histicola (P. histicola), that suppresses disease in the animal model of MS, experimental autoimmune encephalomyelitis (EAE) compared with sham treatment. In the present study we analyzed whether the disease suppressing effects of P. histicola synergize with those of the disease-modifying drug Copaxone® to more effectively suppress disease compared to either treatment alone. Treatment with P. histicola was as effective in suppressing disease as treatment with Copaxone®, whereas the combination of P. histicola plus Copaxone® was not more effective than either individual treatment. P. histicola-treated mice had an increased frequency and number of CD4+FoxP3+ regulatory T cells in periphery as well as gut and a decreased frequency of pro-inflammatory IFN-γ and IL17- producing CD4 T cells in the CNS, suggesting P. histicola suppresses disease by boosting anti-inflammatory immune responses and inhibiting pro-inflammatory immune responses. In conclusion, our study indicates that the human gut commensal P. histicola can suppress disease as efficiently as Copaxone® and may provide an alternative treatment option for MS patients. DOI: 10.3389/fimmu.2019.00462 PMCID: PMC6448018 131. Front Immunol. 2019 Mar 19;10:524. doi: 10.3389/fimmu.2019.00524. eCollection 2019. NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms. Webb LM(1)(2), Narvaez Miranda J(1), Amici SA(1), Sengupta S(1)(2), Nagy G(2), Guerau-de-Arellano M(1)(3)(4)(5). Author information: (1)Division of Medical Laboratory Science, Wexner Medical Center, School of Health and Rehabilitation Sciences, College of Medicine, The Ohio State University, Columbus, OH, United States. (2)Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, United States. (3)Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, United States. (4)Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States. (5)Department of Neuroscience, The Ohio State University, Columbus, OH, United States. Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) mediated by CD4+ T cells and modeled via experimental autoimmune encephalomyelitis (EAE). Inhibition of PRMT5, the major Type II arginine methyltransferase, suppresses pathogenic T cell responses and EAE. PRMT5 is transiently induced in proliferating memory inflammatory Th1 cells and during EAE. However, the mechanisms driving PRMT5 protein induction and repression as T cells expand and return to resting is currently unknown. Here, we used naive mouse and memory mouse and human Th1/Th2 cells as models to identify mechanisms controlling PRMT5 protein expression in initial and recall T cell activation. Initial activation of naive mouse T cells resulted in NF-κB-dependent transient Prmt5 transcription and NF-κB, mTOR and MYC-dependent PRMT5 protein induction. In murine memory Th cells, transcription and miRNA loss supported PRMT5 induction to a lesser extent than in naive T cells. In contrast, NF-κB/MYC/mTOR-dependent non- transcriptional PRMT5 induction played a major role. These results highlight the importance of the NF- κB/mTOR/MYC axis in PRMT5-driven pathogenic T cell expansion and may guide targeted therapeutic strategies for MS. DOI: 10.3389/fimmu.2019.00524 PMCID: PMC6433977 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 98 – Multiple Sklerose: Veröffentlichungen April 2019 132. Front Immunol. 2019 Mar 19;10:516. doi: 10.3389/fimmu.2019.00516. eCollection 2019. Bioinformatics Analyses Determined the Distinct CNS and Peripheral Surrogate Biomarker Candidates Between Two Mouse Models for Progressive Multiple Sclerosis. Omura S(1)(2), Sato F(1)(2), Martinez NE(2), Park AM(1), Fujita M(1), Kennett NJ(3), Cvek U(4), Minagar A(5), Alexander JS(5)(6), Tsunoda I(1)(2)(5). Author information: (1)Department of Microbiology, Kindai University Faculty of Medicine, Osakasayama, Japan. (2)Department of Microbiology and Immunology, Louisiana State University Health Sciences Center- Shreveport, Shreveport, LA, United States. (3)Department of Pathology, University of Utah, Salt Lake City, UT, United States. (4)Department of Computer Science, Louisiana State University Shreveport, Shreveport, LA, United States. (5)Department of Neurology, Louisiana State University Health Sciences Center- Shreveport, Shreveport, LA, United States. (6)Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, United States. Previously, we have established two distinct progressive multiple sclerosis (MS) models by induction of experimental autoimmune encephalomyelitis (EAE) with myelin oligodendrocyte glycoprotein (MOG) in two mouse strains. A.SW mice develop ataxia with antibody deposition, but no T cell infiltration, in the central nervous system (CNS), while SJL/J mice develop paralysis with CNS T cell infiltration. In this study, we determined biomarkers contributing to the homogeneity and heterogeneity of two models. Using the CNS and spleen microarray transcriptome and cytokine data, we conducted computational analyses. We identified up-regulation of immune-related genes, including immunoglobulins, in the CNS of both models. Pro-inflammatory cytokines, interferon (IFN)-γ and interleukin (IL)-17, were associated with the disease progression in SJL/J mice, while the expression of both cytokines was detected only at the EAE onset in A.SW mice. Principal component analysis (PCA) of CNS transcriptome data demonstrated that down- regulation of prolactin may reflect disease progression. Pattern matching analysis of spleen transcriptome with CNS PCA identified 333 splenic surrogate markers, including Stfa2l1, which reflected the changes in the CNS. Among them, we found that two genes (PER1/MIR6883 and FKBP5) and one gene (SLC16A1/MCT1) were also significantly up-regulated and down-regulated, respectively, in human MS peripheral blood, using data mining. DOI: 10.3389/fimmu.2019.00516 PMCID: PMC6434997 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 99 – Multiple Sklerose: Veröffentlichungen April 2019 133. Front Immunol. 2019 Mar 19;10:514. doi: 10.3389/fimmu.2019.00514. eCollection 2019. The MRZ-Reaction and Specific Autoantibody Detection for Differentiation of ANA- Positive Multiple Sclerosis From Rheumatic Diseases With Cerebral Involvement. Venhoff N(1), Thiel J(1), Rizzi M(1), Venhoff A(1), Rauer S(2), Endres D(3), Hentze C(1), Staniek J(1), Huzly D(4), Voll RE(1), Salzer U(1), Hottenrott T(2). Author information: (1)Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg im Breisgau, Germany. (2)Department of Neurology and Neurophysiology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg im Breisgau, Germany. (3)Department of Psychiatry and Psychotherapy, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg im Breisgau, Germany. (4)Faculty of Medicine, Institute of Virology, Medical Center - University of Freiburg, Freiburg im Breisgau, Germany. Objective: Rheumatic diseases with involvement of the central nervous system (RDwCNS) may mimic multiple sclerosis (MS). Inversely, up to 60% of MS-patients have antinuclear autoantibodies (ANAs) and may be misdiagnosed as RDwCNS. The detection of antibodies against extractable nuclear antigens (ENA) and oligoclonal bands (OCB) are established valuable diagnostic tools in the differential diagnosis of RDwCNS and MS. The MRZ-reaction (MRZR) is defined by three antibody indices (AIs) against neurotropic viruses and is frequently positive in MS. To investigate the added value of MRZR combined with testing for antibodies against ENAs and OCB detection to distinguish RDwCNS from ANA positive MS. Methods: MRZR was evaluated in RDwCNS (n = 40) and 68 ANA positive MS-patients. Two stringency levels, MRZR-1 and MRZR-2 (at least one respectively two of three AIs positive) were applied. Autoantibody testing included ANA plus ENA and anti-dsDNA antibodies, antiphospholipid antibodies, and anti-neutrophil cytoplasmic antibodies. Results: Most of the RDwCNS patients (n = 32; 80%) suffered from systemic lupus erythematosus. Within the RDwCNS group 20% had a positive MRZR-1 and 8.5% a positive MRZR-2 compared to 80.9 and 60%, respectively within the MS-group (p < 0.0001 for both comparisons). Oligoclonal bands were found in 28.6% of the RDwCNS patients and 94.3% of the MS-patients (p < 0.0001). Conversely, autoantibodies to specific nuclear antigens or phospholipids were found more frequently in RDwCNS. A positive MRZR in conjunction with the absence of ENA autoantibodies distinguished MS from RDwCNS with high specificity (97.5%). Conclusions: We suggest combining MRZR, OCBs, and specific autoantibody diagnostics to differentiate RDwCNS from MS. DOI: 10.3389/fimmu.2019.00514 PMCID: PMC6433788 134. Front Immunol. 2019 Mar 19;10:488. doi: 10.3389/fimmu.2019.00488. eCollection 2019. The Association Between Vitamin D and Multiple Sclerosis Risk: 1,25(OH)2D3 Induces Super-Enhancers Bound by VDR. Lu M(1)(2), McComish BJ(1), Burdon KP(1), Taylor BV(1), Körner H(1)(3). Author information: (1)Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia. (2)Department of Immunology, Anhui Medical University, Hefei, China. (3)Key Laboratory of Anti- inflammatory and Immunopharmacology, Ministry of Education, Collaborative Innovation Center of Anti- Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China. A super-enhancer (SE) is a cluster of enhancers with a relatively high density of particular chromatin features. SEs typically regulate key genes that can determine cell identity and differentiation. Identifying SEs and their effects may be critical in predicting key regulatory genes, such as master transcription factor genes or oncogenes. Signal inducible SEs are dense stretches of signal terminal transcription factor (TF) binding regions, and may modulate the interaction between environmental factors (e.g., Vitamin D) and genetic factors (i.e., risk variants) in complex diseases such as multiple sclerosis (MS). As a complex autoimmune disease, the etiology and progression of MS, including the interaction between Vitamin D and MS risk variants, is still unclear and can be explored from the aspect of signal SEs. Vitamin D [with its active form: 1,25(OH)2D3], is an environmental risk factor for MS. It binds the Vitamin D receptor (VDR) and regulates gene expression. This study explores the association between VDR super-enhancers (VSEs) and MS risk variants. Firstly, we reanalyse public ChIP-seq and RNA-seq data to classify VSEs into three categories according to their combinations of persistent and secondary VDR binding. Secondly, we indicate the genes with VSE regions that are near MS risk variants. Furthermore, we find that MS risk variants are enriched in VSE regions, and we indicate some genes with a VSE overlapping MS risk variant for further exploration. We also find two clusters of genes from the set of genes showing correlation of expression patterns with the MS risk gene ZMIZ1 that appear to be regulated by VSEs in THP-1 cells. It is the first time that VSEs have been analyzed, and we directly connect the genetic risk factors for MS risk with Vitamin D based on VSEs. DOI: 10.3389/fimmu.2019.00488 PMCID: PMC6433938 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 100 – Multiple Sklerose: Veröffentlichungen April 2019 135. Front Immunol. 2019 Mar 19;10:404. doi: 10.3389/fimmu.2019.00404. eCollection 2019. Abrogation of Endogenous Glycolipid Antigen Presentation on Myelin-Laden Macrophages by D-Sphingosine Ameliorates the Pathogenesis of Experimental Autoimmune Encephalomyelitis. Ban Y(1), Dong W(1), Zhang L(2), Zhou T(3)(4), Altiti AS(5), Ali K(5), Mootoo DR(5), Blaho VA(6)(7), Hla T(6), Ren Y(3), Ma X(1)(2). Author information: (1)Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, United States. (2)State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology, Shanghai Jiaotong University, Shanghai, China. (3)Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United States. (4)Key Laboratory of Biorheological Science and Technology, College of Bioengineering, Chongqing University, Chongqing, China. (5)Department of Chemistry, Hunter College, City University of New York, New York, NY, United States. (6)Department of Pathology and Laboratory Medicine, Center for Vascular Biology, Weill Medical Medicine, New York, NY, United States. (7)Sanford Burnham Prepys Medical Discovery Institute, La Jolla, CA, United States. Background: Although myelin is composed of mostly lipids, the pathological role of myelin lipids in demyelinating diseases remains elusive. The principal lipid of the myelin sheath is β-galactosylceramide (β- Galcer). Its α-anomer (α-Galcer) has been demonstrated to be antigenically presented by macrophages via CD1d, a MHC class I-like molecule. Myelin, which is mostly composed of β-Galcer, has been long considered as an immunologically-inert neuron insulator, because the antigen-binding cleft of CD1d is highly α-form-restricted. Results: Here, we report that CD1d-mediated antigenic presentation of myelin-derived galactosylceramide (Mye-GalCer) by macrophages contributed significantly to the progression of experimental autoimmune encephalomyelitis (EAE). Surprisingly, this presentation was recognizable by α- Galcer:CD1d-specific antibody (clone L363), but incapable of triggering expansion of iNKT cells and production of iNKT signature cytokines (IFNγ and IL-4). Likewise, a synthesized analog of Mye-Galcer, fluorinated α-C-GalCer (AA2), while being efficiently presented via CD1d on macrophages, failed to stimulate production of IFNγ and IL-4. However, AA2 significantly exacerbated EAE progression. Further analyses revealed that the antigenic presentations of both Mye-GalCer and its analog (AA2) in α-form via CD1d promoted IL-17 production from T cells, leading to elevated levels of IL-17 in EAE spinal cords and sera. The IL-17 neutralizing antibody significantly reduced the severity of EAE symptoms in AA2-treated mice. Furthermore, D-sphingosine, a lipid possessing the same hydrophobic base as ceramide but without a carbohydrate residue, efficiently blocked this glycolipid antigen presentation both in vitro and in spinal cords of EAE mice, and significantly decreased IL-17 and ameliorated the pathological symptoms. Conclusion: Our findings reveal a novel pathway from the presentation of Mye-GalCer to IL-17 production, and highlight the promising therapeutic potential of D-sphingosine for the human disorder of multiple sclerosis. DOI: 10.3389/fimmu.2019.00404 PMCID: PMC6433838 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 101 – Multiple Sklerose: Veröffentlichungen April 2019 136. Front Immunol. 2019 Mar 15;10:480. doi: 10.3389/fimmu.2019.00480. eCollection 2019. CSF Cytokines in Aging, Multiple Sclerosis, and Dementia. Hu WT(1)(2), Howell JC(1)(3), Ozturk T(1), Gangishetti U(1), Kollhoff AL(1), Hatcher-Martin JM(4), Anderson AM(5), Tyor WR(1)(6). Author information: (1)Department of Neurology, Emory University, Atlanta, GA, United States. (2)Center for Neurodegenerative Disease, Emory University, Atlanta, GA, United States. (3)Alzheimer's Disease Research Center, Emory University, Atlanta, GA, United States. (4)Jean and Paul Amos Parkinson's Disease and Movement Disorders Program, Emory University, Atlanta, GA, United States. (5)Department of Internal Medicine, Emory University, Atlanta, GA, United States. (6)Atlanta VA Medical Center, Decatur, GA, United States. Inflammation is a common process involved in aging, multiple sclerosis (MS), and age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), but there is limited evidence for the effects of aging on inflammation in the central nervous system. We collected cerebrospinal fluid (CSF) from 105 healthy control subjects representing a wide age range (23-86), and analyzed levels of cytokines associated innate immunity (TNF-α) and different T-helper subtypes: interferon- gamma induced protein 10 (IP-10) for Th1, interleukin-10 (IL-10) for Th2, and interleukin 8 (IL-8/CXCL8) for Th17. We show that CSF levels of TNF-α, IP-10, and IL-8 all increased linearly with age, but levels of IL-10 demonstrated a U-shaped relationship with age. We further found greater age-related increases in TNF-α, IL-10, and IL-8 relative to increases in IP-10 levels, consistent with a shift from Th1 to other inflammatory phenotypes. Finally, when we analyzed the same four cytokines in people with neurological disorders, we found that MS and AD, but not PD or dementia with Lewy bodies, further accentuated the age-related shift from Th1- to non-Th1-related cytokines. We propose that CSF cytokine levels represent powerful surrogates of brain inflammation and aging, and some, but not all, neurological disorders accelerate the shift away from Th1 phenotypes. DOI: 10.3389/fimmu.2019.00480 PMCID: PMC6428695 137. Front Neurol. 2019 Apr 12;10:373. doi: 10.3389/fneur.2019.00373. eCollection 2019. Cognitive Impairment in Multiple Sclerosis Is Reflected by Increased Susceptibility to the Sound-Induced Flash Illusion. Yalach ov Y(1), Bergmann HJ(1), Soydaş D(1), Buschenlange C(1), Fadai Motlagh LY(1), Naumer MJ(2), Kaiser J(2), Frisch S(1)(3), Behrens M(1), Foerch C(1), Gehrig J(1). Author information: (1)Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany. (2)Institute of Medical Psychology, Goethe-University, Frankfurt am Main, Germany. (3)Institute of Psychology, Goethe-University, Frankfurt am Main, Germany. Objective: To determine whether the performance of multiple sclerosis (MS) patients in the sound-induced flash illusion (SiFi), a multisensory perceptual illusion, would reflect their cognitive impairment. Methods: We performed the SiFi task as well as an extensive neuropsychological testing in 95 subjects [39 patients with relapse-remitting MS (RRMS), 16 subjects with progressive multiple sclerosis (PMS) and 40 healthy control subjects (HC)]. Results: MS patients reported more frequently the multisensory SiFi than HC. In contrast, there were no group differences in the control conditions. Essentially, patients with progressive type of MS continued to perceive the illusion at stimulus onset asynchronies (SOA) that were more than three times longer than the SOA at which the illusion was already disrupted for healthy controls. Furthermore, MS patients' degree of cognitive impairment measured with a broad neuropsychological battery encompassing tests for memory, attention, executive functions, and fluency was predicted by their performance in the SiFi task for the longest SOA of 500 ms. Conclusions: These findings support the notion that MS patients exhibit an altered multisensory perception in the SiFi task and that their susceptibility to the perceptual illusion is negatively correlated with their neuropsychological test performance. Since MS lesions affect white matter tracts and cortical regions which seem to be involved in the transfer and processing of both crossmodal and cognitive information, this might be one possible explanation for our findings. SiFi might be considered as a brief, non-expensive, language- and education-independent screening test for cognitive deficits in MS patients. DOI: 10.3389/fneur.2019.00373 PMCID: PMC6474182 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 102 – Multiple Sklerose: Veröffentlichungen April 2019 138. Front Neurol. 2019 Apr 9;10:341. doi: 10.3389/fneur.2019.00341. eCollection 2019. Anti-IL-6 Receptor Antibody Inhibits Spontaneous Pain at the Pre-onset of Experimental Autoimmune Encephalomyelitis in Mice. Serizawa K(1), Tomizawa-Shinohara H(1), Yasuno H(2), Yogo K(1), Matsumoto Y(1). Author information: (1)Product Research Department, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan. (2)Product Research Department, Chugai Pharmaceutical Co., Ltd, Kanagawa, Japan. Chronic pain is a significant symptom in patients with autoimmune encephalomyelitis, such as multiple sclerosis and neuromyelitis optica. The most commonly used animal model of these diseases is experimental autoimmune encephalomyelitis (EAE). We previously reported that evoked pain, such as mechanical allodynia, was improved by an anti-IL-6 receptor antibody in EAE mice. However, few reports have evaluated spontaneous pain in EAE mice. Here, we assessed spontaneous pain in EAE mice by utilizing the Mouse Grimace Scale (MGS, a standardized murine facial expression-based coding system) and evaluated the influence of an anti-IL-6 receptor antibody (MR16-1). EAE was induced in female C57BL/6J mice by subcutaneous immunization with myelin oligodendrocyte glycoprotein 35-55 emulsified in adjuvant and administration of pertussis toxin. Mice were placed individually in cubicles and filmed for about 10 min. Ten clear head shots per mouse from the video recording were given a score of 0, 1, or 2 for each of three facial action units: orbital tightening, nose bulge, and ear position. Clinical symptoms of EAE were also scored. Measurement of 5-HT in the spinal cord and functional imaging of the periaqueductal gray (PAG) were also performed. Compared with control mice, MGS score was significantly higher in EAE mice. MR16-1 prevented this increase, especially in pre-onset EAE mice. Promotion of spinal 5-HT turnover and reduction of PAG activity were observed in pre-onset EAE mice. These results suggest that MR16-1 prevented spontaneous pain developed before EAE onset. DOI: 10.3389/fneur.2019.00341 PMCID: PMC6465542 139. Front Neurol. 2019 Apr 9;10:339. doi: 10.3389/fneur.2019.00339. eCollection 2019. Fatigue in Multiple Sclerosis: General and Perceived Fatigue Does Not Depend on Corticospinal Tract Dysfunction. Mordillo-Mateos L(1), Soto-Leon V(1), Torres-Pareja M(1)(2), Peinado-Palomino D(1)(2), Mendoza-Laiz N(3), Alonso-Bonilla C(1), Dileone M(4), Rotondi M(5), Aguilar J(6), Oliviero A(1). Author information: (1)FENNSI Group, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha, Toledo, Spain. (2)Facultad de Ciencias del Deporte, University of Castilla La Mancha, Toledo, Spain. (3)CAFyD, Universidad Francisco de Vitoria, Madrid, Spain. (4)Advanced Neurorehabilitation Unit, Hospital Los Madroños, Madrid, Spain. (5)Unit of Internal Medicine and Endocrinology, Laboratory for Endocrine Disruptors, IRCCS Scientific Clinical Institutes Maugeri, University of Pavia, Pavia, Italy. (6)Experimental Neurophysiology, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla La Mancha, Toledo, Spain. Background: Multiple sclerosis (MS) is an autoimmune disorder of the CNS in which inflammation, demyelination, and axonal damage of the central nervous system coexist. Fatigue is one of the most disabling symptoms in MS and little is known about the neurophysiological mechanisms involved. Methods: To give more mechanistic insight of fatigue in MS, we studied a cohort of 17 MS patients and a group of 16 age-matched healthy controls. Baseline Fatigue Severity Scales and Fatigue Rating were obtained from both groups to check the level of fatigue and to perform statistical correlations with fatigue-induced neurophysiologic changes. To induce fatigue we used a handgrip task. During the fatiguing task, we evaluated fatigue state (using a dynamometer) and after the task we evaluated the Borg Rating of Perceived Exertion Scale. Transcranial magnetic stimulation and peripheral electric stimulation were used to assess corticospinal tract and peripheral system functions before and after the task. Results: Clinically significant fatigue and central motor conduction time were greater in patients than in controls, while motor cortex excitability was decreased and maximal handgrip strength reduced in patients. Interestingly, fatigue state was positively correlated to perceived fatigue in controls but not in patients. Furthermore, in the presence of similar fatigue state over time, controls showed a significant fatigue-related reduction in motor evoked potential (a putative marker of central fatigue) whereas this effect was not seen in patients. Conclusions: in MS patients the pathogenesis of fatigue seems not driven by the mechanisms directly related to corticospinal function (that characterize fatigue in controls) but seems probably due to other "central abnormalities" upstream to primary motor cortex. DOI: 10.3389/fneur.2019.00339 PMCID: PMC6465550 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 103 – Multiple Sklerose: Veröffentlichungen April 2019 140. Front Neurol. 2019 Apr 5;10:338. doi: 10.3389/fneur.2019.00338. eCollection 2019. Neurofilament Light Chain as a Biomarker in Multiple Sclerosis. Varhaug KN(1)(2)(3), Torkildsen Ø(1)(2)(3), Myhr KM(1)(2)(3), Vedeler CA(1)(2)(3). Author information: (1)Department of Neurology, Haukeland University Hospital, Bergen, Norway. (2)Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway. (3)Neuro-SysMed - Centre of Excellence for Experimental Therapy in Neurology, Department of Neurology, Haukeland University Hospital, and Department of Clinical Medicine, University of Bergen, Bergen, Norway. Due to the unpredictable course and heterogenous treatment response in multiple sclerosis (MS), there is a clear need for biomarkers that reflect disease activity in the clinical follow-up of these patients. Neurofilaments are neuron-specific components of the cytoskeleton that can be assayed in different body compartments. They have been explored as potential biomarkers for many years. Neurofilament light chain (NF-L) appears the most promising biomarker in MS patients, and there is now little doubt that NF-L should have a role in the follow-up of MS patients. Newer assays and techniques for NF-L detection available in serum samples confirms the usefulness of NF-L as a biomarker. Nevertheless, there is still a need for prospective studies, and studies to determine clinical useful cut-off values. This review evaluates the strengths and weaknesses of NF-L as a biomarker in patients with MS. DOI: 10.3389/fneur.2019.00338 PMCID: PMC6460359 141. Front Neurol. 2019 Apr 10;10:337. doi: 10.3389/fneur.2019.00337. eCollection 2019. Cancer Risk and Multiple Sclerosis: Evidence From a Large Italian Cohort. D'Amico E(1), Chisari CG(1), Arena S(1), Zanghì A(1), Toscano S(1), Lo Fermo S(1), Maimone D(2), Castaing M(3), Sciacca S(3), Zappia M(1), Patti F(1). Author information: (1)Section of Neurosciences, Department "GF Ingrassia", University of Catania, Catania, Italy. (2)Azienda Ospedaliera Garibaldi, Catania, Italy. (3)Department of Hygiene, University of Catania, Catania, Italy. Introduction: The complexity of understanding cancer risk in MS is increased by inconsistencies in study design, and the lack of age-, sex-, and ethnicity-specific risk estimates. Aims of our study were to estimate the incidence of cancers in the MS population of Catania (Italy) and to evaluate the impact of disease- modifying treatments (DMTs) in cancer risk. Materials and Methods: We screened 2,730 PwMS according to the MS criteria of Mc Donald 2010 referring to MS center of Catania in the period between 2003 and 2013. We matched database of MS patients with the Integrated Cancer of Catania-Messina-Siracusae-Enna. We calculated age and sex specific standardized incidence ratios (SIR) and the relative risk (RR) of developing cancer in MS patients treated with at least two different DMTs compared to who received one or no treatment. Results: Out of 2,730, 1,180 MS patients (67.1% females; mean age 41.2 ± 12.9) were enrolled. We found 36 cancers. Global SIR was 1.18 (CI95% 0.78-1.58), with a significantly higher risk in men with a range age of 20 to 50 years [2.84; (CI95% 1.59-4.09)] and in women over 50 years [1.82 (CI95% 1.08- 2.55)]. RR of developing cancer was 1.99 (CI95% 1.14-3.45) in MS patients switching one DMT and 3.38 (CI95% 1.83-6.22) in who switched at least twice. Discussion: Our results demonstrated that cancer risk was not increased in our MS population; but age and sex different distribution may partly drive cancer risk. Higher cancer risk in MS patients switching more than two DMTs should take into account in treatment decision making. DOI: 10.3389/fneur.2019.00337 PMCID: PMC6469363 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 104 – Multiple Sklerose: Veröffentlichungen April 2019 142. Front Neurol. 2019 Apr 9;10:334. doi: 10.3389/fneur.2019.00334. eCollection 2019. Standardization of T1w/T2w Ratio Improves Detection of Tissue Damage in Multiple Sclerosis. Cooper G(1)(2)(3), Finke C(2)(4), Chien C(1)(3), Brandt AU(1)(3)(5), Asseyer S(1)(3), Ruprecht K(6), Bellmann-Strobl J(1)(3), Paul F(1)(2)(3)(6), Scheel M(1)(3)(7). Author information: (1)NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany. (2)Einstein Center for Neurosciences, Berlin, Germany. (3)Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany. (4)Berlin School of Mind and Brain, Humboldt-Universität zu Berlin, Berlin, Germany. (5)Department of Neurology, University of California, Irvine, Irvine, CA, United States. (6)Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Berlin, Germany. (7)Department of Neuroradiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany. Normal appearing white matter (NAWM) damage develops early in multiple sclerosis (MS) and continues in the absence of new lesions. The ratio of T1w and T2w (T1w/T2w ratio), a measure of white matter integrity, has previously shown reduced intensity values in MS NAWM. We evaluate the validity of a standardized T1w/T2w ratio (sT1w/T2w ratio) in MS and whether this method is sensitive in detecting MS-related differences in NAWM. T1w and T2w scans were acquired at 3 Tesla in 47 patients with relapsing-remitting MS and 47 matched controls (HC). T1w/T2w and sT1w/T2w ratios were then calculated. We compared between-group variability between T1w/T2w and sT1w/T2w ratio in HC and MS and assessed for group differences. We also evaluated the relationship between the T1w/T2w and sT1w/T2w ratios and clinically relevant variables. Compared to the classic T1w/T2w ratio, the between-subject variability in sT1w/T2w ratio showed a significant reduction in MS patients (p < 0.001) and HC (p < 0.001). However, only sT1w/T2w ratio values were reduced in patients compared to HC (p < 0.001). The sT1w/T2w ratio intensity values were significantly influenced by age, T2 lesion volume and group status (MS vs. HC) (adjusted R2 = 0.30, p < 0.001). We demonstrate the validity of the sT1w/T2w ratio in MS and that it is more sensitive to MS-related differences in NAWM compared to T1w/T2w ratio. The sT1w/T2w ratio shows promise as an easily- implemented measure of NAWM in MS using readily available scans and simple post-processing methods. DOI: 10.3389/fneur.2019.00334 PMCID: PMC6465519 143. Front Neurol. 2019 Apr 2;10:310. doi: 10.3389/fneur.2019.00310. eCollection 2019. Three-Dimensional In vivo Magnetic Resonance Imaging (MRI) of Mouse Facial Nerve Regeneration. Wanner R(1), Abaei A(2), Rasche V(2)(3), Knöll B(1). Author information: (1)Institute of Physiological Chemistry, Ulm University, Ulm, Germany. (2)Core Facility Small Animal MRI, Medical Faculty, Ulm University, Ulm, Germany. (3)Department of Internal Medicine II, University Hospital Ulm, Ulm, Germany. MRI (magnetic resonance imaging) is an indispensable tool in the diagnosis of centrals nervous system (CNS) disorders such as spinal cord injury and multiple sclerosis (MS). In contrast, diagnosis of peripheral nerve injuries largely depends on clinical and electrophysiological parameters. Thus, currently MRI is not regularly used which in part is due to small nerve calibers and isointensity with surrounding tissue such as muscles. In this study we performed translational MRI research in mice to establish a novel MRI protocol visualizing intact and injured peripheral nerves in a non-invasive manner without contrast agents. With this protocol we were able to image even very small nerves and nerve branches such as the mouse facial nerve (diameter 100-300 μm) at highest spatial resolution. Analysis was performed in the same animal in a longitudinal study spanning 3 weeks after injury. Nerve injury caused hyperintense signal in T2-weighted images and an increase in nerve size of the proximal and distal nerve stumps were observed. Further hyperintense signal was observed in a bulb-like structure in the lesion site, which correlated histologically with the production of fibrotic tissue and immune cell infiltration. The longitudinal MR representation of the facial nerve lesions correlated well with physiological recovery of nerve function by quantifying whisker movement. In summary, we provide a novel protocol in rodents allowing for non-invasive, non-contrast agent enhanced, high-resolution MR imaging of small peripheral nerves longitudinally over several weeks. This protocol might further help to establish MRI as an important diagnostic and post-surgery follow-up tool to monitor peripheral nerve injuries in humans. DOI: 10.3389/fneur.2019.00310 PMCID: PMC6454117 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 105 – Multiple Sklerose: Veröffentlichungen April 2019 144. Front Neurol. 2019 Mar 26;10:280. doi: 10.3389/fneur.2019.00280. eCollection 2019. Glial Activation Markers in CSF and Serum From Patients With Primary Progressive Multiple Sclerosis: Potential of Serum GFAP as Disease Severity Marker? Abdelhak A(1)(2), Hottenrott T(3), Morenas-Rodríguez E(4)(5), Suárez-Calvet M(6), Zettl UK(7), Haass C(4)(5)(8), Meuth SG(9), Rauer S(3), Otto M(2), Tumani H(2)(10), Huss A(2). Author information: (1)Department of Neurology, University Hospital of Tuebingen, Tuebingen, Germany. (2)Department of Neurology, University Hospital of Ulm, Ulm, Germany. (3)Department of Neurology, University Hospital of Freiburg, Freiburg, Germany. (4)German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. (5)BioMedical Center (BMC), Ludwig-Maximilians-Universität München, Munich, Germany. (6)Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain. (7)Neuroimmunological Section, Department of Neurology, University Hospital of Rostock, Rostock, Germany. (8)Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. (9)Department of Neurology, University Hospital of Muenster, Münster, Germany. (10)Specialty Hospital Dietenbronn, Schwendi, Germany. Background: In progressive multiple sclerosis (MS), glial activation is thought to be a relevant mechanism of disability progression. Therefore, in vivo assessment of the glial cell activity is, in the emerging treatment era of primary progressive MS (PPMS), more important than ever. Objectives: To test the association of cerebrospinal fluid (CSF) and serum markers of glial activation in PPMS patients; including glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (CHI3L1), soluble variant of triggering receptor expressed on myeloid cells 2 (sTREM2), and marker of neuroaxonal damage (Neurofilament light chain, NfL) as well as clinical severity. Methods: CSF and serum samples from PPMS patients were collected in the MS-centers at Universities of Freiburg (n = 49), Ulm (n = 27), Muenster (n = 11), and Rostock (n = 6). sTREM2 and CHI3L1 levels were measured using the previously reported ELISA assays, while NfL and GFAP were measured using SIMOA assays. Clinical data included age, gender, disease duration, treatment status, and Expanded Disability Status Scale (EDSS). Results: 93 CSF samples and 71 matching serum samples were analyzed. The median age of patients was 49 years and disease duration 4.5 years. GFAPserum correlated with EDSS after correction for age (β = 0.3, p = 0.001). Furthermore, EDSS was higher in patients with a GFAPserum level ≥ 151.7 pg/ml compared to patients with GFAPserum below this cut-off (5.5 vs. 4.0, p = 0.009). Other markers did not correlate with the clinical severity. Moreover, we found a correlation between NfLCSF and GFAPCSF, sTREM2 and CHI3L1 (ρ = 0.4 for GFAPCSF and sTREM2, ρ = 0.3 for CHI3L1, p < 0.01 for sTREM2 and CHI3L1 and <0.001 for GFAPCSF). CHI3L1 did not correlate with GFAPCSF but with sTREM2 (ρ = 0.4, p < 0.01). Discussion: The correlation between the glial activation markers in CSF with the markers of neuroaxonal demise supports the notion of the glial involvement in PPMS. The positive correlation between GFAPCSF with disease duration and GFAPserum with the clinical severity of the disease may highlight a particular role of the astrocytes in PPMS and mark the potential of GFAPserum as a disease severity marker. DOI: 10.3389/fneur.2019.00280 PMCID: PMC6443875 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 106 – Multiple Sklerose: Veröffentlichungen April 2019 145. Front Neurol. 2019 Mar 22;10:253. doi: 10.3389/fneur.2019.00253. eCollection 2019. Best Practices for Long-Term Monitoring and Follow-Up of Alemtuzumab-Treated MS Patients in Real-World Clinical Settings. Barclay K(1), Carruthers R(2), Traboulsee A(2), Bass AD(3), LaGanke C(4), Bertolotto A(5), Boster A(6), Celius EG(7), de Seze J(8), Cruz DD(9), Habek M(10), Lee JM(11), Limmroth V(12), Meuth SG(13), Oreja- Guevara C(14), Pagnotta P(15), Vos C(16), Ziemssen T(17), Baker DP(18), Wijmeersch BV(19). Author information: (1)Vancouver Coastal Health, Vancouver, BC, Canada. (2)University of British Columbia, Vancouver, BC, Canada. (3)Neurology Center of San Antonio, San Antonio, TX, United States. (4)North Central Neurology Associates, Cullman, AL, United States. (5)Azienda Ospedaliero Universitaria San Luigi, Orbassano, Italy. (6)OhioHealth Neurological Physicians, Columbus, OH, United States. (7)Oslo University Hospital Ullevål and Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (8)Clinical Research Center (CIC), INSERM 1434, Strasbourg University, Strasbourg, France. (9)Imperial College Healthcare NHS Trust, London, United Kingdom. (10)University of Zagreb, School of Medicine and University Medical Center, Zagreb, Croatia. (11)Stanford Healthcare, Palo Alto, CA, United States. (12)Klinik für Neurologie und Palliativmedizin, Cologne, Germany. (13)Clinic of Neurology with Institute of Translational Neurology, University Hospital Müenster, Müenster, Germany. (14)El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid, Spain. (15)Neurology Associates, Maitland, FL, United States. (16)Revalidatie & MS Centrum, Overpelt, Belgium. (17)Center of Clinical Neuroscience, University Clinic Carl Gustav Carus, Dresden, Germany. (18)Sanofi, Cambridge, MA, United States. (19)Rehabilitation & MS-Centre Overpelt, Hasselt University, Hasselt, Belgium. Multiple sclerosis (MS) is a chronic autoimmune neurological disease that typically affects young adults, causing irreversible physical disability and cognitive impairment. Alemtuzumab, administered intravenously as 2 initial courses of 12 mg/day (5 consecutive days at baseline, and 3 consecutive days 12 months later), resulted in significantly greater improvements in clinical and MRI outcomes vs. subcutaneous interferon beta- 1a over 2 years in patients with active relapsing-remitting MS (RRMS) who were either treatment-naive (CARE-MS I; NCT00530348) or had an inadequate response to prior therapy (CARE-MS II; NCT00548405). Efficacy with alemtuzumab was maintained over 7 years in subsequent extension studies (NCT00930553; NCT02255656), in the absence of continuous treatment and with a consistent safety profile. There is an increased incidence of autoimmune events in patients treated with alemtuzumab (mainly thyroid events, but also immune thrombocytopenia and nephropathy), which imparts a need for mandatory safety monitoring for 4 years following the last treatment. The risk management strategy for alemtuzumab-treated patients includes laboratory monitoring and a comprehensive patient education and support program that enables early detection and effective management of autoimmune events, yielding optimal outcomes for MS patients. Here we provide an overview of tools and techniques that have been implemented in real-world clinical settings to reduce the burden of monitoring for both patients and healthcare providers, including customized educational materials, the use of social media, and interactive online databases for managing healthcare data. Many practices are also enhancing patient outreach efforts through coordination with specialized nursing services and ancillary caregivers. The best practice recommendations for safety monitoring described in this article, based on experiences in real-world clinical settings, may enable early detection and management of autoimmune events, and help with implementation of monitoring requirements while maximizing the benefits of alemtuzumab treatment for MS patients. DOI: 10.3389/fneur.2019.00253 PMCID: PMC6439479 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 107 – Multiple Sklerose: Veröffentlichungen April 2019 146. Front Neurol. 2019 Mar 22;10:153. doi: 10.3389/fneur.2019.00153. eCollection 2019. Functional Connectivity Changes After Initial Treatment With Fingolimod in Multiple Sclerosis. Petsas N(1), De Giglio L(2)(3), González-Quintanilla V(4), Giuliani M(3), De Angelis F(5), Tona F(3), Carmellini M(3), Mainero C(6)(7), Pozzilli C(2)(3), Pantano P(1)(3). Author information: (1)Department of Radiology, IRCCS NEUROMED, Pozzilli, Italy. (2)Multiple Sclerosis Centre, Azienda Ospedaliera Sant'Andrea, Rome, Italy. (3)Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy. (4)Department of Neurology, University Hospital Marquis of Valdecilla, Santander, Spain. (5)Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom. (6)Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States. (7)Harvard Medical School, Boston, MA, United States. On the basis of recent functional MRI studies, Multiple Sclerosis (MS) has been interpreted as a multisystem disconnection syndrome. Compared to normal subjects, MS patients show alterations in functional connectivity (FC). However, the mechanisms underlying these alterations are still debated. The aim of the study is to investigate resting state (RS) FC changes after initial treatment with fingolimod, a proven anti- inflammatory and immunomodulating agent for MS. We studied 32 right-handed relapsing-remitting MS patients (median Expanded Disability Status Scale: 2.0, mean disease duration: 8.8 years) who underwent both functional and conventional MRI with a 3 Tesla magnet. All assessments were performed 3 weeks before starting fingolimod, then, at therapy-initiation stage and at month 6. Each imaging session included scans at baseline (run1) and after (run2) a 25-min, within-session, motor-practice task, consisting of a paced right-thumb flexion. FC was assessed using a seed on the left primary motor cortex to obtain parametric maps at run1 and task-induced FC change (run2-run1). Comparison between 3-week before- and fingolimod start sessions accounted for a test-retest effect. The main outcome was the changes in both baseline and task-induced changes in FC, between initiation and 6 months. MRI contrast enhancement was detected in 14 patients at initiation and only in 3 at month 6. There was a significant improvement (p < 0.05) in cognitive function, as measured by the Paced Auditory Serial Addition Task, at month 6 compared to initiation. After accounting for test-retest effect, baseline FC significantly decreased at month 6, with respect to initiation (p < 0.05, family-wise error corrected) in bilateral occipito-parietal areas and cerebellum. A task- induced change in FC at month 6 showed a significant increment in all examined sessions, involving not only areas of the sensorimotor network, but also posterior cortical areas (cuneus and precuneus) and areas of the prefrontal and temporal cortices (p < 0.05, family-wise error corrected). Cognitive improvement at month 6 was significantly (p < 0.05) related to baseline FC reduction in posterior cortical areas. This study shows significant changes in functional connectivity, both at baseline and after the execution of a simple motor task following 6 months of fingolimod therapy. DOI: 10.3389/fneur.2019.00153 PMCID: PMC6438876 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 108 – Multiple Sklerose: Veröffentlichungen April 2019 147. Front Neurol. 2019 Mar 20;10:270. doi: 10.3389/fneur.2019.00270. eCollection 2019. A Longitudinally Extensive Spinal Cord Lesion Restricted to Gray Matter in an Adolescent Male. Golub D(1), Williams F(2), Wong T(1), Iyengar N(1), Jolley H(3), Sabadiah S(4), Rhee D(3), Gold-von Simson G(3)(5). Author information: (1)New York University School of Medicine, New York, NY, United States. (2)School of Medicine, Washington University School of Medicine, Saint Louis, MO, United States. (3)Department of Pediatrics, New York University School of Medicine, New York, NY, United States. (4)Department of Neurology, New York University School of Medicine, New York, NY, United States. (5)Health and Hospitals, Clinical Translational Science Institute, New York University, New York, NY, United States. Longitudinally extensive spinal cord lesions (LECL) restricted to gray matter are poorly understood as are their neurodevelopmental repercussions in children. We herein report the critical case of a 13-year-old male presenting with progressive quadriparesis found to have cervical LECL restricted to the anterior horns. Challenged with a rare diagnostic dilemma, the clinical team systematically worked through potential vascular, genetic, infectious, rheumatologic, and paraneoplastic diagnoses before assigning a working diagnosis of acute inflammatory myelopathy. Nuanced consideration of and workup for both potential ischemic causes (arterial dissection, fibrocartilaginous embolism, vascular malformation) and specific inflammatory conditions including Transverse Myelitis, Neuromyelitis Optica Spectrum Disorders (NMOSD), Multiple Sclerosis (MS), Acute Disseminated Encephalomyelitis (ADEM), and Acute Flaccid Myelitis (AFM) is explained in the context of a comprehensive systematic review of the literature on previous reports of gray matter-restricted longitudinally extensive cord lesions in children. Treatment strategy was ultimately based on additional literature review of treatment-refractory acute inflammatory neurological syndromes in children. A combination of high-dose steroids and plasmapheresis was employed with significant improvement in functional outcome, suggesting a potential benefit of combination immune-modulatory treatment in these patients. This case furthermore highlights quality clinical reasoning with respect to the elusive nature of diagnosis, nuances in neuroimaging, and multifocal treatment strategies in pediatric LECL. DOI: 10.3389/fneur.2019.00270 PMCID: PMC6435483 148. Front Neurol. 2019 Mar 20;10:261. doi: 10.3389/fneur.2019.00261. eCollection 2019. Cognitive Impairment in Multiple Sclerosis With Regards to Disease Duration and Clinical Phenotypes. Brochet B(1)(2), Ruet A(1)(2). Author information: (1)Service de Neurologie, CHU de Bordeaux, Bordeaux, France. (2)Team Glia-Neuron Interactions, Neurocentre Magendie, INSERM U1215, Université de Bordeaux, Bordeaux, France. The relationships between cognitive impairment that exist during the clinical course of multiple sclerosis (MS) remain poorly described. The effect of disease duration has been studied in a few longitudinal cohorts and some cross-sectional studies that suggest that cognitive deficits tend to extend with disease duration. However, the effect of disease duration seems to be confounded by the effect of age. At the pre-clinical stage, cognitive deficits have been observed in patients with radiologically isolated syndromes, and their profile is similar than in clinically isolated syndromes (CIS) and relapsing-remitting MS (RRMS). The frequency of cognitive impairment tends to be higher in RRMS than in CIS. In these phenotypes, slowness of information processing speed (IPS) and episodic verbal and visuo-spatial memory deficits are frequently observed, but executive functions, and in particular verbal fluency, could also be impaired. More frequent and severe deficits are reported in SPMS than in RRMS with more severe deficits for memory tests, working memory and IPS. Similarly to what is observed in SPMS, patients with primary progressive MS (PPMS) present with a wide range of cognitive deficits in IPS, attention, working memory, executive functions, and verbal episodic memory with more tests and domains impaired than RRMS patients. Altogether these data suggested that not only the duration of the disease and age play an important role in the cognitive profile of patients, but also the phenotype itself, probably because of its specific pathological mechanism. DOI: 10.3389/fneur.2019.00261 PMCID: PMC6435517 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 109 – Multiple Sklerose: Veröffentlichungen April 2019 149. Front Neurol. 2019 Mar 12;10:210. doi: 10.3389/fneur.2019.00210. eCollection 2019. Corrigendum: A Perspective of Coagulation Dysfunction in Multiple Sclerosis and in Experimental Allergic Encephalomyelitis. Plantone D(1), Inglese M(2), Salvetti M(3)(4), Koudriavtseva T(5). Author information: (1)S.O.C. Neurologia, Ospedale San Biagio, Domodossola, Italy. (2)Department of Neurology, Radiology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States. (3)Department of Neuroscience Mental Health and Sensory Organs (NEMOS), Sapienza University, Sant'Andrea Hospital, Rome, Italy. (4)IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, Italy. (5)Department of Clinical Experimental Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy. Erratum for Front Neurol. 2019 Jan 14;9:1175. [This corrects the article DOI: 10.3389/fneur.2018.01175.]. DOI: 10.3389/fneur.2019.00210 PMCID: PMC6436072 150. Front Neurol. 2019 Mar 15;10:188. doi: 10.3389/fneur.2019.00188. eCollection 2019. Impact of the McDonald Criteria 2017 on Early Diagnosis of Relapsing-Remitting Multiple Sclerosis. Schwenkenbecher P(1), Wurster U(1), Konen FF(1), Gingele S(1), Sühs KW(1), Wattjes MP(2), Stangel M(1), Skripuletz T(1). Author information: (1)Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany. (2)Department of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany. Multiple sclerosis is a chronic immune mediated demyelinating disease leading to neurological disabilities that need to be diagnosed and treated early. Guidelines on multiple sclerosis diagnosis and monitoring experienced comprehensive changes over the last decades. The first McDonald criteria published in 2001 emphasized the importance of MR imaging but also recognized the role of cerebrospinal fluid diagnostics. The demonstration of an intrathecal immunoglobulin G synthesis is a well-established additional component and has a long tradition in the diagnosis of relapsing-remitting multiple sclerosis. However, the role of cerebrospinal fluid for diagnostic purposes was rather diminished in each revision of the McDonald criteria. In the latest revision of the McDonald criteria of 2017, the detection of an intrathecal immunoglobulin G synthesis as oligoclonal bands experienced a revival. Patients with the first clinical event suggesting multiple sclerosis who fulfill the criteria for dissemination in space can be diagnosed with relapsing-remitting multiple sclerosis when oligoclonal bands in cerebrospinal fluid are detected. The diagnostic sensitivity of these novel criteria with a focus on dissemination in time and oligoclonal bands as a substitute for dissemination in time was published in different cohorts in the last year and is of special interest in this review. Recently published data show that by applying the 2017 McDonald criteria, multiple sclerosis can be diagnosed more frequently at the time of first clinical event as compared to the 2010 McDonald criteria. The main effect was due to the implementation of oligoclonal bands as a substitute for dissemination in time. However, careful differential diagnosis is essential in patients with atypical clinical manifestations to avoid misdiagnoses. DOI: 10.3389/fneur.2019.00188 PMCID: PMC6428717 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 110 – Multiple Sklerose: Veröffentlichungen April 2019 151. Front Neurosci. 2019 Apr 12;13:348. doi: 10.3389/fnins.2019.00348. eCollection 2019. Focus on 1,25-Dihydroxyvitamin D3 in the Peripheral Nervous System. Faye PA(1)(2), Poumeaud F(1), Miressi F(1), Lia AS(1)(2), Demiot C(1), Magy L(3), Favreau F(1)(2), Sturtz FG(1)(2). Author information: (1)EA 6309, Myelin Maintenance and Peripheral Neuropathies, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France. (2)Department of Biochemistry and Molecular Genetics, University Hospital of Limoges, Limoges, France. (3)CHU de Limoges, Reference Center for Rare Peripheral Neuropathies, Department of Neurology, Limoges, France. In this review, we draw attention to the roles of calcitriol (1,25-dihydroxyvitamin D3) in the trophicity of the peripheral nervous system. Calcitriol has long been known to be crucial in phosphocalcium homeostasis. However, recent discoveries concerning its involvement in the immune system, anti-cancer defenses, and central nervous system development suggest a more pleiotropic role than previously thought. Several studies have highlighted the impact of calcitriol deficiency as a promoting factor of various central neurological diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Based on these findings and recent publications, a greater role for calcitriol may be envisioned in the peripheral nervous system. Indeed, calcitriol is involved in myelination, axonal homogeneity of peripheral nerves, and neuronal-cell differentiation. This may have useful clinical consequences, as calcitriol supplementation may be a simple means to avoid the onset and/or development of peripheral nervous-system disorders. DOI: 10.3389/fnins.2019.00348 PMCID: PMC6474301 152. Front Neurosci. 2019 Mar 26;13:236. doi: 10.3389/fnins.2019.00236. eCollection 2019. Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review. Yimer EM(1), Hishe HZ(1), Tuem KB(1). Author information: (1)Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, Mekelle University, Mekelle, Ethiopia. To date, there is no cure or disease-modifying agents available for most well-known neurological disorders. Current therapy is typically focused on relieving symptoms and supportive care in improving the quality of life of affected patients. Furthermore, the traditional de novo drug discovery technique is more challenging, particularly for neurological disorders. Therefore, the repurposing of existing drugs for these conditions is believed to be an efficient and dynamic approach that can substantially reduce the investments spent on drug development. Currently, there is emerging evidence that suggests the potential effect of a beta-lactam antibiotic, ceftriaxone (CEF), to alleviate the symptoms of different experimentally-induced neurological disorders: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, epileptic-seizure, brain ischemia, traumatic brain injuries, and neuropathic pain. CEF also affects the markers of oxidative status and neuroinflammation, glutamatergic systems as well as various aggregated toxic proteins involved in the pathogenesis of different neurological disorders. Moreover, it was found that CEF administration to drug dependent animal models improved the withdrawal symptoms upon drug discontinuation. Thus, this review aimed to describe the effects of CEF against multiple models of neurological illnesses, drug dependency, and withdrawal. It also emphasizes the possible mechanisms of neuroprotective actions of CEF with respective neurological maladies. DOI: 10.3389/fnins.2019.00236 PMCID: PMC6444273 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 111 – Multiple Sklerose: Veröffentlichungen April 2019 153. Front Pharmacol. 2019 Apr 5;10:332. doi: 10.3389/fphar.2019.00332. eCollection 2019. Venlafaxine Improves the Cognitive Impairment and Depression-Like Behaviors in a Cuprizone Mouse Model by Alleviating Demyelination and Neuroinflammation in the Brain. Zhang Y(1), Bi X(2), Adebiyi O(1), Wang J(3), Mooshekhian A(1), Cohen J(4), Wei Z(1), Wang F(5), Li XM(6). Author information: (1)Department of Psychiatry, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada. (2)Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China. (3)Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. (4)Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada. (5)Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, China. (6)Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada. Growing evidence has implicated that myelin deficits and neuroinflammation are the coexisted pathological features that contribute to the mood swing and cognitive decline in major depressive disorder (MDD) and multiple sclerosis (MS). Therefore, attenuation of neuroinflammation and reduction of demyelination became newly emerging treatment strategies for the mood and cognitive symptoms. Antidepressant venlafaxine has been used in depression and anxiety through its multiple neuroprotective effects. However, it is unclear whether venlafaxine can improve myelin integrity and alter inflammation status in the brain. By using a well- established cuprizone-induced acute mouse model of demyelination, we investigated the protective effects of venlafaxine on these facets. The cuprizone-fed animals exhibited cognitive impairment and mood disturbances together with myelin loss and prominent neuroinflammation in the brain. Our present study showed that a high dose of venlafaxine alleviated the loss of myelin and oligodendrocytes (OLs), mitigated depression-like behaviors, and improved cognitive function in cuprizone-fed animals. Data from the present study also showed that venlafaxine reduced microglia-mediated inflammation in the brains of cuprizone-fed animals. These findings suggest that venlafaxine may exert its therapeutic effects via facilitating myelin integrity and controlling neuroinflammation, which may provide extra benefits to MS patients with depression and anxiety beyond the symptom management. DOI: 10.3389/fphar.2019.00332 PMCID: PMC6460225 154. Front Pharmacol. 2019 Mar 22;10:286. doi: 10.3389/fphar.2019.00286. eCollection 2019. Targeting Microglia and Macrophages: A Potential Treatment Strategy for Multiple Sclerosis. Wang J(1), Wang J(1), Wang J(1), Yang B(1), Weng Q(1)(2), He Q(1)(2). Author information: (1)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. Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS). The early stage is characterized by relapses and the later stage, by progressive disability. Results from experimental and clinical investigations have demonstrated that microglia and macrophages play a key part in the disease course. These cells actively initiate immune infiltration and the demyelination cascade during the early phase of the disease; however, they promote remyelination and alleviate disease in later stages. This review aims to provide a comprehensive overview of the existing knowledge regarding the neuromodulatory function of macrophages and microglia in the healthy and injured CNS, and it discusses the feasibility of harnessing microglia and macrophage physiology to treat MS. The review encourages further investigations into macrophage-targeted therapy, as well as macrophage-based drug delivery, for realizing efficient treatment strategies for MS. DOI: 10.3389/fphar.2019.00286 PMCID: PMC6438858 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 112 – Multiple Sklerose: Veröffentlichungen April 2019 155. Front Psychiatry. 2019 Mar 20;10:141. doi: 10.3389/fpsyt.2019.00141. eCollection 2019. Depression in Somatic Disorders: Is There a Beneficial Effect of Exercise? Roeh A(1), Kirchner SK(1), Malchow B(2), Maurus I(1), Schmitt A(1)(3), Falkai P(1), Hasan A(1). Author information: (1)Department of Psychiatry and Psychotherapy, University Hospital, Ludwig- Maximilians University Munich, Munich, Germany. (2)Department of Psychiatry and Psychotherapy, Universitätsklinikum Jena, Jena, Germany. (3)Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of São Paulo, São Paulo, Brazil. Background: The beneficial effects of exercise training on depressive symptoms are well-established. In the past years, more research attention has been drawn to the specific effects of exercise training on depressive symptoms in somatically ill patients. This reviews aims at providing a comprehensive overview of the current findings and evidence of exercise interventions in somatic disorders to improve depressive symptoms. Methods: We systematically searched PubMed and Cochrane databases and extracted meta-analyses from somatically ill patients that underwent exercise interventions and provided information about the outcome of depressive symptoms. Results: Of the 4123 detected publications, 39 were selected for final analysis. Various diseases were included (breast-cancer, prostate cancer, mixed-cancer, cardiovascular disease, coronary heart disease, hemodialysis, fibromyalgia syndrome, acute leukemia, other hematological malignancies, heart failure, HIV, multiple sclerosis, mixed neurological disorders, Parkinson's disease, stroke, ankylosing spondylitis, traumatic brain injury, lupus erythematodes). Most meta-analyses (33/39) found beneficial effects on depressive symptoms, but quality of the included studies as well as duration, intensity, frequency, and type of exercise varied widely. Conclusion: Exercise training has the potential to improve depressive symptoms in patients with somatic disorders. For specific training recommendations, more high quality studies with structured exercise programs and better comparability are needed. DOI: 10.3389/fpsyt.2019.00141 PMCID: PMC6435577 156. Front Psychiatry. 2019 Mar 20;10:131. doi: 10.3389/fpsyt.2019.00131. eCollection 2019. Autoimmune Diseases and Psychotic Disorders. Jeppesen R(1), Benros ME(1). Author information: (1)Mental Health Centre Copenhagen, Gentofte Hospital, Copenhagen University Hospital, Hellerup, Denmark. The notion of immunological pathways playing a role in the etiology of a subset of psychotic disorders has received increased interest in the last decades. One of the findings that has spiked interest herein, is an apparent link between autoimmune diseases and psychotic disorders. This is supported by genetic findings associating immune-related genetic markers with schizophrenia and clinical studies finding increased levels of inflammatory markers in patients with psychosis. Several large-scale epidemiologic studies have found positive associations between autoimmune diseases and psychosis. Particularly, autoimmune diseases as multiple sclerosis and lupus are known to have higher frequencies of neuropsychiatric symptoms, including psychosis, compared to healthy controls. Cross sectional studies have found higher prevalence of psychiatric diagnoses among those with autoimmune diseases, and longitudinal studies have shown bidirectional associations between several autoimmune diseases and increased risks associated with schizophrenia. Moreover, a family history of autoimmune diseases has been shown to be associated with an increased risk of psychotic disorders and vice versa. In this review we will summarize the epidemiologic evidence on associations between autoimmune diseases and psychosis. Possible mechanisms accountable for the association will be discussed, amongst others the probable role of shared genetic risk factors, the impact of infections on both autoimmunity and the development of psychotic disorders, and the potential role of the microbiome. We discuss the findings on and influence of autoantibodies and dysregulation of T- and B-cells in both disease categories, and why further research hereon is needed. In addition to the potential importance of autoimmunity in etiological mechanisms of psychotic disorders, the association also brings important attention to somatic comorbidity in patients with psychotic disorders. DOI: 10.3389/fpsyt.2019.00131 PMCID: PMC6435494 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 113 – Multiple Sklerose: Veröffentlichungen April 2019 157. Glia. 2019 Apr 7. doi: 10.1002/glia.23618. [Epub ahead of print] Glutamate versus GABA in neuron-oligodendroglia communication. Habermacher C(1)(2), Angulo MC(1)(2), Benamer N(1)(2). Author information: (1)Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France. (2)Université Paris Descartes, Paris, France. In the central nervous system (CNS), myelin sheaths around axons are formed by glial cells named oligodendrocytes (OLs). In turn, OLs are generated by oligodendrocyte precursor cells (OPCs) during postnatal development and in adults, according to a process that depends on the proliferation and differentiation of these progenitors. The maturation of OL lineage cells as well as myelination by OLs are complex and highly regulated processes in the CNS. OPCs and OLs express an array of receptors for neurotransmitters, in particular for the two main CNS neurotransmitters glutamate and GABA, and are therefore endowed with the capacity to respond to neuronal activity. Initial studies in cell cultures demonstrated that both glutamate and GABA signaling mechanisms play important roles in OL lineage cell development and function. However, much remains to be learned about the communication of glutamatergic and GABAergic neurons with oligodendroglia in vivo. This review focuses on recent major advances in our understanding of the neuron-oligodendroglia communication mediated by glutamate and GABA in the CNS, and highlights the present controversies in the field. We discuss the expression, activation modes and potential roles of synaptic and extrasynaptic receptors along OL lineage progression. We review the properties of OPC synaptic connectivity with presynaptic glutamatergic and GABAergic neurons in the brain and consider the implication of glutamate and GABA signaling in activity-driven adaptive myelination. © 2019 Wiley Periodicals, Inc. DOI: 10.1002/glia.23618 158. Glia. 2019 Apr 29. doi: 10.1002/glia.23635. [Epub ahead of print] Uncovering the biology of myelin with optical imaging of the live brain. Hill RA(1), Grutzendler J(2). Author information: (1)Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire. (2)Departments of Neurology and Neuroscience, Yale School of Medicine, New Haven, Connecticut. Myelin has traditionally been considered a static structure that is produced and assembled during early developmental stages. While this characterization is accurate in some contexts, recent studies have revealed that oligodendrocyte generation and patterns of myelination are dynamic and potentially modifiable throughout life. Unique structural and biochemical properties of the myelin sheath provide opportunities for the development and implementation of multimodal label-free and fluorescence optical imaging approaches. When combined with genetically encoded fluorescent tags targeted to distinct cells and subcellular structures, these techniques offer a powerful methodological toolbox for uncovering mechanisms of myelin generation and plasticity in the live brain. Here, we discuss recent advances in these approaches that have allowed the discovery of several forms of myelin plasticity in developing and adult nervous systems. Using these techniques, long-standing questions related to myelin generation, remodeling, and degeneration can now be addressed. © 2019 Wiley Periodicals, Inc. DOI: 10.1002/glia.23635 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 114 – Multiple Sklerose: Veröffentlichungen April 2019 159. Glia. 2019 Apr 16. doi: 10.1002/glia.23620. [Epub ahead of print] Low-intensity transcranial magnetic stimulation promotes the survival and maturation of newborn oligodendrocytes in the adult mouse brain. Cullen CL(1), Senesi M(1), Tang AD(2), Clutterbuck MT(1), Auderset L(1), O'Rourke ME(1), Rodger J(2)(3), Young KM(1). Author information: (1)Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. (2)Experimental and Regenerative Neurosciences, School of Biological Sciences, University of Western Australia, Perth, Western Australia, Australia. (3)Brain Plasticity Lab, Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia. Neuronal activity is a potent extrinsic regulator of oligodendrocyte generation and central nervous system myelination. Clinically, repetitive transcranial magnetic stimulation (rTMS) is delivered to noninvasively modulate neuronal activity; however, the ability of rTMS to facilitate adaptive myelination has not been explored. By performing cre-lox lineage tracing, to follow the fate of oligodendrocyte progenitor cells in the adult mouse brain, we determined that low intensity rTMS (LI-rTMS), administered as an intermittent theta burst stimulation, but not as a continuous theta burst or 10 Hz stimulation, increased the number of newborn oligodendrocytes in the adult mouse cortex. LI-rTMS did not alter oligodendrogenesis per se, but instead increased cell survival and enhanced myelination. These data suggest that LI-rTMS can be used to noninvasively promote myelin addition to the brain, which has potential implications for the treatment of demyelinating diseases such as multiple sclerosis. © 2019 Wiley Periodicals, Inc. DOI: 10.1002/glia.23620 160. Glia. 2019 Apr 10. doi: 10.1002/glia.23607. [Epub ahead of print] Diversity in the oligodendrocyte lineage: Plasticity or heterogeneity? Foerster S(1), Hill MFE(1), Franklin RJM(1). Author information: (1)Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Clifford Allbutt Building, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK. Heterogeneity is a widely recognized phenomenon within the majority of cell types in the body including cells of the central nervous system (CNS). The heterogeneity of neurons based on their distinct transmission modes and firing patterns has been recognized for decades, and is necessary to coordinate the immense variety of functions of the CNS. More recently, heterogeneity in glial cells has been identified, including heterogeneity in oligodendrocyte progenitor cells (OPCs) and oligodendrocytes. OPC subpopulations have been described based on their developmental origin, anatomical location in the grey or white matter, and expression of surface receptors. Oligodendrocytes are categorised according to differences in gene expression, myelinogenic potential, and axon specificity. Much of what is described as heterogeneity in oligodendrocyte lineage cells (OLCs) is based on phenotypic differences. However, without evidence for functional differences between putative subgroups of OLCs, distinguishing heterogeneity from plasticity and lineage state is difficult. Identifying functional differences between phenotypically distinct groups are therefore necessary for a deeper understanding of the role of OLCs in health and disease. © 2019 Wiley Periodicals, Inc. DOI: 10.1002/glia.23607 161. HeartRhythm Case Rep. 2018 Dec 31;5(4):196-200. doi: 10.1016/j.hrcr.2018.12.009. eCollection 2019 Apr. Venoarterial extracorporeal membrane oxygenation and implantable cardioverter- defibrillator implantation in a hemodynamically unstable infant with ventricular tachycardia from multiple cardiac rhabdomyomas. Kieu V(1), Czosek RJ(2), Knilans TK(2), Quintessenza JA(1)(2), Bryant R 3rd(2), Mohan S(1). Author information: (1)Kentucky Children's Hospital, University of Kentucky, UK Healthcare, Lexington, Kentucky. (2)The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. DOI: 10.1016/j.hrcr.2018.12.009 PMCID: PMC6453152 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 115 – Multiple Sklerose: Veröffentlichungen April 2019 162. Histochem Cell Biol. 2019 Apr 23. doi: 10.1007/s00418-019-01786-4. [Epub ahead of print] Continuous cuprizone intoxication allows active experimental autoimmune encephalomyelitis induction in C57BL/6 mice. Yakimov V(1)(2), Schweiger F(1)(2), Zhan J(2), Behrangi N(2), Horn A(3), Schmitz C(1), Hochstrasser T(1), Kipp M(4). Author information: (1)Institute of Anatomy II, Faculty of Medicine, LMU Munich, Pettenkoferstrasse 11, 80336, Munich, Germany. (2)Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, 18057, Rostock, Germany. (3)Institute of Anatomy I, Faculty of Medicine, LMU Munich, Pettenkoferstrasse 11, 80336, Munich, Germany. (4)Institute of Anatomy, Rostock University Medical Center, Gertrudenstrasse 9, 18057, Rostock, Germany. [email protected]. Oligodendrocyte degeneration is a hallmark of multiple sclerosis pathology, and protecting oligodendrocytes and myelin is likely to be of clinical relevance. Traditionally, oligodendrocyte and myelin degeneration are viewed as a direct consequence of an inflammatory attack, but metabolic defects might be equally important. Appropriate animal models to study the interplay of inflammation and metabolic injury are, therefore, needed. Here, we describe that in spite of its immunosuppressive effects, a continuous intoxication with cuprizone allows the induction of active experimental autoimmune encephalomyelitis (EAE) by myelin oligodendrocyte glycoprotein (MOG35-55) immunization. Although the clinical severity of EAE is ameliorated in cuprizone- intoxicated mice, the recruitment of granulocytes, and especially, CD3+ lymphocytes into the forebrain is triggered by the cuprizone insult. Such combined lesions are further characterized by oligodendrocyte apoptosis and microglia activation, closely mimicking type III multiple sclerosis lesions. In summary, we provide a protocol that allows to study the direct interplay of immune-mediated and metabolic oligodendrocyte injury and its consequences for the cerebral white and grey matters. DOI: 10.1007/s00418-019-01786-4 163. Histopathology. 2019 Apr 19. doi: 10.1111/his.13876. [Epub ahead of print] High-grade Oncocytic Tumor (HOT) of Kidney in a Patient with Tuberous Sclerosis Complex. Trpkov K(1), Bonert M(2), Gao Y(1), Kapoor A(3), He H(4), Yilmaz A(1), Gill AJ(5), Williamson SR(6), Comperat E(7), Tretiakova M(8), Magi-Galluzzi C(9), Brimo F(10), Hes O(11). Author information: (1)Department of Pathology and Laboratory Medicine, Calgary Laboratory Services, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. (2)Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada. (3)Department of Surgery, Division of Urology, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada. (4)Department of Pathology, Peking University, Health Science Center, Beijing, China. (5)Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research St Leonards NSW 2065 and University of Sydney, Sydney, NSW, 2006, Australia. (6)Department of Pathology, Henry Ford Health System, Detroit, MI, US. (7)Sorbonne Université Service d'Anatomie et Cytologie Pathologiques, Hôpital Tenon, HUEP, Paris, France. (8)Department of Anatomic Pathology, Harborview Medical Center, Seattle, WA, US. (9)Department of Anatomic Pathology, University of Alabama, Birmingham, AL, US. (10)Department of Pathology, McGill University, Montreal, QC, Canada. (11)Department of Pathology, Charles University, Medical Faculty and Charles University Hospital Plzen, Czech Republic. High-grade oncocytic tumor (HOT) was recently proposed as a novel renal entity that is currently not included in the WHO classification. The first published series by He et al included 14 tumors, collected from multiple institutional files. Recently, Chen et al reported another series of 7 morphologically very similar tumors that they designated "sporadic renal cell carcinomas with eosinophilic and vacuolated cytoplasm". Using Next-generation sequencing they identified somatic inactivating mutations of TSC2 in 3 of 5 tumors tested or activating mutations of MTOR (in 2 of 5 tumors tested). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/his.13876 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 116 – Multiple Sklerose: Veröffentlichungen April 2019 164. Hong Kong Physiother J. 2018 Jun;38(1):53-61. doi: 10.1142/S1013702518500063. Epub 2018 Apr 4. Clinical assessment of balance using BBS and SARAbal in cerebellar ataxia: Synthesis of findings of a psychometric property analysis. Winser SJ(1), Smith CM(2), Hale LA(2), Claydon LS(3), Whitney SL(4)(5). Author information: (1)Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hong Kong. (2)School of Physiotherapy, University of Otago, New Zealand. (3)Department of Allied and Public Health, Anglia Ruskin University, UK. (4)School of Health and Rehabilitation Sciences, Department of Physical Therapy University of Pittsburgh, USA. (5)Rehabilitation Research Chair at King Saud University, Saudi Arabia. Background: In the previous psychometric analysis paper in our series for identifying the core set of balance measures for the assessment of balance, we recommended the Berg Balance Scale (BBS) and balance sub- components of the Scale for the assessment and rating of ataxia (SARAbal) as psychometrically sound measures of balance for people with cerebellar ataxia (CA) secondary to multiple sclerosis. Objective: The present study further examined the suitability of BBS and SARAbal for the assessment of balance in CA with regard to psychometric property strength, appropriateness, interpretability, precision, acceptability and feasibility. Methods: Criteria to fulfill each factor was defined according to the framework of Fitzpatrick et al. (1998). Based on the findings of our previous psychometric analysis, each criterion was further analyzed. Results: The psychometric analysis reported good reliability and validity estimates for the BBS and SARAbal recommending them as psychometrically sound measures; they fulfilled both criteria for appropriateness and interpretability, the measures showed evidence for precision and acceptability, and they were found to be feasible in terms of the time and cost involved for the balance assessment. Conclusion: We have provided evidence for the use of the BBS and SARAbal for the assessment of balance among people with CA. DOI: 10.1142/S1013702518500063 PMCID: PMC6385546 165. Hum Brain Mapp. 2019 Apr 24. doi: 10.1002/hbm.24609. [Epub ahead of print] Precentral degeneration and cerebellar compensation in amyotrophic lateral sclerosis: A multimodal MRI analysis. Qiu T(1), Zhang Y(1), Tang X(1), Liu X(1), Wang Y(1), Zhou C(2), Luo C(3), Zhang J(4)(5). Author information: (1)Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China. (2)Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China. (3)Department of Neurology, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China. (4)Department of Radiology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, People's Republic of China. (5)Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, People's Republic of China. Amyotrophic lateral sclerosis (ALS) is a progressive and intractable neurodegenerative disease of human motor system characterized by progressive muscular weakness and atrophy. A considerable body of research has demonstrated significant structural and functional abnormalities of the primary motor cortex in patients with ALS. In contrast, much less attention has been paid to the abnormalities of cerebellum in this disease. Using multimodal magnetic resonance imagining data of 60 patients with ALS and 60 healthy controls, we examined changes in gray matter volume (GMV), white matter (WM) fractional anisotropy (FA), and functional connectivity (FC) in patients with ALS. Compared with healthy controls, patients with ALS showed decreased GMV in the left precentral gyrus and increased GMV in bilateral cerebellum, decreased FA in the left corticospinal tract and body of corpus callosum, and decreased FC in multiple brain regions, involving bilateral postcentral gyrus, precentral gyrus and cerebellum anterior lobe, among others. Meanwhile, we found significant intermodal correlations among GMV of left precentral gyrus, FA of altered WM tracts, and FC of left precentral gyrus, and that WM microstructural alterations seem to play important roles in mediating the relationship between GMV and FC of the precentral gyrus, as well as the relationship between GMVs of the precentral gyrus and cerebellum. These findings provided evidence for the precentral degeneration and cerebellar compensation in ALS, and the involvement of WM alterations in mediating the relationship between pathologies of the primary motor cortex and cerebellum, which may contribute to a better understanding of the pathophysiology of ALS. © 2019 Wiley Periodicals, Inc. DOI: 10.1002/hbm.24609 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 117 – Multiple Sklerose: Veröffentlichungen April 2019 166. Ideggyogy Sz. 2019 Mar 30;72(3-4):135-139. doi: 10.18071/isz.72.0135. [Symptomatic trigeminal autonomic cephalalgia without headache]. [Article in Hungarian; Abstract available in Hungarian from the publisher] Rózsa A (1), Kovács K (1), Guba K (1), Gács G (1). Author information: (1)Péterfy Sándor Utcai Kórház, Neurológiai Osztály, Budapest. We report the case of a 60-year-old man who exhibited trigeminal autonomic symptoms on his right side (numbness of the face, reddening of the eye, nasal congestion) occurring several times a day, for a maximum of 60 se-conds, without any pain. The complaints were similar to trigeminal autonomic cephalalgia, just without any headache. Our 60-year-old male patient underwent a craniocervical MRI as part of his neurological workup, which revealed lesions indicative of demyelination. Further testing was guided (ophthalmological examination, VEP, CSF test) by the presumptive diagnosis of multiple sclerosis. It is likely that in his case the cause of these trigeminal and autonomic paroxysms is MS. Here we present an overview of the few cases we found in the literature, although we did not find any similar case reports. Perhaps the most interesting among these is one in which the author describes a family: a 54-year-old female exhibiting the autonomic characteristics of an episodic cluster headache, only without actual headache, her son, who had typical episodic cluster headaches with autonomic symptoms, and the woman's father, whose short-term periorbital headaches were present without autonomic symptoms. We had not previously encountered a case of trigeminal autonomic cephalalgia without headache in our practice, nor have we had an MS patient exhibiting similar neurologic symptoms. The significance of our case lies in its uniqueness. Publisher: Egy 60 éves férfi esetét ismertetjük, akinek jobb oldali trigeminalis és cranialis vegetatív tünetei (jobb oldali arczsibbadás, szem kivörösödése, orrdugulás) jelent•keztek napi több alkalommal, maximum 60 másodperces időtartamban, mindennemű fájdalom nélkül. A panaszok a trigemino-autonóm fejfájások közé tartozó SUNCT szindrómára emlékeztettek, de fájdalomérzés nem fordult elő. Neurológiai ivizsgálás során a koponya- és nyaki MR-vizsgálat demyelinisatióra jellemző góco at ábrázolt. További vizsgálataink (szemészet, EP, liquorvizsgálat) a órismét támogattá . alószínű, hogy sclerosis multiple áll a trigeminalis és autonóm aktiválódással járó paro•xysmusok hátterében. Az irodalomban talált eseteket tekintettük át, bár hasonló esetleírással nem találkoztunk. Ezek közül talán a legérdekesebb, amelyben a szerző egy családról számol be, egy 54 éves nőbetegről, a ine cluster fejfájásra jellemző vegetatív tünetei voltak, csak éppen fejfájás nélkül, a fiáról, akinek típusos epizodikus cluster fejfájása volt vegetatív tünete el, illetve a nőbeteg édesapjáról, akinek rövid ideig tartó periorbita•lis fejfájása jelentkezett, vegetatív tünetek nél ül. i magun nem talál oztun még ilyen esettel, sem „trigemino-autonóm fejfájással” fejfájás nélkül, sem olyan SM-beteggel, akinek betegsége hasonló neurológiai tünetekkel járt volna. Esetünket egyedisége miatt gondoljuk jelentősne . DOI: 10.18071/isz.72.0135 167. Immunobiology. 2019 Apr 13. pii: S0171-2985(19)30049-X. doi: 10.1016/j.imbio.2019.04.005. [Epub ahead of print] GAS8 and its naturally occurring antisense RNA as biomarkers in multiple sclerosis. Patoughi M(1), Ghafouri-Fard S(2), Arsang-Jang S(3), Taheri M(4). Author information: (1)Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (2)Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: [email protected]. (3)Clinical Research Development Center (CRDU), Qom University of Medical Sciences, Qom, Iran. (4)Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: [email protected]. Expressions of the Growth arrest specific 8 (GAS8) and its naturally occurring anti-sense RNA (GAS8-AS1) have been assessed in tumoral tissues of different origins. However, their association with immune-related disorders has been poorly understood. In the current study, we evaluated expression levels of these genes in 50 relapsing-remitting multiple sclerosis (RRMS) patients compared with age- and sex-matched controls. Expressions of both genes were significantly higher in total MS patients compared with controls (P = 0.001 and P < 0.0001 respectively). The difference in GAS8 expression was also significant in total female patients and females aged less than 50 when compared with the corresponding control subjects (P = 0.002 and 0.006 respectively). GAS8-AS1 was higher in male patients in both age-based subgroups compared with the corresponding healthy subjects (P < 0.0001). Expressions of both genes were inversely correlated with age of male study participants but no other subgroups. GAS8-AS1 transcript levels had 99.6% accuracy in diagnosis of disease status in male subjects. The current study shows significance of GAS8 and GAS8-AS1 in the pathogenesis of MS and the putative role of GAS8-AS1 as a diagnostic biomarker in a subset of patients. Copyright © 2019 Elsevier GmbH. All rights reserved. DOI: 10.1016/j.imbio.2019.04.005 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 118 – Multiple Sklerose: Veröffentlichungen April 2019 168. Immunol Med. 2018 Sep;41(3):120-128. doi: 10.1080/25785826.2018.1531190. Epub 2018 Nov 30. Blood-brain barrier dysfunction in immuno-mediated neurological diseases. Shimizu F(1), Nishihara H(1), Kanda T(1). Author information: (1)a Department of Neurology and Clinical Neuroscience , Yamaguchi University Graduate School of Medicine , Ube , Japan. The blood-brain barrier (BBB) is the brain-specific endothelial cell barrier that is important for maintaining brain homeostasis and preventing the entry of toxic substances. Pathological BBB dysfunction is a critical step of the disease process in several immuno-mediated neurological diseases, including multiple sclerosis (MS), neuromyelitis optica (NMO), neuropsychiatric systemic lupus erythematosus (NPSLE) and neuro- Behçet diseases. The pathological findings from patients with secondary progressive (SP) MS, NMO and NPSLE showed leaky BBB in the active lesions. NMO is a disease with strong evidence of disease-specific and pathogenic autoantibodies (aquaporin 4 [AQP4] autoantibodies). In the development of NMO, circulating AQP4 autoantibodies need to pass through the BBB in order to reach AQP4 on the astrocyte endfeet. Strong evidence suggests that NPSLE is associated with the disruption of the BBB and NPSLE patients frequently have antibodies bound to endothelial cells in their sera. We recently identified two BBB-reactive autoantibodies in immuno-mediated neurological diseases: galectin-3 autoantibodies in SPMS and GRP78 autoantibodies in NMO. In the present review article, we describe the basic structure and cellular biology of the BBB, discuss recent insights regarding the pathophysiology of the BBB breakdown in the setting of immuno-mediated neurological diseases, and describe our recent findings of autoantibody-mediated BBB breakdown. DOI: 10.1080/25785826.2018.1531190 169. Indian J Ophthalmol. 2019 May;67(5):653-654. doi: 10.4103/ijo.IJO_175_19. Commentary: Ganglion cell complex of retinal layer thickness by optical coherence tomography in cases of multiple sclerosis without optic neuritis compared to healthy eyes. Sudhakar P(1). Author information: (1)Department of Neurology and Ophthalmology, University of Kentucky, 740 S Limestone, Lexington, KY, USA. DOI: 10.4103/ijo.IJO_175_19 Conflict of interest statement: None 170. Indian J Ophthalmol. 2019 May;67(5):648-653. doi: 10.4103/ijo.IJO_1378_18. Macular ganglion cell complex parameters by optical coherence tomography in cases of multiple sclerosis without optic neuritis compared to healthy eyes. Lotfy NM(1), Alasbali T(2), Khandekar R(3). Author information: (1)Department of Ophthalmology, Faculty of Medicine, Cairo University, Cairo, Egypt; Department of Ophthalmology, Specialised Medical Hospital, Riyadh, Saudi Arabia. (2)Imam Mohammed bin Saud Islamic University College of Medicine; Department of Ophthalmology, Specialised Medical Hospital, Riyadh, Saudi Arabia. (3)Department of Research, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. Purpose: To compare different macular thickness parameters and peripapillary retinal nerve fiber layer (RNFL) thickness between recently diagnosed cases of multiple sclerosis (MS) without optic neuropathy (ON) and healthy individuals. Methods: This cross-sectional study was performed between June 2014 and June 2015. All subjects underwent ocular and retinal examination. Spectral domain optical coherence tomography (SD-OCT) was used to measure the thickness of different layers of the retina at macular and peripapillary regions and at different quadrants. Between groups comparison was performed with P < 0.05 indicating statistical significance. Results: There were 32 eyes in the MS group and 74 eyes in the control group. The MS group was significantly younger than the control group (P < 0.001). The mean ganglion cell complex (GCL++) thickness in superior macular area was 64.1 ± 8.9 μ in the MS group and 71.1 ± 5.9 μ in the control group. The thickness of the RNFL did not statistically differ in each of the quadrants between groups. Despite controlling for age, the macular thickness parameters were significantly thinner in eyes with MS compared to healthy eyes (P < 0.01). Conclusion: The macular ganglion cell complex (mGCC) parameters were significantly reduced in recently diagnosed cases of MS as compared to healthy individuals. DOI: 10.4103/ijo.IJO_1378_18 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 | L.DE.MKT.SM.02.2017.5323 – 119 – Multiple Sklerose: Veröffentlichungen April 2019 171. Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738419843690. doi: 10.1177/2058738419843690. Autoimmune thyroid disease following treatment with alemtuzumab for multiple sclerosis. Alamo A(1), Condorelli RA(1), La Vignera S(1), Calogero AE(1). Author information: (1)Department of Clinical and Experimental Medicine, University of Catania, Policlinico 'G. Rodolico', Catania, Italy. Alemtuzumab, an anti-CD52 monoclonal antibody, is effective in the treatment of relapsing-remitting multiple sclerosis (RRMS). Common adverse effects include the development of autoimmune diseases, and Graves' disease is one of the most frequent presentations. We report here a case of alemtuzumab-induced thyroid disease in a female patient who showed a phase of thyrotoxicosis with positive anti-thyroglobulin (anti-Tg) and anti-thyroid peroxidase (TPO) antibodies, but a negative TSH receptor antibody, spontaneously followed by hypothyroidism. The aim is to illustrate the clinical presentation, evaluation over time, and the possibility to consider a conservative management up to the spontaneous resolution of the thyrotoxicosis. All these are intended to emphasize the importance of pretreatment screening and follow-up in the management of treatment with alemtuzumab. DOI: 10.1177/2058738419843690 PMCID: PMC6458661 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 120 – Multiple Sklerose: Veröffentlichungen April 2019 172. Int J Mol Sci. 2019 Mar 29;20(7). pii: E1584. doi: 10.3390/ijms20071584. Dulaglutide Modulates the Development of Tissue-Infiltrating Th1/Th17 Cells and the Pathogenicity of Encephalitogenic Th1 Cells in the Central Nervous System. Chiou HC(1), Lin MW(2)(3)(4), Hsiao PJ(5)(6), Chen CL(7), Chiao S(8), Lin TY(9), Chen YC(10)(11), Wu DC(12)(13)(14), Lin MH(15)(16)(17)(18)(19). Author information: (1)Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan. [email protected]. (2)Department of Medical Research, E-Da Hospital/E-Da Cancer Hospital, Kaohsiung City 824, Taiwan. [email protected]. (3)School of Medicine, College of Medicine, I-Shou University, Kaohsiung City 824, Taiwan. [email protected]. (4)Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (5)Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan. [email protected]. (6)Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (7)Department of Biological Science, National Sun Yat-Sen University, Kaohsiung City 804, Taiwan. [email protected]. (8)Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (9)Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (10)Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (11)Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (12)Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (13)Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (14)Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan. [email protected]. (15)Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (16)Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (17)Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (18)M.Sc. Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. [email protected]. (19)Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan. [email protected]. GLP-1 (glucagon-like peptide-1) has been reported to play a vital role in neuroprotection. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model widely used to study human multiple sclerosis, a chronic demyelination disease in the central nervous system (CNS). Recently, important studies have designated that the signaling axis of GLP-1 and its receptor controls the clinical manifestations and pathogenesis of EAE. However, it is elusive whether GLP-1 receptor signaling regulates the phenotype of autoreactive T cells in the CNS. We administered dulaglutide, a well-established GLP-1 receptor agonist (GLP-1 RA), to treat EAE mice prophylactically or semi-therapeutically and subsequently analyzed the mononuclear cells of the CNS. In this study, dulaglutide treatment significantly alleviates the clinical manifestations and histopathological outcomes of EAE. Dulaglutide decreases incidences of encephalitogenic Th1/Th17 cells and Th1 granulocyte-macrophage-colony-stimulating factor (GM-CSF) expression in the CNS. Administration of dulaglutide failed to control the chemotactic abilities of encephalitogenic Th1 and Th17 cells; however, prophylactic treatment considerably decreased the populations of dendritic cells and macrophages in the CNS parenchyma. These results obtained indicate that dulaglutide modulates the differentiation of encephalitogenic Th1/Th17 and the pathogenicity of Th1 cells by influencing antigen presenting cells quantities, providing mechanism insight on T cells regulation in ameliorating EAE by GLP-1. DOI: 10.3390/ijms20071584 PMCID: PMC6479396 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 121 – Multiple Sklerose: Veröffentlichungen April 2019 173. Int J Mol Sci. 2019 Apr 5;20(7). pii: E1702. doi: 10.3390/ijms20071702. Delayed Astrogliosis Associated with Reduced M1 Microglia Activation in Matrix Metalloproteinase 12 Knockout Mice during Theiler's Murine Encephalomyelitis. Hansmann F(1), Zhang N(2), Herder V(3), Leitzen E(4), Baumgärtner W(5). Author information: (1)Department of Pathology, University of Veterinary Medicine Hannover; Center for Systems Neuroscience 30559 Hannover, Germany. [email protected]. (2)Department of Pathology, University of Veterinary Medicine Hannover; Center for Systems Neuroscience 30559 Hannover, Germany. [email protected]. (3)Department of Pathology, University of Veterinary Medicine Hannover; Center for Systems Neuroscience 30559 Hannover, Germany. Vanessa.Herder@tiho- hannover.de. (4)Department of Pathology, University of Veterinary Medicine Hannover; Center for Systems Neuroscience 30559 Hannover, Germany. [email protected]. (5)Department of Pathology, University of Veterinary Medicine Hannover; Center for Systems Neuroscience 30559 Hannover, Germany. [email protected]. Theiler's murine encephalomyelitis (TME) represents a versatile animal model for studying the pathogenesis of demyelinating diseases such as multiple sclerosis. Hallmarks of TME are demyelination, astrogliosis, as well as inflammation. Previous studies showed that matrix metalloproteinase 12 knockout (Mmp12-/-) mice display an ameliorated clinical course associated with reduced demyelination. The present study aims to elucidate the impact of MMP12 deficiency in TME with special emphasis on astrogliosis, macrophages infiltrating the central nervous system (CNS), and the phenotype of microglia/macrophages (M1 or M2). SJL wild-type and Mmp12-/- mice were infected with TME virus (TMEV) or vehicle (mock) and euthanized at 28 and 98 days post infection (dpi). Immunohistochemistry or immunofluorescence of cervical and thoracic spinal cord for detecting glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), chemokine receptor 2 (CCR2), CD107b, CD16/32, and arginase I was performed and quantitatively evaluated. Statistical analyses included the Kruskal⁻Wallis test followed by Mann⁻Whitney U post hoc tests. TMEV-infected Mmp12-/- mice showed transiently reduced astrogliosis in association with a strong trend (p = 0.051) for a reduced density of activated/reactive microglia/macrophages compared with wild-type mice at 28 dpi. As astrocytes are an important source of cytokine production, including proinflammatory cytokines triggering or activating phagocytes, the origin of intralesional microglia/macrophages as well as their phenotype were determined. Only few phagocytes in wild-type and Mmp12-/- mice expressed CCR2, indicating that the majority of phagocytes are represented by microglia. In parallel to the reduced density of activated/reactive microglia at 98 dpi, TMEV-infected Mmp12-/- showed a trend (p = 0.073) for a reduced density of M1 (CD16/32- and CD107b-positive) microglia, while no difference regarding the density of M2 (arginase I- and CD107b-positive) cells was observed. However, a dominance of M1 cells was detected in the spinal cord of TMEV-infected mice at all time points. Reduced astrogliosis in Mmp12-/- mice was associated with a reduced density of activated/reactive microglia and a trend for a reduced density of M1 cells. This indicates that MMP12 plays an important role in microglia activation, polarization, and migration as well as astrogliosis and microglia/astrocyte interaction. DOI: 10.3390/ijms20071702 PMCID: PMC6480673 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 122 – Multiple Sklerose: Veröffentlichungen April 2019 174. Int J Mol Sci. 2019 Apr 1;20(7). pii: E1620. doi: 10.3390/ijms20071620. Interferon-Stimulated Genes-Mediators of the Innate Immune Response during Canine Distemper Virus Infection. Klotz D(1), Gerhauser I(2). Author information: (1)Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany. [email protected]. (2)Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany. [email protected]. The demyelinating canine distemper virus (CDV)-leukoencephalitis represents a translational animal model for multiple sclerosis. The present study investigated the expression of type I interferon (IFN-I) pathway members in CDV-induced cerebellar lesions to gain an insight into their role in lesion development. Gene expression of 110 manually selected genes in acute, subacute and chronic lesions was analyzed using pre- existing microarray data. Interferon regulatory factor (IRF) 3, IRF7, signal transducer and activator of transcription (STAT) 1, STAT2, MX protein, protein kinase R (PKR), 2'-5'-oligoadenylate synthetase (OAS) 1 and interferon-stimulated gene (ISG) 15 expression were also evaluated using immunohistochemistry. Cellular origin of STAT1, STAT2, MX and PKR were determined using immunofluorescence. CDV infection caused an increased expression of the antiviral effector proteins MX, PKR, OAS1 and ISG15, which probably contributed to a restricted viral replication, particularly in neurons and oligodendrocytes. This increase might be partly mediated by IRF-dependent pathways due to the lack of changes in IFN-I levels and absence of STAT2 in astrocytes. Nevertheless, activated microglia/macrophages showed a strong expression of STAT1, STAT2 and MX proteins in later stages of the disease, indicating a strong activation of the IFN-I signaling cascade, which might be involved in the aggravation of bystander demyelination. DOI: 10.3390/ijms20071620 PMCID: PMC6480560 175. Int J Vitam Nutr Res. 2019 Apr 16:1-8. doi: 10.1024/0300-9831/a000580. [Epub ahead of print] The Association between Vitamin D Deficiency and variants of Vitamin D Binding protein gene among Healthy Iranian Adults. Pooyan S(1), Rahimi MH(1), Mollahosseini M(1), Khorrami-Nezhad L(1), Maghbooli Z(2), Mirzaei K(1). Author information: (1)1 Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran. (2)2 Assistant Professor of Medical Genetics, Multiple Sclerosis Research Center, Sina hospital, Tehran University of Medical Sciences, Tehran, Iran. BACKGROUND: The high prevalence of vitamin D deficiency may be due to both genetic and environment factors. The aim of this study was to demonstrate that vitamin D deficiency may be due to variants of vitamin D binding protein ( DBP) among otherwise healthy Iranian adults. METHODS: This cross-sectional study was conducted on 265 healthy adults in Tehran. Anthropometric and biochemical parameters were assessed. Dietary vitamin D intake was assessed with a Food Frequency Questionnaire (FFQ), and participant DBP genotypes were determined by polymerase chain reactions - restriction fragment length polymorphism. RESULTS: Significant associations were found between vitamin D status and low-density lipoprotein cholesterol (P < 0.001), total cholesterol (P < 0.001), and fasting blood sugar (P < 0.001), after adjustment for confounder factors. This study demonstrated that "rs7041" gene was associated with vitamin D deficiency (OR = 0.63, β ± SE = -0.46 ± 0.14, P < 0.0001). After considering the "GG" genotype of the "rs7041" polymorphism as a reference, the prevalence of vitamin D deficiency was found to be higher in the individuals with "TT" genotype from the "rs7041" polymorphism. CONCLUSION: It was found that the prevalence of vitamin D deficiency was higher in individuals with T allele carriers in the "rs7041" polymorphism. DOI: 10.1024/0300-9831/a000580 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 123 – Multiple Sklerose: Veröffentlichungen April 2019 176. Interact J Med Res. 2019 Apr 5;8(2):e8423. doi: 10.2196/ijmr.8423. Differences in the Level of Electronic Health Literacy Between Users and Nonusers of Digital Health Services: An Exploratory Survey of a Group of Medical Outpatients. Holt KA(1), Karnoe A(2)(3), Overgaard D(1), Nielsen SE(4), Kayser L(2), Røder ME(4)(5), From G(4). Author information: (1)Department of Nursing, Faculty of Health, University College Copenhagen, Copenhagen N, Denmark. (2)Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. (3)Danish Multiple Sclerosis Society, Copenhagen, Denmark. (4)Medical Department, Herlev-Gentofte University Hospital, Copenhagen, Denmark. (5)Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark. BACKGROUND: Digitalization of health services ensures greater availability of services and improved contact to health professionals. To ensure high user adoption rates, we need to understand the indicators of use and nonuse. Traditionally, these have included classic sociodemographic variables such as age, sex, and educational level. Electronic health literacy (eHL) describes knowledge, skills, and experiences in the interaction with digital health services and technology. With our recent introduction of 2 new multidimensional instruments to measure eHL, the eHL questionnaire (eHLQ) and the eHL assessment (eHLA) toolkit, eHL provides a multifaceted approach to understand use and nonuse of digital health solutions in detail. OBJECTIVE: The aim of this study was to investigate how users and nonusers of digital services differ with respect to eHL, in a group of patients with regular contact to a hospital outpatient clinic. Furthermore, to examine how usage and nonusage, and eHL levels are associated with factors such as age, sex, educational level, and self-rated health. METHODS: Outpatients were asked to fill out a survey comprising items about usage of digital services, including digital contact to general practitioner (GP) and communication via the national health portal sundhed.dk, the eHLQ, and the eHLA toolkit, as well as items on age, sex, education, and self-rated health. In total, 246 patients completed the survey. A Mann-Whitney test was used to test for differences between users and nonusers of digital services. Correlation tests described correlations between eHL scales (eHEALSs) and age, education, and self-rated health. A significance level of .0071 was used to reject the null hypothesis in relation to the eHEALSs and usage of digital services. RESULTS: In total, 95.1% (234/246) of the participants used their personal digital ID (NemID), 57.7% (142/246) were in contact with their GPs electronically, and 54.0% (133/246) had used the national health portal (sundhed.dk) within the last 3 months. There were no differences between users and nonusers of sundhed.dk with respect to age, sex, educational level, and self-rated health. Users of NemID scored higher than nonusers in 6 of the 7 dimensions of eHLQ, the only one which did not differ was dimension 2: Understanding of health concepts and language. Sundhed.dk users had a higher score in all of the 7 dimensions except for dimension 4: Feel safe and in control. The eHLA toolkit showed that users of sundhed.dk and NemID had higher levels of eHL with regard to tools 2, 5, 6, and 7. Furthermore, users of sundhed.dk had higher levels of eHL with regard to tools 3 and 4. CONCLUSIONS: Information about patients' eHL may provide clinicians an understanding of patients' reasons for not using digital health services, better than sociodemographic data or self-rated health. ©Kamila Adellund Holt, Astrid Karnoe, Dorthe Overgaard, Sidse Edith Nielsen, Lars Kayser, Michael Einar Røder, Gustav From. Originally published in the Interactive Journal of Medical Research (http://www.i- jmr.org/), 05.04.2019. DOI: 10.2196/ijmr.8423 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 124 – Multiple Sklerose: Veröffentlichungen April 2019 177. Invest Ophthalmol Vis Sci. 2019 Apr 1;60(5):1372-1383. doi: 10.1167/iovs.18-26096. Quantification of Visual Fixation in Multiple Sclerosis. Nij Bijvank JA(1)(2), Petzold A(1)(2)(3), Coric D(2), Tan HS(1), Uitdehaag BMJ(2), Balk LJ(2), van Rijn LJ(1)(4). Author information: (1)Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Department of Ophthalmology, Neuro-ophthalmology Expertise Center, Neuroscience Amsterdam, Amsterdam, The Netherlands. (2)Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Neurology, Multiple Sclerosis Center and Neuro-ophthalmology Expertise Center, Neuroscience Amsterdam, Amsterdam, The Netherlands. (3)Moorfields Eye Hospital, The National Hospital for Neurology and Neurosurgery, the University College London Institute of Neurology, London, United Kingdom. (4)Onze Lieve Vrouwe Gasthuis, Department of Ophthalmology, Amsterdam, The Netherlands. Purpose: Eye movement abnormalities are common in multiple sclerosis (MS), and infrared oculography is a noninvasive method for quantification. This study aims to describe and classify abnormalities of visual fixation and their clinical relevance in MS. Methods: A validated standardized infrared oculography protocol, Demonstrate Eye Movement Networks with Saccades, was used for quantifying gaze stability during a fixation task in MS patients and healthy controls. Saccadic intrusions, gaze drift, and stability of fixation around the drift line were used to subclassify MS patients by performing receiver operating characteristic analyses of different parameters. The relationship between the presence of abnormalities of fixation and visual functioning was analyzed using logistic regression models, which was adjusted for possible confounders. Results: This cross-sectional study included 213 subjects with MS and 57 healthy controls. Square wave jerk abnormalities were present in 24% of MS patients. The prevalence was higher in more disabled subjects. The presence of larger square wave jerks (with a higher amplitude) in the MS patients was related to complaints of focusing on stationary objects (odds ratio, 2.2; P = 0.035) and a lower vision- related quality of life (odds ratio, 2.56; P = 0.012). Conclusions: This study provided a comprehensive overview of the characteristics of problems with visual fixation in subjects with MS. The most important and most common finding was the presence of larger square wave jerks during fixation, which was related to visual functioning in daily life. DOI: 10.1167/iovs.18-26096 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 125 – Multiple Sklerose: Veröffentlichungen April 2019 178. IUBMB Life. 2019 Apr 7. doi: 10.1002/iub.2045. [Epub ahead of print] Gold Nanoparticles and Polyethylene Glycol Alleviate Clinical Symptoms and Alter Cytokine Secretion in a Mouse Model of Experimental Autoimmune Encephalomyelitis. Aghaie T(1), Jazayeri MH(1)(2), Avan A(3), Anissian A(4), Salari AA(5). Author information: (1)Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. (2)Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran. (3)Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. (4)Department of Veterinary Pathology, Islamic Azad University, Abhar, Iran. (5)Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Gold nanoparticles (GNPs) are attractive nanoparticles with unique electronic and optical properties in the nanotechnology field and are widely used in various biomedical fields. Studies have shown that these particles also exhibit antioxidant and anti-inflammatory properties. On the other hand, polyethylene glycol (PEG) that used to stabilize GNPs also exhibits antioxidant and anti-inflammatory properties due to their membrane resealing properties. The aim of this study was to evaluate the ameliorative effect of GNPs and PEG in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). EAE was induced in female C57BL/6 mice with injection of an emulsion of myelin oligodendrocyte glycoprotein (MOG35-55) peptide and Freund's adjuvant. GNPs measuring 25 nm were prepared, and their size was determined using transmission electron microscopy (TEM), then intraperitoneal injection of GNPs and PEG (MW 1500; 30% w/v) was initiated after immunization and continued until the day 27 postimmunization (13 injections in total). The EAE clinical scores and body weights were evaluated. We analyzed cental nervous system's cell infiltration and demyelinated lesions using hematoxylin and eosin and luxol fast blue staining, respectively. Also, interleukin-23 and interleukin-27 were examined using the ELISA technique. The severity of MS symptoms was significantly decreased in the treated groups with GNPs and PEG. Histological examination of the spinal cord showed that the number and severity of cells' infiltration and demyelinated lesions decreased significantly, and also the cytokine levels of IL-23 and IL-27 altered in treated groups. These results show that GNPs and PEG ameliorate the clinical course of EAE in mice. Our findings demonstrate proof of principle for potential of GNPs and PEG as novel agents for therapeutic approaches in the alleviated clinical symptoms of MS. © 2019 IUBMB Life, 1-9, 2019. © 2019 International Union of Biochemistry and Molecular Biology. DOI: 10.1002/iub.2045 179. J Agric Biol Environ Stat. 2019 Mar;24(1):112-129. doi: 10.1007/s13253-018-00344-0. Epub 2018 Dec 7. Modeling and Prediction of Multiple Correlated Functional Outcomes. Cao J(1), Soiaporn K(#)(2), Carroll RJ(3), Ruppert D(4). Author information: (1)Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC V5A1S6, Canada ([email protected]). (2)Capital One, Vienna, VA 22180, USA ([email protected]). (3)Department of Statistics, Texas A&M University, College Station, TX 77843, USA and School of Mathematical and Physical Sciences, University of Technology Sydney, Broadway, NSW 2007, Australia ([email protected]). (4)Department of Statistical Science and School of Operations Research and Information Engineering, Cornell University, Ithaca, NY 14850, USA ([email protected]). (#)Contributed equally We propose a copula-based approach for analyzing functional data with correlated multiple functional outcomes exhibiting heterogeneous shape characteristics. To accommodate the possibly large number of parameters due to having several functional outcomes, parameter estimation is performed in two steps: first, the parameters for the marginal distributions are estimated using the skew t family, and then the dependence structure both within and across outcomes is estimated using a Gaussian copula. We develop an estimation algorithm for the dependence parameters based on the Karhunen-Loève expansion and an EM algorithm that significantly reduces the dimension of the problem and is computationally efficient. We also demonstrate prediction of an unknown outcome when the other outcomes are known. We apply our methodology to diffusion tensor imaging data for multiple sclerosis (MS) patients with three outcomes and identify differences in both the marginal distributions and the dependence structure between the MS and control groups. Our proposed methodology is quite general and can be applied to other functional data with multiple outcomes in biology and other fields. DOI: 10.1007/s13253-018-00344-0 PMCID: PMC6447061 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 126 – Multiple Sklerose: Veröffentlichungen April 2019 180. J Am Med Inform Assoc. 2019 Apr 2. pii: ocz012. doi: 10.1093/jamia/ocz012. [Epub ahead of print] Data linkages between patient-powered research networks and health plans: a foundation for collaborative research. Agiro A(1), Chen X(1), Eshete B(1), Sutphen R(2), Bourquardez Clark E(2), Burroughs CM(2), Nowell WB(3), Curtis JR(4), Loud S(5), McBurney R(5), Merkel PA(6), Sreih AG(6), Young K(7), Haynes K(1). Author information: (1)HealthCore, Wilmington, Delaware, USA. (2)Heath Informatics Institute, University of South Florida, Tampa, Florida, USA. (3)Global Healthy Living Foundation, Upper Nyack, New York, USA. (4)Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA. (5)Accelerated Cure Project, Waltham, Massachusetts, USA. (6)Division of Rheumatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. (7)Vasculitis Foundation, Kansas City, Missouri, USA. OBJECTIVE: Patient-powered research networks (PPRNs) are a valuable source of patient-generated information. Diagnosis code-based algorithms developed by PPRNs can be used to query health plans' claims data to identify patients for research opportunities. Our objective was to implement privacy- preserving record linkage processes between PPRN members' and health plan enrollees' data, compare linked and nonlinked members, and measure disease-specific confirmation rates for specific health conditions. MATERIALS AND METHODS: This descriptive study identified overlapping members from 4 PPRN registries and 14 health plans. Our methods for the anonymous linkage of overlapping members used secure Health Insurance Portability and Accountability Act-compliant, 1-way, cryptographic hash functions. Self-reported diagnoses by PPRN members were compared with claims-based computable phenotypes to calculate confirmation rates across varying durations of health plan coverage. RESULTS: Data for 21 616 PPRN members were hashed. Of these, 4487 (21%) members were linked, regardless of any expected overlap with the health plans. Linked members were more likely to be female and younger than nonlinked members were. Irrespective of duration of enrollment, the confirmation rates for the breast or ovarian cancer, rheumatoid or psoriatic arthritis or psoriasis, multiple sclerosis, or vasculitis PPRNs were 72%, 50%, 75%, and 67%, increasing to 91%, 67%, 93%, and 80%, respectively, for members with ≥5 years of continuous health plan enrollment. CONCLUSIONS: This study demonstrated that PPRN membership and health plan data can be successfully linked using privacy-preserving record linkage methodology, and used to confirm self-reported diagnosis. Identifying and confirming self-reported diagnosis of members can expedite patient selection for research opportunities, shorten study recruitment timelines, and optimize costs. © The Author(s) 2019. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: [email protected]. DOI: 10.1093/jamia/ocz012 181. J Am Osteopath Assoc. 2019 May 1;119(5):282a-283. doi: 10.7556/jaoa.2019.048. Doming the Diaphragm in a Patient With Multiple Sclerosis. Bordoni B. DOI: 10.7556/jaoa.2019.048 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 127 – Multiple Sklerose: Veröffentlichungen April 2019 182. J Autoimmun. 2019 Apr 20. pii: S0896-8411(19)30129-5. doi: 10.1016/j.jaut.2019.04.002. [Epub ahead of print] Small non-coding RNAs as important players, biomarkers and therapeutic targets in multiple sclerosis: A comprehensive overview. Piket E(1), Zheleznyakova GY(1), Kular L(1), Jagodic M(2). Author information: (1)Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. (2)Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: [email protected]. Multiple sclerosis (MS) is a leading cause of progressive disability among young adults caused by inflammation, demyelination and axonal loss in the central nervous system. Small non-coding RNAs (sncRNAs) are important regulators of various biological processes and could therefore play important roles in MS. Over the past decade, a large number of studies investigated sncRNAs in MS patients, focusing primarily on microRNAs (miRNAs). Overwhelming 500 miRNAs have been reported as dysregulated in MS. Nevertheless, owing to a large heterogeneity between studies it is challenging to evaluate the reproducibility of findings, in turn hampering our knowledge about the functional roles of miRNAs in disease. We systematically searched main databases and evaluated results from all studies that examined sncRNAs in MS to date (n = 61) and provided a detailed overview of experimental design and findings of these studies. We focused on the mechanisms of the most dysregulated sncRNAs and used predicted targets of the most dysregulated sncRNAs as input for functional enrichment analysis to highlight affected pathways. The prime affected pathway was TGF-β signaling. This multifunctional cytokine is important in the differentiation and function of T helper type 17 (Th17) and regulatory T (Treg) cells, with opposing functions in the disease. Recent studies demonstrate the importance of miRNAs in controlling the balance between Th17/Th1 cells and Tregs and, importantly, the potential to exploit this paradigm for therapeutic purposes. Additionally, some of the discussed miRNAs could potentially serve as biomarkers of disease. In order to assist researchers in evaluating the evidence of a particular sncRNA in the pathogenesis of MS, we provide a detailed overview of experimental design and findings of these studies to date. Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved. DOI: 10.1016/j.jaut.2019.04.002 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 128 – Multiple Sklerose: Veröffentlichungen April 2019 183. J Autoimmun. 2019 Apr 19. pii: S0896-8411(19)30019-8. doi: 10.1016/j.jaut.2019.04.003. [Epub ahead of print] Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation. Didonna A(1), Cantó E(2), Shams H(2), Isobe N(2), Zhao C(2), Caillier SJ(2), Condello C(3), Yamate-Morgan H(4), Tiwari-Woodruff SK(5), Mofrad MRK(6), Hauser SL(2), Oksenberg JR(2). Author information: (1)Department of Neurology and Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, 94158, USA. Electronic address: [email protected]. (2)Department of Neurology and Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, 94158, USA. (3)Department of Neurology and Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, 94158, USA; Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94158, USA. (4)Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA, 92521, USA; Neuroscience Graduate Program, University of California Riverside, Riverside, CA, 92521, USA. (5)Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA, 92521, USA; Neuroscience Graduate Program, University of California Riverside, Riverside, CA, 92521, USA; Center for Glial-Neuronal Interactions, UCR School of Medicine, CA, 92506, USA. (6)Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, CA, 94720, USA; Physical Biosciences Division, Lawrence Berkeley National Lab, Berkeley, CA, 94720, USA. The molecular events underlying the transition from initial inflammatory flares to the progressive phase of multiple sclerosis (MS) remain poorly understood. Here, we report that the microtubule-associated protein (MAP) Tau exerts a gender-specific protective function on disease progression in the MS model experimental autoimmune encephalomyelitis (EAE). A detailed investigation of the autoimmune response in Tau-deficient mice excluded a strong immunoregulatory role for Tau, suggesting that its beneficial effects are presumably exerted within the central nervous system (CNS). Spinal cord transcriptomic data show increased synaptic dysfunctions and alterations in the NF-kB activation pathway upon EAE in Tau-deficient mice as compared to wildtype animals. We also performed the first comprehensive characterization of Tau post-translational modifications (PTMs) in the nervous system upon EAE. We report that the methylation levels of the conserved lysine residue K306 are significantly decreased in the chronic phase of the disease. By combining biochemical assays and molecular dynamics (MD) simulations, we demonstrate that methylation at K306 decreases the affinity of Tau for the microtubule network. Thus, the down-regulation of this PTM might represent a homeostatic response to enhance axonal stability against an autoimmune CNS insult. The results, altogether, position Tau as key mediator between the inflammatory processes and neurodegeneration that seems to unify many CNS diseases. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.jaut.2019.04.003 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 129 – Multiple Sklerose: Veröffentlichungen April 2019 184. J Cell Biochem. 2019 Apr 8. doi: 10.1002/jcb.28670. [Epub ahead of print] Mesenchymal stem cell mediated effects on microglial phenotype in cuprizone- induced demyelination model. Barati S(1), Ragerdi Kashani I(2), Moradi F(1), Tahmasebi F(2), Mehrabi S(3), Barati M(4), Joghataei MT(1). Author information: (1)Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. (2)Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. (3)Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. (4)Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran. Microglial cells have an essential role in neurodegenerative disorders, such as multiple sclerosis. They are divided into two subgroups: M1 and M2 phenotypes. Mesenchymal stem cells (MSC), with neuroprotective and immunomodulating properties, could improve these diseases. We evaluate the immunomodulating effects of MSC on microglial phenotypes and the improvement of demyelination in a cuprizone (CPZ) model of multiple sclerosis (MS). For inducing the chronic demyelination model, C57BL6 mice were given a diet with 0.2% CPZ (w/w) for 12 weeks. In the MSC group, cells were transplanted into the right lateral ventricle of mice. The expression of targeted genes was assessed by real-time polymerase chain reaction. M1 and M2 microglial phenotypes were assessed by immunohistochemistry of inducible nitric oxide synthase (iNOS) and Arg-1, respectively. Remyelination was studied by luxal fast blue (LFB) staining and electron microscopy (EM). We found that MSC transplantation reduced the expression level of M1-specific messenger RNA (mRNA; iNOS and CD86) but increased the expression level of M2 specific genes (CD206, Arg-1, and CX3CR1) in comparison to the CPZ group. Moreover, cell therapy significantly decreased the M1 marker (iNOS+ cells), but M2 marker (Arg-1+ cells) significantly increased in comparison with the CPZ group. In addition, MSC treatment significantly increased the CX3CL1 expression level in comparison with the CPZ group and led to improvement in remyelination, which was confirmed by LFB and EM images. The results showed that MSC transplantation increases the M2 and decreases the M1 phenotype in MS. This change was accompanied by decrease in demyelination and axonal injury and indicated that MSCs have a positive effect on MS by modification of microglia cells. © 2019 Wiley Periodicals, Inc. DOI: 10.1002/jcb.28670 185. J Cell Physiol. 2019 Apr 24. doi: 10.1002/jcp.28725. [Epub ahead of print] Survivin modulatory role in autoimmune and autoinflammatory diseases. Pahlavan Y(1)(2)(3)(4), Kahroba H(2)(3)(4), Samadi N(1)(2)(3)(5), Karimi A(2), Ansarin K(2)(6), Khabbazi A(2)(7). Author information: (1)Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. (2)Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. (3)Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. (4)Students Research Committee, University of Tabriz Medical Sciences, Tabriz, Iran. (5)Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. (6)Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. (7)Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Baculoviral IAP repeat containing 5 (BIRC5) gene encodes the important protein as survivin, a multifunctional protein, which is involved in cellular and molecular networks, progression of cell cycle, homeostasis, developmental morphogenesis, and apoptosis. The proximal BIRC5 promoter possesses specific binding sites for key transcription factors such as nuclear factor κB and signal transducer and activator of transcription 3. Upregulation of survivin exacerbates the autoimmune diseases (AIDs) including multiple sclerosis and myasthenia gravis by reducing the activity threshold of survivin-specific cytotoxic T cells. DNA damage along with upregulation or downregulation of survivin have been demonstrated in initiation and pathogenesis of cancers and AIDs. However, detailed mechanism of survivin function in pathogenesis of AIDs is not well understood. This review focuses on the structure, specificity, regulation, and function of survivin in physiologic conditions and pathogenesis of AIDs. © 2019 Wiley Periodicals, Inc. DOI: 10.1002/jcp.28725 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 130 – Multiple Sklerose: Veröffentlichungen April 2019 186. J Cell Physiol. 2019 Apr 10. doi: 10.1002/jcp.28583. [Epub ahead of print] Altered expression patterns of complement factor H and miR-146a genes in acute- chronic phases in experimental autoimmune encephalomyelitis mouse. Gharibi S(1), Moghimi B(2), Haghmorad D(3)(4), Mahmoudi MB(2), Shahvazian E(1), Yadegari M(5), Yazd EF(2)(6), Tahoori MT(7). Author information: (1)Department of Genetics, Faculty of Medicine, International Campus, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran. (2)Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran. (3)Department of Pathology and Laboratory Medicine, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran. (4)Department of Immunology, School of Medicine, Semnan University of Medical Sciences and Health Services, Semnan, Iran. (5)Department of Biology & Anatomical Sciences, Shahid Sadoughi University of Medical Sciences and Health Services, Faculty of Medicine, Yazd, Iran. (6)Genetic Engineering and Genome Editing Laboratory, Stem Cell Biology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. (7)Department of Immunology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran. Considerable advances have been made in identification of the involvement of immune modulators in diseases. There is growing evidence on the role of complement pathway in pathogenesis and course of multiple sclerosis (MS). Moreover, it has been recognized that microRNAs (miRNAs) play an essential role in modulation and development of immune response in the central nervous system. We aimed to investigate the expression profile of complement factor H (CFH) and miR-146a genes in experimental autoimmune encephalomyelitis (EAE) mouse model of MS to detect the possible roles of CFH and miR-146a as biomarkers of MS disease stats. Expression of CFH and miR-146a genes in liver and brain tissues of EAE mice was measured in acute and chronic phases of disease compared to matched controls using real-time polymerase chain reaction. In the liver, increased expression of CFH gene was observed in the chronic phase compared to the acute phase. However, no significant difference was observed between acute and chronic phase mice with normal mice, while miR-146a expression was significantly decreased in livers of EAE mice in chronic group compared to acute and control groups. The expression of CFH gene in brain had a significant decrease in acute and chronic phases compared to healthy mice. Taken together, these observations indicate probable implication of complement system and miR-146a in course of immune-related diseases and reveal more facts about the pathogenesis of MS. However, further work is needed to determine protein levels of CFH and other possible targets of miR-146a in serum and cerebrospinal fluid of MS patients. © 2019 Wiley Periodicals, Inc. DOI: 10.1002/jcp.28583 187. J Child Neurol. 2019 Apr 23:883073819842420. doi: 10.1177/0883073819842420. [Epub ahead of print] Insights and Recommendations From Parents Receiving a Diagnosis of Pediatric Multiple Sclerosis for Their Child. Hebert D(1), Geisthardt C(1), Hoffman H(1). Author information: (1)1 Central Michigan University College of Medicine, Mount Pleasant, MI, USA. Forty-two parents of 41 children reported on their experiences receiving a diagnosis of pediatric-onset multiple sclerosis for their child through semistructured phone interviews. Time to diagnosis ranged from 8 hours to 16 years, with the mean age at diagnosis of 13.7 years. The most common initial symptoms included visual disturbances and numbness. The mean number of medical visits to receive a diagnosis was 3.6. Parents reported feeling frustrated and overwhelmed during the diagnosis process, as well as shocked when told their child had multiple sclerosis. Parents emphasized the need for more awareness of pediatric- onset multiple sclerosis. Numerous parents reported encountering physicians who believed multiple sclerosis did not occur in childhood, contributing to a longer time to diagnosis. Parents preferred physicians first share the diagnosis with the parents without the child present. Finally, parents appreciated when physicians provided a variety of resources to help them cope with the diagnosis. DOI: 10.1177/0883073819842420 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 131 – Multiple Sklerose: Veröffentlichungen April 2019 188. J Clin Med. 2019 Apr 2;8(4). pii: E446. doi: 10.3390/jcm8040446. K Index is a Reliable Marker of Intrathecal Synthesis, and an Alternative to IgG Index in Multiple Sclerosis Diagnostic Work-Up. Crespi I(1), Vecchio D(2)(3), Serino R(4), Saliva E(5), Virgilio E(6), Sulas MG(7), Bellomo G(8), Dianzani U(9)(10), Cantello R(11)(12), Comi C(13)(14). Author information: (1)Laboratory of Clinical Biochemistry, Department of Health Sciences, AOU Maggiore della Carità, University ofPiemonte Orientale, corso Mazzini 18, 28100 Novara, Italy. [email protected]. (2)Institute of Neurology, Department of Transational Medicine, AOU Maggiore della Carità, University of PiemonteOrientale, corso Mazzini 18, 28100 Novara, Italy. [email protected]. (3)Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Health Sciences,University of Piemonte Orientale, Novara, 28100, Italy. [email protected]. (4)Laboratory of Clinical Biochemistry, Department of Health Sciences, AOU Maggiore della Carità, University ofPiemonte Orientale, corso Mazzini 18, 28100 Novara, Italy. [email protected]. (5)Laboratory of Clinical Biochemistry, Department of Health Sciences, AOU Maggiore della Carità, University ofPiemonte Orientale, corso Mazzini 18, 28100 Novara, Italy. [email protected]. (6)Institute of Neurology, Department of Transational Medicine, AOU Maggiore della Carità, University of PiemonteOrientale, corso Mazzini 18, 28100 Novara, Italy. [email protected]. (7)Laboratory of Clinical Biochemistry, Department of Health Sciences, AOU Maggiore della Carità, University ofPiemonte Orientale, corso Mazzini 18, 28100 Novara, Italy. [email protected]. (8)Laboratory of Clinical Biochemistry, Department of Health Sciences, AOU Maggiore della Carità, University ofPiemonte Orientale, corso Mazzini 18, 28100 Novara, Italy. [email protected]. (9)Laboratory of Clinical Biochemistry, Department of Health Sciences, AOU Maggiore della Carità, University ofPiemonte Orientale, corso Mazzini 18, 28100 Novara, Italy. [email protected]. (10)Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Health Sciences,University of Piemonte Orientale, Novara, 28100, Italy. [email protected]. (11)Institute of Neurology, Department of Transational Medicine, AOU Maggiore della Carità, University of PiemonteOrientale, corso Mazzini 18, 28100 Novara, Italy. [email protected]. (12)Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Health Sciences,University of Piemonte Orientale, Novara, 28100, Italy. [email protected]. (13)Institute of Neurology, Department of Transational Medicine, AOU Maggiore della Carità, University of PiemonteOrientale, corso Mazzini 18, 28100 Novara, Italy. [email protected]. (14)Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Health Sciences,University of Piemonte Orientale, Novara, 28100, Italy. [email protected]. The K free light chain (K) index has been suggested as a reliable marker of intrathecal synthesis,despite the 2017 McDonald criteria for multiple sclerosis (MS) suggesting to "interpret with caution positiveimmunoglobulin G (IgG) index when testing for oligoclonal bands (OB) is negative or not performed". Theaim of this study was to compare the performance of K and IgG indexes for MS diagnosis and OB detectionin a cohort of Italian patients. We enrolled 385 patients (127 MS, 258 non-MS) who had cerebrospinal fluid(CSF) analysis, including isoelectric focusing (IEF), to detect OB in the diagnostic work- up. Albumin, IgGand free light chains were measured by nephelometry and used to calculate IgG and K indexes. Althoughthe two markers were highly related (r = 0.75, r2 = 0.55, p < 0.0001), the K index showed greater sensitivity andnegative predictive value (versus the IgG index) for OB detection (97% versus 48% and 97% versus 71%) andMS diagnosis (96% versus 50% and 98% versus 78%). These results support K index (and not IgG index) as afirst-line marker for MS, followed by IEF, according to a sequential testing approach in CSF analysis. DOI: 10.3390/jcm8040446 Conflict of interest statement: Domizia Vecchio received a Merk–Serono fellowship. All the other authors have nothing to disclose and 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 | L.DE.MKT.SM.02.2017.5323 – 132 – Multiple Sklerose: Veröffentlichungen April 2019 189. J Clin Med. 2019 Apr 11;8(4). pii: E493. doi: 10.3390/jcm8040493. Illuminating an Invisible Epidemic: A Systemic Review of the Clinical and Economic Benefits of Early Diagnosis and Treatment in Inflammatory Disease and Related Syndromes. Wylezinski LS(1)(2), Gray JD(3), Polk JB(4), Harmata AJ(5), Spurlock CF 3rd(6)(7). Author information: (1)Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. [email protected]. (2)IQuity, Inc., Nashville, TN 37203, USA. [email protected]. (3)IQuity, Inc., Nashville, TN 37203, USA. [email protected]. (4)IQuity, Inc., Nashville, TN 37203, USA. [email protected]. (5)IQuity, Inc., Nashville, TN 37203, USA. [email protected]. (6)Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. [email protected]. (7)IQuity, Inc., Nashville, TN 37203, USA. [email protected]. Healthcare expenditures in the United States are growing at an alarming level with the Centers for Medicare and Medicaid Services (CMS) projecting that they will reach $5.7 trillion per year by 2026. Inflammatory diseases and related syndromes are growing in prevalence among Western societies. This growing population that affects close to 60 million people in the U.S. places a significant burden on the healthcare system. Characterized by relatively slow development, these diseases and syndromes prove challenging to diagnose, leading to delayed treatment against the backdrop of inevitable disability progression. Patients require healthcare attention but are initially hidden from clinician's view by the seemingly generalized, non- specific symptoms. It is imperative to identify and manage these underlying conditions to slow disease progression and reduce the likelihood that costly comorbidities will develop. Enhanced diagnostic criteria coupled with additional technological innovation to identify inflammatory conditions earlier is necessary and in the best interest of all healthcare stakeholders. The current total cost to the U.S. healthcare system is at least $90B dollars annually. Through unique analysis of financial cost drivers, this review identifies opportunities to improve clinical outcomes and help control these disease-related costs by 20% or more. DOI: 10.3390/jcm8040493 Conflict of interest statement: The authors declare no conflict of interest. IQuity is a data science company whose goal is to develop tools to aid in the diagnosis and treatment of human disease. 190. J Clin Neurosci. 2019 Mar 30. pii: S0967-5868(18)31442-5. doi: 10.1016/j.jocn.2019.03.034. [Epub ahead of print] White matter lesion loads associated with dynamic functional connectivity within attention network in patients with relapsing-remitting multiple sclerosis. Huang M(1), Zhou F(2), Wu L(1), Wang B(1), Guo L(1), Zhao Y(1), Wan H(3), Li F(3), Zeng X(1), Gong H(1). Author information: (1)Department of Radiology, the First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi Province 330006, China; Jiangxi Province Medical Imaging Research Institute, Nanchang, Jiangxi Province 330006, China. (2)Department of Radiology, the First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi Province 330006, China; Jiangxi Province Medical Imaging Research Institute, Nanchang, Jiangxi Province 330006, China. Electronic address: [email protected]. (3)Department of Neurology, the First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi Province 330006, China. Using time-variant of blood oxygenation level dependent (BOLD) signal to investigate the temporal changes in functional connectivity (FC) between key nodes may shed light on the dynamic characteristics of network. Twenty-two relapsing-remitting multiple sclerosis (RRMS) and 22 well-matched healthy control subjects (HCs) participated in this study. Previously validated key nodes of attention network seeds were defined as spherical regions of interests (ROIs); then, we captured the pattern of dFC using sliding window correlation of ROIs in the RRMS and HCs during rest. Furthermore, correlation analysis between altered dFC of paired- ROIs with clinical measures in RRMS were performed. Compared with the HCs, the RRMS showed: a certain specificity transient pattern of FC of attention network at time window levels, including decreased dFC within dorsal attention network [connections of left intraparietal sulcus (LIPS)-right intraparietal sulcus (RIPS), LIPS-right frontal eye field (RFEF) and left frontal eye field (LFEF)-RIPS] and ventral attention network [connection of right ventral frontal cortex (RVFC)-right temporal parietal junction (RTPJ)], increased dFC between dorsal and ventral attention network (connections of LIPS-RTPJ and LIPS-RVFC). Secondary analysis indicated that the dFC coefficients of the connections of LIPS-RIPS (r = -0.467, P = 0.023) and RVFC-RTPJ (r = -0.452, P = 0.043) were significant negative correlated with the total white matter lesion load. In conclusion, we found that the instantaneous configuration pattern of FC in attention network of RRMS are relate to lesions loads. Copyright © 2019. Published by Elsevier Ltd. DOI: 10.1016/j.jocn.2019.03.034 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 133 – Multiple Sklerose: Veröffentlichungen April 2019 191. J Clin Neurosci. 2019 Apr 20. pii: S0967-5868(18)32201-X. doi: 10.1016/j.jocn.2019.04.001. [Epub ahead of print] Surgical management of patients with coexistent multiple sclerosis and cervical stenosis: A systematic review and meta-analysis. Yerneni K(1), Nichols N(1), Burke JF(1), Traynelis VC(2), Tan LA(3). Author information: (1)Department of Neurological Surgery, UCSF Medical Center, San Francisco, CA, United States. (2)Department of Neurological Surgery, Rush Medical Center, Chicago, IL, United States. (3)Department of Neurological Surgery, UCSF Medical Center, San Francisco, CA, United States. Electronic address: [email protected]. Multiple sclerosis (MS) and cervical stenosis (CS) are two unique pathologies that can present with overlapping symptoms. In patients with concurrent MS and CS, the exact cause for worsening of symptoms is often difficult to decipher. In this study, we aimed to review the medical literature on the benefits of surgical decompression surgery in patients with coexisting CS and MS. We systematically reviewed the literature for articles published prior to December 1st, 2018 describing outcomes (improvement of symptoms of radiculopathy, myelopathy, and neck pain) in patients with coexisting MS and CS undergoing cervical decompression surgery. Effect sizes were calculated demonstrating the effect of surgical decompression on improving symptoms. We identified eight articles that satisfied our selection criteria, of which six provided data regarding symptoms after surgery. Our meta-analysis indicates that cervical decompression surgery in patients with coexisting MS and CS is beneficial in improving symptoms of myelopathy (ES 0.74, 95% CI 0.38-1.10, p < 0.0001), radiculopathy (ES 1.29, 95% CI 0.15-2.42, p < 0.001), and neck pain (ES 1.66, 95% CI 1.02-2.31, p < 0.0001). Our meta-analysis indicates that there is paucity of high level of evidence studies regarding the benefit of cervical decompression surgery in patients with concomitant CS and MS. However, the literature suggests that cervical decompression may be beneficial to such patients, providing stabilization or improvement in symptoms of myelopathy, radiculopathy, and neck pain. Spine surgeons must carefully delineate the cause of symptoms in patients to decide whether this is the optimal treatment for each individual patient. Copyright © 2019. Published by Elsevier Ltd. DOI: 10.1016/j.jocn.2019.04.001 192. J Emerg Med. 2019 Apr 23. pii: S0736-4679(19)30137-4. doi: 10.1016/j.jemermed.2019.03.011. [Epub ahead of print] Challenges in the Diagnosis of Euglycemic Diabetic Ketoacidosis in a Patient With Multiple Sclerosis Taking a Sodium-Glucose Cotransporter 2 Inhibitor. Allison R(1), Goldstein D(1), Musso MW(1). Author information: (1)Emergency Medicine Residency Program-Baton Rouge Campus, Louisiana State University, Baton Rouge, Louisiana. BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been reported to cause euglycemic diabetic ketoacidosis (eDKA), a diagnosis that may be challenging to establish in the emergency department (ED). CASE REPORT: This is a case report of missed eDKA in a 47-year-old male taking empagliflozin (a SGLT2 inhibitor) that presented to the ED with generalized weakness. His past medical history included multiple sclerosis (MS) diagnosed 4 years ago and type 2 diabetes mellitus. The patient attributed his weakness to MS. His neurologist was consulted and agreed with the plan to discharge the patient with diagnoses of asthenia and dehydration and a prescription of prednisone. The patient returned to the ED the next day with similar symptoms and was admitted to the hospital for treatment of eDKA. He was eventually treated per the hospital diabetic ketoacidosis (DKA) protocol and discharged home with instructions to discontinue empagliflozin. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The increasing utilization of SGLT2 inhibitor in patients with type 2 diabetes mellitus will inevitably lead to more cases of eDKA seen in the ED. Emergency physicians need to consider this diagnosis in patients taking these medications that present with symptoms including weakness, nausea, vomiting, abdominal pain, and dehydration. Patients taking these medications should be warned about these symptoms, especially because they may be falsely reassured by relatively low plasma glucose levels on home glucometer readings. Copyright © 2019 Elsevier Inc. All rights reserved. DOI: 10.1016/j.jemermed.2019.03.011 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 134 – Multiple Sklerose: Veröffentlichungen April 2019 193. J Headache Pain. 2019 Apr 25;20(1):40. doi: 10.1186/s10194-019-0990-3. The burden of headache disorders in the Eastern Mediterranean Region, 1990-2016: findings from the Global Burden of Disease study 2016. Vosoughi K(1)(2), Stovner LJ(3)(4), Steiner TJ(3)(5)(6), Moradi-Lakeh M(7), Fereshtehnejad SM(8)(9), Farzadfar F(10), Heydarpour P(11), Malekzadeh R(12), Naghavi M(13), Sahraian MA(11), Sepanlou SG(12), Tehrani-Banihashemi A(14)(15), Majdzadeh R(16), Feigin VL(13)(17), Vos T(13), Mokdad AH(13), Murray CJL(13). Author information: (1)Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran. (2)Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA. (3)Department of Neuromedicine and Movement Science (INB), Norwegian University of Science and Technology (NTNU), Trondheim, Norway. (4)Department of Neurology and Clinical Neurophysiology, Norwegian Advisory Unit on Headache, St Olavs University Hospital, Trondheim, Norway. (5)Division of Brain Sciences, Imperial College London, London, UK. (6)Lifting The Burden, London, UK. (7)Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran. [email protected]. (8)Division of Neurology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada. (9)Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden. (10)Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. (11)Multiple Sclerosis Research Center, Tehran University of Medical Sciences, Tehran, Iran. (12)Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran. (13)Department of Health Metrics Sciences, University of Washington, Seattle, WA, USA. (14)Preventive Medicine and Public Health Research Center, Social Health Institute, Iran University of Medical Sciences, Tehran, Iran. (15)Department of Community Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. (16)Knowledge Utilization Research Center, Tehran University of Medical Sciences, Tehran, Iran. (17)National Institute for Stroke and Applied Neurosciences, Auckland University of Technology, Auckland, New Zealand. OBJECTIVES: Using the findings of the Global Burden of Disease Study (GBD), we report the burden of primary headache disorders in the Eastern Mediterranean Region (EMR) from 1990 to 2016. METHODS: We modelled headache disorders using DisMod-MR 2.1 Bayesian meta-regression tool to ensure consistency between prevalence, incidence, and remission. Years lived with disability (YLDs) were calculated by multiplying prevalence and disability weight (DW) of migraine and tension-type headache (TTH). We assumed primary headache disorders as non-fatal, so their YLD is equal to disability-adjusted life years (DALYs). RESULTS: Migraine and TTH were the second and twentieth leading causes of YLDs in EMR. Between 1990 and 2016, the absolute YLD numbers of migraine and TTH increased from 2.3 million (95% uncertainty interval (UI): 1.5-3.2) to 4.7 million (95%UI: 3-6.5) and from 383 thousand (95%UI: 240-562) to 816 thousand (95%UI: 516-1221), respectively. During the same period, age-standardised YLD rates of migraine and TTH in EMR increased by 0.7% and 2.5%, respectively, in comparison to a small decrease in the global rates (0.2% decrease in migraine and TTH). The bulk of burden due to headache occurred in the 30-49 year age group, with a peak at ages 35-44 years. The age-standardised YLD rates of both headache disorders were higher in women with female to male ratio of 1.69 for migraine and 1.38 for TTH. All countries of the EMR except for Somalia and Djibouti had higher age-standardised YLD rates for migraine and TTH in compare to the global rates. Libya and Saudi Arabia had the highest increase in age-standardised YLD rates of migraine and TTH, respectively. CONCLUSION: The findings of this study show that primary headache disorders are a major and a growing cause of disability in EMR. Since 1990, burden of primary headache disorders has constantly been higher in EMR compared to rest of the world, which indicates that health systems in EMR must focus further on developing and implementing preventive and management strategies to control headache. DOI: 10.1186/s10194-019-0990-3 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 135 – Multiple Sklerose: Veröffentlichungen April 2019 194. J Immunol. 2019 Apr 15;202(8):2177-2187. doi: 10.4049/jimmunol.1801416. Dysregulation of Inflammasome Priming and Activation by MicroRNAs in Human Immune-Mediated Diseases. Boxberger N(1), Hecker M(2)(3), Zettl UK(2). Author information: (1)Division of Neuroimmunology, Department of Neurology, University of Rostock, 18147 Rostock, Germany; and [email protected]. (2)Division of Neuroimmunology, Department of Neurology, University of Rostock, 18147 Rostock, Germany; and. (3)Steinbeis Transfer Center for Proteome Analysis, 18057 Rostock, Germany. Inflammasomes are protein complexes that respond to a wide range of pathogens and cellular damage signals. Their activation prompts the caspase-1-mediated cleavage of the proinflammatory cytokines IL-1β and IL-18. Inflammasome dysregulation has been demonstrated to play a role in a range of diseases involving the adaptive immune system like multiple sclerosis, rheumatic diseases, and type 1 diabetes. Priming and activation of inflammasomes can be modulated by microRNAs (miRNAs), small noncoding RNAs that regulate gene expression posttranscriptionally. miRNAs, such as miR-223-3p, have been demonstrated to directly target the inflammasome components NLRP3, caspase-1, and caspase-8. Other miRNAs like miR-155-5p modulate TLR-, IL-1R-, TNFR-, and IFNAR-mediated signaling pathways upstream of the inflammasomes. In this study, we discuss how a more detailed elucidation of miRNA-driven inflammasome regulation helps in understanding the molecular processes underlying immune-mediated human diseases, holds potential for the identification of biomarkers and may offer novel targets for the development of future therapeutics. Copyright © 2019 by The American Association of Immunologists, Inc. DOI: 10.4049/jimmunol.1801416 195. J Int Med Res. 2019 Apr 14:300060519840550. doi: 10.1177/0300060519840550. [Epub ahead of print] Does cognitive dysfunction correlate with neurofilament light polypeptide levels in the CSF of patients with multiple sclerosis? Kalatha T(1), Arnaoutoglou M(1), Koukoulidis T(1), Hatzifilippou E(1), Bouras E(2), Baloyannis S(1), Koutsouraki E(1). Author information: (1)1 First Neurology Clinic, AHEPA Hospital, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece. (2)2 Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece. OBJECTIVE: To investigate whether neurofilament light polypeptide (NfL) level in cerebrospinal fluid (CSF), currently a prognostic biomarker of neurodegeneration in patients with multiple sclerosis (MS), may be a potential biomarker of cognitive dysfunction in MS. METHODS: This observational case-control study included patients with MS. CSF levels of NfL were determined using enzyme-linked immunosorbent assay. Cognitive function was measured with the Brief International Cognitive Assessment for MS (BICAMS) battery and Paced Auditory Serial Addition Test (PASAT3), standardized to the Greek population. RESULTS: Of 39 patients enrolled (aged 42.7 ± 13.6 years), 36% were classified as cognitively impaired according to BICAMS z-scores (-0.34 ± 1.13). Relapsing MS was significantly better than progressive forms regarding BICAMS z-score (mean difference [MD] 1.39; 95% confidence interval [CI] 0.54, 2.24), Symbol Digit Modality Test score (MD 1.73; 95% CI 0.46, 3.0) and Greek Verbal Learning Test (MD 1.77; 95% CI 0.82, 2.72). An inversely proportional association between CSF NfL levels and BICAMS z-scores was found in progressive forms of MS (rp = -0.944). CONCLUSIONS: This study provides preliminary evidence for an association between CSF NfL levels and cognition in progressive forms of MS, which requires validation in larger samples. DOI: 10.1177/0300060519840550 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 136 – Multiple Sklerose: Veröffentlichungen April 2019 196. J Intern Med. 2019 Apr 7. doi: 10.1111/joim.12912. [Epub ahead of print] Neural stimulations regulate the infiltration of immune cells into the CNS. Kamimura D(1), Murakami M(1). Author information: (1)Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan. The systemic regulation of immune reactions by the nervous system is well studied and depends on the release of hormones. Some regional regulations of immune reactions, on the other hand, depend on specific neural pathways. Better understanding of these regulations will expand therapeutic applications for neuroimmune and organ-to-organ functional interactions. Here, we discuss one regional neuroimmune interaction, the gateway reflex, which converts specific neural inputs into local inflammatory outputs in the CNS. Neurotransmitters released by the inputs stimulate specific blood vessels to express chemokines, which serve as a gateway for immune cells to extravasate into the target organ such as the brain or spinal cord. Several types of gateway reflexes have been reported, and each controls distinct CNS blood vessels to form gateways that elicit local inflammation, particularly in the presence of autoreactive immune cells. For example, neural stimulation by gravity creates the initial entry point to the CNS by CNS-reactive pathogenic CD4+ T cells at the dorsal vessels of fifth lumbar spinal cord, while pain opens the gateway at the ventral side of blood vessels in the spinal cord. In addition, it was recently found that local inflammation by the gateway reflex in the brain triggers the activation of otherwise resting neural circuits to dysregulate organ functions in the periphery including the upper gastrointestinal tract and heart. Therefore, the gateway reflex represents a novel bidirectional neuroimmune interaction that regulates organ functions and could be a promising target for bioelectric medicine. © 2019 The Association for the Publication of the Journal of Internal Medicine. DOI: 10.1111/joim.12912 197. J Magn Reson Imaging. 2019 Apr 22. doi: 10.1002/jmri.26758. [Epub ahead of print] Probing demyelination and remyelination of the cuprizone mouse model using multimodality MRI. Wang N(1)(2), Zhuang J(2), Wei H(2), Dibb R(1), Qi Y(1), Liu C(3)(4). Author information: (1)Center for in vivo Microscopy, Duke University, Durham, North Carolina, USA. (2)Brain Imaging and Analysis Center, Duke University, Durham, North Carolina, USA. (3)Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, USA. (4)Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA. BACKGROUND: Various studies by MRI exhibit that the corpus callosum (CC) is the most vulnerable to cuprizone administration, detecting the demyelination and remyelination process using different MRI parameters are, however, lacking. PURPOSE: To investigate the sensitivity of multiparametric MRI both in vivo and ex vivo for demyelination and remyelination. STUDY TYPE: Prospective. ANIMAL MODEL: A cuprizone mice model with an age-matched control group (n = 5), 4-week cuprizone exposure group followed by 9-week on a normal diet (n = 6), and a 13-week cuprizone exposure group (n = 6). FIELD STRENGTH/SEQUENCE: 3D gradient recalled echo, T2 -weighted, and diffusion tensor imaging (DTI) at 7.0T and 9.4T. ASSESSMENT: Quantification of DTI metrics, quantitative susceptibility mapping (QSM), and T2 -weighted imaging intensity in major white matter bundles. STATISTICAL TESTS: Nonparametric permutation tests were used with a cluster-forming threshold as 3.09 (equivalent to P = 0.001), and the significant level as P = 0.05 with family-wise correction. RESULTS: In vivo susceptibility values increased from -11.7 to -0.7 ppb (P < 0.001) in CC and from -13.7 to -5.1 ppb (P < 0.001) in the anterior commissure (AC) after the 13-week cuprizone exposure. Ex vivo susceptibility values increased from -25.4 to 7.4 ppb (P < 0.001) in CC and from -41.6 to -15.8 ppb (P < 0.001) in AC. Susceptibility values showed high variations to demyelination for in vivo studies (94.0% in CC, 62.8% in AC). Susceptibility values exhibited higher variations than radial diffusivity for ex vivo studies (129.1% vs. 28.3% in CC, 62.0% vs. 25.0% in AC). In addition to the differential susceptibility variations in different white matter tracts, intraregional demyelination variation was also present not only in CC but also in the AC area by voxel-based analysis. DATA CONCLUSION: QSM is sensitive to the demyelination process of cuprizone exposure, which can be a complementary technique to conventional T2 -weighted images and DTI metrics. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019. © 2019 International Society for Magnetic Resonance in Medicine. DOI: 10.1002/jmri.26758 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 137 – Multiple Sklerose: Veröffentlichungen April 2019 198. J Matern Fetal Neonatal Med. 2019 Apr 28:1-231. doi: 10.1080/14767058.2019.1613365. [Epub ahead of print] Fetal heart rhabdomyomatosis: a single-center experience. Pavlicek J(1)(2), Klaskova E(3), Kapralova S(3), Prochazka M(4), Vrtel R(4), Gruszka T(1), Kacerovsky M(2)(5). Author information: (1)a Department of Pediatrics and Prenatal Cardiology , University Hospital Ostrava , Ostrava , Czech Republic. (2)b Biomedical Research Centre , University Hospital Hradec Kralove , Hradec Kralove , Czech Republic. (3)c Department of Pediatrics , Palacky University Hospital , Palacky University, Olomouc , Czech Republic. (4)d Department of Medical Genetics , Palacky University Hospital , Palacky University, Olomouc , Czech Republic. (5)e Department of Obstetrics and Gynecology , University Hospital Hradec Kralove , Hradec Kralove , Czech Republic. OBJECTIVES: The primary aim of the study was to evaluate the prevalence of fetal heart tumors in a single tertiary referral center over a period of 15 years. The secondary aim was to confirm the presence of tuberous sclerosis complex (TSC) through the evaluation of germline mutation in TSC1/TSC2 and assess the outcomes in affected fetuses and newborns. METHODS: A retrospective study was conducted between 2003 and 2017. Fetal echocardiography was performed in the second trimester of pregnancy in the study population. The identification of heart tumors and further follow-up were performed by a pediatric cardiologist. Molecular genetic analysis was conducted on fetuses and children in cases where TSC was suspected. RESULTS: In total, 39 018 fetuses were examined between 2003 and 2017. Heart tumors were detected in nine fetuses, and were diagnosed as rhabdomyomas in all cases. We identified mutations in one of the TSC1 or TSC2 genes in all cases with multiple rhabdomyomas (8/9). In all born children (5/9), the genetically confirmed diagnosis of TSC was established, and clinically pathological deposits in the brain were found. CONCLUSION: Fetal heart tumors are usually represented by rhabdomyomas having a good cardiac prognosis. However, rhabdomyoma is usually the first symptom of TSC with subsequent brain disorder and impaired neurological development. DOI: 10.1080/14767058.2019.1613365 199. J Med Chem. 2019 Apr 23. doi: 10.1021/acs.jmedchem.9b00318. [Epub ahead of print] Discovery and Lead-optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase. Harris PA, Faucher N, George N, Eidam PM, King BW, White G, Anderson NA, Bandyopadhyay D, Beal AM, Beneton V, Berger SB, Campobasso N, Campos S, Capriotti CA, Cox JA, Daugan A, Donche F, Fouchet MH, Finger JN, Geddes B, Gough PJ, Grondin P, Hoffman B, Hoffman SJ, Hutchinson S, Jeong JU, Jigorel E, Lamoureux P, Leister LK, Lich JD, Mahajan MK, Meslamani J, Mosley JE, Nagilla R, Nassau P, Ng SL, Ouellette MT, Pasikanti K, Potvain F, Reilly MA, Rivera EJ, Sautet S, Schaeffer MC, Sehon CA, Sun HH, Thorpe JH, Totoritis RD, Ward P, Wellaway N, Wisnoski DD, Woolven JM, Bertin J, Marquis RW. RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis and ulcerative colitis, and neuro-logical diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In this paper we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead- optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa. DOI: 10.1021/acs.jmedchem.9b00318 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 138 – Multiple Sklerose: Veröffentlichungen April 2019 200. J Mol Histol. 2019 Apr 23. doi: 10.1007/s10735-019-09824-0. [Epub ahead of print] Oligoprotective effect of metformin through the AMPK-dependent on restoration of mitochondrial hemostasis in the cuprizone-induced multiple sclerosis model. Largani SHH(1), Borhani-Haghighi M(1), Pasbakhsh P(1), Mahabadi VP(2), Nekoonam S(1), Shiri E(1), Kashani IR(3), Zendehdel A(4). Author information: (1)Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. (2)Neuroscience Research Center, Iran University of Medical Sciences, Poursina Street, 1417613151, Tehran, Iran. (3)Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. [email protected]. (4)Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany. Oxidative stress with mitochondrial defects has a central role in the development and deterioration of Multiple sclerosis (MS). According to new findings of the effects of metformin on mitochondrial function, has attracted a lot of attention. Furthermore, it is suggested that metformin exerts its beneficial influence through AMP-activated protein kinase (AMPK) pathway. In the current study, we investigated the possible protective effects of metformin on oxidative stress and mitochondrial function by activating the AMPK pathway in the cuprizone-induced demyelination. Mice were fed with cuprizone for 6 weeks. Animals simultaneously received metformin. After sacrificing animals, myelinations, and gliosis, changes in transcription factor and biochemical analysis were assessed. Transmission electron microscopy and luxol fast blue staining revealed that the myelinated axons within corpus callosum of cuprizone-induced demyelination animals increased after administration of metformin. Metformin also upregulated the expression of mitochondrial biogenesis genes. Furthermore, the biochemical analysis demonstrated that metformin ameliorated the oxidative stress induced by cuprizone. Immunohistochemistry analysis showed that astrogliosis and microgliosis were decreased after metformin administration while it enhanced the number of oligodendrocytes. Our data implicated that metformin exerts its therapeutic effects on MS by AMPK signaling improved mitochondrial homeostasis and protected oligodendrocytes. DOI: 10.1007/s10735-019-09824-0 201. J Neuroimaging. 2019 Apr 16. doi: 10.1111/jon.12617. [Epub ahead of print] Functional Neurosonology Reveals Impaired Cerebrovascular Reactivity in Multiple Sclerosis. Krogias C(1), Christou I(2), Tsivgoulis G(2), Koutroulou I(3), Schroeder C(1), Lantinioti C(2), Richter D(1), Karapanayiotides T(3), Haghikia A(1), Gold R(1), Voumvourakis K(2). Author information: (1) Department of Neurology, St. Josef-Hospital, Medical Faculty, Ruhr University, Bochum, Germany. (2)Second Department of Neurology, "Attikon" Hospital, School of Medicine , University of Athens, Greece. (3)Second Department of Neurology, AHEPA Hospital, Aristotle University of Thessaloniki, Greece. BACKGROUND AND PURPOSE: Vascular aspects like global cerebral hypoperfusion are frequently reported in patients with multiple sclerosis (MS). Although mechanistic question remains unanswered, this hemodynamic impairment may be caused by a widespread endothelial dysfunction. Furthermore, impaired cerebrovascular reactivity (CVR) has been described in patients with MS by means of hypercapnic perfusion magnetic resonance imaging (MRI). We sought to further evaluate potential hemodynamic restriction in patients with MS using functional sonographic methods. METHODS: We evaluated consecutive patients with MS and healthy controls with adequate bilateral transtemporal window. CVR was assessed by bilateral transcranial Doppler monitoring of proximal middle cerebral arteries. Mean flow velocities were recorded before and after 30 seconds of breath holding. Vasomotor response was quantified by breath holding index (BHI). RESULTS: A total of 42 patients with MS (mean age 39 ± 12 years; 69% women) were compared to 31 healthy controls (mean age 35 ± 11 years; 71% women). BHI was lower in patients with MS compared to healthy controls (.70 ± .43 vs. .93 ± .55; P = .006), documenting a lower cerebrovascular response to hypercapnia. There was no correlation between patient age (r = .1254; P = .277), expanded disability status scale (r = .1838; P = .109), and disease duration (r = .1882; P = .101) with BHI in patients with MS. CONCLUSIONS: These preliminary sonographic findings appear to independently corroborate the previously reported observation of impaired CVR on brain MRI in patients with MS. However, the underlying pathophysiological mechanisms as well as the clinical impact of this observation remain elusive. © 2019 by the American Society of Neuroimaging. DOI: 10.1111/jon.12617 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 139 – Multiple Sklerose: Veröffentlichungen April 2019 202. J Neuroimmune Pharmacol. 2019 Apr 23. doi: 10.1007/s11481-019-09852-3. [Epub ahead of print] Dopaminergic Therapeutics in Multiple Sclerosis: Focus on Th17-Cell Functions. Melnikov M(1)(2), Rogovskii V(3), Boykо A(4), Pashenkov M(5). Author information: (1)Department of Neurology, Neurosurgery and Medical Genetics of Pirogov Russian National Research Medical University, Ostrovitianov str. 1, 117997, Moscow, Russia. [email protected]. (2)Laboratory of Clinical Immunology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency, 115478, Moscow, Russia. [email protected]. (3)Department of Molecular Pharmacology and Radiobiology of Pirogov Russian National Research Medical University, 117997, Moscow, Russia. (4)Department of Neurology, Neurosurgery and Medical Genetics of Pirogov Russian National Research Medical University, Ostrovitianov str. 1, 117997, Moscow, Russia. (5)Laboratory of Clinical Immunology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency, 115478, Moscow, Russia. Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with an autoimmune mechanism of development. Currently, one of the most promising directions in the study of MS pathogenesis are the neuroimmune interactions. Dopamine is one of the key neurotransmitters in CNS. Furthermore, dopamine is a direct mediator of interactions between the immune and nervous systems and can influence MS pathogenesis by modulating immune cells activity and cytokine production. Recent studies have shown that dopamine can enhance or inhibit the functions of innate and adaptive immune system, depending on the activation of different dopaminergic receptors, and can therefore influence the course of experimental autoimmune encephalomyelitis (EAE) and MS. In this review, we discuss putative dopaminergic therapeutics in EAE and MS with focus on Th17-cells, which are thought to play crucial role in MS pathogenesis. We suggest that targeting dopaminergic receptors could be explored as a new kind of disease-modifying treatment of MS. Graphical Abstract. DOI: 10.1007/s11481-019-09852-3 203. J Neuroimmune Pharmacol. 2019 Apr 2. doi: 10.1007/s11481-019-09842-5. [Epub ahead of print] Resveratrol (3, 5, 4'-Trihydroxy-trans-Stilbene) Attenuates a Mouse Model of Multiple Sclerosis by Altering the miR-124/Sphingosine Kinase 1 Axis in Encephalitogenic T Cells in the Brain. Gandy KAO(1), Zhang J(2), Nagarkatti P(1), Nagarkatti M(3)(4)(5). Author information: (1)Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, 29209, USA. (2)Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA. (3)Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, 29209, USA. [email protected]. (4)Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA. [email protected]. (5)WJB Dorn VA Medical Center, Columbia, SC, 29208, USA. [email protected]. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) (RES) is a naturally-derived phytoestrogen found in the skins of red grapes and berries and has potential as a novel and effective therapeutic agent. In the current study, we investigated the role of microRNA (miRNA) in RES-mediated attenuation of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Administration of RES effectively decreased disease severity, including inflammation and central nervous system immune cell infiltration. miRNA microarray analysis revealed an altered miRNA profile in encephalitogenic CD4+ T cells from EAE mice exposed to RES treatment. Additionally, bioinformatics and in silico pathway analysis suggested the involvement of RES-induced miRNA in pathways and processes that regulated cellular proliferation. Additional studies confirmed that RES affected cell cycle progression and apoptosis in activated T cells, specifically in the brain. RES treatment significantly upregulated miR-124 during EAE, while suppressing associated target gene, sphingosine kinase 1 (SK1), and this too was specific to mononuclear cells in the brains of treated mice, as peripheral immune cells remained unaltered upon RES treatment. Collectively, these studies demonstrate that RES treatment leads to amelioration of EAE development through mechanism(s) potentially involving suppression of neuroinflammation via alteration of the miR-124/SK1 axis, thereby halting cell-cycle progression and promoting apoptosis in activated encephalitogenic T cells. Graphical Abstract Resveratrol alters the miR-124/sphingosine kinase 1 (SK1) axis in encephalitogenic T cells, promotes cell-cycle arrest and apoptosis, and decreases neuroinflammation in experiemental autoimmune encephalomyelitis (EAE). DOI: 10.1007/s11481-019-09842-5 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 140 – Multiple Sklerose: Veröffentlichungen April 2019 204. J Neuroimmunol. 2019 Mar 20;332:16-30. doi: 10.1016/j.jneuroim.2019.03.012. [Epub ahead of print] Toll-like receptors in the pathogenesis of neuroinflammation. Kumar V(1). Author information: (1)Children Health Clinical Unit, School of Clinical Medicine, Faculty of Medicine, Mater Research, University of Queensland, ST Lucia, Brisbane, Queensland 4078, Australia; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, ST Lucia, Brisbane, Queensland 4078, Australia. Electronic address: [email protected]. Toll-like receptors (TLRs) are discovered as crucial pattern recognition receptors (PRRs) involved in the recognition of pathogen-associated molecular patterns (PAMPs). Later studies showed their involvement in the recognition of various damage/danger-associated molecular patterns (DAMPs) generated by host itself. Thus, TLRs are capable of recognizing wide-array of patterns/molecules derived from pathogens and host as well and initiating a proinflammatory immune response through the activation of NF-κB and other transcription factors causing synthesis of proinflammatory molecules. The process of neuroinflammation is seen under both sterile and infectious inflammatory diseases of the central nervous system (CNS) and may lead to the development of neurodegeneration. The present article is designed to highlight the importance of TLRs in the pathogenesis of neuroinflammation under diverse conditions. TLRs are expressed by various immune cells present in CNS along with neurons. However out of thirteen TLRs described in mammals, some are present and active in these cells, while some are absent and are described in detail in main text. The role of various immune cells present in the brain and their role in the pathogenesis of neuroinflammation depending on the type of TLR expressed is described. Thereafter the role of TLRs in bacterial meningitis, viral encephalitis, stroke, Alzheimer's disease (AD), Parkinson's disease (PD), and autoimmune disease including multiple sclerosis (MS) is described. The article is designed for both neuroscientists needing information regarding TLRs in neuroinflammation and TLR biologists or immunologists interested in neuroinflammation. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2019.03.012 205. J Neuroimmunol. 2019 Apr 21;332:147-154. doi: 10.1016/j.jneuroim.2019.04.011. [Epub ahead of print] IL-17A is associated with the breakdown of the blood-brain barrier in relapsing- remitting multiple sclerosis. Setiadi AF(1), Abbas AR(1), Jeet S(1), Wong K(1), Bischof A(2), Peng I(1), Lee J(1), Bremer M(1), Eggers EL(3), DeVoss J(1), Staton T(1), Herman A(1), von Büdingen HC(3), Townsend MJ(4). Author information: (1)Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (2)Weill Institute for Neurosciences, Department of Neurology, UCSF, 675 Nelson Rising Lane, San Francisco, California 94158, USA; Neurology and Neurologic Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland. (3)Weill Institute for Neurosciences, Department of Neurology, UCSF, 675 Nelson Rising Lane, San Francisco, California 94158, USA. (4)Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected]. IL-17 has been implicated in the pathogenesis of multiple sclerosis (MS). Here, we show that blockade of IL- 17A, but not IL-17F, attenuated experimental autoimmune encephalomyelitis (EAE). We further show that IL- 17A levels were elevated in the CSF of relapsing-remitting MS (RRMS) patients and that they correlated with the CSF/serum albumin quotient (Qalb), a measure of blood-brain barrier (BBB) dysfunction. We then demonstrated that the combination of IL-17A and IL-6 reduced the expression of tight junction (TJ)- associated genes and disrupted monolayer integrity in the BBB cell line hCMEC/D3. However, unlike IL-17A, IL-6 in the CSF from RRMS patients did not correlate with Qalb. These data highlight the potential importance of targeting IL-17A in preserving BBB integrity in RRMS. Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2019.04.011 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 141 – Multiple Sklerose: Veröffentlichungen April 2019 206. J Neuroimmunol. 2019 Apr 18. pii: S0165-5728(19)30194-8. doi: 10.1016/j.jneuroim.2019.04.008. [Epub ahead of print] Regenerative neuroimmunology: The impact of immune and neural stem cell interactions for translation in neurodegeneration and repair. Imitola J(1). Author information: (1)Laboratory for Neural Stem Cells and Functional Neurogenetics, Division of Neuroimmunology and Multiple Sclerosis, Department of Neurology, The Ohio State University, Wexner Medical Center, Columbus, OH, United States. Electronic address: [email protected]. DOI: 10.1016/j.jneuroim.2019.04.008 207. J Neuroimmunol. 2019 Apr 1;332:78-90. doi: 10.1016/j.jneuroim.2019.03.019. [Epub ahead of print] The PD-1/PD-Ls pathway is up-regulated during the suppression of experimental autoimmune encephalomyelitis treated by Astragalus polysaccharides. Sun Y(1), Jing Y(2), Huang M(2), Ma J(1), Peng X(1), Wang J(1), Li G(1), Cheng X(3). Author information: (1)Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China. (2)School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. (3)Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. Electronic address: [email protected]. Multiple sclerosis (MS) is an inflammatory demyelinating disease of CNS. Astragalus polysaccharides (APS), the main active extract from astragalus membranaceus which is a kind of traditional Chinese medicinal herb, is associated with a variety of immunomodulatory activities. We have evaluated the therapeutic effects of APS in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). It was found that APS could effectively alleviate EAE through inhibiting MOG35-55-specific T cell proliferation and reducing the expression of proinflammatory cytokines, which is mediated by up-regulating the expression of PD-1/PD-Ls signaling pathway. Our results demonstrated that EAE could be suppressed significantly by APS administration. It indicated that APS might be a potential of developing innovative drug for the therapy of MS. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2019.03.019 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 142 – Multiple Sklerose: Veröffentlichungen April 2019 208. J Neurol. 2019 Apr 23. doi: 10.1007/s00415-019-09328-7. [Epub ahead of print] Pathologic and MRI analysis in acute atypical inflammatory demyelinating lesions. Ayrignac X(1)(2), Rigau V(3), Lhermitte B(4), Vincent T(5), de Champfleur NM(6), Carra-Dalliere C(7), Charif M(7), Collongues N(8), de Seze J(8), Hebbadj S(9), Ahle G(10), Oesterlé H(11), Cotton F(12), Durand- Dubief F(13), Marignier R(13), Vukusic S(13), Taithe F(14), Cohen M(15), Guennoc AM(16), Kerbrat A(17), Edan G(17), Carsin-Nicol B(18), Allou T(19), Sablot D(19), Thouvenot E(20), Ruet A(21), Magy L(22), Boncoeur-Martel MP(23), Labauge P(7), Kremer S(9). Author information: (1)Department of Neurology, Multiple Sclerosis Center, Montpellier University Hospital, 80 rue Augustin Fliche, 34295, Montpellier, Cedex 05, France. [email protected]. (2)The Institute for Neurosciences of Montpellier, Inserm UMR1051, Saint Eloi Hospital, University of Montpellier, Montpellier, France. [email protected]. (3)Department of Pathology, Montpellier University Hospital, Montpellier, France. (4)Department of Pathology, Strasbourg University Hospital, Strasbourg, France. (5)Department of Immunology, Montpellier University Hospital, Montpellier, France. (6)Department of Neuroradiology, Montpellier University Hospital, Montpellier, France. (7)Department of Neurology, Multiple Sclerosis Center, Montpellier University Hospital, 80 rue Augustin Fliche, 34295, Montpellier, Cedex 05, France. (8)Department of Neurology and Clinical Investigation Center, Strasbourg University Hospital, Strasbourg, France. (9)Department of Radiology, Strasbourg University Hospital, Strasbourg, France. (10)Department of Neurology, Colmar Hospital, Colmar, France. (11)Department of Pathology, Colmar Hospital, Colmar, France. (12)Department of Radiology, Centre hospitalier Lyon-Sud, hospices civils de Lyon, Lyon, France. (13)Department of Neurology, Hôpital Neurologique Pierre Wertheimer Hospices Civils de Lyon, Lyon, France. (14)Department of Neurology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France. (15)Department of Neurology, Nice University Hospital, Nice, France. (16)Department of Neurology, Tours University Hospital, Tours, France. (17)Department of Neurology, Rennes University Hospital, Rennes, France. (18)Department of Neuroradiology, Rennes University Hospital, Rennes, France. (19)Department of Neurology, Perpignan Hospital, Perpignan, France. (20)Department of Neurology, Nimes University Hospital, Nîmes, France. (21)Department of Neurology, Bordeaux University Hospital, Bordeaux, France. (22)Department of Neurology, Limoges University Hospital, Limoges, France. (23)Department of Neuroradiology, Limoges University Hospital, Limoges, France. BACKGROUND: The diagnosis of atypical inflammatory demyelinating lesions can be difficult. Brain biopsy is often required to exclude neoplasms. Moreover, the relationship between these lesions and multiple sclerosis and NMOSD is not clear. OBJECTIVES: Our objectives were to describe radiological and pathological characteristics of patients with acute inflammatory demyelinating lesions. METHODS: We retrospectively identified patients with brain biopsy performed for diagnostic uncertainty revealing a demyelinating lesion. A complete clinical, biological, radiological and pathological analysis was performed. RESULTS: Twenty patients (15 with a single lesion) were included. MRI disclosed a wide range of lesions including infiltrative lesions (40%), ring-like lesion (15%) Baló-like lesion (15%) and acute haemorrhagic leukoencephalitis (20%). In spite of a marked heterogeneity, some findings were common: a peripheral B1000 hyperintense rim (70%), a slight oedema with mild mass effect (75%) and an open-rim peripheral enhancement (75%). Histopathology revealed that all cases featured macrophages distributed throughout, extensive demyelination, axonal preservation and absence of haemorrhagic changes. In the majority of cases, macrophages were the predominant inflammatory infiltrate and astrocytes were reactive and dystrophic. Aquaporin-4 staining was systematically preserved. After a mean follow-up of 5 years (1-12), 16/20 patients had a diagnosis of monophasic acute atypical inflammatory demyelinating lesion. One patient was diagnosed with MS and 3 with AQP4 negative NMOSD. DISCUSSION: Although imaging findings in patients with atypical inflammatory demyelinating lesions are heterogeneous, some common features such as peripheral DWI hyperintense rim with open-rim enhancement and absence of oedema argue in favour of a demyelinating lesion and should preclude a brain biopsy. In this context, AQP4 staining is systematically preserved and argues against an AQP4-positive NMOSD. Moreover, long-term follow-up is characterized by low recurrence rate. DOI: 10.1007/s00415-019-09328-7 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 143 – Multiple Sklerose: Veröffentlichungen April 2019 209. J Neurol. 2019 Apr 19. doi: 10.1007/s00415-019-09311-2. [Epub ahead of print] In search of distinct MS-related fatigue subtypes: results from a multi-cohort analysis in 1.403 MS patients. Pust GEA(1)(2), Pöttgen J(1), Randerath J(2)(3), Lau S(1), Heesen C(1)(4), Gold SM(1)(5)(6), Penner IK(7)(8). Author information: (1)Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany. (2)Department of Psychology, University of Konstanz, Constance, Germany. (3)Lurija Institute for Rehabilitation and Health Sciences at the University of Konstanz, Schmieder Foundation for Sciences and Research, Allensbach, Germany. (4)Klinik und Poliklinik für Neurologie, Universitätsklinikum Hamburg- Eppendorf (UKE), Hamburg, Germany. (5)Charité Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychotherapie, Campus Benjamin Franklin, Berlin, Germany. (6)Charité Universitätsmedizin Berlin, Medizinische Klinik m.S. Psychosomatik, Campus Benjamin Franklin, Berlin, Germany. (7)Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. Iris- [email protected]. (8)COGITO Center for Applied Neurocognition and Neuropsychological Research, Düsseldorf, Germany. [email protected]. Fatigue is among the most disabling symptoms in patients with multiple sclerosis (PwMS). The common distinction between cognitive and motor fatigue is typically incorporated in self-rating instruments, such as the Chalder Fatigue Questionnaire (CFQ), the Fatigue Scale for Motor and Cognitive Functions (FSMC) or the Modified Fatigue Impact Scale (MFIS). The present study investigated the factor structure of the CFQ, the FSMC and the MFIS utilizing exploratory (EFA) and confirmatory factor analysis (CFA) as well as exploratory structural equation modeling (ESEM). Data of 1.403 PwMS were analyzed, utilizing four samples. The first sample (N = 605) was assessed online and split into two stratified halves to perform EFA, CFA, and ESEM on the CFQ and FSMC. The second sample (N = 293) was another online sample. It served to calculate CFA and ESEM on the CFQ and FSMC. The third sample was gathered in a clinical setting (N = 196) and analyzed by applying CFA and ESEM to the FSMC. The fourth sample (N = 309) was assessed in a clinical setting and allowed to run a CFA and ESEM on the MFIS. Proposed factor structures of all questionnaires were largely confirmed in EFA. However, none of the calculated CFAs and ESEMs could verify the proposed factor structures of the three measures, even with oblique rotation techniques. The findings might have implications for future research into the pathophysiological basis of MS-related fatigue and could affect the suitability of such measures as outcomes for treatment trials, presumably targeting specific sub-components of fatigue. DOI: 10.1007/s00415-019-09311-2 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 144 – Multiple Sklerose: Veröffentlichungen April 2019 210. J Neurol Neurosurg Psychiatry. 2019 Apr 9. pii: jnnp-2018-320106. doi: 10.1136/jnnp-2018-320106. [Epub ahead of print] Neurofilament light chain as a biomarker in neurological disorders. Gaetani L(1), Blennow K(2)(3), Calabresi P(4)(5), Di Filippo M(4), Parnetti L(4), Zetterberg H(2)(3)(6)(7). Author information: (1)Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy [email protected]. (2)Institute of Neuroscience and Physiology Department of Psychiatry and Neurochemistry, The Sahlgrenska AcademyUniversity of Gothenburg, Mölndal, Sweden. (3)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. (4)Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy. (5)Laboratory of Neurophysiology, IRCCS Fondazione Santa Lucia, Rome, Italy. (6)Department of Molecular Neuroscience, UCL Institute of Neurology Queen Square, London, UK. (7)UK Dementia Research Institute at UCL, London, United Kingdom. In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to easily and repeatedly measure NfL for monitoring diseases' courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future. Here we review the most important results on CSF and blood NfL and we discuss its potential applications and future directions. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/jnnp-2018-320106 Conflict of interest statement: Competing interests: LG received travel grants from Biogen-Idec, Biogen, Novartis, Teva, Genzyme and Almirall to attend national and international conferences. KB has served as a consultant or at advisory boards for Alzheon, BioArctic, Biogen, Eli Lilly, Fujirebio Europe, IBL International, Pfizer and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. PC receives research support from Bayer Schering, Biogen-Dompé, Boehringer Ingelheim, Eisai, Lundbeck, Merck-Serono, Novartis, Sanofi- Aventis, Sigma-Tau and UCB Pharma. MDF participated to advisory boards of Biogen Idec, Teva and Bayer, received travel grants from Bayer Schering, Biogen-Dompé, Biogen-Idec, Merck-Serono, Novartis and Sanofi-Aventis to attend national and international conferences, and received speaker and writing honoraria from Biogen Idec, Novartis and Sanofi-Genzyme. HZ has served at advisory boards for Eli Lilly, Roche Diagnostics and Pharmasum Therapeutics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. LP reports 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 | L.DE.MKT.SM.02.2017.5323 – 145 – Multiple Sklerose: Veröffentlichungen April 2019 211. J Neurol Neurosurg Psychiatry. 2019 Apr 5. pii: jnnp-2018-320287. doi: 10.1136/jnnp-2018-320287. [Epub ahead of print] Neurofilament light chain serum levels reflect disease severity in MOG-Ab associated disorders. Mariotto S(1), Ferrari S(2), Gastaldi M(3), Franciotta D(3), Sechi E(4), Capra R(5), Mancinelli C(5), Schanda K(6), Alberti D(2), Orlandi R(2), Bombardi R(7), Zuliani L(8), Zoccarato M(9), Benedetti MD(2), Tanel R(10), Calabria F(11), Rossi F(12), Pavone A(13), Grazian L(14), Sechi G(15), Batzu L(4), Murdeu N(4), Janes F(16), Fetoni V(17), Fulitano D(18), Stenta G(19), Federle L(19), Cantalupo G(20), Reindl M(6), Monaco S(2), Gajofatto A(2). Author information: (1)Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Neurology, University of Verona, Verona, Italy [email protected]. (2)Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Neurology, University of Verona, Verona, Italy. (3)Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy, Pavia, Italy. (4)Department of Clinical and Experimental Medicine, Neurology Unit, University of Sassari, Sassari, Italy. (5)MS Center, Spedali Civili of Brescia, Brescia, Italy. (6)Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. (7)Neurology Unit, San Bassiano Hospital, Bassano Del Grappa, Italy. (8)Department of Neurology, Ospedale Ca' Foncello, Treviso, Italy. (9)O.S.A, Padova, Italy, Neurology Unit, Padova, Italy. (10)U.O. Neurologia, S. Chiara Hospital, Trento, Italy. (11)AOUI Verona, Neurology Unit, Verona, Italy. (12)Neurology Unit, Mater Salutis Hospital, Legnago, Verona, Italy, Verona, Italy. (13)Neurology Unit, Garibaldi Hospital, Catania, Italy, Catania, Italy. (14)Pediatric Unit, ULSS 2 Marca Trevigiana, Ca' Foncello Hospital, Treviso, Italy, Treviso, Italy. (15)Department of Clinical and Experimental Medicine, NeurologyUnit, University of Sassari, Sassari, Italy. (16)Neurology Unit, Department of Neuroscience ASUIUD, Udine, Italy, Udine, Italy. (17)Neurology Department, ASST Fatebenefratelli Sacco, Milano, Italy, Milano, Italy. (18)Neurology Unit, Rovigo, Italy, Rovigo, Italy. (19)Multiple Sclerosis Centre, S. Bortolo Hospital, Vicenza, Italy, Vicenza, Italy. (20)Child Neuropsychiatry, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy. DOI: 10.1136/jnnp-2018-320287 Conflict of interest statement: Competing interests: SMA was sponsored by Merck and Euroimmun for attending scientific meeting. SF was sponsored by Shire and Euroimmun for attending scientific meeting. RC received lecture fees and/or travel grants from Novartis, Biogen, Celgene, Novartis, TEVA, Genzyme and Sanofi-Aventis. MR was supported by a research grant from the Austrian Science Promotion Agency (FFG). The University Hospital and Medical University of Innsbruck (Austria; MR) receives payments for antibody assays (MOG, AQP4, and other autoantibodies) and for MOG and AQP4 antibody validation experiments organised by Euroimmun (Lübeck, Germany). SMO received honoraria from Biogen. AG received research support funding from Merck. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 146 – Multiple Sklerose: Veröffentlichungen April 2019 212. J Neurol Neurosurg Psychiatry. 2019 Apr 4. pii: jnnp-2018-319634. doi: 10.1136/jnnp-2018-319634. [Epub ahead of print] Cortical grey matter sodium accumulation is associated with disability and secondary progressive disease course in relapse-onset multiple sclerosis. Brownlee WJ(1), Solanky B(2), Prados F(2)(3), Yiannakas M(2), Da Mota P(2), Riemer F(4), Cardoso MJ(3), Ourselin S(3), Golay X(5), Gandini Wheeler-Kingshott C(2)(6)(7), Ciccarelli O(2)(8). Author information: (1)Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, United Kingdom [email protected]. (2)Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, United Kingdom. (3)Translational Imaging Group, Centre for Medical Image Computing (CMIC), Department of Medical Physics and Bioengineering, University College London, London, United Kingdom. (4)Department of Radiology, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. (5)Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom. (6)BrainMRI 3T Research Centre, IRCCS Mondino Foundation, Pavia, Italy. (7)Departmentof Brain and Behavioural Sciences, University of Pavia, Pavia, Italy. (8)National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London, United Kingdom. OBJECTIVE: Sodium (23Na)-MRI is an emerging imaging technique to investigate in vivo changes in tissue viability, reflecting neuroaxonal integrity and metabolism. Using an optimised 23Na-MRI protocol with smaller voxel sizes and improved tissue contrast, we wanted to investigate whether brain total sodium concentration (TSC) is a biomarker for long-term disease outcomes in a cohort of patients with relapse-onset multiple sclerosis (MS), followed from disease onset. METHODS: We performed a cross-sectional study in 96 patients followed up ~ 15 years after a clinically isolated syndrome (CIS) and 34 healthy controls. Disease course was classified as CIS, relapsing-remitting MS or secondary progressive MS (SPMS). We acquired 1H-MRI and 23Na-MRI and calculated the TSC in cortical grey matter (CGM), deep grey matter, normal- appearing white matter (WM) and WM lesions. Multivariable linear regression was used to identify independent associations of tissue-specific TSC with physical disability and cognition, with adjustment for tissue volumes. RESULTS: TSC in all tissues was higher in patients with MS compared with healthy controls and patients who remained CIS, with differences driven by patients with SPMS. Higher CGM TSC was independently associated with Expanded Disability Status Scale (R2=0.26), timed 25-foot walk test (R2=0.23), 9-hole peg test (R2=0.23), Paced Auditory Serial Addition Test (R2=0.29), Symbol Digit Modalities Test (R2=0.31) and executive function (R2=0.36) test scores, independent of grey matter atrophy. CONCLUSIONS: Sodium accumulation in CGM reflects underlying neuroaxonal metabolic abnormalities relevant to disease course heterogeneity and disability in relapse-onset MS. TSC and should be considered as an outcome measure in future neuroprotection trials. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/jnnp-2018-319634 Conflict of interest statement: Competing interests: WJB has received speaker fees from Merck Serono, Sanofi Genzyme and Roche. BS, FP, MY, PDM, FR, MJC, SO and XG report no financial disclosures relevant to this manuscript. OC serves as a consultant for Novartis, Teva, Roche, Genzyme and Biogen Idec. 213. J Neurol Neurosurg Psychiatry. 2019 Apr;90(4):371. doi: 10.1136/jnnp-2019-320455. The real p(atient) value. Roman S(1). Author information: (1)JNNP, BMJ Publishing Group, London, UK [email protected]. DOI: 10.1136/jnnp-2019-320455 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 | L.DE.MKT.SM.02.2017.5323 – 147 – Multiple Sklerose: Veröffentlichungen April 2019 214. J Neurol Sci. 2019 Mar 29;401:43-50. doi: 10.1016/j.jns.2019.03.030. [Epub ahead of print] Induction of apoptosis in CD4(+) T-cells is linked with optimal treatment response in patients with relapsing-remitting multiple sclerosis treated with Glatiramer acetate. Boziki M(1), Lagoudaki R(1), Melo P(1), Kanidou F(1), Bakirtzis C(1), Nikolaidis I(1), Grigoriadou E(1), Afrantou T(1), Tatsi T(1), Matsi S(2), Grigoriadis N(3). Author information: (1)Multiple Sclerosis Center, B' Neurological University Department, AHEPA General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece. (2)Specifar, Kifisias Ave. 44, 15125 Maroussi, Athens, Greece. (3)Multiple Sclerosis Center, B' Neurological University Department, AHEPA General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece. Electronic address: [email protected]. BACKGROUND: Induction of T-cell apoptosis constitutes a mechanism of action for Glatiramer Acetate (GA). We investigated whether activation of apoptotic T-cell death may be indicative of optimal treatment response in patients with relapsing-remitting Multiple Sclerosis (RRMS), with respect to radiological activity. METHODS: We studied apoptotic markers on blood T-cells of forty patients with RRMS, 19 patients under GA and 21 patients under interferon-β (IFNβ), by flow cytometry. Patients were relapse-free and were further classified into optimal and sub-optimal responders based on radiological activity. Eighteen patients (8 patients under GA and 10 patients under IFNβ were additionally evaluated at a 12-month follow-up and were relapse- and radiological activity-free. For these patients, apoptosis was also evaluated by molecular techniques. RESULTS: At inclusion, optimal responders to GA exhibited increased (23.6 ± 1.976) relative % frequency of CD4(+)AnnexinV(+)7AAD(-) T-cells, compared to sub-optimal responders (14.478 ± 1.204, p = 0.001). Similarly, relative % frequency of caspase-3(+) T-cells was 1.517 ± 0.436 versus 0.45 ± 0.149 (p = 0.041), respectively. Anti-apoptotic molecule bcl-2 showed an inverse pattern 4.532 ± 1.321 versus 13.094 ± 3.987, p = 0.044, respectively. These differences were not evident for IFNβ-treated patients. CONCLUSIONS: T-cell apoptotic markers may be applied as a biomarker useful in evaluating optimal treatment response under GA, thus allowing for personalized treatment decisions. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.jns.2019.03.030 215. J Neuroophthalmol. 2019 Apr 23. doi: 10.1097/WNO.0000000000000803. [Epub ahead of print] Literature Commentary. [No authors listed] In this issue of JNO, M. Tariq Bhatti and Mark L. Moster discuss the following 6 articles:1. Brownlee WJ, Miszkiel KA, Tur C, Barkhof F, Miller DH, Ciccarelli O. Inclusion of optic nerve involvement in dissemination in space criteria for multiple sclerosis. Neurology. 2018;91:e1130-e1134.2. Cossack M, Nabrinsky E, Turner H, Abraham A, Gratton S. Timolol eyedrops in the treatment of acute migraine attacks: a randomized crossover study. JAMA Neurol. 2018;75:1024-1025.3. Rotenstein LS, Torre M, Ramos MA, Rosales RC, Guille C, Sen S, Mata DA. Prevalence of burnout among physicians: a systematic review. JAMA. 2018;320:1131-1150.4. Shosha E, Dubey D, Palace J, Nakashima I, Jacob A, Fujihara K, Takahashi T, Whittam D, Leite MI, Misu T, Yoshiki T, Messina S, Elsone L, Majed M, Flanagan E, Gadoth A, Huebert C, Sagen J, Greenberg BM, Levy M, Banerjee A, Weinshenker B, Pittock SJ. Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD. Neurology. 2018;91:e1642-e1651.5. Raynowska J, Miskin DP, Pramanik B, Asiry S, Anderson T, Boockvar J, Najjar S, Harel A. Retinal vasculopathy with cerebral leukoencephalopathy (RVCL): a rare mimic of tumefactive MS. Neurology. 2018;91:e1423-e1428.6. O'Bryhim BE, Apte RS, Kung N, Coble D, Van Stavern GP. Association of preclinical Alzheimer disease with optical coherence tomographic angiography findings. JAMA Ophthalmol. 2018;136:1242-1248. DOI: 10.1097/WNO.0000000000000803 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 148 – Multiple Sklerose: Veröffentlichungen April 2019 216. J Neuropathol Exp Neurol. 2019 May 1;78(5):406-415. doi: 10.1093/jnen/nlz022. A Highly Sensitive Sandwich ELISA to Detect CSF Progranulin: A Potential Biomarker for CNS Disorders. Li Y(1), Wang D(1), Li Y(1), Zhu J(1), Zhao J(1), Deng Y(2), Rogalski EJ(3), Bigio EH(3)(4), Rademaker AW(3)(5), Xia H(1), Mao Q(4). Author information: (1)Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, P.R. China. (2)Department of Neurology, Xijing Hospital, Air Force Medical School, Xi'an, Shaanxi, P.R. China. (3)Mesulam Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. (4)Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. (5)Division of Biostatistics, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Progranulin (PGRN) plays critical roles in inflammation, tumorigenesis, and neurodegeneration. PGRN levels in blood and cerebrospinal fluid (CSF) are being increasingly investigated as potential biomarkers for these disorders. However, the value of CSF PGRN as a biomarker has been limited because currently available commercial enzyme-linked immunosorbent assay (ELISA) kits have suboptimal sensitivity for detecting CSF PGRN. In this study, pairs of monoclonal antibodies (MAbs) were first screened from eleven monoclonal antiPGRN antibodies using indirect ELISA, then a sandwich ELISA was established using the 2 optimized MAbs. This system displayed high sensitivity, with a lower limit of detection of 60.0 pg/mL and a lower limit of quantification of 150 pg/mL. By using this ELISA system, we showed varied CSF PGRN levels in different brain disorders. For example, as compared with the normal controls, patients with Alzheimer disease or multiple sclerosis showed mildly increased CSF PGRN; those with aseptic encephalitis or neuropsychiatric systemic lupus erythematosus showed moderately increased CSF PGRN; those with bacterial leptomeningitis showed severely increased CSF PGRN. Additionally, determining CSF PGRN levels could monitor CNS metastasis and CSF seeding of carcinomas. These results indicate that this system can be valuable in studying the diagnostic and prognostic value of CSF PGRN in brain disorders. © 2019 American Association of Neuropathologists, Inc. All rights reserved. DOI: 10.1093/jnen/nlz022 217. J Neuropsychiatry Clin Neurosci. 2019 Apr 3:appineuropsych18070164. doi: 10.1176/appi.neuropsych.18070164. [Epub ahead of print] Neuroprotective Benefits of Antidepressants in Multiple Sclerosis: Are We Missing the Mark? Grech LB(1), Butler E(1), Stuckey S(1), Hester R(1). Author information: (1)From the Department of Psychological Sciences, Swinburne University, Melbourne, Australia (Grech); the Department of Cancer Experiences Research, Peter MacCallum Cancer Centre, Melbourne, Australia (Grech); the Melbourne School of Psychological Sciences, University of Melbourne, Australia (Grech, Hester); the Department of Neurology, Monash Health, Victoria, Australia (Butler); the Department of Imaging, Monash Health, Victoria, Australia (Stuckey); and the Department of Imaging, School of Clinical Sciences, Monash Health, Monash University, Victoria, Australia (Stuckey). The potential of antidepressant medication to have a neuroprotective effect for people with multiple sclerosis (MS) has received increased interest in recent years. The possibility of antidepressants, particularly fluoxetine, for potential repurposing to treat primary progressive and secondary progressive MS is of interest as a result of the relative lack of disease-modifying medications for these subtypes. A number of animal studies have found positive results for a neuroprotective effect of antidepressant use in MS, with human studies showing mixed results. These human studies all have a significant limitation: they exclude people with moderate to severe depressive symptoms, a core symptom of MS beyond that of reactive depression. It is likely that reregulation of the common mechanisms in depression and MS, such as inflammation, serotonin, norepinephrine, glutamate and brain-derived neurotropic factor disruption, and hypothalamic- pituitary-thalamic axis dysregulation, are important to the neuroprotective value of antidepressant medication. Given that MS is known for its heterogeneity, the question might be less about whether antidepressant medication provides neuroprotective benefits to people with multiple sclerosis but for whom they provide benefits and whether we are designing studies that will detect a benefit. To answer these questions, studies must include people with MS and depressive symptoms as well as people with relapsing remitting and chronic subtypes. DOI: 10.1176/appi.neuropsych.18070164 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 149 – Multiple Sklerose: Veröffentlichungen April 2019 218. J Neurosurg. 2019 Apr 12:1-9. doi: 10.3171/2019.1.JNS183093. [Epub ahead of print] Percutaneous glycerol rhizotomy for trigeminal neuralgia in patients with multiple sclerosis: a long-term retrospective cohort study. Staudt MD(1), Joswig H(1), Pickett GE(2), MacDougall KW(1), Parrent AG(1). Author information: (1)1Department of Clinical Neurological Sciences, Division of Neurosurgery, London Health Sciences Centre, Western University, London, Ontario, Canada; and. (2)2Division of Neurosurgery, Halifax Infirmary, Dalhousie University, Halifax, Nova Scotia, Canada. OBJECTIVEThe prevalence of trigeminal neuralgia (TN) in patients with multiple sclerosis (MS-TN) is higher than in the general population (idiopathic TN [ITN]). Glycerol rhizotomy (GR) is a percutaneous lesioning surgery commonly performed for the treatment of medically refractory TN. While treatment for acute pain relief is excellent, long-term pain relief is poorer. The object of this study was to assess the efficacy of percutaneous retrogasserian GR for the treatment of MS-TN versus ITN.METHODSA retrospective chart review was performed, identifying 219 patients who had undergone 401 GR procedures from 1983 to 2018 at a single academic institution. All patients were diagnosed with medically refractory MS-TN (182 procedures) or ITN (219 procedures). The primary outcome measures of interest were immediate pain relief and time to pain recurrence following initial and repeat GR procedures. Secondary outcomes included medication usage and presence of periprocedural hypesthesia.RESULTSThe initial pain-free response rate was similar between groups (p = 0.726): MS-TN initial GR 89.6%; MS-TN repeat GR 91.9%; ITN initial GR 89.6%; ITN repeat GR 87.0%. The median time to recurrence after initial GR was similar between MS-TN (2.7 ± 1.3 years) and ITN (2.1 ± 0.6 years) patients (p = 0.87). However, there was a statistically significant difference in the time to recurrence after repeat GR between MS-TN (2.3 ± 0.5 years) and ITN patients (1.2 ± 0.2 years; p < 0.05). The presence of periprocedural hypesthesia was highly predictive of pain-free survival (p < 0.01).CONCLUSIONSPatients with MS-TN achieve meaningful pain relief following GR, with an efficacy comparable to that following GR in patients with ITN. Initial and subsequent GR procedures are equally efficacious. DOI: 10.3171/2019.1.JNS183093 219. J Org Chem. 2019 Apr 19;84(8):4856-4866. doi: 10.1021/acs.joc.8b03290. Epub 2019 Apr 12. Chemoenzymatic Synthesis of a Chiral Ozanimod Key Intermediate Starting from Naphthalene as Cheap Petrochemical Feedstock. Uthoff F(1), Löwe J(1), Harms C(1), Donsbach K(2), Gröger H(1). Author information: (1)Chair of Industrial Organic Chemistry and Biotechnology, Faculty of Chemistry , Bielefeld University , Universitätsstr. 25 , 33615 Bielefeld , Germany. (2)PharmaZell GmbH , Rosenheimer Str. 43 , 83064 Raubling , Germany. Ozanimod represents a recently developed, promising active pharmaceutical ingredient (API) molecule in combating multiple sclerosis. Addressing the goal of a scalable, economically attractive, and technically feasible process for the manufacture of this drug, a novel alternative synthetic approach toward ( S)-4-cyano- 1-aminoindane as a chiral key intermediate for ozanimod has been developed. The total synthesis of this intermediate is based on the utilization of naphthalene as a readily accessible, economically attractive, and thus favorable petrochemical starting material. At first, naphthalene is transformed into 4-carboxy-indanone within a four-step process by means of an initial Birch reduction, followed by an isomerization of the ═ double bond, o idative ═ cleavage, and intramolecular Friedel-Crafts acylation. The transformation of the 4-carboxy-indanone into ( S)-4-cyano-1-aminoindane then represents the key step for introducing the chirality and the desired absolute S configuration. When evaluating complementary biocatalytic approaches based on the use of a lipase and transaminase, respectively, the combination of a chemical reductive amination of the 4-carboxyindanone followed by a subsequent lipase-catalyzed resolution turned out to be the most efficient route, leading to the desired key intermediate ( S)-4-cyano-1-aminoindane in satisfactory yield and with excellent enantiomeric excess of 99%. DOI: 10.1021/acs.joc.8b03290 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 150 – Multiple Sklerose: Veröffentlichungen April 2019 220. J Pharmacopuncture. 2019 Mar;22(1):7-15. doi: 10.3831/KPI.2019.22.001. Epub 2019 Mar 31. A Pharmacological Review on Portulaca oleracea L.: Focusing on Anti- Inflammatory, Anti- Oxidant, Immuno-Modulatory and Antitumor Activities. Rahimi VB(1)(2), Ajam F(2), Rakhshandeh H(2), Askari VR(2)(3). Author information: (1)Student Research Committee, Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. (2)Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran. (3)Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Portulaca oleracea L. (PO) or Purslane is an annual grassy plant that is distributed in many parts of the world, especially the tropical and subtropical areas. PO has some pharmacological properties such as analgesic, antibacterial, skeletal muscle-relaxant, wound-healing, anti- inflammatory and a radical scavenger. This review article is focused on the anti-inflammatory, immuno-modulatory, anti-oxidant and anti-tumor activities of the PO. Anti-inflammatory, immuno-modulatory, anti-oxidant and Anti-tumor effects of PO were searched using various databases until the end of August 2018. The online literature was searched using PubMed, Science Direct, Scopus, Google Scholar and Web of Science. Our review showed that PO exerts its effects through anti-inflammatory properties and balancing the adaptive and innate immune system depending on situations. PO acts as immune-modulator and anti-oxidant agent in both inflammatory states by the dominance of Th2 response such as asthma, cancer and atopic dermatitis and evoked Th1 disorders including hepatitis and multiple sclerosis. DOI: 10.3831/KPI.2019.22.001 PMCID: PMC6461301 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 151 – Multiple Sklerose: Veröffentlichungen April 2019 221. J Sex Med. 2019 Apr 19. pii: S1743-6095(19)30467-9. doi: 10.1016/j.jsxm.2019.03.011. [Epub ahead of print] Prevalence and Psychopathological Determinants of Sexual Dysfunction and Related Distress in Women With and Without Multiple Sclerosis. Gava G(1), Visconti M(2), Salvi F(3), Bartolomei I(3), Seracchioli R(2), Meriggiola MC(2). Author information: (1)Gynecology and Physiopathology of Human Reproduction, S. Orsola-Malpighi Hospital, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy. Electronic address: [email protected]. (2)Gynecology and Physiopathology of Human Reproduction, S. Orsola-Malpighi Hospital, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy. (3)Center for Rare and Neuroimmunological Diseases, Scientific Institute for Research, Hospitalization and Health Care (IRCCS), Istituto delle Scienze Neurologiche di Bologna, Bellaria Hospital, Bologna, Italy. INTRODUCTION: Sexual dysfunction (SD) is common but still underdiagnosed in women with multiple sclerosis (MS); in fact, the lack of a consistent use of validated diagnostic tools makes the prevalence of SD and related distress difficult to define precisely. AIM: To assess the prevalence of SD in Italian women with MS compared with age-matched healthy control subjects (HC) and the association with demographic, psychological, and MS-related characteristics. METHODS: The Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale were administered to 153 women with MS and 153 HC. Demographic, gynecologic, and neurologic data were obtained. Disability was assessed using the Expanded Disability Status Scale. Psychological symptoms were evaluated in MS patients with Profile of Mood State and the Beck Depression Inventory II. MAIN OUTCOMES MEASURES: Prevalence of SD and sexual distress in women with MS compared with HC. RESULTS: Among women sexually active in the last month, we found an increased prevalence of SD in MS patients compared with HC subjects (42.0% vs 16.0%, P = .0001). The prevalence of dysfunctional FSFI global scores (<26.55) was higher in women with MS compared with HC (49.6% vs 33.6%, P = .014). In the MS group, the prevalence of SD was similar between pre- and post- menopausal women. Both premenopausal and postmenopausal MS women presented a greater prevalence of SD if compared with the premenopausal and postmenopausal HC groups (30/79 [37.9%] vs. 5/74 [6.8%], P = .0001 and 20/40 [50.0%] vs 16/57 [28.1%], P = .03, respectively). A negative correlation was observed between the FSFI global score and age and Expanded Disability Status Scale. Depressive symptoms were more common in women with MS and SD than in those without. CLINICAL IMPLICATIONS: This study suggests that sexual function investigation should always be a standard part of the consultation with healthcare professionals for MS. STRENGTH & LIMITATIONS: The strength of this study was the comparison with an age-matched healthy control group and the use of validated questionnaires to assess both sexual function and sexual distress. Larger and multicenter studies may further support our findings. CONCLUSION: In our cohort, the prevalence of SD and sexual distress was higher in women with MS compared to the HC group. Age, disability, and depressive symptoms were associated with increased SD. Gava G, Visconti M, Salvi F, et al. Prevalence and Psychopathological Determinants of Sexual Dysfunction and Related Distress in Women With and Without Multiple Sclerosis. J Sex Med 2019;XX:XXX-XXX. Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.jsxm.2019.03.011 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 152 – Multiple Sklerose: Veröffentlichungen April 2019 222. J Vis Exp. 2019 Mar 26;(145). doi: 10.3791/59249. Visualizing Impairment of the Endothelial and Glial Barriers of the Neurovascular Unit during Experimental Autoimmune Encephalomyelitis In Vivo. Tietz SM(1), Engelhardt B(2). Author information: (1)Theodor Kocher Institute, University of Bern. (2)Theodor Kocher Institute, University of Bern; [email protected]. The neurovascular unit (NVU) is composed of microvascular endothelial cells forming the blood-brain barrier (BBB), an endothelial basement membrane with embedded pericytes, and the glia limitans composed by the parenchymal basement membrane and astrocytic end-feed embracing the abluminal aspect of central nervous system (CNS) microvessels. In addition to maintaining CNS homeostasis the NVU controls immune cell trafficking into the CNS. During immunosurveillance of the CNS low numbers of activated lymphocytes can cross the endothelial barrier without causing BBB dysfunction or clinical disease. In contrast, during neuroinflammation such as in multiple sclerosis or its animal model experimental autoimmune encephalomyelitis (EAE) a large number of immune cells can cross the BBB and subsequently the glia limitans eventually reaching the CNS parenchyma leading to clinical disease. Immune cell migration into the CNS parenchyma is thus a two-step process that involves a sequential migration across the endothelial and glial barrier of the NVU employing distinct molecular mechanisms. If following their passage across the endothelial barrier, T cells encounter their cognate antigen on perivascular antigen-presenting cells their local reactivation will initiate subsequent mechanisms leading to the focal activation of gelatinases, which will enable the T cells to cross the glial barrier and enter the CNS parenchyma. Thus, assessing both, BBB permeability and MMP activity in spatial correlation to immune cell accumulation in the CNS during EAE allows to specify loss of integrity of the endothelial and glial barriers of the NVU. We here show how to induce EAE in C57BL/6 mice by active immunization and how to subsequently analyze BBB permeability in vivo using a combination of exogenous fluorescent tracers. We further show, how to visualize and localize gelatinase activity in EAE brains by in situ zymogaphy coupled to immunofluorescent stainings of BBB basement membranes and CD45+ invading immune cells. DOI: 10.3791/59249 223. JAMA Neurol. 2019 Apr 8. doi: 10.1001/jamaneurol.2019.0522. [Epub ahead of print] Fulminant Hepatitis Associated With Echovirus 25 During Treatment With Ocrelizumab for Multiple Sclerosis. Nicolini LA(1)(2), Canepa P(1), Caligiuri P(1), Mikulska M(1)(2), Novi G(3), Viscoli C(1)(2), Uccelli A(3)(4). Author information: (1)Department of Health Sciences, University of Genoa, Genoa, Italy. (2)Infectious Diseases Unit, Ospedale Policlinico San Martino-Istituto Di Ricovero e Cura a Carattere Scientifico, Genoa, Italy. (3)Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy. (4)Ospedale Policlinico San Martino-Istituto Di Ricovero e Cura a Carattere Scientifico, Genoa, Italy. DOI: 10.1001/jamaneurol.2019.0522 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 153 – Multiple Sklerose: Veröffentlichungen April 2019 224. JAMA Neurol. 2019 Apr 29. doi: 10.1001/jamaneurol.2019.0905. [Epub ahead of print] Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis. Gasperi C(1), Salmen A(2)(3), Antony G(4), Bayas A(5), Heesen C(6), Kümpfel T(7), Linker RA(8), Paul F(9)(10)(11)(12), Stangel M(13), Tackenberg B(14), Bergh FT(15)(16), Warnke C(17)(18), Weber F(19)(20), Wiendl H(21)(22), Wildemann B(23), Zettl UK(24), Ziemann U(25), Zipp F(26)(27)(28)(29), Tumani H(30)(31), Gold R(2), Hemmer B(1)(32); German Competence Network of Multiple Sclerosis. Author information: (1)Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. (2)Department of Neurology, St, Josef Hospital, Ruhr-University Bochum, Bochum, Germany. (3)Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. (4)Central Information Office German Competence Network of Multiple Sclerosis, Philipps University Marburg, Marburg, Germany. (5)Department of Neurology, Klinikum Augsburg, Augsburg, Germany. (6)Institute of Neuroimmunology and Multiple Sclerosis, Department of Neurology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. (7)Institute of Clinical Neuroimmunology, Ludwig- Maximilians-Universität, Munich, Germany. (8)Department of Neurology, University Hospital Erlangen, Erlangen, Germany. (9)NeuroCure Clinical Research Center, Charité-Univeritätsmedizin Berlin, Berlin, Germany. (10)Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany. (11)NeuroCure Clinical Research Center, Berlin, Germany. (12)Institute of Health, Berlin, Germany. (13)Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany. (14)Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, Marburg, Germany. (15)Department of Neurology, University of Leipzig, Leipzig, Germany. (16)Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany. (17)Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. (18)Department of Neurology, University Hospital Cologne, Cologne, Germany. (19)Max Planck Institute of Psychiatry, Munich, Germany. (20)Neurological Clinic Cham, Cham, Germany. (21)Department of Neurology University of Münster, Münster, Germany. (22)Hertie-Institute for Clinical Brain Research, Eberhard-Karls-Universität Tübingen, Tübingen, Germany. (23)Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany. (24)Department of Neurology, University of Rostock, Rostock, Germany. (25)Department of Neurology & Stroke, Eberhard-Karls-Universität Tübingen, Tübingen, Germany. (26)Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (27)Focus Program Translational Neurosciences, Johannes Gutenberg University Mainz, Mainz, Germany. (28)Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (29)Rhine-Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (30)Department of Neurology, University of Ulm, Ulm, Germany. (31)Clinic of Neurology Dietenbronn, Schwendi, Germany. (32)Munich Cluster for Systems Neurology, Munich, Germany. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 154 – Multiple Sklerose: Veröffentlichungen April 2019 Importance: Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed. Objective: To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing- remitting MS or clinically isolated syndrome. Design, Setting, and Participants: Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018. Exposure: Patients were offered standard immunotherapies per national treatment guidelines. Main Outcomes and Measures: A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated. Results: Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found. Conclusions and Relevance: Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions. DOI: 10.1001/jamaneurol.2019.0905 225. JCI Insight. 2019 Apr 2;5. pii: 126520. doi: 10.1172/jci.insight.126520. Deficiency of Socs3 leads to brain-targeted EAE via enhanced neutrophil activation and ROS production. Yan Z, Yang W, Parkitny L, Gibson SA, Lee KS, Collins F, Deshane JS, Cheng W, Weinmann AS, Wei H, Qin H, Benveniste EN. Dysregulation of the JAK/STAT signaling pathway is associated with Multiple Sclerosis (MS) and its mouse model, Experimental Autoimmune Encephalomyelitis (EAE). Suppressors Of Cytokine Signaling (SOCS) negatively regulate the JAK/STAT pathway. We previously reported a severe, brain-targeted, atypical form of EAE in mice lacking Socs3 in myeloid cells (Socs3ΔLysM), which is associated with cerebellar neutrophil infiltration. There is emerging evidence that neutrophils are detrimental in the pathology of MS/EAE, however, their exact function is unclear. Here we demonstrate that neutrophils from the cerebellum of Socs3ΔLysM mice show a hyper-activated phenotype with excessive production of reactive oxygen species (ROS) at the peak of EAE. Neutralization of ROS in vivo delayed the onset and reduced severity of atypical EAE. Mechanistically, Socs3-deficient neutrophils exhibit enhanced STAT3 activation, a hyper-activated phenotype in response to G-CSF, and upon G-CSF priming, increased ROS production. Neutralization of G- CSF in vivo significantly reduced the incidence and severity of the atypical EAE phenotype. Overall, our work elucidates that hypersensitivity of G-CSF/STAT3 signaling in Socs3ΔLysM mice leads to atypical EAE by enhanced neutrophil activation and increased oxidative stress, which may explain the detrimental role of G-CSF in MS patients. DOI: 10.1172/jci.insight.126520 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 155 – Multiple Sklerose: Veröffentlichungen April 2019 226. JCI Insight. 2019 Apr 18;4(8). pii: 126329. doi: 10.1172/jci.insight.126329. eCollection 2019 Apr 18. Myelin repair stimulated by CNS-selective thyroid hormone action. Hartley MD(1)(2), Banerji T(1), Tagge IJ(3), Kirkemo LL(1)(2), Chaudhary P(2)(4), Calkins E(2)(4), Galipeau D(2)(4), Shokat MD(1), DeBell MJ(1), Van Leuven S(1), Miller H(1), Marracci G(2)(4), Pocius E(2)(4), Banerji T(1), Ferrara SJ(1), Meinig JM(1), Emery B(4)(5), Bourdette D(2)(4), Scanlan TS(1). Author information: (1)Department of Physiology & Pharmacology and Program in Chemical Biology, Oregon Health & Science University, Portland, Oregon, USA. (2)VA Portland Health Care System, Portland, Oregon, USA. (3)Advanced Imaging Research Center. (4)Department of Neurology, and. (5)Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, Oregon, USA. Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair. DOI: 10.1172/jci.insight.126329 227. JMIR Res Protoc. 2019 Apr 22;8(4):e12045. doi: 10.2196/12045. The Effect of Vitamin D Supplements on Clinical and Para-Clinical Outcomes in Patients With Multiple Sclerosis: Protocol for a Systematic Review. Ghajarzadeh M(1), Keshtkar AA(2), Azimi A(3), Sahraian MA(3), Mohammadifar M(4), Ramagopalan SV(5). Author information: (1)Universal Council of Epidemiology, Universal Scientific Education and Research Network, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran. (2)Department of Health Sciences Education Development, School of Public Health, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran. (3)MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran. (4)Department of Radiology, Zanjan University of Medical Sciences, Zanjan, Islamic Republic of Iran. (5)Bristol-Myers Squibb, Uxbridge, United Kingdom. BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease, which has a wide range of effects on patients. There are controversies regarding the role of vitamin D in clinical and laboratory improvements in MS patients. OBJECTIVE: The aim of this systematic review protocol is to evaluate the efficacy of vitamin D supplements on relapse rate, gadolinium-enhancing lesions of magnetic resonance imaging (MRI), and cytokine profiles. METHODS: We will search PubMed, Scopus, EMBASE, CINAHL, Web of Science, Ovid, ProQuest, American College of Physicians Journal Club database, Health Technology Assessment Database (The Cochrane Collaboration), and National Health System Economic Evaluation Database (The Cochrane Collaboration) and gray literature including reference of included studies and conference abstracts. Clinical trials reporting the effect of any doses of vitamin D on relapse rate, gadolinium-enhancing lesions of MRI, and cytokine profiles will be included. In total, 2 independent researchers will independently assess the studies, extract data, and evaluate the quality of primary studies. RESULTS: This systematic review was started in September 2017 and the process is continuing. The included articles are evaluated and researchers are going to extract the data. CONCLUSIONS: To our knowledge, this will be the first comprehensive systematic review aiming to assess the effect of vitamin D supplements on clinical and para- clinical outcomes in patients with multiple sclerosis. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12045. ©Mahsa Ghajarzadeh, Abbas Ali Keshtkar, Amirreza Azimi, Mohammad Ali Sahraian, Mehdi Mohammadifar, Sreeram V Ramagopalan. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 22.04.2019. DOI: 10.2196/12045 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 156 – Multiple Sklerose: Veröffentlichungen April 2019 228. Kidney Int Rep. 2019 Feb 13;4(4):594-602. doi: 10.1016/j.ekir.2019.02.005. eCollection 2019 Apr. Estimating the Change in Renal Function During the First Year of Therapy in ANCA- Associated Vasculitis. Lepeytre F(1), Royal V(2), Lavoie PL(1), Bollée G(3), Gougeon F(4), Beauchemin S(5), Rhéaume M(6), Brachemi S(3), Laurin LP(5), Troyanov S(1). Author information: (1)Nephrology Division, Hôpital du Sacré-Coeur de Montréal, Québec, Canada. (2)Pathology Department, Hôpital Maisonneuve-Rosemont, Québec, Canada. (3)Nephrology Division, Centre Hospitalier de l'Université de Montréal, Québec, Canada. (4)Pathology Department, Centre Hospitalier de l'Université de Montréal, Québec, Canada. (5)Nephrology Division, Hôpital Maisonneuve- Rosemont, Québec, Canada. (6)Internal Medicine Division, Hôpital du Sacré-Coeur de Montréal, Québec, Canada. Introduction: Studies in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) consistently show that the months following diagnosis have the greatest impact on the long-term renal function. Yet, it remains uncertain how much early gain should be expected with treatment. We sought to determine the factors associated with the change in glomerular filtration rate (GFR) throughout the first year. Methods: We retrospectively reviewed patients from 3 university hospitals who received treatments. We assessed the proportions of glomeruli with crescents, with global sclerosis, the AAV glomerulonephritis classification, the severity of chronic vascular and tubulo-interstitial disease, and the presence of acute tubular injury (ATI). We used repeated-measures analyses of variance (ANOVAs) to determine factors associated with the change in GFR throughout the first year. Results: There were 162 individuals with AAV identified, 96 with a valid renal biopsy and 82 with at least 12 months of follow-up. The initial GFR of 30 ± 25 ml/min per 1.73 m2 rose by 15 ± 20 during the first year. The severity of pathology findings, myeloperoxidase positivity, and those with kidney- and lung-limited disease presented with a lower GFR. Younger patients with a lower initial GFR and the presence of ATI correlated with a greater increase in GFR by 12 months. A higher proportion of crescents did not predict the change in GFR, contrary to global glomerulosclerosis, where each 10% increase added a loss of 2.7 ± 1.3 ml/min per 1.73 m2 per year (P = 0.03). These factors remained independent of each other. Conclusion: Multiple factors influence renal recovery during the first year of therapy. Estimating the change in GFR early on will help identify and reassess outliers. DOI: 10.1016/j.ekir.2019.02.005 PMCID: PMC6451086 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 157 – Multiple Sklerose: Veröffentlichungen April 2019 229. Klin Monbl Augenheilkd. 2019 Apr;236(4):425-428. doi: 10.1055/a-0853-1721. Epub 2019 Apr 18. Normal Visual Recovery after Optic Neuritis Despite Significant Loss of Retinal Ganglion Cells in Patients with Multiple Sclerosis. Sherif M(1), Bergin C(1), Borruat FX(1). Author information: (1)Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Lausanne, Switzerland. BACKGROUND: Optic neuritis (ON) is a frequent manifestation of demyelinating attack in multiple sclerosis (MS). Initial visual loss can vary from minimal to complete. Visual improvement occurs in about 95% of patients, some of them recovering to normal [visual acuity (VA), color vision, visual field (VF)]. We analyzed retinal ganglion cell layer (RGCL) thickness in MS patients who recovered their normal vision after ON to determine whether a relative preservation of RGCL existed in these patients. MATERIALS AND METHODS: We conducted a retrospective study of all patients with MS and ON examined by one of us (F. X. B.) between 2013 and 2018. Inclusion criteria were strictly unilateral ON, full recovery of vision, computerized visual field, and T e aminations. Full recovery of vision was defined as ≥ 10/10, Ishihara ≥ 11/13, and VF mean defect ( D) ≤ 2.6 dB. Evaluation of RGCL was obtained with spectral domain optical coherence tomography (SD-OCT). The normal fellow eye of all patients served as the control group. Relative thinning of RGCL, expressed as percentage, was calculated by comparing results from the affected eye to the fellow eye of the same patient. RESULTS: Twenty-one patients (21 affected eyes - Group 1, 21 normal fellow eyes - Group 2) satisfying the inclusion criteria were retrieved from our database. All patients exhibited the relapsing- remitting form of MS. There were 16 women and 5 men. Mean age was 39.3 years old. There were no statistically significant differences between Group 1 and Group 2 for either VA (p = 0.3934) or Ishihara (p = 0.140), but a significant difference was found for VF MD (p = 0.0405). A markedly significant difference for RGCL thickness (p = 0.0001) was found, without any correlation with the degree of visual recovery. A subgroup of patients (n = 14) was examined at the time of initial visual loss. We correlated their results of visual function to the final RGCL thickness, and a correlation was found between either the initial VA loss or the initial VF loss and the final loss of RGCL (R2 = 0.4075 and R2 = 0.00739, respectively). CONCLUSIONS: In our study, all patients with ON lost a significant amount of RGCL despite a full recovery of vision, as defined by our criteria. The percentage of RGCL loss varied from 5 - 27% and could not be correlated with any final visual indices. However, a correlation was found with the degree of initial visual loss. Despite sometimes marked RGCL loss after ON, patients with MS can recover normal visual function, according to standard clinical tests. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 158 – Multiple Sklerose: Veröffentlichungen April 2019 Publisher: Neuritis nervi optici (NNO), auch Sehnervenentzündung genannt, ist eine häufige Manifestation von demyelinisierenden Erkrankungen wie der multiplen Sklerose (MS). Die Bandbreite des anfänglichen Verlustes der Sehkraft reicht von minimal bis vollständig. Bei fast 95% aller Patienten stellt sich aber eine Besserung der Sehkraft ein, einige Betroffene erfahren gar eine Wiederherstellung der normalen Sehkraft (Sehschärfe, Farbwahrnehmung, Gesichtsfeld). Wir untersuchten die Dicke der Ganglienzellschicht in der Retina von MS-Patienten, die nach einer Sehnervenentzündung ihre normale Sehkraft wiedererlangt hatten, um herauszufinden, ob die relative Dicke der retinalen Ganglienzellschicht bei diesen Patienten erhalten bleibt.Wir führten eine retrospektive Studie von allen MS-Patienten mit einer früheren Sehnervenentzündung durch, die von einem der Autoren (F. X. B.) zwischen 2013 und 2018 untersucht worden waren. Einschlusskriterien waren eine einseitige NNO, die vollständige Visuswiederherstellung sowie computergestützte Gesichtsfeld- und OCT-Untersuchungen. Die vollständige Visuswiederherstellung wurde definiert als Sehschärfe ≥ 10/10, Ishihara-Test ≥ 11/13 und mittlerer Gesichtsfelddefekt ≤ 2,6 dB. Die retinale Ganglienzellschicht wurde mithilfe der Spectral Domain optischen Kohärenztomografie (SD-OCT) untersucht. Das andere, normale Auge des Patienten diente jeweils als Kontrolle. Die Untersuchungsergebnisse für das betroffene Auge wurden mit den Untersuchungsergebnissen für das normale Auge beim selben Patienten verglichen, um die relative Ausdünnung der retinalen Ganglienzellschicht zu ermitteln (Angaben in Prozent).Die Daten zu 21 Patienten (betroffenes Auge von 21 Patienten: Gruppe 1; das andere normale Auge der 21 Patienten: Gruppe 2), die die Einschlusskriterien erfüllten, wurden unserer Datenbank entnommen. Alle Patienten hatten eine schubförmig-remittierende Form von MS. Die Patientengruppe bestand aus 16 Frauen und 5 Männern. Das Durchschnittsalter betrug 39,3 Jahre. Es gab keine statistisch signifikanten Unterschiede zwischen Gruppe 1 und Gruppe 2 hinsichtlich der Sehschärfe (p = 0,3934) oder des Ishihara-Tests (p = 0,140), aber es bestand ein statistisch signifikanter Unterschied zwischen den Gruppen bezüglich des mittleren Gesichtsfelddefekts (p = 0,0405). Der statistisch signifikante Unterschied war für die Dicke der retinalen Ganglienzellschicht besonders stark ausgeprägt (p = 0,0001), ohne dass der Unterschied mit dem Ausmaß an Wiederherstellung der Sehkraft korrelierte. Eine Untergruppe von Patienten (n = 14) wurde zum Zeitpunkt ihres ursprünglichen Visusverlusts untersucht. Die Daten ihrer Sehleistung wurden mit der endgültigen Dicke ihrer retinalen Ganglienzellschicht verglichen. Es stellte sich heraus, dass es eine Korrelation gab zwischen dem anfänglichen Verlust an Sehschärfe bzw. dem anfänglichen Gesichtsfeldverlust und dem endgültigen Verlust an retinaler Ganglienzellschichtdicke (R2 = 0,4075 resp. R2 = 0,00739).Es stellte sich in unserer Studie heraus, dass die retinale Ganglienzellschichtdicke bei allen Patienten mit NNO erheblich abgenommen hatte, auch wenn alle Patienten, gemäß den Kriterien, ihre Sehkraft vollumfänglich wiedererlangt hatten. Das Ausmaß des Verlusts an Ganglienzellschichtdicke variierte zwischen 5 und 27% und korrelierte mit keinem der endgültigen Ergebnisse der Sehfunktionsprüfung. Es gab aber eine Korrelation mit dem Ausmaß des ursprünglichen Sehkraftverlusts. Obwohl es bei einer NNO zu einem erheblichen Verlust der retinalen Ganglienzellschichtdicke kommen kann, zeigen klinische Standardtests, dass MS-Patienten ihre normale Sehkraft wiedererlangen können. Georg Thieme Verlag KG Stuttgart · New York. DOI: 10.1055/a-0853-1721 Conflict of interest statement: The authors declare that they have 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 | L.DE.MKT.SM.02.2017.5323 – 159 – Multiple Sklerose: Veröffentlichungen April 2019 230. Laryngorhinootologie. 2019 Apr;98(4):268-275. doi: 10.1055/a-0747-6916. Epub 2019 Apr 9. [Susac Syndrome: A Diagnostic Chameleon]. [Article in German] Stefanou MI, Doycheva D, Ebrahimi A, Dörr JM, Ziemann U. Susac's syndrome (SuS) is a rare, probably autoimmune endotheliopathy of the central nervous system, retina and inner ear. It is characterized by a clinical triad of encephalopathy, branch retinal artery occlusions (BRAOs) and sensorineural hearing loss. To date, more than 300 cases of SuS have been reported in the literature. However, SuS remains an under- and misdiagnosed entity in the clinical setting. This report presents an exemplary case of a patient, who was initially misdiagnosed with relapsing-remitting multiple sclerosis. At initial presentation, the patient did not demonstrate the complete clinical triad, and the interval between symptom onset and diagnosis was 4 months. Typical diagnostic features, which enabled the diagnosis of SuS were: a) MRI findings with T2-hyperintense snowball-like lesions of the corpus callosum and subcortical white matter and hyperintense lesions in diffusionweighted imaging with reduced apparent diffusion coefficient; b) BRAOs and vessel wall hyperfluorescence in fluorescein angiography and a significant thickness reduction of the inner retinal layers in optical coherence tomography; c) bilateral sensorineural hearing loss. The patient was aggressively treated with cyclophosphamide, rituximab, glucocorticoids and acetylsalicylic acid with a good response to therapy. This report draws attention to the need to take SuS into consideration in the differential diagnosis at the interface of neurological, psychiatric, ophthalmological and otorhinolaryngological disorders. As SuS may result in severe and persistent neurological deficits, an interdisciplinary collaboration is fundamental for the prompt diagnosis and initiation of adequate immunosuppressive treatment. © Georg Thieme Verlag KG Stuttgart · New York. DOI: 10.1055/a-0747-6916 Conflict of interest statement: J. Dörr erhielt Honorare für Beraterleistungen und Referententätigkeiten von Allergan, Bayer, Biogen, Genzyme, Novartis und Teva; Kongressunterstützungen von Bayer, Biogen und Novartis, sowie finanzielle Unterstützung zur Durchführung von Investigator-initiierten Studien von Bayer und Novartis. U. Ziemann erhielt für Beraterleistungen Honorare von Bayer Vital GmbH, Biogen GmbH, Bristol Myers Squibb GmbH, CorTec GmbH, Janssen Pharmaceuticals NV, Medtronic, Servier, sowie finanzielle Unterstützung zur Durchführung von Investigator initiierten Studien von Biogen und Servier. Die anderen Autoren geben an, dass kein Interessenkonflikt besteht. 231. Lung India. 2019 May-Jun;36(3):207-211. doi: 10.4103/lungindia.lungindia_219_18. Patient characteristics and outcomes of a home mechanical ventilation program in a developing country. Saiphoklang N(1), Kanitsap A(1), Ruchiwit P(1), Pirompanich P(1), Sricharoenchai T(1), Cooper CB(2). Author information: (1)Department of Medicine, Faculty of Medicine, Thammasat University, Klongluang, Pathumthani, Thailand. (2)Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, United States. Background: There are limited data on home mechanical ventilation (HMV) in developing countries. This study aimed to describe the patient characteristics, feasibility, and outcomes of an HMV program at a university hospital in Thailand. Materials and Methods: Data were collected on all patients who were discharged with HMV between October 2014 and August 2015 at Thammasat University Hospital. Results: Twelve patients (eight men and four women) underwent HMV. They were aged 71.5 ± 17.6 years; mean ± standard deviation. Indications for HMV were 6 neurologic diseases (4 amyotrophic lateral sclerosis, 1 multiple system atrophy, and 1 stroke), 2 chronic obstructive pulmonary disease (COPD), 1 tracheomalacia, and 3 combined neurologic diseases and respiratory diseases (2 stroke and COPD, 1 stroke and tracheomalacia). The duration of follow-up was 799.5 ± 780.5 days. The ratio of family income to cost of HMV usage was 77.2:1 ± 5.5:1. All patients had tracheostomies. Modes of HMV were biphasic positive airway pressure (66.7%), pressure-controlled ventilation (16.7%), pressure-support ventilation (8.3%), and volume-controlled ventilation (8.3%). Complications occurred in ten patients (83.3%), including tracheobronchitis (20 events) and ventilator-associated pneumonia (12 events). Overall mortality was 41.7% (5/12 patients), including two patients who died due to ventilator-associated pneumonia. There were no instances of ventilator malfunction. Conclusions: HMV is feasible for patients with neurological diseases and COPD in a developing country. The relatively high rate of complications indicates the need for more comprehensive clinical services for chronic ventilator-dependent patients in this setting. DOI: 10.4103/lungindia.lungindia_219_18 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 | L.DE.MKT.SM.02.2017.5323 – 160 – Multiple Sklerose: Veröffentlichungen April 2019 232. Magn Reson Imaging. 2019 Apr 4;60:44-51. doi: 10.1016/j.mri.2019.04.003. [Epub ahead of print] Clinical feasibility of brain quantitative susceptibility mapping. Zhang S(1), Liu Z(2), Nguyen TD(3), Yao Y(4), Gillen KM(3), Spincemaille P(3), Kovanlikaya I(3), Gupta A(3), Wang Y(5). Author information: (1)Department of Radiology, Weill Cornell Medicine, New York, NY, USA; 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; Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA. (3)Department of Radiology, Weill Cornell Medicine, New York, NY, USA. (4)Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (5)Department of Radiology, Weill Cornell Medicine, New York, NY, USA; Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA. Electronic address: [email protected]. PURPOSE: To evaluate the quality of brain quantitative susceptibility mapping (QSM) that is fully automatically reconstructed in clinical MRI of various neurological diseases. METHODS: 393 consecutive patients in one month were recruited for this evaluation study. QSM was reconstructed using Morphology Enabled Dipole Inversion without zero reference regularization (MEDI) and using MEDI with cerebrospinal fluid automatic zero-reference regularization to generate susceptibility values (MEDI+0). Two neuroradiologists independently assessed the image quality of MEDI+0 and MEDI and image concordance between them. Lesion susceptibility values were measured in 20 cases of glioma, 21 cases of ischemic stroke and 43 multiple sclerosis (MS) cases on both MEDI+0 and MEDI images. RESULTS: The two neuroradiologists rated the MEDI+0 image qualities of the 393 cases as 351 (89.3%) and 362 (92.1%) excellent, 29 (7.4%) and 24 (6.1%) diagnostic, and 13 (3.3%) and 7 (1.8%) poor, and scored the concordances between MEDI+0 and MEDI as 364 (92.6%) and 351 (89.3%) excellent, 13 (3.3%) and 31 (7.9%) good, 14 (3.6%) and 9 (2.3%) intermediate, 2 (0.5%) and 2 (0.5%) poor, and 0 (0%) and 0 (0%) none. There was good correlation between MEDI+0 and MEDI in lesion susceptibility contrast of glioma, ischemic stroke, and MS cases (all p < 0.05). The MS lesion susceptibility time course from this patient cohort was found to be similar to the reported pattern: isointense initially for acute enhancing lesions, and hyperintense over the following years for active chronic lesions. CONCLUSION: Brain QSM images of various neurological diseases have reliable diagnostic quality in clinical MRI, with MEDI+0 providing susceptibility values automatically referenced to CSF in longitudinal and cross-center studies. Copyright © 2019 Elsevier Inc. All rights reserved. DOI: 10.1016/j.mri.2019.04.003 233. Magn Reson Med. 2019 Apr 8. doi: 10.1002/mrm.27757. [Epub ahead of print] Magnetic resonance elastography of brain: Comparison between anisotropic and isotropic stiffness and its correlation to age. Kalra P(1), Raterman B(1), Mo X(2), Kolipaka A(1). Author information: (1)Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, Ohio. (2)Center for Biostatistics, Department of Biomedical Informatics, Ohio State University, Columbus, Ohio. PURPOSE: Noninvasive measurement of mechanical properties of brain tissue using magnetic resonance elastography (MRE) has been a promising method for investigating neurologic disorders such as multiple sclerosis, hydrocephalus, and Alzheimer's. However, because of the regional and directional dependency of brain stiffness, estimating anisotropic stiffness is important. This study investigates isotropic and anisotropic stiffness as a function of age as well as the correlation between isotropic and anisotropic stiffness. METHODS: MRE and diffusion tensor imaging (DTI) were performed on 28 healthy subjects with age ranges between 18-62 y. Isotropic and anisotropic stiffness was measured and compared with age for different regions of interest such as the thalamus, corpus callosum, gray matter, white matter, and whole brain. RESULTS: Isotropic stiffness in gray matter (rs = -0.57; P = 0.001) showed a significant decrease with age. Anisotropic stiffness in gray matter showed a significant decrease with age in C11 through C66 and in the thalamus, only in C33 . Between anisotropic and isotropic stiffness, gray matter showed a significant positive correlation in C11 through C66 , C22 and C66 showed a significant negative correlation in the thalamus and whole brain, and C44 showed a negative correlation in the corpus callosum. No significant difference between genders was observed in any measurements. CONCLUSION: This study demonstrated a change in isotropic and anisotropic stiffness with age in different regions of the brain along with a correlation of anisotropic stiffness to isotropic stiffness. © 2019 International Society for Magnetic Resonance in Medicine. DOI: 10.1002/mrm.27757 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 161 – Multiple Sklerose: Veröffentlichungen April 2019 234. Mater Sociomed. 2018 Dec;30(4):270-275. doi: 10.5455/msm.2018.30.270-275. How Cost-of-Illness (COI) Study Provides Direct and Indirect Costs of Multiple Sclerosis (MS) in Bosnia and Herzegovina ? Catic T(1), Suljic E(2), Gojak R(2), Culig J(3). Author information: (1)School of Medicine, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina. (2)Department for Science, Teaching and Clinical Trials, Clinical Centre University of Sarajevo, Sarajevo, Bosnia and Herzegovina. (3)Institute of Public Health " ndrija Štampar", Zagreb, Croatia. Background: This cost-of-illness (COI) study provides deep insight in direct and indirect costs of multiple sclerosis (MS) in Bosnia and Herzegovina (BH). Aim: Objective of this study was to analyze the costs and quality of life (QoL) of patients with MS in BH. Patients and methods: We applied the same methodology already used in study conducted across nine European countries. Sixty-two patients participated with EDSS score not higher than 6.5. Costs are collected using a questionnaire quality of life was measured by EQ-5D and MSQOL-54 questionnaires. Results: Mean age of respondents was 39.8 The mean utility measured by EQ-5D-3L was 0.68 at the beginning and 0.63 at the end of the study. QoL measured by MSQoL-54 showed improvement at the end of the trial. Costs are presented from the societal and payer perspective. Cost of MS in Bosnia and Herzegovina annually amount 124.8 million BAM. Cost driver where indirect and DMDs costs, with significant differences among subgroups. Conclusions: This study provides an in-depth analysis of MS costs in BH providing data for health policies development and information for future cost-effectiveness evaluations of new therapeutic options as well as for comparison of MS costs with other countries. DOI: 10.5455/msm.2018.30.270-275 PMCID: PMC6377925 235. Med Care. 2019 May;57 Suppl 5 Suppl 1:S31-S37. doi: 10.1097/MLR.0000000000001088. Turning Feed-forward and Feedback Processes on Patient-reported Data into Intelligent Action and Informed Decision-making: Case Studies and Principles. Oliver BJ(1)(2)(3)(4), Nelson EC(4)(5), Kerrigan CL(6)(7)(8). Author information: (1)Department of Community and Family Medicine, the Dartmouth Institute for Health Policy and Clinical Practice, Lebanon. (2)Department of Psychiatry at Geisel School of Medicine at Dartmouth College, Hanover, NH. (3)Department of Veterans Affairs National Quality Scholars Program, White River Junction, VT. (4)Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon. (5)Department of Community and Family Medicine at Geisel School of Medicine at Dartmouth College, Hanover. (6)Patient Reported Outcomes, Dartmouth Hitchcock Medical Center. (7)Department of Surgery, the Dartmouth Institute for Health Policy and Clinical Practice, Lebanon. (8)Geisel School of Medicine at Dartmouth College, Hanover, NH. INTRODUCTION: The collection of patient-reported outcomes (PROs) in routine clinical practice provides opportunities to "feed-forward" the patient's perspective to his/her clinical team to inform planning and management. This data can also be aggregated to "feedback" population-level analytics that can inform treatment decision-making, predictive modeling, population-based care, and system-level quality improvement efforts. METHODS AIDING INTERPRETATION AND ACTING ON RESULTS: Three case studies demonstrate a number of system-level features which aid effective PRO interpretation: (1) feed- forward and feedback information flows; (2) score interpretation aids; (3) cascading measurement; (4) registry-enabled learning health care systems; and (5) the maturational development of information systems. DISCUSSION: The case studies describe the developmental span of feed-forward PRO programs-from simple to mature applications. The Concord Hospital (CH) Multiple Sclerosis Neurobehavioral Clinic exemplifies a simple application in which PRO data are used before and during clinic visits by patients and clinicians to inform care. The Dartmouth-Hitchcock (D-H) Spine Center exemplifies a mature program which utilizes population-level analytics to provide decision support by predicting outcomes for different treatment options. The Swedish Rheumatology Quality (SRQ) Registry epitomizes an exceptional application which has spread to multiple systems across an entire country. KEY POINTS: Feed-forward and feedback PRO information systems can better inform, involve, and support clinicians, patients and families, and allow health systems to monitor and improve system performance and population health outcomes. Ideal systems have the capability for multilevel analyses at patient, system, and population levels, and an information technology infrastructure that is linked to associated workflows and a supportive practice culture. As systems mature, they progress beyond the ability to describe and inform towards higher level capabilities including prediction and decision support. Finally, there is additional promise for the integration of patient-reported information that is adjusted (or weighted) by preferences and values to guide shared decision-making and inform individualized precision health care in the future. DOI: 10.1097/MLR.0000000000001088 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 162 – Multiple Sklerose: Veröffentlichungen April 2019 236. Medicine (Baltimore). 2019 Apr;98(17):e15185. doi: 10.1097/MD.0000000000015185. Acute exacerbation of Hashimoto's thyroiditis in a patient treated with dimethyl fumarate for multiple sclerosis: A case report. Ciurleo R, Sessa E, Marino S, D'Aleo G, Bramanti P, Rifici C. INTRODUCTION: Dimethyl fumarate (DMF) has been recently approved for first-line monotherapy of Multiple Sclerosis (MS). Its effects are due to mechanism modulating the immune system and activating antioxidative and neuroprotective pathways. PATIENT CONCERNS: A 59-year-old female patient affected by chronic Hashimoto's thyroiditis (HT) from 10 years was diagnosed with relapsing remitting MS in 2013. She started therapy with DMF in November 2016. DIAGNOSIS: After 2 months of therapy with DMF, the results of thyroid function test were abnormal. Thyroid ultrasonography confirmed the diagnosis of acute exacerbation of HT. INTERVENTIONS: This condition led to discontinuation of DMF therapy. OUTCOME: Two months after the interruption of DMF therapy, the findings of thyroid function test were within normal limits. CONCLUSION: The association of MS with autoimmune thyroid diseases supports a common immune-mediated pathogenic mechanism. We assume that the acute exacerbation of HT in our MS patient is associated not with the immunomodulatory effect of DMF but rather with its antioxidative mechanism.Constant monitoring of thyroid hormone levels should be recommended especially if the MS patients in treatment with DMF are affected by concomitant autoimmune thyroid diseases. DOI: 10.1097/MD.0000000000015185 237. Medicine (Baltimore). 2019 Apr;98(17):e15047. doi: 10.1097/MD.0000000000015047. Functional connectivity in multiple sclerosis after robotic rehabilitative treatment: A case report. Bonanno L(1), Russo M(1), Bramanti A(2), Calabrò RS(1), Marino S(1). Author information: (1)Scientific Institute of medical Research (IRCCS) Centro Neurolesi Bonino-Pulejo. (2)Institute of Applied Science and Intelligent System "ISASI Eduardo Caianiello", National Research Council (CNR), Messina, Italy. RATIONALE: Multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system and it is associated with an impaired motor function status. The efficacy of rehabilitation in promoting functional recovery and increasing quality of life in MS patients has been demonstrated. PATIENT CONCERNS: A 47-year-old woman was diagnosed with relapsing-remitting multiple sclerosis (RRMS) in November 2014 because of left upper limb hypoesthesia and weakness with difficulty in hand manipulation skills (there was a 1-point Expanded Disability Status Scale (EDSS) progression, i.e., 2.5 vs 1.5). Magnetic resonance image (MRI) showed a new frontal right cortical high-signal-intensity lesion. DIAGNOSIS: Neurological and MRI examination were suggestive of MS diagnosis. INTERVENTIONS: Patient was treated with robotic rehabilitation and evaluated by a Glove Analyzer for fMRI system (GAF). Functional MRI (fMRI) was acquired before and at the end of rehabilitative treatment performed with robotic device (Armeo-power). OUTCOMES: At the end of the rehabilitation program, most of the behavioral parameters, GAF and fMRI evaluation, showed a significative improvement. Moreover, fMRI showed a significantly increased functional activation within the sensory-motor network in the active, motor task. LESSONS: Our findings suggest a possible restorative effect of robotics on brain networks. Moreover, we may argue that GAF may be a valuable tool in assessing functional recovery after upper limb rehabilitation, especially of associated to fMRI examination. DOI: 10.1097/MD.0000000000015047 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 163 – Multiple Sklerose: Veröffentlichungen April 2019 238. Mol Cell Neurosci. 2019 Apr 4. pii: S1044-7431(18)30368-3. doi: 10.1016/j.mcn.2019.04.001. [Epub ahead of print] An FTLD-associated SQSTM1 variant impacts Nrf2 and NF-κB signalling and is associated with reduced phosphorylation of p62. Foster A(1), Scott D(2), Layfield R(2), Rea SL(3). Author information: (1)Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Western Australia, Australia; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. (2)School of Life Sciences, University of Nottingham, Nottingham, United Kingdom. (3)Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Western Australia, Australia; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. Electronic address: [email protected]. Elevated oxidative stress has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). In response to oxidative stress, the Nrf2 transcription factor activates protective antioxidant genes. A critical regulator of Nrf2 is the inhibitory protein Keap1, which mediates Nrf2 degradation. In response to cellular stress an interaction between Keap1 and SQSTM1/p62 (p62), a signalling adaptor protein, allows for increased Nrf2 signalling as it escapes degradation. Mutations in SQSTM1 (encoding p62) are linked with ALS-FTLD. Previously, two ALS-FTLD-associated p62 mutant proteins within the Keap1 interacting region (KIR) of p62 were found to be associated with decreased Keap1- p62 binding and Nrf2 activation. Here we report that a non-KIR domain FTLD-associated variant of p62 (p.R110C), affecting a residue close to the N-terminal PB1 oligomerisation domain, also reduces Keap1-p62 binding in cellulo and thereby reduces Nrf2 activity in reporter assays. Further, we observed that expression of p.R110C increased NF-κB activation compared with wild type p62. Altered signalling appeared to be linked with reduced phosphorylation of p62 at Serine residues -349 and -403. Our results confirm that ALS- FTLD mutations affecting multiple domains of p62 result in a reduced stress response, suggesting that altered stress signalling may directly contribute to the pathology of some ALS-FTLD cases. Copyright © 2019. Published by Elsevier Inc. DOI: 10.1016/j.mcn.2019.04.001 239. Mol Genet Metab Rep. 2019 Apr 6;19:100470. doi: 10.1016/j.ymgmr.2019.100470. eCollection 2019 Jun. Influence of genetic copy number variants of the human GLUT3 glucose transporter gene SLC2A3 on protein expression, glycolysis and rheumatoid arthritis risk: A genetic replication study. Simpfendorfer KR(1)(2), Li W(1), Shih A(1), Wen H(1), Kothari HP(1), Einsidler EA(1), Wuster A(3), Hunkapiller J(3), Behrens TW(3), Graham RR(3), Townsend MJ(4), Behar DM(5), Hu R(5), Greenspan E(5), Gregersen PK(1)(2). Author information: (1)Robert S. Boas Center for Genomics and Human Genetics, the Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York, USA. (2)Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, USA. (3)Department of Human Genetics, Genentech Inc., 1 DNA Way, South San Francisco, California, USA. (4)Department of Biomarker Discovery OMNI, Genentech Inc., 1 DNA Way, South San Francisco, California, USA. (5)Gene by Gene, Genomic Research Center, Houston, TX, USA. Objectives: The gene encoding glucose transporter 3 (GLUT3, SLC2A3) is present in the human population at variable copy number. An overt disease phenotype of SLC2A3 copy number variants has not been reported; however, deletion of SLC2A3 has been previously reported to protect carriers from rheumatoid arthritis, implicating GLUT3 as a therapeutic target in rheumatoid arthritis. Here we aim to perform functional analysis of GLUT3 copy number variants in immune cells, and test the reported protective association of the GLUT3 copy number variants for rheumatoid arthritis in a genetic replication study. Methods: Cells from genotyped healthy controls were analyzed for SLC2A3/GLUT3 expression and glycolysis capacity. We genotyped the SLC2A3 copy number variant in four independent cohorts of rheumatoid arthritis and controls and one cohort of multiple sclerosis and controls. Results: Heterozygous deletion of SLC2A3 correlates directly with expression levels of GLUT3 and influences glycolysis rates in the human immune system. The frequency of the SLC2A3 copy number variant is not different between rheumatoid arthritis, multiple sclerosis and control groups. Conclusions: Despite a robust SLC2A3 gene copy number dependent phenotype, our study of large groups of rheumatoid arthritis cases and controls provides no evidence for rheumatoid arthritis disease protection in deletion carriers. These data emphasize the importance of well powered replication studies to confirm or refute genetic associations, particularly for relatively rare variants. DOI: 10.1016/j.ymgmr.2019.100470 PMCID: PMC6453668 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 164 – Multiple Sklerose: Veröffentlichungen April 2019 240. Mol Genet Metab Rep. 2019 Mar 23;19:100465. doi: 10.1016/j.ymgmr.2019.100465. eCollection 2019 Jun. Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing. van Rensburg SJ(1), Peeters AV(2), van Toorn R(3), Schoeman J(3), Moremi KE(1), van Heerden CJ(4), Kotze MJ(5). Author information: (1)Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. (2)Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. (3)Paediatric Medicine and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. (4)Central Analytical Facility (CAF), DNA Sequencing Unit, Stellenbosch University, Stellenbosch, South Africa. (5)Division of Chemical Pathology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, National Health Laboratory Service (NHLS), Cape Town, South Africa. Background: Multiple sclerosis is a disorder related to demyelination of axons. Iron is an essential cofactor in myelin synthesis. Previously, we described two children (males of mixed ancestry) with relapsing-remitting multiple sclerosis (RRMS) where long-term remission was achieved by regular iron supplementation. A genetic defect in iron metabolism was postulated, suggesting that more advanced genetic studies could shed new light on disease pathophysiology related to iron. Methods: Whole exome sequencing (WES) was performed to identify causal pathways. Blood tests were performed over a 10 year period to monitor the long-term effect of a supplementation regimen. Clinical wellbeing was assessed quarterly by a pediatric neurologist and regular feedback was obtained from the schoolteachers. Results: WES revealed gene variants involved in iron absorption and transport, in the transmembrane protease, serine 6 (TMPRSS6) and transferrin (TF) genes; multiple genetic variants in CUBN, which encodes cubilin (a receptor involved in the absorption of vitamin B12 as well as the reabsorption of transferrin-bound iron and vitamin D in the kidneys); SLC25A37 (involved in iron transport into mitochondria) and CD163 (a scavenger receptor involved in hemorrhage resolution). Variants were also found in COQ3, involved with synthesis of Coenzyme Q10 in mitochondria. Neither of the children had the HLA-DRB1*1501 allele associated with increased genetic risk for MS, suggesting that the genetic contribution of iron-related genetic variants may be instrumental in childhood MS. In both children the RRMS has remained stable without activity over the last 10 years since initiation of nutritional supplementation and maintenance of normal iron levels, confirming the role of iron deficiency in disease pathogenesis in these patients. Conclusion: Our findings highlight the potential value of WES to identify heritable risk factors that could affect the reabsorption of transferrin-bound iron in the kidneys causing sustained iron loss, together with inhibition of vitamin B12 absorption and vitamin D reabsorption (CUBN) and iron transport into mitochondria (SLC25A37) as the sole site of heme synthesis. This supports a model for RRMS in children with an apparent iron-deficient biochemical subtype of MS, with oligodendrocyte cell death and impaired myelination possibly caused by deficits of energy- and antioxidant capacity in mitochondria. DOI: 10.1016/j.ymgmr.2019.100465 PMCID: PMC6434495 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 165 – Multiple Sklerose: Veröffentlichungen April 2019 241. Mol Immunol. 2019 Apr 5;111:32-42. doi: 10.1016/j.molimm.2019.03.015. [Epub ahead of print] PI3K activity in dendritic cells exerts paradoxical effects during autoimmune inflammation. Datler H(1), Vogel A(2), Kerndl M(2), Baumgartinger C(1), Musiejovsky L(1), Makivic N(1), Frech S(1), Niederreiter B(3), Haider T(4), Pühringer M(1), Brunner JS(2), Sharif O(5), Schabbauer G(6). Author information: (1)Institute for Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria. (2)Institute for Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism for Rheumatoid Arthritis and Thrombosis Research, Vienna, Austria. (3)Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. (4)Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria. (5)Institute for Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism for Rheumatoid Arthritis and Thrombosis Research, Vienna, Austria. Electronic address: [email protected]. (6)Institute for Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism for Rheumatoid Arthritis and Thrombosis Research, Vienna, Austria. Electronic address: [email protected]. The peripheral activation of autoreactive T cells and subsequent central nervous system (CNS) immune cell infiltration are key events relevant for experimental autoimmune encephalomyelitis (EAE), a commonly employed multiple sclerosis (MS) model, influenced by TH1 and TH17 mediated immunity. The phosphoinositide-3-kinase (PI3K)-AKT kinase pathway modulates outcome during EAE, with direct actions of PI3K on adaptive immunity implicated in deleterious and effects on antigen presenting cells involved in beneficial responses during EAE. Here, by genetically deleting the regulatory subunit of Class Ia PI3K, p85α, in selective myeloid cells, we aimed to resolve the impact of PI3K in EAE. While genetically deleting PI3K in LysM expressing cells exerted unremarkable effects, attenuating PI3K function in CD11c+ dendritic cells (DCs), promoted secretion of pathogenic EAE promoting cytokines, particularly skewing TH1 and TH17 immunity, while notably, improving health in EAE. Neutralizing IFN-γ activity using blocking antibodies revealed a prolonged TH1 response was critical for the decreased disease of these animals. Thus, PI3K- AKT signaling in DCs acts in a paradoxical manner. While attenuating EAE associated TH1 and TH17 responses, it impairs health during autoimmune inflammation. Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved. DOI: 10.1016/j.molimm.2019.03.015 242. Motor Control. 2019 Apr 15:1-20. doi: 10.1123/mc.2018-0044. [Epub ahead of print] Brain Activation Changes During Balance- and Attention-Demanding Tasks in Middle- and Older-Aged Adults With Multiple Sclerosis. Hernandez ME(1), O'Donnell E(1), Chaparro G(1), Holtzer R(2), Izzetoglu M(3), Sandroff BM(4), Motl RW(4). Author information: (1)1 University of Illinois at Urbana-Champaign. (2)2 Yeshiva University. (3)3 Villanova University. (4)4 The University of Alabama at Birmingham. Functional near-infrared spectroscopy was used to evaluate prefrontal cortex activation differences between older adults with multiple sclerosis (MS) and healthy older adults (HOA) during the performance of a balance- and attention-demanding motor task. Ten older adults with MS and 12 HOA underwent functional near-infrared spectroscopy recording while talking, virtual beam walking, or virtual beam walking while talking on a self-paced treadmill. The MS group demonstrated smaller increases in prefrontal cortex oxygenation levels than HOA during virtual beam walking while talking than talking tasks. These findings indicate a decreased ability to allocate additional attentional resources in challenging walking conditions among MS compared with HOA. This study is the first to investigate brain activation dynamics during the performance of balance- and attention-demanding motor tasks in persons with MS. DOI: 10.1123/mc.2018-0044 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 166 – Multiple Sklerose: Veröffentlichungen April 2019 243. Mult Scler. 2019 Apr 9:1352458519832259. doi: 10.1177/1352458519832259. [Epub ahead of print] Immune profiling of a patient with alemtuzumab-associated progressive multifocal leukoencephalopathy. Gerevini S(1), Capra R(2), Bertoli D(3), Sottini A(4), Imberti L(4). Author information: (1)Department of Neuroradiology, IRCCS San Raffaele Hospital, Milan, Italy. (2)Multiple Sclerosis Center, ASST Spedali Civili di Brescia, Brescia, Italy. (3)Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy/Centro di Ricerca Emato-oncologica AIL (CREA), Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy. (4)Centro di Ricerca Emato-oncologica AIL (CREA), Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy. A 31-year-old woman affected by multiple sclerosis (MS) experienced generalized tonic-clonic seizures 2 months after the second alemtuzumab cycle. Positive JC virus (JCV)-DNA in cerebrospinal fluid (CSF) and lesion iconography at magnetic resonance imaging (MRI) were suggestive of progressive multifocal leukoencephalopathy (PML). After 1 month, during full-blown immune reconstitution inflammatory syndrome, JCV-DNA became negative and symptoms gradually improved. New T- and B-cell output and T- and B-cell diversity were low and lymphocytes poorly responded to stimulation. This is the first case of an alemtuzumab-treated patient with clinical symptoms and radiological features compatible with PML. The lack of large T- and B-cell diversity, necessary for JCV recognition, is likely to have concurred to PML insurgence. DOI: 10.1177/1352458519832259 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 167 – Multiple Sklerose: Veröffentlichungen April 2019 244. Mult Scler. 2019 Apr 8:1352458519841810. doi: 10.1177/1352458519841810. [Epub ahead of print] Magnetisation transfer ratio abnormalities in primary and secondary progressive multiple sclerosis. Brown JWL(1), Chowdhury A(2), Kanber B(3), Prados Carrasco F(4), Eshaghi A(2), Sudre CH(5), Pardini M(6), Samson RS(2), van de Pavert SH(2), Wheeler-Kingshott CG(7), Chard DT(8). Author information: (1)NMR Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, UK/Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. (2)NMR Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, UK. (3)NMR Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, UK/Centre for Medical Image Computing (CMIC), Department of Medical Physics and Biomedical Engineering, University College London, UK/National Institute for Health Research (NIHR) Biomedical Research Centre, University College London Hospitals (UCLH), London, UK/Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, UK. (4)NMR Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, UK/Centre for Medical Image Computing (CMIC), Department of Medical Physics and Biomedical Engineering, University College London, UK/eHealth Center, Universitat Oberta de Catalunya, Barcelona, Spain. (5)Centre for Medical Image Computing (CMIC), Department of Medical Physics and Biomedical Engineering, University College London, UK/Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK/School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK. (6)NMR Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, UK/Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, and IRCCS AOU San Martino- IST, Genoa, Italy. (7)NMR Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, UK/Brain MRI 3T Mondino Research Center, IRCCS Mondino Foundation, Pavia, Italy/Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. (8)NMR Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, UK/National Institute for Health Research (NIHR) Biomedical Research Centre, University College London Hospitals (UCLH), London, UK. BACKGROUND: In relapse-onset multiple sclerosis (MS), tissue abnormality - as assessed with magnetisation transfer ratio (MTR) imaging - is greater in the outer cortical and inner periventricular layers. The cause of this remains unknown but meningeal inflammation has been implicated, particularly lymphoid follicles, which are seen in secondary progressive (SP) but not primary progressive (PP) MS. Cortical and periventricular MTR gradients might, therefore, differ in PPMS and SPMS if these follicles are responsible. OBJECTIVE: We assessed cortical and periventricular MTR gradients in PPMS, and compared gradients between people with PPMS and SPMS. METHODS: Using an optimised processing pipeline, periventricular normal-appearing white matter and cortical grey-matter MTR gradients were compared between 51 healthy controls and 63 people with progressive MS (28 PPMS, 35 SPMS). RESULTS: The periventricular gradient was significantly shallower in healthy controls (0.122 percentage units (pu)/band) compared to PPMS (0.952 pu/band, p < 0.0001) and SPMS (1.360 pu/band, p < 0.0001). The cortical gradient was also significantly shallower in healthy controls (-2.860 pu/band) compared to PPMS (-3.214 pu/band, p = 0.038) and SPMS (- 3.328 pu/band, p = 0.016). CONCLUSION: Abnormal periventricular and cortical MTR gradients occur in both PPMS and SPMS, suggesting comparable underlying pathological processes. DOI: 10.1177/1352458519841810 245. Mult Scler. 2019 Apr 4:1352458519841505. doi: 10.1177/1352458519841505. [Epub ahead of print] Are children with multiple sclerosis really "old" adults. Banwell B(1). Author information: (1)Chief of Child Neurology, Children's Hospital of Philadelphia Professor of Neurology and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. DOI: 10.1177/1352458519841505 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 168 – Multiple Sklerose: Veröffentlichungen April 2019 246. Mult Scler. 2019 Apr 4:1352458519829698. doi: 10.1177/1352458519829698. [Epub ahead of print] Childhood multiple sclerosis is associated with reduced brain volumes at first clinical presentation and brain growth failure. Bartels F(1), Nobis K(2), Cooper G(3), Wendel E(4), Cleaveland R(2), Bajer-Kornek B(5), Blaschek A(6), Schimmel M(7), Blankenburg M(8), Baumann M(9), Karenfort M(10), Finke C(1), Rostásy K(2). Author information: (1)Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany/ Berlin School of Mind and Brain, Humboldt-Universität zu Berlin, Berlin, Germany. (2)Department of Paediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln, Germany. (3)Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany. (4)Department of Paediatric Neurology, Olgahospital, Stuttgart, Germany. (5)Department of Neurology, Medical University of Vienna, Vienna, Austria. (6)Department of Paediatric Neurology and Developmental Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany. (7)Department of Paediatric Neurology, Children's Hospital Augsburg, Augsburg, Germany. (8)Department of Paediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln, Germany/ Department of Paediatric Neurology, Olgahospital, Stuttgart, Germany. (9)Division of Paediatric Neurology, Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria. (10)Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany. BACKGROUND:: Paediatric multiple sclerosis (pedMS) patients at a single site were shown to have reduced brain volumes and failure of age-expected brain growth compared to healthy controls. However, the precise time of onset of brain volume loss remains unclear. OBJECTIVE:: To longitudinally study brain volumes in a multi-centre European cohort at first presentation and after 2 years. METHODS:: Brain volumes of high- resolution magnetic resonance imaging (MRI) data from 37 pedMS patients at first presentation prior to steroid therapy and at 2-year follow-up ( n = 21) were compared to matched longitudinal MRI data from the NIH Paediatric MRI Data Repository. RESULTS:: Patients showed significantly reduced whole brain, grey and white matter and increased ventricular volumes at initial presentation and at follow-up compared to controls. Over 2 years, patients exhibited significant reduction of whole brain and white matter volumes, accompanied by increased ventricular volume. Brain volume loss at follow-up correlated with a higher number of infratentorial lesions, relapses and an increased Expanded Disability Status Scale (EDSS) score. CONCLUSIONS:: In pedMS patients, brain volume loss is present already at first clinical presentation and accelerated over 2 years. Increased disease activity is associated with more severe brain volume loss. MRI brain volume change might serve as an outcome parameter in future prospective pedMS studies. DOI: 10.1177/1352458519829698 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 169 – Multiple Sklerose: Veröffentlichungen April 2019 247. Mult Scler. 2019 Apr 15:1352458519841829. doi: 10.1177/1352458519841829. [Epub ahead of print] Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis. Phelps R(1), Winston JA(2), Wynn D(3), Habek M(4), Hartung HP(5), Havrdová EK(6), Markowitz GS(7), Margolin DH(8), Rodriguez CE(9), Baker DP(10), Coles AJ(11). Author information: (1)Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK. (2)Mount Sinai School of Medicine, New York, NY, USA. (3)Consultants in Neurology MS Center, Northbrook, IL, USA. (4)Department of Neurology, School of Medicine, University of Zagreb and University Hospital Center, Zagreb, Croatia. (5)Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany. (6)Department of Neurology, First Medical Faculty, Charles University, Prague, Czech Republic. (7)Department of Pathology and Cell Biology, Columbia University, New York, NY, USA. (8)Sanofi, Cambridge, MA, USA/Cerevance Inc., Boston, MA, USA. (9)Sanofi, Cambridge, MA, USA/Sunovion Pharmaceuticals, Marlborough, MA, USA. (10)Sanofi, Cambridge, MA, USA. (11)School of Medicine, University of Cambridge, Cambridge, UK. BACKGROUND: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. OBJECTIVE: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. METHODS: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. RESULTS: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti- glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. CONCLUSION: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely. DOI: 10.1177/1352458519841829 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 170 – Multiple Sklerose: Veröffentlichungen April 2019 248. Mult Scler. 2019 Apr 11:1352458519843048. doi: 10.1177/1352458519843048. [Epub ahead of print] Evidence of diffuse cerebellar neuroinflammation in multiple sclerosis by 11C- PBR28 MR-PET. Barletta VT(1), Herranz E(1), Treaba CA(1), Ouellette R(2), Mehndiratta A(3), Loggia M(1), Klawiter EC(4), Ionete C(5), Jacob SA(6), Mainero C(1). Author information: (1)Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA/Harvard Medical School, Boston, MA, USA. (2)Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA/Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. (3)Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA. (4)Department of Neurology, Massachusetts General Hospital, Boston, MA, USA/Harvard Medical School, Boston, MA, USA. (5)Multiple Sclerosis Center, UMass Memorial Medical Center, Worcester, MA, USA. (6)Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA/Harvard Medical School, Boston, MA, USA. BACKGROUND: Activated microglia, which can be detected in vivo by 11C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. OBJECTIVES: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures. METHODS: Twenty- eight MS patients and 16 healthy controls underwent 11C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11C-PBR28 binding was assessed in regions of interest using 60-90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores. RESULTS: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability. CONCLUSION: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment. DOI: 10.1177/1352458519843048 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 171 – Multiple Sklerose: Veröffentlichungen April 2019 249. Mult Scler. 2019 Apr 10:1352458519843055. doi: 10.1177/1352458519843055. [Epub ahead of print] Pregnancy outcomes in patients with multiple sclerosis treated with teriflunomide: Clinical study data and 5 years of post-marketing experience. Vukusic S(1), Coyle PK(2), Jurgensen S(3), Truffinet P(4), Benamor M(4), Afsar S(3), Purvis A(3), Poole EM(3), Chambers C(5). Author information: (1)Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro- inflammation, Hôpital Neurologique Pierre Wertheimer, Centre Hospitalo-Universitaire de Lyon (Hospices Civils de Lyon), Bron, France/Observatoire Français de la Sclérose en Plaques, Centre des Neurosciences de Lyon, INSERM 1028 et CNRS UMR5292, Lyon, France/Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France. (2)Comprehensive Care Center, School of Medicine, Stony Brook University, Stony Brook, NY, USA. (3)Sanofi, Cambridge, MA, USA. (4)Sanofi, Chilly-Mazarin, France. (5)Department of Pediatrics, Rady Children's Hospital and University of California San Diego, La Jolla, CA, USA. BACKGROUND: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception. OBJECTIVES: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting. METHODS: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017). RESULTS: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports. CONCLUSIONS: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies. DOI: 10.1177/1352458519843055 250. Mult Scler. 2019 Apr 1:1352458519840746. doi: 10.1177/1352458519840746. [Epub ahead of print] MOG-related disorders: A new cause of imaging-negative myelitis? Macaron G(1), Ontaneda D(1). Author information: (1)Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. Knowledge on the clinical and radiological phenotype of myelin oligodendrocyte glycoprotein (MOG)-related disorders has been growing. We report the case of a patient who presented with subacute onset myelitis after an upper respiratory tract infection with normal cord imaging at onset and follow-up after 4 months (absence of lesions and atrophy), high-titer positive MOG-IgG, and a broad workup excluding other etiologies. The full clinical and radiological spectrum of MOG-related disorders is yet to be completely understood. Testing for MOG-IgG using cell-based assays should be considered in imaging-negative myelitis particularly if initial testing is non-revealing. DOI: 10.1177/1352458519840746 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 172 – Multiple Sklerose: Veröffentlichungen April 2019 251. Mult Scler Int. 2019 Mar 21;2019:2027947. doi: 10.1155/2019/2027947. eCollection 2019. Occupational Therapy in Fatigue Management in Multiple Sclerosis: An Umbrella Review. Angela S(1), Tullia SD(1), Giorgia F(1), Valter S(1), Teresa P(1). Author information: (1)Complex Unit of Physical Medicine and Rehabilitation, Policlinico Umberto I Hospital, Sapienza University of Rome, Italy. Background. Fatigue is one of the most invalidant symptoms of Multiple Sclerosis (MS) that negatively affects occupational and work performance and social participation. Occupational therapy (OT) assessment and treatment of impairments related to fatigue can have a significant and positive impact on the quality of life. Methods. An umbrella review has been carried out to provide rehabilitative decision makers in healthcare with insight into the role of OT in fatigue management in Multiple Sclerosis. The question is, what type of treatment provided by occupational therapist is more effective in reducing fatigue in Multiple Sclerosis? A search of literature published until June 2018 was undertaken by three independent reviewers using PubMed, PEDro, and Cochrane Library database including systematic reviews and meta-analyses of the last 10 years. Results. 10 studies were selected (5 systematic reviews, 1 meta-analysis, 3 reviews, and 1 guideline). Conclusions. Fatigue management programs have moderate evidence; other strategies such as OT strategies and telerehabilitation show low evidence. DOI: 10.1155/2019/2027947 PMCID: PMC6448334 252. Mult Scler J Exp Transl Clin. 2019 Apr 16;5(2):2055217319843673. doi: 10.1177/2055217319843673. eCollection 2019 Apr-Jun. Predictors of hospital-based multidisciplinary rehabilitation effects in persons with multiple sclerosis: a large-scale, single-centre study. Groppo E(1), Signori A(2), Sormani MP(2), Grosso C(1), Mantia L(1), Cattaneo D(3), Rovaris M(1). Author information: (1)Multiple Sclerosis Center and Neurorehabilitation Unit, IRCCS Fondazione Don Gnocchi, Italy. (2)Department of Health Sciences (DISSAL), University of Genoa, Italy. (3)LaRICE Research Laboratory, IRCCS Fondazione Don Gnocchi, Italy. Background: Persons with multiple sclerosis may benefit from hospital-based multidisciplinary rehabilitation. Objectives: To investigate the effects of hospital-based multidisciplinary rehabilitation and to identify their potential predictors in a large sample of persons with multiple sclerosis. Methods: From the charts of 655 persons with multiple sclerosis consecutively admitted to our unit, disease profiles, modified Barthel index, Expanded Disability Status Scale (EDSS), pain numerical rating score and type of interventions were retrospectively collected. We defined an improvement at discharge as follows: modified Barthel index increase of at least 5 points, EDSS decrease of 1.0 if baseline score was 5.5 or less and of 0.5 if baseline score was greater than 5.5; any numerical rating score decrease. Results: After a median admission period of 36 days, at discharge 65%, 22% and 89% of persons with multiple sclerosis improved for modified Barthel index, EDSS and numerical rating score, respectively. The modified Barthel index improvement was associated with shorter disease duration, lower EDSS at baseline and with access to psychological counselling. EDSS improvement was associated with shorter disease duration, relapsing-remitting course, female gender and longer duration of the admission period. Conclusions: Inpatient multidisciplinary rehabilitation was associated with improved autonomy in activities of daily living in a relevant proportion of persons with multiple sclerosis. The effect seems to be more evident in individuals with shorter multiple sclerosis duration and relapsing-remitting disease course. DOI: 10.1177/2055217319843673 PMCID: PMC6469285 253. Mult Scler Relat Disord. 2019 May;30:A1. doi: 10.1016/j.msard.2019.03.023. Three suggestions to decrease the financial burden of MS treatments. Waubant E, Giovannoni G, Hawkes C, Lechner-Scott J, Levy M. DOI: 10.1016/j.msard.2019.03.023 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 173 – Multiple Sklerose: Veröffentlichungen April 2019 254. Mult Scler Relat Disord. 2019 May;30:293. doi: 10.1016/j.msard.2019.03.013. Epub 2019 Mar 26. Corrigendum to "Changes in patient-reported outcomes between continuers and discontinuers of disease modifying therapy in patients with multiple sclerosis over age 60" [Multiple Sclerosis and Related Disorders 30 (2019) 252-256]. Hua LH(1), Harris H(2), Conway D(3), Thompson NR(4). Author information: (1)Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA. Electronic address: [email protected]. (2)Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA. (3)Cleveland Clinic Mellen Center for Multiple Sclerosis, Cleveland, OH, USA. (4)Cleveland Clinic Department of Quantitative Health Sciences, Cleveland, OH, USA. Erratum for Mult Scler Relat Disord. 2019 May;30:252-256. DOI: 10.1016/j.msard.2019.03.013 255. Mult Scler Relat Disord. 2019 May;30:292. doi: 10.1016/j.msard.2019.03.010. Epub 2019 Mar 20. Corrigendum to: "A case of Takotsubo syndrome during a multiple sclerosis brainstem relapse" [Mult. Scler. Relat. Disord. 24 (2018) 1-2]. Prestipino E(1), Squitieri M(1), Razzolini L(2), Pastò L(1), Forleo P(1), Amato MP(3). Author information: (1)University of Florence, NUEROFARBA Department, Neuroscience section, Viale Pieraccini 6, 50139, Florence, Italy. (2)University of Florence, NUEROFARBA Department, Neuroscience section, Viale Pieraccini 6, 50139, Florence, Italy. Electronic address: [email protected]. (3)University of Florence, NUEROFARBA Department, Neuroscience section, Viale Pieraccini 6, 50139, Florence, Italy; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy. Erratum for Mult Scler Relat Disord. 2018 Aug;24:1-2. DOI: 10.1016/j.msard.2019.03.010 256. Mult Scler Relat Disord. 2019 May;30:291. doi: 10.1016/j.msard.2019.02.024. Epub 2019 Mar 23. Corrigendum to "Foxp3+ regulatory T cells expression in Neuromyelitis optica spectrum disorders" [Multiple Sclerosis and Related Disorders 30 (2019) 114-118]. Brill L(1), Lavon I(2), Vaknin-Dembinsky A(3). Author information: (1)Department of Neurology and the Multiple Sclerosis Center, the Agnes-Ginges Center for Neurogenetics, Hadassah- Medical Center, Hebrew University, Ein Karem, P.O.B.12000, Jerusalem 91120, Israel. (2)Department of Neurology and the Multiple Sclerosis Center, the Agnes-Ginges Center for Neurogenetics, Hadassah- Medical Center, Hebrew University, Ein Karem, P.O.B.12000, Jerusalem 91120, Israel; Leslie and Michael Center for Neuro-oncology, Hadassah- Medical Center, Jerusalem, Israel. (3)Department of Neurology and the Multiple Sclerosis Center, the Agnes-Ginges Center for Neurogenetics, Hadassah- Medical Center, Hebrew University, Ein Karem, P.O.B.12000, Jerusalem 91120, Israel. Electronic address: [email protected]. Erratum for Mult Scler Relat Disord. 2019 May;30:114-118. DOI: 10.1016/j.msard.2019.02.024 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 174 – Multiple Sklerose: Veröffentlichungen April 2019 257. Mult Scler Relat Disord. 2019 Mar 30;31:157-164. doi: 10.1016/j.msard.2019.03.022. [Epub ahead of print] Teriflunomide real-world evidence: Global differences in the phase 4 Teri-PRO study. Coyle PK(1), Khatri B(2), Edwards KR(3), Meca-Lallana JE(4), Cavalier S(5), Rufi P(6), Benamor M(7), Poole EM(8), Robinson M(9), Gold R(10). Author information: (1)Stony Brook University Medical Center, Department of Neurology, HSC T12-020, SUNY at Stony Brook, Stony Brook, NY 11794-8121, USA. Electronic address: [email protected]. (2)The Regional MS Center, Center for Neurological Disorders at Wheaton Franciscan Healthcare, Milwaukee, WI 3237, USA. Electronic address: [email protected]. (3)MS Center of Northeastern New York, 1182 Troy-Schenectady Road, Suite 203, Latham, NY 12110, USA. Electronic address: [email protected]. (4)National Multiple Sclerosis Reference Center (CSUR), Hospital Virgen de la Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120, Murcia, Spain; Clinical Neuroimmunology and Multiple Sclerosis Cathedra. UCAM. Universidad Católica San Antonio. Campus de los Jerónimos, Guadalupe, Murcia 30107, Spain. Electronic address: [email protected]. (5)Sanofi, 50 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected]. (6)Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin 91385, France. Electronic address: [email protected]. (7)Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin 91385, France. Electronic address: [email protected]. (8)Sanofi, 50 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected]. (9)Sanofi, 55 Corporate Drive, Bridgewater, NJ 08807, USA. Electronic address: [email protected]. (10)St. Josef-Hospital, Ruhr University Bochum, Gudrunstrasse 56, Bochum D-44791, Germany. Electronic address: Ralf.Gold@ruhr-uni- bochum.de. BACKGROUND: The demographics and management of patients with multiple sclerosis (MS) differ across geographical regions, but it is unclear whether/how these differences affect treatment outcomes. The aim of this post-hoc analysis was to assess teriflunomide use and patient-reported outcomes in the United States (US) and the rest of the world (ROW) in the phase 4 Teri-PRO study (NCT01895335). METHODS: In the phase 4, real-world, Teri-PRO study, patients with relapsing forms of MS received teriflunomide for 48 weeks according to local labeling. The primary endpoint was treatment satisfaction measured using the Treatment Satisfaction Questionnaire for Medication Version 1.4 (TSQM 1.4). Secondary endpoints included scores on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Performance Scale (MSPS), and Patient- Determined Disease Steps (PDDS), and occurrence of adverse events. Primary and secondary endpoints were assessed at baseline and Week 48. An exploratory subgroup analysis assessed PROs in the black patient population. RESULTS: The US and ROW groups included 545 and 455 patients, respectively. The mean age of patients in the ROW group was lower, they had a shorter mean time since first symptoms of MS, and had lower mean EDSS scores at baseline, compared with the US group (all p < 0.0001). Black patients made up 9% of US patients vs 0.2% of ROW patients. TSQM global satisfaction scores and effectiveness, side effects, and convenience subscale scores were significantly improved from baseline to Week 48 (all p < 0.0001). Disability measures were stable from baseline to Week 48 for both groups, despite different baseline level scores between the two groups. The overall proportion of patients who experienced an AE was similar across both groups. Fewer patients in the US group vs the ROW group reported hair thinning (16.1% vs 31.2%). Black patients showed comparable baseline demographics and disease characteristics and similar change over time in PROs compared with the overall US group. CONCLUSION: Patient differences observed at baseline between the US and ROW groups suggest variation in teriflunomide prescribing practices in the real-world Teri-PRO study. Improvement in treatment satisfaction and stability of disability measures were comparable between patients in the US and ROW. This suggests that teriflunomide was effective despite differences in baseline demographics and possible cultural and management differences between these geographical regions. Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2019.03.022 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 175 – Multiple Sklerose: Veröffentlichungen April 2019 258. Mult Scler Relat Disord. 2019 Mar 30;31:101-105. doi: 10.1016/j.msard.2019.03.020. [Epub ahead of print] Resting-state functional connectivity networks associated with fatigue in multiple sclerosis with early age onset. Stefancin P(1), Govindarajan ST(1), Krupp L(1), Charvet L(1), Duong TQ(2). Author information: (1)Departments of Radiology, Stony Brook Medicine, Stony Brook, NY 11794, United States; Department of Neurology, New York University School of Medicine, New York, NY, United States. (2)Departments of Radiology, Stony Brook Medicine, Stony Brook, NY 11794, United States; Department of Neurology, New York University School of Medicine, New York, NY, United States. Electronic address: [email protected]. BACKGROUND: Fatigue is one of the most commonly experienced symptoms in multiple sclerosis (MS). The neural correlates of fatigue in MS, in general and specifically in early onset, remain poorly understood. This study employed resting-state fMRI (rsfMRI) to investigate the functional connectivity of fatigue in MS patients with early age onset. METHODS: Twenty-seven relapsing-remitting MS patients (20 ± 7yo at the age of diagnosis and 26.0 ± 5.5yo at the time of study) were recruited and 22 patients were studied. Structural and rsfMRI sequences were performed on a 3-Tesla Seimens MRI scanner. Seed-based analysis was performed using CONN Functional Connectivity Toolbox for Statistic Parametric Mapping. The Fatigue Severity Scale (FSS) and the Modified Fatigue Impact scale (MFIS) as well as EDSS, Beck Depression Inventory, and symptomatology were measured. Non-fatigued (N = 12) and fatigued patients (N = 10) were separated based on FSS scores, with a score of 5 or greater being classified as fatigued. Group differences in rsfMRI between non-fatigued and fatigued patients were analyzed. Correlations between these functional connectivity differences and behavioral fatigue scores were also analyzed. RESULTS: Ages, disease duration, lesion load, lesion volume, and neurologic disability were not significantly different between non- fatigued and fatigued patients (p > 0.05). Fatigued patients showed significantly stronger connectivity between the right thalamus and right precentral gyrus (T = 4.58, p = 0.015), and a trending increase in connectivity between the left hippocampus and left precentral gyrus (T = 7.55, p = 0.051). Patients with fatigue showed significantly reduced connectivity between the right thalamus and left parietal operculum (T= -4.28, p = 0.0002), left thalamus and right superior frontal gyrus (T=-5.54, p = 0.046), and between the left insula and posterior cingulate (T=-9.4, p = 0.003). The connectivity between the left insula and posterior cingulate was significantly correlated with the cognitive score of MFIS (R2 = -0.471, p = 0.027) and FSS (R2 = -0.719, p = 0.0001). The connectivity between the right thalamus and left parietal operculum was significantly correlated with MFIS cognitive scores (R2 = -0.431, p = 0.045) and with FSS scores (R2 = 0.402, p = 0.006). Correlations remained significant after accounting for depression scores. CONCLUSIONS: rsfMRI identified Alterations in two distinct connections (the connectivity between insula and posterior cingulate gyrus and between the right thalamus and right precentral gyrus) that differed between fatigued and non- fatigued patients, as well as correlated with cognitive fatigue severity. These findings suggest that disruption of sensorimotor, high-order motor, and non-motor executive function likely contributes to the neural mechanism of fatigue in MS. Knowledge of the neural mechanisms of underlying MS fatigue could inform more effective treatment strategies. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.03.020 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 176 – Multiple Sklerose: Veröffentlichungen April 2019 259. Mult Scler Relat Disord. 2019 Mar 29;31:74-81. doi: 10.1016/j.msard.2019.03.021. [Epub ahead of print] Characterization of gray-matter multiple sclerosis lesions using double inversion recovery, diffusion, contrast-enhanced, and volumetric MRI. Parra Corral MA(1), Govindarajan ST(2), Stefancin P(2), Bangiyev L(2), Coyle PK(2), Duong TQ(3). Author information: (1)Departments of Radiology and Neurology, Stony Brook University Hospital 101 Nicolls Rd, Stony Brook Medicine, Stony Brook, New York, 11794, USA. Electronic address: maria.parra- [email protected]. (2)Departments of Radiology and Neurology, Stony Brook University Hospital 101 Nicolls Rd, Stony Brook Medicine, Stony Brook, New York, 11794, USA. (3)Departments of Radiology and Neurology, Stony Brook University Hospital 101 Nicolls Rd, Stony Brook Medicine, Stony Brook, New York, 11794, USA. Electronic address: [email protected]. PURPOSE: To investigate gray-matter (GM) lesions in relapsing-remitting multiple sclerosis (MS) using double-inversion recovery (DIR) MRI, determine GM lesions prevalence, spatial distribution and characterize their contrast-enhancement, diffusion characteristics and compare them to white-matter (WM) lesions. This is the first study, to our knowledge, to investigate GM MS lesions using double-inversion recovery MRI, to determine GM lesion prevalence and location, and characterize contrast-enhancement and diffusion characteristics, compared to WM lesion characteristics in the same patients. We also correlated GM lesion counts, volume and apparent diffusion coefficient (ADC) with total brain, WM, and GM volumes, as well as 25-foot walk test as a clinical disability. MATERIALS AND METHODS: This retrospective study included 44 relapsing-remitting MS patients (12M/32F, 41 ± 13 years) and 24 age-matched healthy controls (14M/10F, 36 ± 13 years). Lesions were segmented based on DIR and grouped into GM, subcortical WM, and periventricular WM lesions. ADC was tabulated for contrast-enhancing and non-enhancing lesions. Unpaired two sample t-tests were used for comparison between groups. Linear regression was used to evaluate the relationship between number of GM lesions, number of total lesions, total GM lesion volume, and total WM lesion volume with brain volumes and clinical data. RESULTS: GM MS lesions were present in the majority (86.4%, 38/44) of RRMS patients based on DIR, suggesting GM damage plays an important role in MS pathogenesis. The majority of the GM lesions were located in the frontal lobe. The percentage of lesions in GM that were contrast-enhanced was similar to those in WM, suggesting that blood-brain barrier integrity is likely affected similarly in GM and WM. Contrast-enhanced GM lesions showed higher ADC. GM lesion count and volume were correlated with global and regional brain atrophy, and with more severe disability group. CONCLUSION: This study characterized GM MS lesions using double-inversion recovery, contrast- enhanced and diffusion MRI. Understanding GM lesion pathophysiology using MRI in vivo, may prove useful for improving targeted therapy and monitoring disease progression. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2019.03.021 260. Mult Scler Relat Disord. 2019 Mar 28;31:72-73. doi: 10.1016/j.msard.2019.03.019. [Epub ahead of print] Seeing function in structure: "incidental" eye findings on OCT in a patient with multiple sclerosis. Conger D(1), Beh SC(2). Author information: (1)Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas TX 75390, United States. (2)Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas TX 75390, United States. Electronic address: [email protected]. A 17-year-old girl with relapsing-remitting multiple sclerosis (MS) was referred for a 2-year history of visual blurriness. Her bedside examination was remarkable for gait unsteadiness only. Optical coherence tomography was performed as part of her workup. Unexpectedly, Spectralis© video imaging revealed left torsional nystagmus that was not apparent on bedside examination. Review of previous brain magnetic resonance images (MRI) revealed left ocular deviation, as well as a left dorsolateral medullary MS plaque, which was the cause of her torsional nystagmus. We highlight how Spectralis© scanning confocal laser ophthalmoscopy allows video imaging that can capture torsional ocular movements. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.03.019 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 177 – Multiple Sklerose: Veröffentlichungen April 2019 261. Mult Scler Relat Disord. 2019 Mar 26;31:65-71. doi: 10.1016/j.msard.2019.03.017. [Epub ahead of print] Evaluation of natalizumab pharmacokinetics and pharmacodynamics with standard and extended interval dosing. Foley JF(1), Goelz S(2), Hoyt T(3), Christensen A(3), Metzger RR(3). Author information: (1)Rocky Mountain MS Research Group, Salt Lake City, UT, USA. Electronic address: [email protected]. (2)Oregon Health and Science University, Department of Neurology, Portland, OR, USA. (3)Rocky Mountain MS Research Group, Salt Lake City, UT, USA. BACKGOUND: Natalizumab (NTZ) is a highly efficacious therapeutic for multiple sclerosis (MS), but treatment is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). Extended interval dosing (EID) of NTZ has been proposed as an alternative dosing strategy to reduce PML risk. Pharmacokinetic (PK) and pharmacodynamic (PD) profiles of standard interval dosing (SID) and EID under real-world circumstances remain poorly characterized. OBJECTIVE: To evaluate PK and PD parameters of NTZ for SID and EID in the context of patient and treatment characteristics. METHODS: An observational cohort study was conducted to measure NTZ serum concentrations in MS patients at SID and EID nadir timepoints. NTZ occupancy of α4-integrin receptor sites, and cell surface expression of α4-integrin, was also measured. Patient body weight, age, and treatment exposure metrics were collected. RESULTS: NTZ serum concentrations were lower for EID than SID (mean = 18.2 versus 35.7 μg/ml, respectively; p < 0.001). Patient body weight, age, and treatment duration impacted concentrations with SID, though their influences were reduced or absent with EID. α4-integrin receptor occupancy by NTZ was lower for EID than SID (mean = 78.2 versus 87.4%, respectively; p < 0.001). Body weight impacted α4-integrin receptor occupancy differentially for EID versus SID. α4-integrin cell surface expression was modestly higher for EID than SID (267.2 versus 238.1 MFI, respectively; p < 0.001). CONCLUSIONS: EID of NTZ reduces nadir serum drug levels and α4-integrin receptor occupancy, as well as increases α4-integrin cell surface expression. The resulting increase in the number of open α4-intregrin receptors may enhance immune surveillance of JCV and prevention of PML. Body weight plays a significant role in the pharmacokinetic and pharmacodynamic responses to NTZ treatment. Further research is warranted to help establish pharmacological thresholds of NTZ efficacy and safety, which could help guide decision-making for dosing of NTZ. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.03.017 262. Mult Scler Relat Disord. 2019 Mar 26;31:62-64. doi: 10.1016/j.msard.2019.03.018. [Epub ahead of print] A case of ADEM-like presentation with anti-MOG antibody following tumefactive demyelinating lesion. Miyaue N(1), Yamanishi Y(2), Tada S(2), Ando R(2), Yabe H(3), Nagai M(2), Nomoto M(2). Author information: (1)Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Ehime, Japan; Department of Neurology, Saiseikai Matsuyama Hospital, Ehime, Japan. Electronic address: [email protected]. (2)Department of Neurology and Clinical Pharmacology, Ehime University Graduate School of Medicine, Ehime, Japan. (3)Department of Neurology, Saiseikai Matsuyama Hospital, Ehime, Japan. A 20-year-old woman suffered right facial paralysis. The patient showed an abnormality in the perception of speech at an age of 25 years. At an age of 32 years, she developed acute headache and fever. Brain magnetic resonance imaging (MRI) showed an expanded high signal intensity lesion with gadolinium enhancement in the white matter of the left frontal lobe, which was suggestive of tumefactive demyelinating lesion (TDL). A brain tumor was suspected because TDL is a large demyelinating brain lesion mimicking a primary brain tumor. After initiation of steroid therapy, the symptoms and MRI abnormalities improved. At an age of 34 years, she was referred to our hospital with the main complaint of weakness of lips on the left side. Brain MRI showed hyperintense lesions involving the left frontal and the right parietal white matter lobes, and the left ventrolateral pons, which was suggestive of acute disseminated encephalomyelitis (ADEM). Analysis of anti-MOG antibodies identified anti-MOG antibodies both in the serum and in the CSF. Steroid therapy led to complete clinical recovery. MOG antibodies in both serum and CSF were negative six months after the previous measurement. The patient fulfilled the diagnostic criteria for multiple sclerosis (MS) and TDL is one of the rare variants of MS. This study suggests that anti-MOG antibodies can be associated with repetitive encephalitis including TDL and ADEM-like presentation. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2019.03.018 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 178 – Multiple Sklerose: Veröffentlichungen April 2019 263. Mult Scler Relat Disord. 2019 Apr 5;32:54-63. doi: 10.1016/j.msard.2019.04.003. [Epub ahead of print] Management strategies for female patients of reproductive potential with multiple sclerosis: An evidence-based review. Coyle PK(1), Oh J(2), Magyari M(3), Oreja-Guevara C(4), Houtchens M(5). Author information: (1)Department of Neurology, Stony Brook University, Stony Brook, NY, USA. Electronic address: [email protected]. (2)St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. (3)Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark. (4)Hospital Clínico San Carlos, Universidad Complutense de Madrid, IdISSC, Madrid, Spain. (5)Brigham and Women's Hospital, Harvard Medical School, Brookline, MA, USA. Multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative, immune-mediated disease primarily diagnosed in early adulthood. Multiple sclerosis mostly impacts women of reproductive potential, with pregnancy and birth outcomes being major concerns for many patients. While there is ample evidence that the disease itself has no impact on pregnancy, many women living with MS still question their ability to have children, and the impact of childbearing on their disease in the short and long term. Such questions emphasize the importance of proper guidance from healthcare professionals, particularly neurologists. Management considerations are also complicated by the growing list of available treatment options. This review will summarize current evidence and expert opinion around the management of female MS patients of reproductive potential, from family planning to the postpartum period. Current guidelines on the use of disease-modifying therapies throughout pregnancy will be discussed, as well as other general medical recommendations, to minimize MS disease activity in the peripartum period. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.04.003 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 179 – Multiple Sklerose: Veröffentlichungen April 2019 264. Mult Scler Relat Disord. 2019 Apr 4;31:112-117. doi: 10.1016/j.msard.2019.03.028. [Epub ahead of print] The association between dietary sugar intake and neuromyelitis optica spectrum disorder: A case-control study. Rezaeimanesh N(1), Razeghi Jahromi S(1), Ghorbani Z(2), Beladi Moghadam N(3), Hekmatdoost A(4), Naser Moghadasi A(5), Azimi AR(5), Sahraian MA(6). Author information: (1)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (2)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran. (3)Department of Neurology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (4)Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (5)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. (6)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: [email protected]. BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon autoimmune disease of the central nerves system (CNS) by inflammatory nature. The effects of high dietary sugar intake on inflammation and dysbiosis have been received more attention in recent years. The aim of the present study was to investigate the association between various types of dietary sugar intake and NMOSD odds and clinical features. METHOD: The current case-control study was conducted among 70 patients with definite NMOSD diagnosis based on 2015 international consensus criteria and 164 hospital-based controls. Demographic and anthropometric information in all participants and disease characteristics just in case group were obtained. Dietary data during the past year of study attendance was collected by a validated 168-item food frequency questionnaire. Participants were stratified into 3 tertiles according to each type of sugar intake and the third tertile considered as reference in multivariate regression models. The correlation between dietary sugar and disease features were analyzed using Pearson correlation test. RESULTS: The mean ± SD of total sugar intake increased from 80.73 ± 17.71 to 208.71 ± 57.93 g/day across tertiles of total sugar intake. In fully adjusted model, lower intake of sugar was associates with decreased odds of NMOSD in the first tertile vs third tertile by ORs of: 0.02(CI:0.00-0.08; p-for-trend:0.00), 0.02(CI:0.00-0.10; p-for- trend:0.00), 0.23(CI:0.08-0.61; p-for-trend:0.00), 0.19(CI:0.06-0.58; p-for-trend:0.00) and 0.16(CI:0.05-0.51; p-for-trend:0.00) for glucose, fructose, galactose, lactose and sucrose, respectively. The odds of NMOSD had a 1.72-fold (CI: 1.43-2.03; p-for-trend:0.00) significant raise per every 10 g increase for total sugar intake. There was no significant correlation between various types of dietary sugar intakes and relapse rate or patients' disability. CONCLUSION: The present study proposes a possible direct association between high intake of various sugar types and odds of suffering from NMOSD. More investigations are needed to prove this results. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.03.028 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 180 – Multiple Sklerose: Veröffentlichungen April 2019 265. Mult Scler Relat Disord. 2019 Apr 3;31:141-147. doi: 10.1016/j.msard.2019.04.001. [Epub ahead of print] Racial differences in retinal neurodegeneration as a surrogate marker for cortical atrophy in multiple sclerosis. Samuel LM(1), Sara R(2), Kalyan Y(1), Fen B(1), Carla SM(3), Navid SB(1), Evanthia B(4). Author information: (1)The Sastry Family Foundation, Advanced Imaging Laboratory, Department of Neurology, Wayne State University School of Medicine, 4201 St. Antoine, Detroit, MI, USA. (2)The Sastry Family Foundation, Advanced Imaging Laboratory, Department of Neurology, Wayne State University School of Medicine, 4201 St. Antoine, Detroit, MI, USA; Multiple Sclerosis Center, Wayne State University School of Medicine, Detroit, MI, USA. (3)Multiple Sclerosis Center, Wayne State University School of Medicine, Detroit, MI, USA. (4)The Sastry Family Foundation, Advanced Imaging Laboratory, Department of Neurology, Wayne State University School of Medicine, 4201 St. Antoine, Detroit, MI, USA; Multiple Sclerosis Center, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: [email protected]. BACKGROUND: Multiple sclerosis (MS) has both an inflammatory and a neurodegenerative component, with gray matter (GM) atrophy being an important contributor to disability. Optical coherence tomography (OCT) may serve as a prognostic tool for neuroaxonal health by measuring ganglion cell inner plexiform layer (GCIPL) thickness. There is a paucity of literature regarding the effects of race on pathobiology of MS, as racial minorities are underrepresented in research studies. OBJECTIVE: The aim of this paper is to compare the correlation between GM fraction (GMF) and GCIPL thickness in Caucasian Americans with MS (CAMS) and African Americans with MS (AAMS). METHODS: Fifty-nine patients with relapsing-remitting multiple sclerosis (RRMS) were included. Using a cross-sectional design, we compared the OCT (GCIPL thickness) and MRI (GMF) data of 32 CAMS and 27 AAMS patients. RESULTS: No significant correlation was observed between GMF and GCIPL in our study group (p = 0.127, r = 0.148). CAMS exhibited a significant correlation between these measures (p = 0.0004, r = 0.434), while in AAMS these measures did not correlate significantly (p = 0.187, r = -0.201). CONCLUSION: GCIPL might be a sensitive biomarker predicting GM atrophy and disability in CAMS, but not in AAMS. Larger studies are needed to investigate reliable biomarkers across races. Inclusion of AAMS in research studies is necessary to shed more light on the pathobiology of MS. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.04.001 266. Mult Scler Relat Disord. 2019 Apr 3;31:134-140. doi: 10.1016/j.msard.2019.03.026. [Epub ahead of print] Whole-body vibration impedes the deterioration of postural control in patients with multiple sclerosis. Krause A(1), Lee K(2), Freyler K(2), Bührer T(2), Gollhofer A(2), Ritzmann R(3). Author information: (1)Department of Sport Science, University of Freiburg, Schwarzwaldstraße 175, 79117 Freiburg, Germany; Institute of Training and Computer Science, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933 Cologne, Germany. Electronic address: [email protected]. (2)Department of Sport Science, University of Freiburg, Schwarzwaldstraße 175, 79117 Freiburg, Germany. (3)Department of Sport Science, University of Freiburg, Schwarzwaldstraße 175, 79117 Freiburg, Germany; Department of Biomechanics, Praxisklinik Rennbahn, Switzerland. OBJECTIVE: The current study aimed to investigate if whole-body vibration (WBV) might attenuate the processing functional and neuromuscular degeneration of postural control in patients with MS. DESIGN: Performance in postural control was assessed before and after 6 weeks of a control (CON) and a WBV intervention period. SETTING: Laboratory at the University of Freiburg & home-based training PARTICIPANTS: Out of 29 interested participants, 15 subjects with severe MS fit inclusion criteria. MAIN OUTCOME MEASURES: Centre of pressure displacement (COP), muscle activity and co-contraction indices of m. soleus (SOL), gastrocnemius medialis (GM), tibialis anterior (TA), biceps (BF) and rectus femoris (RF) as well as SOL H/M-ratios. RESULTS: After CON, COP was significantly enhanced with reduced muscle activity in RF and diminished shank muscle co-contraction. After WBV, no changes were observed in COP and neuromuscular control. However, over time, TA activity was reduced, but with no changes in muscle activation of SOL, GM and BF or H/M-ratios. CONCLUSIONS: After CON, MS patients experienced substantial deteriorations in postural control which have previously been associated with greater postural instability. No further disease-associated deteriorations were observed following the intervention. Thus, WBV might alleviate neurodegeneration of postural control in people with MS. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.03.026 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 181 – Multiple Sklerose: Veröffentlichungen April 2019 267. Mult Scler Relat Disord. 2019 Apr 3;31:131-133. doi: 10.1016/j.msard.2019.04.002. [Epub ahead of print] Cervical spondylotic myelopathy mimicking transverse myelitis. Wang Y(1), Newsome SD(2). Author information: (1)Johns Hopkins University School of Medicine, Department of Neurology, Division of Neuroimmunology and Neuroinfectious Disorders. 600 N. Wolfe Street. Pathology 627, Baltimore, MD 21287, USA. (2)Johns Hopkins University School of Medicine, Department of Neurology, Division of Neuroimmunology and Neuroinfectious Disorders. 600 N. Wolfe Street. Pathology 627, Baltimore, MD 21287, USA. Electronic address: [email protected]. OBJECTIVE: To describe two cases of cervical spondylotic myelopathy initially misdiagnosed as transverse myelitis. METHODS: Case series. RESULTS: A 44- and 56-year-old man presented with chronic progressive myelopathy. Initial work up revealed cervical spondylosis and an enhancing intramedullary cervical cord lesion. The younger individual was diagnosed with multiple sclerosis, and the other as an unspecified autoimmune demyelinating disorder. They were both treated with immune therapies, but had progression in their symptoms and functional decline, prompting re-evaluation. Due to persistent enhancement of the intramedullary cervical cord lesion on repeat imaging, lack of new lesion formation over time, and lack of intrathecal antibody production, all of which are atypical for a primary demyelinating disorder, both men ultimately underwent cervical decompressive surgery. Interestingly, though symptoms and disability level improved or stabilized, persistent enhancement of the intramedullary cord lesion years after surgery was noted for both individuals. CONCLUSION: Spondylotic myelopathy is an important consideration in the differential of inflammatory myelopathy, especially since misdiagnosis may result in serious consequences as was seen in the cases presented, including exposure to unnecessary costly treatments and irreversible neurological disability from delayed appropriate surgical intervention. Intramedullary spinal cord enhancement can occur with spondylotic myelopathies, albeit rare, and may persistently enhance for an extended period of time even after decompressive surgery. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.04.002 268. Mult Scler Relat Disord. 2019 Apr 23;32:30-32. doi: 10.1016/j.msard.2019.04.022. [Epub ahead of print] Recurrent atrial fibrillation after pulse corticosteroid treatment for a relapse of multiple sclerosis. Pavičić T(1), uš a B(1), damec I(1), Habe ( ). Author information: (1)University Hospital Center Zagreb, Department of Neurology, Referral Center for Autonomic Nervous System Disorders, Zagreb, Croatia. (2)University Hospital Center Zagreb, Department of Neurology, Referral Center for Autonomic Nervous System Disorders, Zagreb, Croatia; School of Medicine, University of Zagreb, Zagreb, Croatia. Electronic address: [email protected]. Standard therapy for a relapse of multiple sclerosis is a high dose pulse corticosteroid therapy. Cardiovascular adverse events ranging from palpitations to serious arrhythmias like atrial fibrillation and ventricular tachycardia have been associated with this treatment. The underlying mechanism behind the development of atrial fibrillation and treatment of multiple sclerosis relapse with steroids is still unclear. In this case, a 27-year-old male with multiple sclerosis is presented who developed atrial fibrillation on two occasions following two consecutive treatments with high dose methylprednisolone for the treatment of multiple sclerosis relapse. Extensive work-up revealed mild sympathetic autonomic system dysfunction. Based on this case and previous studies, we propose that a disturbed function of the autonomic system increases the risk of atrial fibrillation and/or other arrhythmias in people with multiple sclerosis. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2019.04.022 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 182 – Multiple Sklerose: Veröffentlichungen April 2019 269. Mult Scler Relat Disord. 2019 Apr 21;32:37-40. doi: 10.1016/j.msard.2019.04.024. [Epub ahead of print] The relationship between cognitive function and body mass index in multiple sclerosis patients. Owji M(1), Ashraf-Ganjouei A(1), Sahraian MA(1), Bidadian M(2), Ghadiri F(1), Naser Moghadasi A(3). Author information: (1)Multiple Sclerosis Research Center; Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. (2)Department of Psychology, School of Humanities, Tarbiat Modares University, Tehran, Iran. (3)Multiple Sclerosis Research Center; Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: [email protected]. BACKGROUND: Many patients with multiple sclerosis (MS) endure cognitive impairment, which affects their everyday life and lowers their life quality. It has been demonstrated that obesity can result in poor cognitive performance in healthy individuals through various mechanisms. Therefore, we aimed at assessing the association between body mass index (BMI) and cognitive function in MS patients, using minimal assessment of cognitive functions in MS (MACFIMS) battery. METHOD: This study included eighty-one patients with relapsing-remitting MS (RRMS). After collecting the demographic data, patients' height and weight were measured in order to calculate BMI. Then, MACFIMS battery was administered in one session, after obtaining information using expanded disability status scale (EDSS). RESULTS: Paced Auditory Serial Addition Test (PASAT) and Symbol Digit Modalities Test (SDMT) scores were negatively correlated with BMI (P values are equal to 0.005 and 0.037, respectively). PASAT score correlated with BMI after controlling for sex, age, and EDSS, but SDMT score did not correlate. Nevertheless, no significant variation was observed in the BMI level among individuals having MS with or without cognitive deficit. CONCLUSION: We have shown that, BMI is associated with poor cognitive performance in some tests which, MACFIMS battery was included. This could suggest that obesity might be an important factor, which have effect on the cognitive performance. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2019.04.024 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 183 – Multiple Sklerose: Veröffentlichungen April 2019 270. Mult Scler Relat Disord. 2019 Apr 2;31:93-96. doi: 10.1016/j.msard.2019.03.027. [Epub ahead of print] CSF oligoclonal bands and normal appearing white matter periventricular damage in patients with clinically isolated syndrome suggestive of MS. Pardini M(1), Gualco L(2), Bommarito G(2), Roccatagliata L(3), Schiavi S(4), Solaro C(5), Mancardi G(6), Uccelli A(7), Capello E(8), Inglese M(9). Author information: (1)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico, San Martino, Genova. Electronic address: [email protected]. (2)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy. (3)IRCCS Ospedale Policlinico, San Martino, Genova; Department of Health Sciences, University of Genoa, Genoa, Italy. (4)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Computer Science Department, University of Verona, Verona, Italy. (5)Rehabilitation Department, Mons. L. Novarese Institute, Moncrivello, Italy. (6)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, University of Genoa, Genoa, Italy. (7)IRCCS Ospedale Policlinico, San Martino, Genova; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, University of Genoa, Genoa, Italy. (8)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico, San Martino, Genova. (9)IRCCS Ospedale Policlinico, San Martino, Genova; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, University of Genoa, Genoa, Italy; Departments of Neurology, Radiology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States. BACKGROUND: A periventricular gradient of normal appearing white matter (NAWM) damage has been described in multiple sclerosis (MS), including subjects with clinically isolated syndrome (CIS). The pathological mechanisms underlying this gradient is not currently understood. METHODS: 34 CIS subjects were enrolled and underwent cerebrospinal fluid oligo-clonal bands (CSF-OCB) evaluation. Moreover, all CIS subjects and 24 healthy controls underwent a brain MRI scan. Diffusion weighted imaging was used to compute mean diffusivity (MD) values in periventricular and deep NAWM for all groups. RESULTS: CSF- OCB were present in 24 CIS subjects (CSF-OCB+) out of 34 tested. Periventricular NAWM MD values were significantly higher in CIS subjects with than in those without CSF-OCB (0.78 ± 0.06 mm3/10-3 vs. 0.72 ± 0.06 mm3/10-3; p = 0.01), while there was no difference between groups in deep NAWM MD values. The periventricular gradient of damage, expressed in z score based on healthy controls data, was more marked in CSF-OCB+ than in CSF-OCB- (0.65 ± 0.05 vs. 0.17 ± 0.04 p < 0.001). There was no difference in periventricular lesion load between the two groups. CONCLUSIONS: In CIS, the presence of CSF-OCB is associated with the severity of periventricular NAWM damage gradient. Intrathecal inflammation could play a role in NAWM damage distribution. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.03.027 271. Mult Scler Relat Disord. 2019 Apr 17;32:23-26. doi: 10.1016/j.msard.2019.04.018. [Epub ahead of print] Tumefactive multiple sclerosis which initially presented with brainstem encephalitis with a long-term follow-up. Mitsutake A(1), Sato T(2), Katsumata J(2), Nakamoto FK(2), Seki T(2), Maekawa R(2), Hideyama T(2), Shimizu J(3), Shiio Y(2). Author information: (1)Department of Neurology, Tokyo Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo 102-8798, Japan; Department of Neurology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address: [email protected]. (2)Department of Neurology, Tokyo Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo 102-8798, Japan. (3)Department of Neurology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tumefactive demyelinating lesions (TDLs) are rare in multiple sclerosis (MS). We herein report a case of tumefactive MS which initially presented with brainstem encephalitis with a long-term follow-up. The patient had experienced relapse mostly in the brainstem in the first twenty years, and then in the periventricular white matter afterwards. The patient responded well to steroid treatment recovered without sequalae. However, immunodeficiency due to the long-term use of oral prednisolone made aggressive therapy during the relapse impossible, so recovery after steroid therapy is incomplete. Our case is different from classical MS in clinical course and response to treatment. Our report offers rare information on long-term outcome of tumefactive MS. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2019.04.018 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 184 – Multiple Sklerose: Veröffentlichungen April 2019 272. Mult Scler Relat Disord. 2019 Apr 16;32:46-53. doi: 10.1016/j.msard.2019.04.011. [Epub ahead of print] Perceived fatigue and cognitive performance change in multiple sclerosis: Uncovering predictors beyond baseline fatigue. Hu M(1), Muhlert N(2), Robertson N(3), Winter M(4). Author information: (1)University Hospital Wales, Cardiff, UK. Electronic address: [email protected]. (2)School of Psychology, Cardiff University, Cardiff, UK; School of Psychological Sciences, University of Manchester, Manchester, UK. (3)University Hospital Wales, Cardiff, UK; Institute of Psychological Medicine & Clinical Neurosciences, Cardiff University, UK. (4)University Hospital Wales, Cardiff, UK; School of Psychology, Cardiff University, Cardiff, UK. BACKGROUND: Fatigue is a common and disabling symptom in multiple sclerosis (MS) with a variety of direct and indirect influences, but remains poorly understood. Perceived fatigue and cognitive performance fatigability may only be weakly correlated and may have independent predictors. We adopted a multifactorial approach, utilising a measure of concurrent cognitive performance change in order to examine the clinical, psychological, and cognitive factors influencing perceived and cognitive performance fatigability in MS. METHODS: Individuals with adult-onset MS were identified from a regional patient database and invited to complete an assessment battery during a home visit. Baseline perceived fatigue was measured using the Modified Fatigue Impact Scale, Fatigue Assessment Instrument, and a Visual Analogue Scale (VAS). The Conners Continuous Performance Test 3 (CCPT3) and VAS were administered before and after our intervention of roughly 2.5 hours of assessment, which represented a period of cognitive effort. The differences in scores formed measures of cognitive performance fatigability and perceived fatigue change, respectively. We examined differences across baseline fatigue, fatigue change and performance change classifications, using regression analysis to uncover predictors of perceived fatigue and performance change. RESULTS: The sample comprised 61 participants who were recruited from an existing cohort of MS patients. Positive relationships with depression and emotion-focused coping, and a negative one with sleep, each predicted baseline perceived fatigue with the model explaining 53.5% of variance. Increased perceived fatigue change was not associated with baseline fatigue, cognitive impairment, disease variables or levels of disability, but was linked with higher anxiety, lower self-efficacy and gender. Most CCPT3 performance change variables did not show significant correlations with baseline clinical, psychological, or fatigue variables. However, two variables were predicted by positive relationships with estimated intelligence, whilst a negative relationship with self-efficacy and a positive one with post-intervention fatigue predicted one each. CONCLUSION: Fatigue in MS is a multifactorial construct, with perceived fatigue and cognitive performance fatigability largely influenced by indirect psychological and cognitive factors. Future studies need to take these influences into account when developing fatigue assessment tools. Further, targeting influential fatigue drivers such as psychological variables may improve the burden of fatigue and quality of life of people with MS. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.04.011 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 185 – Multiple Sklerose: Veröffentlichungen April 2019 273. Mult Scler Relat Disord. 2019 Apr 16;32:41-45. doi: 10.1016/j.msard.2019.04.019. [Epub ahead of print] Callosal lesions on magnetic resonance imaging with multiple sclerosis, neuromyelitis optica spectrum disorder and acute disseminated encephalomyelitis. Cai MT(1), Zhang YX(1), Zheng Y(1), Fang W(2), Ding MP(3). Author information: (1)Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China. (2)Department of Neurology, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China. (3)Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China. Electronic address: [email protected]. OBJECTIVE: To clarify the features of callosal lesions on magnetic resonance imaging (MRI) in Multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and acute disseminated encephalomyelitis (ADEM). METHODS: Chinese patients diagnosed with MS (n = 33), NMOSD (n = 31), and ADEM (n = 18) were enrolled. Characteristics of lesions in corpus callosum were evaluated with 1.5 Tesla MRI scanners. Chi-squared test (Fisher's exact test) was used to analyze the data. RESULTS: In corpus callosum, NMOSD and ADEM lesions tend to have a diffuse distribution (p = 0.006, p = 0.033) and blurred margins (p < 0.001, p = 0.017), when compared with MS; lesions in NMOSD were less ovoid (p = 0.006), while fewer lesions in ADEM existed in the rostrum and genu (p = 0.002). NMOSD has the most heterogeneous intensity on post-enhancement sequences (p = 0.016, p = 0.001). Radial-like lesions were more common in MS and NMOSD (p = 0.019, p < 0.001). CONCLUSION: MS lesions were most likely focally-localized with clear margins. Radial callosal lesions are characteristic of MS and NMOSD but rarely seen in ADEM. The signal intensities of the lesion were the most heterogeneous in NMOSD. Therefore, the lesion patterns in corpus callosum may serve as a useful clue for correct diagnosis, facilitating early treatment. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.04.019 274. Mult Scler Relat Disord. 2019 Apr 15;32:27-29. doi: 10.1016/j.msard.2019.04.021. [Epub ahead of print] Successful intravenous immunoglobulin treatment in relapsing MOG-antibody- associated disease. Tsantes E(1), Curti E(2), Siena E(2), Granella F(3). Author information: (1)Neurosciences Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy. Electronic address: [email protected]. (2)Neurosciences Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy. (3)Neurosciences Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy. Electronic address: [email protected]. Treatment of MOG Ab-associated disease is poorly standardized: several drugs have been employed, with variable results. A 50-year-old Caucasian male was admitted to hospital in 2009, with severe acute transverse myelitis. A brain and spinal cord MRI showed multiple demyelinating lesions and cerebrospinal fluid analysis revealed no oligoclonal bands (OCBs). A diagnosis of multiple sclerosis (MS) was made. He was treated with interferon-beta 1a, then with fingolimod, and finally with rituximab. All these treatments were ineffective: he experienced several spinal and brainstem relapses, with residual disability. Finally, an empirical therapy with IVIg was started. Calling into question the diagnosis of MS, we performed anti-MOG test (positive). IVIg therapy was continued and the patient experienced only one mild relapse during a 24- month follow-up. Our patient, with an aggressive and atypical MOG Ab-associated disease, showed a very good response to longterm IVIg treatment. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.04.021 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 186 – Multiple Sklerose: Veröffentlichungen April 2019 275. Mult Scler Relat Disord. 2019 Apr 15;32:1-8. doi: 10.1016/j.msard.2019.04.017. [Epub ahead of print] Worsening of disability caused by relapses in multiple sclerosis: A different approach. Koch-Henriksen N(1), Thygesen LC(2), Sørensen PS(3), Magyari M(4). Author information: (1)The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: [email protected]. (2)National Institute of Public Health, University of Southern Denmark in Copenhagen, Denmark. (3)Department of Neurology, Danish Multiple Sclerosis Center Rigshospitalet, University of Copenhagen, Denmark. (4)The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, Copenhagen, Denmark; Department of Neurology, Danish Multiple Sclerosis Center Rigshospitalet, University of Copenhagen, Denmark. BACKGROUND: In multiple sclerosis (MS) the quantitative role of relapses in Expanded Disability Status Scale (EDSS) worsening beyond the recovery phase is not well known. Most studies have examined the predictive role of early relapses in more distant endpoints. Relapses and worsening may be associated because they could be independent effects of the same underlying disease characteristics without causal relationship. With the design of the present study we aim to estimate the direct effect on disability of relapses. METHODS: We used data from the obligatory bi-annually registration in the Danish Multiple Sclerosis Registry of relapses and EDSS for all patients treated with disease modifying drugs for relapsing/remitting MS from 1996 to 2015 with exclusion of patients in whom no relapses had ever been recorded during treatment. We paired two consecutive control periods into study intervals which were the actual study units. Study intervals were qualified and included if they were at length 12-24 months, with EDSS ≤ 5.5 at start, and if a preceding relapse had been no closer than nine months to the EDSS assessment at the start or end of the study interval to eliminate relapse-related temporary EDSS worsening. We compared EDSS worsening in study intervals with and without relapses. The same patients could contribute with study intervals with and without relapses. For statistical analyses we used Generalized Estimating Equations to account for intra-patient correlations. RESULTS: We analysed 5187 study intervals from 2015 MS patients. The mean of EDSS increase was 0.205 units in qualifying study intervals with relapses and 0.065 without relapses when adjusted for length of study interval, sex, and EDSS at start of interval; p < 0.0001. However, the effect of relapses on EDSS was absent in male patients (p = 0.521), and when EDSS was ≥ 4.0 at start of the study interval (p = 0.726). CONCLUSION: Relapses play an independent and significant role for worsening of MS in patients under disease-modifying therapy (DMT) and eliminating relapses would not only free the patients from the temporary perils of relapses but would also reduce the worsening of the disease. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.04.017 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 187 – Multiple Sklerose: Veröffentlichungen April 2019 276. Mult Scler Relat Disord. 2019 Apr 13;32:13-18. doi: 10.1016/j.msard.2019.04.013. [Epub ahead of print] Capturing fatigue parameters: The impact of vagal processing in multiple sclerosis related cognitive fatigue. Sander C(1), Modes F(2), Schlake HP(3), Eling P(4), Hildebrandt H(5). Author information: (1)Institute of Psychology, Carl von Ossietzy University of Oldenburg, Department VI - Medicine and Health Sciences, Ammerländer Heerstr. 114-11826129, Oldenburg, Germany; Median Klinik Wilhelmshaven, Department of Neurology, Bremer Straße 2, 26382 Wilhelmshaven, Germany. Electronic address: [email protected]. (2)Institute of Psychology, Carl von Ossietzy University of Oldenburg, Department VI - Medicine and Health Sciences, Ammerländer Heerstr. 114-11826129, Oldenburg, Germany. Electronic address: [email protected]. (3)Median Klinik Wilhelmshaven, Department of Neurology, Bremer Straße 2, 26382 Wilhelmshaven, Germany. Electronic address: [email protected]. (4)Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Montessorilaan 3, 6525 HR, Nijmegen, Netherlands. Electronic address: [email protected]. (5)Institute of Psychology, Carl von Ossietzy University of Oldenburg, Department VI - Medicine and Health Sciences, Ammerländer Heerstr. 114-11826129, Oldenburg, Germany; Klinikum Bremen-Ost, Department of Neurology, Züricher Str. 40, 28325 Bremen, Germany. Electronic address: helmut.hildebrandt@uni- oldenburg.de. BACKGROUND: Causes of fatigue in Multiple Sclerosis remain elusive. Recently, we developed a model linking cognitive fatigue to inflammatory processes based on a neuroinflammatory reflex-arc instantiated by the vagus nerve. The relation between experienced autonomic dysfunctions, based on vagal processing, and cognitive fatigue is well-known, but an examination of the association of objectively measured vagal activity and cognitive fatigue is missing. An attempt was made to collect behavioral and physiological evidence that can be associated with experienced autonomic dysfunctions and fatigue in Multiple Sclerosis patients. METHODS: Behavioral performance (response bias) and autonomic functioning (Heart rate variability and Skin conductance level) during an acoustic vigilance task were investigated in 53 Multiple Sclerosis patients. We assessed trait fatigue (independent from task), and time-on-task related increase of fatigue. Regression analysis was used to predict the fatigue status with physiological and behavioral scores. RESULTS: Response bias, indicating a reduced responsiveness, and high and very low frequency components of Heart rate variability, indicating an increased parasympathetic activity, contribute to the regression of trait fatigue. Reduced Heart rate variability (SDNN) and increased parasympathetic activity (pNN50) remained in the regression model predicting time-on-task fatigue. CONCLUSION: Cognitive fatigue in MS is related to parasympathetic activity and reduced responsiveness, supporting our model representing fatigue as inflammatory processes in the brain. Standardized subjective and objective autonomous dysfunction measures might be considered as additional assessments in MS. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2019.04.013 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 188 – Multiple Sklerose: Veröffentlichungen April 2019 277. Mult Scler Relat Disord. 2019 Apr 13;31:151-156. doi: 10.1016/j.msard.2019.04.015. [Epub ahead of print] Evaluation of a web-based fall prevention program among people with multiple sclerosis. Kannan M(1), Hildebrand A(2), Hugos CL(3), Chahine R(4), Cutter G(5), Cameron MH(6). Author information: (1)University of Virginia, 1221 Lee Street, Charlottesville, VA 22908, USA. Electronic address: [email protected]. (2)Oregon Health & Science University, VA Portland Health Care System, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA. Electronic address: [email protected]. (3)Oregon Health & Science University, VA Portland Health Care System, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA. (4)University of Alabama Birmingah, School of Public Health, Birmingham, AL, USA. Electronic address: [email protected]. (5)University of Alabama Birmingah, School of Public Health, Birmingham, AL, USA. Electronic address: [email protected]. (6)Oregon Health & Science University, VA Portland Health Care System, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA. Electronic address: [email protected]. BACKGROUND: Falls are common and impactful in people with multiple sclerosis (MS) but currently there is no accepted standard of care for fall prevention in MS. Evidence supports that the in-person, group-based, Free from Falls (FFF) program is associated with both immediate and six-month sustained improvements in mobility and balance and a reduction in falls, but program attendance is limited by access to the class at a given time and location and by the cost and availability of trained facilitators. Therefore, we developed and evaluated an online, web-based version of FFF, Free from Falls Online (FFFO). METHODS: Thirty people with MS who reported falling at least twice in the previous two months were randomized to FFFO or to a control group. FFFO consists of eight weekly sessions, each with an instructional and exercise component. Subjects in the control group were given a brochure on minimizing fall risk, a letter was sent to their treating physician informing them that the subject reported falling, and these subjects were invited to use the FFFO program at study completion. Outcomes included baseline demographics, falls prospectively reported for the eight weeks of intervention and the following three months, and a program satisfaction survey for the active group. Regression models were used to test for associations between treatment group and fall incidence. RESULTS: Subjects' mean age was 55.8 years, 70% were female, 73% had progressive MS, median Expanded Disability Status Scale (EDSS) score was 6.0, and subjects reported a median of two falls in the month prior to study enrollment. Although, in general, regression models demonstrated trends that those in the intervention group were less likely to fall than those in the control group, statistical significance was only achieved (p = 0.0038) with a post hoc model evaluating the relationship between the square of days and the probability of not falling. This model supported that those in the intervention group were slightly less likely to fall than those in the control group. This difference was most prominent in the first month of the study, less prominent in the following month, and not sustained three months following the intervention. User experience with FFFO was overall positive, with over 75% reporting the web-based program easy to learn and to use, 85% reporting the program was easy to follow, 62% reporting the material to be useful, and 77% finding the exercises to be a useful component of the program. CONCLUSION: This study supports the viability of online delivery of self-management strategies in MS, suggests that FFFO may help prevent falls in people with MS, and provides the preliminary data needed to verify the findings of this pilot study of FFFO with a fully powered randomized controlled trial in people with MS. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.04.015 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 189 – Multiple Sklerose: Veröffentlichungen April 2019 278. Mult Scler Relat Disord. 2019 Apr 13;31:148-150. doi: 10.1016/j.msard.2019.04.009. [Epub ahead of print] A SCA7 premutation may be a novel Mendelian modifier of MS course: A case report. Sundal C(1), Axelsson M(1), Wiklund L(2), Lindberg C(3), Andersen O(4). Author information: (1)Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. (2)Neurology Unit, Department of Medicine, Sunderby Hospital, Luleå, Sweden. (3)Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Clinical Genetics, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. (4)Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: [email protected]. A proportion of patients with the phenotype of complex genetic disorders carry dominantly inherited Mendelian traits, exemplified by hereditary spastic paraparesis influencing pyramidal symptoms in some MS cases. We here describe a mutable ATXN7 gene, a SCA7 premutation, in a patient fulfilling contemporary definitions of primary progressive MS. His onset age, and onset with a severely progressive cerebellar ataxia syndrome, was outside the reported range of symptoms in a representative MS material. We suggest that an ATXN7 premutation is a novel genetic modifier of the course of MS. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.04.009 279. Mult Scler Relat Disord. 2019 Apr 1;31:118-123. doi: 10.1016/j.msard.2019.03.024. [Epub ahead of print] Cognitive and physical fatigue are associated with distinct problems in daily functioning, role fulfilment, and quality of life in multiple sclerosis. Gullo HL(1), Fleming J(2), Bennett S(2), Shum DHK(3). Author information: (1)The University of Queensland, School of Health and Rehabilitation Sciences, Australia. Electronic address: [email protected]. (2)The University of Queensland, School of Health and Rehabilitation Sciences, Australia. (3)Griffith University, Griffith Health and Menzies Institute, Australia and The Hong Kong Polytechnic University, China. OBJECTIVE: To examine whether cognitive and physical fatigue are differentially associated with problems in self-care, mobility, relationships, participation, psychological well-being, and quality of life in people with multiple sclerosis. METHODS: A cross-sectional study involving seventy-four community-dwelling people with MS was undertaken. Between-groups analysis was used to compare ratings on the Perceived Impact of Problem Profile (PIPP) in a range of functional domains and the SF-36 quality of life measure, across median-split groups based on level of both physical and cognitive fatigue using the Modified Fatigue Impact Scale. RESULTS: The impact of poor psychological well-being (p = .005), and associated distress (p = .008) on PIPP was greater in the 'high-level' cognitive fatigue group than the 'low-level' cognitive fatigue group. By contrast, the 'high-level' and 'low-level' physical fatigue groups differed significantly in their self-reported impact of problems in the areas of mobility (p = .002), relationships (p = .014), participation (p = .001), and psychological well-being (p = .004). Overall mental quality of life was significantly lower (p < .001) in those high in cognitive fatigue comparative to the low-level group, and overall physical quality of life was significantly lower (p = .002) in people with multiple sclerosis high in physical fatigue as opposed to low. CONCLUSION: Cognitive and physical fatigue were associated with distinct problems in daily functioning, which impact differentially on role fulfilment and quality of life in multiple sclerosis. Therefore, these two types of fatigue should be considered distinct domains of the fatigue experience in MS. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.03.024 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 190 – Multiple Sklerose: Veröffentlichungen April 2019 280. Mult Scler Relat Disord. 2019 Apr 1;31:106-111. doi: 10.1016/j.msard.2019.03.029. [Epub ahead of print] Plasma brain-derived neurotrophic factor (BDNF) and sphingosine-1-phosphat (S1P) are NOT the main mediators of neuroprotection induced by resistance training in persons with multiple sclerosis-A randomized controlled trial. Jørgensen MLK(1), Kjølhede T(2), Dalgas U(1), Hvid LG(3). Author information: (1)Section for Sport Science, Department of Public Health, Aarhus University, Dalgas Avenue 4, DK-8000 Aarhus, Denmark. (2)Section for Sport Science, Department of Public Health, Aarhus University, Dalgas Avenue 4, DK-8000 Aarhus, Denmark; Centre for Innovative Medical Technology, Odense University Hospital (OUH), Denmark. (3)Section for Sport Science, Department of Public Health, Aarhus University, Dalgas Avenue 4, DK-8000 Aarhus, Denmark. Electronic address: [email protected]. Resistance training (RT) has been shown to elicit neuroprotective effects in persons with multiple sclerosis (pwMS). Brain-derived neurotrophic factor (BDNF) and Sphingosine-1-phosphat (S1P) have been put forward as potent mediators of the neuroprotective effects induced by RT. However, while increases have been shown in acute and chronic circulating BDNF levels in pwMS following aerobic exercise alone or in combination with other exercise regimes, no studies have examined this in response to RT. As a novel 'proof-of-concept' approach, we therefore examined the effects of 24 weeks of RT on acute and chronic circulating BDNF and S1P levels in the same pwMS whom our group had previously observed RT-induced neuroprotective effects in (i.e. increased cortical thickness and preservation of whole brain volume). A total of n = 30 relapsing-remitting pwMS were randomized into a training group (TG: 24 weeks of progressive high intensity resistance training, 2 sessions per week; n = 16, age 44[40:51] years, EDSS score 3.0[2.0:3.5] (median[IQR]) or a control group (CG: 24 weeks of habitual lifestyle; n = 14, age 45[37:47] years, EDSS score 3.0[2.5:3.5]). Plasma levels of BDNF and S1P were assessed by ELISA kits before and after the 24- week intervention period. No within- or between group changes were observed in acute or chronic circulating levels of BDNF. A substantial proportion of the participants had S1P levels below the detection limit, yet no within- or between changes were observed in chronic S1P plasma levels in the remaining samples. Thus, the present findings do not support that circulating plasma BDNF or S1P levels are the main mediators of the neuroprotective effects previously reported in the same group of pwMS. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.03.029 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 191 – Multiple Sklerose: Veröffentlichungen April 2019 281. Mult Scler Relat Disord. 2019 Apr 1;31:87-92. doi: 10.1016/j.msard.2019.03.030. [Epub ahead of print] Relationship of High-mobility group box 1 levels and multiple sclerosis: A systematic review and meta-analysis. Zhen C(1), Wang Y(2), Li D(1), Zhang W(1), Zhang H(1), Yu X(3), Wang X(4). Author information: (1)Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province 266071, China. (2)Department of Emergency, Qilu Hospital of Shandong University (Qingdao), Qingdao, China. (3)Central Laboratories, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China. (4)Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghai Middle Road, Qingdao, Shandong Province 266071, China. Electronic address: [email protected]. BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) affecting more than 2.5 million people worldwide. However, the exact etiology of MS remains unknown, recent research indicated that High-mobility group box 1(HMGB1) might contribute to MS pathogenesis. By evaluating HMGB1 levels of peripheral blood mononuclear cells (PBMC), serum and cerebrospinal fluid (CSF) in multiple sclerosis (MS) patients and the controls, to reveal the relationship of HMGB1 levels and MS patients. METHODS: The PubMed, EMBASE, the Cochrane library, China National Knowledge Infrastructure (CNKI) and WanFangData were searched for relevant studies. Pooled standardized mean difference (SMD) and 95% confidence interval (CI) were calculated as effect size, random-effects model was used when I2 > 50%. Subgroup analysis was conducted by subtype of MS, categories of controls, country and mean age. RESULTS: A total of 7 studies with 364 patients of MS and 222 controls were included. The results of this study showed that HMGB1 protein levels of PBMC and CSF in patients with MS were significantly higher than those of controls (SMD = 4.36, 95% CI = 3.69-5.02, and SMD = 0.85, 95% CI = 0.42-1.28, respectively), but we found no significant difference in HMGB1 mRNA level of PBMC and serum HMGB1 protein level between MS patients and controls. In the subgroup analysis, RRMS patients had a higher HMGB1 level in serum (p < 0.05) and CSF (p < 0.01) compared to healthy controls and non-inflammatory neurological disorder controls. In Asians, MS patients had a considerably higher HMGB1 level in serum (p < 0.05), PBMC (protein) (p < 0.01) and CSF (p < 0.01) compared to healthy controls and non-inflammatory neurological disorder controls. CONCLUSION: MS patients had higher HMGB1 protein levels in PBMC and CSF compared to controls. HMGB1 might be a new treatment target for MS. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.msard.2019.03.030 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 192 – Multiple Sklerose: Veröffentlichungen April 2019 282. Mult Scler Relat Disord. 2019 Apr 1;31:82-86. doi: 10.1016/j.msard.2019.03.025. [Epub ahead of print] Acute effects of aerobic intensities on the cytokine response in women with mild multiple sclerosis. Berkowitz S(1), Achiron A(2), Gurevich M(3), Sonis P(4), Kalron A(5). Author information: (1)Department of Physical Therapy, School of Health Professions, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel; Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Israel. Electronic address: [email protected]. (2)Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Israel. Electronic address: [email protected]. (3)Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Israel. Electronic address: [email protected]. (4)Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Israel. Electronic address: [email protected]. (5)Department of Physical Therapy, School of Health Professions, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Israel. Electronic address: [email protected]. BACKGROUND: There is limited information as to the effects of aerobic exercise on the immune system in people with multiple sclerosis (PwMS). One of the unresolved questions is which training intensity level is optimal for PwMS. OBJECTIVE: The purpose of this study is to compare the effects of moderate intensity with the effects of vigorous intensity on cytokine levels in women with mild MS. METHODS: The study included 15 women with MS and a control of 10 healthy women. The initial session determined the value of the maximum oxygen consumption and was carried out on an instrumented treadmill with a portable system for monitoring gases. During the second session, the participant walked on the treadmill for 15-minutes at a moderate capacity level (∼50% VO2 peak). Blood samples were taken at baseline, immediately after exercise and two hours later. IL-4, IL-6, IL-10, IL-17A, TNF-α and IFN-ɣ cytokines were tested. The third session was identical to the second except for a vigorous training intensity session (∼80% VO2 peak). RESULTS: IL-6 increased after moderate exercise for both the MS (p = 0.02) and control group (p = 0.02). IL- 10 decreased during the vigorous session only in the MS group (p = 0.02). No other differences were seen over time in either group for all other cytokine measurements. CONCLUSIONS: With the exception of IL-10, women with mild MS have similar inflammatory reactions to moderate and high intensity exercise as do healthy women. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2019.03.025 283. Nat Neurosci. 2019 May;22(5):709-718. doi: 10.1038/s41593-019-0369-4. Epub 2019 Apr 15. Aberrant oligodendroglial-vascular interactions disrupt the blood-brain barrier, triggering CNS inflammation. Niu J(1)(2), Tsai HH(1), Hoi KK(1), Huang N(2), Yu G(2), Kim K(1), Baranzini SE(1), Xiao L(2), Chan JR(1), Fancy SPJ(3)(4)(5)(6). Author information: (1)Department of Neurology, University of California at San Francisco, San Francisco, CA, USA. (2)Department of Histology and Embryology, Collaborative Innovation Center for Brain Research, Third Military Medical University, Chongqing, China. (3)Department of Neurology, University of California at San Francisco, San Francisco, CA, USA. [email protected]. (4)Department of Pediatrics, University of California at San Francisco, San Francisco, CA, USA. [email protected]. (5)Division of Neuroimmunology and Glial Biology, University of California at San Francisco, San Francisco, CA, USA. [email protected]. (6)Newborn Brain Research Institute, University of California at San Francisco, San Francisco, CA, USA. [email protected]. Disruption of the blood-brain barrier (BBB) is critical to initiation and perpetuation of disease in multiple sclerosis (MS). We report an interaction between oligodendroglia and vasculature in MS that distinguishes human white matter injury from normal rodent demyelinating injury. We find perivascular clustering of oligodendrocyte precursor cells (OPCs) in certain active MS lesions, representing an inability to properly detach from vessels following perivascular migration. Perivascular OPCs can themselves disrupt the BBB, interfering with astrocyte endfeet and endothelial tight junction integrity, resulting in altered vascular permeability and an associated CNS inflammation. Aberrant Wnt tone in OPCs mediates their dysfunctional vascular detachment and also leads to OPC secretion of Wif1, which interferes with Wnt ligand function on endothelial tight junction integrity. Evidence for this defective oligodendroglial-vascular interaction in MS suggests that aberrant OPC perivascular migration not only impairs their lesion recruitment but can also act as a disease perpetuator via disruption of the BBB. DOI: 10.1038/s41593-019-0369-4 PMCID: PMC6486410 [Available on 2019-10-15] Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 193 – Multiple Sklerose: Veröffentlichungen April 2019 284. Nat Neurosci. 2019 Apr 22. doi: 10.1038/s41593-019-0385-4. [Epub ahead of print] Bassoon proteinopathy drives neurodegeneration in multiple sclerosis. Schattling B(1), Engler JB(1), Volkmann C(1), Rothammer N(1), Woo MS(1), Petersen M(2), Winkler I(1), Kaufmann M(1), Rosenkranz SC(1), Fejtova A(3)(4), Thomas U(3), Bose A(1), Bauer S(1), Träger S(1), Miller KK(2), Brück W(5), Duncan KE(2), Salinas G(6), Soba P(2), Gundelfinger ED(3)(7), Merkler D(8), Friese MA(9). Author information: (1)Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. (2)Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. (3)Leibniz-Institute für Neurobiologie, Magdeburg, Germany. (4)Psychiatrische und Psychotherapeutische Klinik, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. (5)Institut für Neuropathologie, Universitätsmedizin Göttingen, Georg-August-Universität Göttingen, Göttingen, Germany. (6)Transkriptomanalyselabor, Institut für Entwicklungsbiochemie, Universitätsmedizin Göttingen, Georg-August-Universität Göttingen, Göttingen, Germany. (7)Center for Behavioral Brain Sciences and Medical Faculty, Otto von Guericke Universität, Magdeburg, Germany. (8)Department of Pathology and Immunology, Service of Clinical Pathology, Geneva Faculty of Medicine, Geneva, Switzerland. (9)Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. [email protected]. Multiple sclerosis (MS) is characterized by inflammatory insults that drive neuroaxonal injury. However, knowledge about neuron-intrinsic responses to inflammation is limited. By leveraging neuron-specific messenger RNA profiling, we found that neuroinflammation leads to induction and toxic accumulation of the synaptic protein bassoon (Bsn) in the neuronal somata of mice and patients with MS. Neuronal overexpression of Bsn in flies resulted in reduction of lifespan, while genetic disruption of Bsn protected mice from inflammation-induced neuroaxonal injury. Notably, pharmacological proteasome activation boosted the clearance of accumulated Bsn and enhanced neuronal survival. Our study demonstrates that neuroinflammation initiates toxic protein accumulation in neuronal somata and advocates proteasome activation as a potential remedy. DOI: 10.1038/s41593-019-0385-4 285. Nat Rev Neurol. 2019 Apr 2. doi: 10.1038/s41582-019-0170-8. [Epub ahead of print] Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis. Rotstein D(1), Montalban X(2)(3). Author information: (1)Division of Neurology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. (2)Division of Neurology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. [email protected]. (3)Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain. [email protected]. Personalized treatment is ideal for multiple sclerosis (MS) owing to the heterogeneity of clinical features, but current knowledge gaps, including validation of biomarkers and treatment algorithms, limit practical implementation. The contemporary approach to personalized MS therapy depends on evidence-based prognostication, an initial treatment choice and evaluation of early treatment responses to identify the need to switch therapy. Prognostication is directed by baseline clinical, environmental and demographic factors, MRI measures and biomarkers that correlate with long-term disability measures. The initial treatment choice should be a shared decision between the patient and physician. In addition to prognosis, this choice must account for patient-related factors, including comorbidities, pregnancy planning, preferences of the patients and their comfort with risk, and drug-related factors, including safety, cost and implications for treatment sequencing. Treatment response has traditionally been assessed on the basis of relapse rate, MRI lesions and disability progression. Larger longitudinal data sets have enabled development of composite outcome measures and more stringent standards for disease control. Biomarkers, including neurofilament light chain, have potential as early surrogate markers of prognosis and treatment response but require further validation. Overall, attainment of personalized treatment for MS is complex but will be refined as new data become available. DOI: 10.1038/s41582-019-0170-8 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 194 – Multiple Sklerose: Veröffentlichungen April 2019 286. Nat Rev Neurol. 2019 Apr 18. doi: 10.1038/s41582-019-0183-3. [Epub ahead of print] Epidemiology and treatment of multiple sclerosis in elderly populations. Vaughn CB(1), Jakimovski D(2), Kavak KS(1), Ramanathan M(3), Benedict RHB(1), Zivadinov R(2)(4), Weinstock-Guttman B(5). Author information: (1)Jacobs Multiple Sclerosis Center for Treatment and Research, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, NY, USA. (2)Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, NY, USA. (3)Department of Pharmaceutical Sciences, Jacobs School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, NY, USA. (4)Center for Biomedical Imaging at the Clinical Translational Science Institute, State University of New York (SUNY), Buffalo, NY, USA. (5)Jacobs Multiple Sclerosis Center for Treatment and Research, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, NY, USA. [email protected]. The prevalence of multiple sclerosis (MS) and the age of affected patients are increasing owing to increased longevity of the general population and the availability of effective disease-modifying therapies. However, ageing presents unique challenges in patients with MS largely as a result of their increased frequency of age-related and MS-related comorbidities as well as transition of the disease course from an inflammatory to a neurodegenerative phenotype. Immunosenescence (the weakening of the immune system associated with natural ageing) might be at least partly responsible for this transition, which further complicates disease management. Currently approved therapies for MS are effective in preventing relapse but are not as effective in preventing the accumulation of disability associated with ageing and disease progression. Thus, ageing patients with MS represent a uniquely challenging population that is currently underserved by existing therapeutic regimens. This Review focuses on the epidemiology of MS in ageing patients. Unique considerations relevant to this population are discussed, including the immunology and pathobiology of the complex relationship between ageing and MS, the safety and efficacy of disease-modifying therapies, when discontinuation of treatment might be appropriate and the important role of approaches to support wellness and cognition. DOI: 10.1038/s41582-019-0183-3 287. Nat Rev Neurol. 2019 Apr 15. doi: 10.1038/s41582-019-0174-4. [Epub ahead of print] Immunoneuropsychiatry - novel perspectives on brain disorders. Pape K(1), Tamouza R(2)(3)(4), Leboyer M(2)(3)(4), Zipp F(5). Author information: (1)Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (2)Inserm, U955, Institut Mondor de la Recherche Biomédicale, Créteil, France. (3)Fondation FondaMental, Créteil, France. (4)AP-HP, Department of Psychiatry of Mondor University Hospital, DHU PePsy, University of Paris-Est-Créteil, Créteil, France. (5)Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. zipp@uni- mainz.de. Immune processes have a vital role in CNS homeostasis, resilience and brain reserve. Our cognitive and social abilities rely on a highly sensitive and fine-tuned equilibrium of immune responses that involve both innate and adaptive immunity. Autoimmunity, chronic inflammation, infection and psychosocial stress can tip the scales towards disruption of higher-order networks. However, not only classical neuroinflammatory diseases, such as multiple sclerosis and autoimmune encephalitis, are caused by immune dysregulation that affects CNS function. Recent insight indicates that similar processes are involved in psychiatric diseases such as schizophrenia, autism spectrum disorder, bipolar disorder and depression. Pathways that are common to these disorders include microglial activation, pro-inflammatory cytokines, molecular mimicry, anti- neuronal autoantibodies, self-reactive T cells and disturbance of the blood-brain barrier. These discoveries challenge our traditional classification of neurological and psychiatric diseases. New clinical paths are required to identify subgroups of neuropsychiatric disorders that are phenotypically distinct but pathogenically related and to pave the way for mechanism-based immune treatments. Combined expertise from neurologists and psychiatrists will foster translation of these paths into clinical practice. The aim of this Review is to highlight outstanding findings that have transformed our understanding of neuropsychiatric diseases and to suggest new diagnostic and therapeutic criteria for the emerging field of immunoneuropsychiatry. DOI: 10.1038/s41582-019-0174-4 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 195 – Multiple Sklerose: Veröffentlichungen April 2019 288. Nat Rev Neurol. 2019 Apr 1. doi: 10.1038/s41582-019-0179-z. [Epub ahead of print] Author Correction: 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, Bari, Italy. [email protected]. (2)Department NEUROFARBA, Section Neurosciences, University of Florence, Florence, Italy. Erratum for Nat Rev Neurol. 2018 Jan 31;14(2):72-74. In the originally published article, Maria Pia Amato's affiliation was incomplete - it should have included IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy. This correction notice has been appended to the PDF version of the manuscript. DOI: 10.1038/s41582-019-0179-z 289. Nat Rev Rheumatol. 2019 May;15(5):288-302. doi: 10.1038/s41584-019-0212-z. Involvement of the myeloid cell compartment in fibrogenesis and systemic sclerosis. Kania G(1), Rudnik M(1), Distler O(2). Author information: (1)Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland. (2)Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland. [email protected]. Systemic sclerosis (SSc) is an autoimmune fibrotic disease of unknown aetiology that is characterized by vascular changes in the skin and visceral organs. Autologous haematopoietic stem cell transplantation can improve skin and organ fibrosis in patients with progressive disease and a high risk of organ failure, indicating that cells originating in the bone marrow are important contributors to the pathogenesis of SSc. Animal studies also indicate a pivotal function of myeloid cells in the development of fibrosis leading to changes in the tissue architecture and dysfunction in multiple organs such as the heart, lungs, liver and kidney. In this Review, we summarize current knowledge about the function of myeloid cells in fibrogenesis that occurs in patients with SSc. Targeted therapies currently in clinical studies for SSc might affect myeloid cell-related pathways. Therefore, myeloid cells might be used as cellular biomarkers of disease through the application of high-dimensional techniques such as mass cytometry and single-cell RNA sequencing. DOI: 10.1038/s41584-019-0212-z 290. Neural Regen Res. 2019 Aug;14(8):1380-1382. doi: 10.4103/1673-5374.253521. Galectin-3 prospects as a therapeutic agent for multiple sclerosis. Thomas L(1), Pasquini LA(1). Author information: (1)Department of Biological Chemistry, School of Pharmacy and Biochemistry, Institute of Chemistry Biological Physicochemistry (IQUIFIB), University of Buenos Aires and National Research Council (CONICET), Buenos Aires, Argentina. DOI: 10.4103/1673-5374.253521 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 | L.DE.MKT.SM.02.2017.5323 – 196 – Multiple Sklerose: Veröffentlichungen April 2019 291. Neurochem Int. 2019 Jun;126:229-238. doi: 10.1016/j.neuint.2019.03.018. Epub 2019 Mar 30. Pathological changes in mice with long term cuprizone administration. Nomura T(1), Bando Y(2), Nakazawa H(3), Kanemoto S(3), Yoshida S(3). Author information: (1)Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Midorigaoka-higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan. Electronic address: t- [email protected]. (2)Department of Anatomy, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan. (3)Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Midorigaoka-higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). In MS, a long disease duration is known to be a strong risk factor for converting the clinical course of the disease from relapse remitting MS to secondary progressing MS. There is a hypothesis that long sustained demyelination may exhaust neurons, however, pathological changes induced in neurons following demyelination remain unknown. Cuprizone administration can induce and sustain demyelination in the mouse CNS. We examined pathological changes in mice following long sustained demyelination caused by up to 34-week cuprizone administration. Twelve-week cuprizone administration induced severe demyelination in the cerebral cortex, corpus callosum and deep cerebellar nuclei. Demyelination persisted up to 34 weeks, as shown by myelin basic protein immunohistochemistry. In contrast, cuprizone administration developed demyelination in the striatum by week 34. In these demyelinated regions, no neuronal loss was observed. However, in the striatum and deep cerebellar nuclei, cuprizone-induced demyelination changed the intracellular distribution of parvalbumin (PV). Furthermore, in the striatum, there was an increase in PV in the demyelinated axons and most PV immunoreactivity did not co-localize with SMI32 immunoreactivity in mice with 34-week cuprizone administration. Further, mice with 34-week cuprizone administration showed motor coordination dysfunction in the balance beam test. However, 12- week withdrawal from the cuprizone diet induced remyelination in the regions and motor coordination dysfunction recovered. These results indicate that 34-week cuprizone administration induces and sustains demyelination and results in reversible motor coordination dysfunction. The change of intracellular PV distribution suggests that PV may protect demyelinated axons by Ca2+ buffering. This model may be useful to investigate pathological and behavioral changes following demyelination in the CNS. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.neuint.2019.03.018 292. Neurodegener Dis Manag. 2019 Apr 18. doi: 10.2217/nmt-2018-0043. [Epub ahead of print] Abdominal functional electrical stimulation for bowel management in multiple sclerosis. Street T(1), Peace C(2), Padfield E(1), Singleton C(2). Author information: (1)Salisbury NHS Foundation Trust, UK. (2)Birmingham Community Healthcare NHS Foundation Trust, UK. Aim: Functional constipation is common in multiple sclerosis (MS) and first line treatments are frequently ineffective. The current study explored the use of abdominal functional electrical stimulation (ABFES) for treating constipation in MS. Patients/methods: Twenty people with MS and constipation (ROME IV criteria). The patient assessment of constipation-related quality of life questionnaire was administered at baseline and after 6 weeks of ABFES treatment alongside semi-structured interviews. Results: All patient assessment of constipation-related quality of life subscales were significant: satisfaction (p = 0.003), psychosocial discomfort (p = 0.008), physical discomfort (p = 0.001) and worries and concerns (p = 0.003). A long-term therapeutic effect, reduction in laxative use and improved sexual functioning were also reported. Conclusion: ABFES provides a potential alternative treatment intervention for people with MS and constipation. DOI: 10.2217/nmt-2018-0043 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 197 – Multiple Sklerose: Veröffentlichungen April 2019 293. Neurogastroenterol Motil. 2019 Apr 8:e13592. doi: 10.1111/nmo.13592. [Epub ahead of print] Bowel symptoms predate the diagnosis among many patients with multiple sclerosis: A 14-year cohort study. Almeida MN(1)(2), Silvernale C(1)(2), Kuo B(1)(2), Staller K(1)(2)(3). Author information: (1)Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. (2)Center for Neurointestinal Health, Massachusetts General Hospital, Boston, Massachusetts. (3)Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts. BACKGROUND: Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease frequently complicated by bowel symptoms. Multiple sclerosis typically first manifests with a demyelination event, also known as a clinically isolated syndrome (CIS). We sought to examine the prevalence of prodromal bowel symptoms predating a CIS in patients with MS as part of a recently characterized prodromal phase of disease. METHODS: We constructed a retrospective cohort of MS patients with bowel symptoms and an identifiable CIS at two tertiary care centers over 14 years using administrative and billing data. We determined the date of onset of reported bowel symptoms in comparison with the date of first CIS and determined the overall prevalence of prediagnosis bowel symptoms within 1, 2, 3, and >3 years from a CIS. We used multivariable modeling to determine demographic and clinical risk factors for prediagnosis bowel symptoms. KEY RESULTS: Among 385 MS patients with reported bowel symptoms, 122 (31.6%) reported bowel symptoms prior to CIS. The most common first bowel symptom was constipation (50.0%), followed by diarrhea (29.5%). The average lead time between a first bowel symptom and a CIS event was 3.7 ± 3.4 years. Pre-CIS fatigue (OR 4.48, 95% CI: 2.68-7.51, P < 0.001) and pre-CIS sensory disturbances (OR 1.88, 95% CI: 1.15-3.08, P < 0.05) were all associated with bowel symptoms prior to a CIS event. CONCLUSIONS AND INFERENCES: Nearly a third of MS patients with bowel symptoms reported bowel symptoms prior to a demyelinating event/CIS. Characterization of a prodromal phase of disease may provide important insights into understanding disease progression. © 2019 John Wiley & Sons Ltd. DOI: 10.1111/nmo.13592 294. Neuroimage. 2019 Mar 29;195:373-383. doi: 10.1016/j.neuroimage.2019.03.060. [Epub ahead of print] DeepQSM - using deep learning to solve the dipole inversion for quantitative susceptibility mapping. Bollmann S(1), Rasmussen KGB(2), Kristensen M(2), Blendal RG(2), Østergaard LR(2), Plocharski M(2), O'Brien K(3), Langkammer C(4), Janke A(5), Barth M(5). Author information: (1)Centre for Advanced Imaging, The University of Queensland, Building 57 of University Dr, St Lucia, QLD, 4072, Brisbane, Australia. Electronic address: [email protected]. (2)Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 7, 9000, Aalborg, Denmark. (3)Centre for Advanced Imaging, The University of Queensland, Building 57 of University Dr, St Lucia, QLD, 4072, Brisbane, Australia; Siemens Healthcare Pty Ltd, Brisbane, Australia. (4)Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036, Graz, Austria. (5)Centre for Advanced Imaging, The University of Queensland, Building 57 of University Dr, St Lucia, QLD, 4072, Brisbane, Australia. Quantitative susceptibility mapping (QSM) is based on magnetic resonance imaging (MRI) phase measurements and has gained broad interest because it yields relevant information on biological tissue properties, predominantly myelin, iron and calcium in vivo. Thereby, QSM can also reveal pathological changes of these key components in widespread diseases such as Parkinson's disease, Multiple Sclerosis, or hepatic iron overload. While the ill-posed field-to-source-inversion problem underlying QSM is conventionally assessed by the means of regularization techniques, we trained a fully convolutional deep neural network - DeepQSM - to directly invert the magnetic dipole kernel convolution. DeepQSM learned the physical forward problem using purely synthetic data and is capable of solving the ill-posed field-to-source inversion on in vivo MRI phase data. The magnetic susceptibility maps reconstructed by DeepQSM enable identification of deep brain substructures and provide information on their respective magnetic tissue properties. In summary, DeepQSM can invert the magnetic dipole kernel convolution and delivers robust solutions to this ill-posed problem. Copyright © 2019 Elsevier Inc. All rights reserved. DOI: 10.1016/j.neuroimage.2019.03.060 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 198 – Multiple Sklerose: Veröffentlichungen April 2019 295. Neuroimage. 2019 Apr 3;196:1-15. doi: 10.1016/j.neuroimage.2019.03.068. [Epub ahead of print] Multi-branch convolutional neural network for multiple sclerosis lesion segmentation. Aslani S(1), Dayan M(2), Storelli L(3), Filippi M(3), Murino V(4), Rocca MA(3), Sona D(5). Author information: (1)Pattern Analysis and Computer Vision (PAVIS), Istituto Italiano di Tecnologia (IIT), Genoa, Italy; Science and Technology for Electronic and Telecommunication Engineering, University of Genoa, Italy. Electronic address: [email protected]. (2)Pattern Analysis and Computer Vision (PAVIS), Istituto Italiano di Tecnologia (IIT), Genoa, Italy; Human Neuroscience Platform, Fondation Campus Biotech Geneva, Switzerland. (3)Neuroimaging Research Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. (4)Pattern Analysis and Computer Vision (PAVIS), Istituto Italiano di Tecnologia (IIT), Genoa, Italy; Dipartimento di Informatica, University of Verona, Italy. (5)Pattern Analysis and Computer Vision (PAVIS), Istituto Italiano di Tecnologia (IIT), Genoa, Italy; NeuroInformatics Laboratory, Fondazione Bruno Kessler, Trento, Italy. Electronic address: [email protected]. In this paper, we present an automated approach for segmenting multiple sclerosis (MS) lesions from multi- modal brain magnetic resonance images. Our method is based on a deep end-to-end 2D convolutional neural network (CNN) for slice-based segmentation of 3D volumetric data. The proposed CNN includes a multi-branch downsampling path, which enables the network to encode information from multiple modalities separately. Multi-scale feature fusion blocks are proposed to combine feature maps from different modalities at different stages of the network. Then, multi-scale feature upsampling blocks are introduced to upsize combined feature maps to leverage information from lesion shape and location. We trained and tested the proposed model using orthogonal plane orientations of each 3D modality to exploit the contextual information in all directions. The proposed pipeline is evaluated on two different datasets: a private dataset including 37 MS patients and a publicly available dataset known as the ISBI 2015 longitudinal MS lesion segmentation challenge dataset, consisting of 14 MS patients. Considering the ISBI challenge, at the time of submission, our method was amongst the top performing solutions. On the private dataset, using the same array of performance metrics as in the ISBI challenge, the proposed approach shows high improvements in MS lesion segmentation compared with other publicly available tools. Copyright © 2019 Elsevier Inc. All rights reserved. DOI: 10.1016/j.neuroimage.2019.03.068 296. Neurol Med Chir (Tokyo). 2019 Apr 17. doi: 10.2176/nmc.oa.2018-0287. [Epub ahead of print] Usefulness of [11C] Methionine PET in the Differentiation of Tumefactive Multiple Sclerosis from High Grade Astrocytoma. Hashimoto S(1), Inaji M(1)(2), Nariai T(1)(2), Kobayashi D(3), Sanjo N(4), Yokota T(4), Ishii K(2), Taketoshi M(1). Author information: (1)Department of Neurosurgery, Tokyo Medical and Dental University. (2)Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology. (3)Department of Human Pathology, Tokyo Medical and Dental University. (4)Department of Neurology and Neurological Science, Tokyo Medical and Dental University. Tumefactive multiple sclerosis (tumefactive MS) is an atypical variant of MS characterized by a large isolated demyelinating lesion. Because tumefactive MS mimics high grade astrocytoma clinically and radiologically, it is difficult to distinguish between the two using only traditional diagnostic modalities, such as routine magnetic resonance imaging. [11C] methionine positron emission tomography (MET PET) has been known as a useful diagnostic tool for glioma. However, it has not been established as a diagnostic tool for tumefactive MS yet. Therefore, the objective of this study was to evaluate the performance of MET PET in differentiating tumefactive MS from high grade astrocytoma. We studied patients with tumefactive MS [six patients (three men, three women), 7 lesions] and 77 patients with astrocytoma (World Health Organization grade II: 13 patients, grade III: 28 patients, and grade IV: 36 patients), and we compared MET uptake of tumefactive demyelinating lesions and astrocytoma. For MET PET analysis, Lesion/Normal region ratios (L/N ratios) were calculated and compared between tumefactive demyelinating lesions and astrocytoma. On MET PET, the L mean/N ratio of tumefactive MS was 1.18 ± 0.50, which was significantly lower than that of high- grade glioma (astrocytoma grade III: 1.95 ± 0.62, P = 0.006; grade IV: 2.35 ± 0.54, P <0.0001). The L maximum (L max)/N ratio of tumefactive demyelinating lesion was also significantly lower than that of high grade astrocytoma (tumefactive MS: 1.89 ± 0.55; astrocytoma grade III: 3.37 ± 1.36, P = 0.0232; astrocytoma grade IV: 4.35 ± 1.30, P <0.0001). In conclusion, MET PET can help differentiate tumefactive MS from high grade astrocytoma. DOI: 10.2176/nmc.oa.2018-0287 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 199 – Multiple Sklerose: Veröffentlichungen April 2019 297. Neurol Res. 2019 Apr 26:1-8. doi: 10.1080/01616412.2019.1609203. [Epub ahead of print] Cognitive and physical disability in Egyptian patients with multiple sclerosis: genetic and optical coherence tomography study. Abdel Naseer M(1), Fathi S(1), Roshdy NK(2), Labib DM(1), Khalil DH(3), Ibrahim W(4), Magdy R(1). Author information: (1)a Department of Neurology, Faculty of Medicine , Cairo University , Cairo , Egypt. (2)b Department of Medical Biochemistry and Molecular Biology , Future University , Khartoum , Egypt. (3)c Department of Ophthalmology, Faculty of Medicine , Cairo University , Cairo , Egypt. (4)d Department of Medical Biochemistry, Faculty of Medicine , Cairo University , Cairo , Egypt. OBJECTIVES: The aim of this study was to explore the relationship between cognitive dysfunction, neurodegeneration, and genetic factors among multiple sclerosis (MS) patients. METHODS: Fifty patients of definite MS were included. Physical disability was assessed by expanded disability status scale (EDSS). Cognitive functions were assessed by using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). For each eye, optical coherence tomography (OCT) was used to track thickness of retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC), respecting the previous history of optic neuritis (ON). All patients were genotyped for glutamate N-methyl-D-aspartate receptors (NMDARs). RESULTS: A statistically significant negative correlation was found between scores of EDSS and each of neuropsychological tests scores and thickness of both RNFL and GCC. The predictor for progressive disability assessed by EDSS was Symbol Digit Modalities Test (SDMT) (P = 0.021), that is dependent on the educational level of the patients (P = 0.016). A statistically significant positive correlation was found between scores of all neuropsychological tests and the thickness of both RNFL and GCC. Eighty-three percent of MS patients with CC genotype reported previous attacks of ON with significant thinning in RNFL and GCC despite their higher cognitive performance in comparison to other genotypes. DISCUSSION: Deficit in information processing speed measured by SDMT is a predictor of early progressive disability in MS patients. Thinning of RNFL and GCC is a potential biomarker for cognitive and physical disability in MS. The CC genotype of glutamate NMDAR gene has a divergent effect on visual and cognitive functions. DOI: 10.1080/01616412.2019.1609203 298. Neurol Sci. 2019 May;40(5):1099-1100. doi: 10.1007/s10072-019-03880-w. Correction to: Normative values of the Rao's Brief Repeatable Battery in an Italian young adolescent population: the influence of age, gender, and education. Falco F(1), Moccia M(2), Chiodi A(3), Carotenuto A(1), D'Amelio A(3), Rosa L(4), Piscopo K(4), Falco A(1), Costabile T(1), Lauro F(1), Brescia Morra V(1), Lanzillo R(1). Author information: (1)Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Via Sergio Pansini, 5 - Building 17, Ground floor, Naples, Italy. (2)Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Via Sergio Pansini, 5 - Building 17, Ground floor, Naples, Italy. [email protected]. (3)Clinical Psychology Unit, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy. (4)Active Inclusion and Student Participation Service, Federico II University of Naples, Naples, Italy. Erratum for Neurol Sci. 2019 Apr;40(4):713-717. The published version of this article unfortunately contained a mistake in Table 2. DOI: 10.1007/s10072-019-03880-w Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 200 – Multiple Sklerose: Veröffentlichungen April 2019 299. Neurol Sci. 2019 Apr 23. doi: 10.1007/s10072-019-03875-7. [Epub ahead of print] Aging with multiple sclerosis: prevalence and profile of cognitive impairment. Branco M(1)(2), Ruano L(1)(2)(3), Portaccio E(4), Goretti B(4)(5), Niccolai C(5), Patti F(6), Chisari C(6), Gallo P(7), Grossi P(7)(8), Ghezzi A(9), Roscio M(9), Mattioli F(10), Bellomi F(10), Simone M(11), Viterbo RG(12), Amato MP(13)(14). Author information: (1)Neurology Department, Centro Hospitalar de Entre Douro e Vouga, Santa Maria da Feira, Portugal. (2)Departamento de Epidemiologia Clínica Medicina Preditiva e Saúde Pública, Faculdade de Medicina da Universidade do Porto, Porto, Portugal. (3)EPIUnit, Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal. (4)SOC Neurologia - Firenze, AUSL Toscana Centro, Florence, Italy. (5)Department NEUROFARBA, Section Neurosciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy. (6)University of Catania, Catania, Italy. (7)University of Padova, Padova, Italy. (8)Department, ASST Crema, Neuroimmunology Center, Cardiocerebrovascular, Crema, Italy. (9)Gallarate Hospital, Varese, Italy. (10)ASST Spedali Civili Brescia Neuropsychology Unit, Brescia, Italy. (11)Department of Basic Medical Sciences, Child and Adolescence Neuropsychiatry Unit, Neuroscience and Sense Organs, University "Aldo Moro" Bari, Bari, Italy. (12)University of Bari, Bari, Italy. (13)Department NEUROFARBA, Section Neurosciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy. [email protected]. (14)IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy. [email protected]. BACKGROUND: The increase in life expectancy of patients with multiple sclerosis (MS) requires a better knowledge of disease features in the older patients group. OBJECTIVE: To describe the prevalence and profile of cognitive impairment (CI) in older patients with MS and perform a comparison with younger patients. METHODS: Patients were consecutively recruited for 6 months. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop Test. CI was defined as impairment in ≥ 2 cognitive domains. RESULTS: We identified 111 patients older than 55 years (mean age 59.7 years). The prevalence of CI was 77.4%, which was significantly higher than in younger patients (42.8%; p < 0.01). Information processing speed was the most impaired domain (68.8%), followed by verbal learning (49.5%), executive function (47.7%), and visuospatial learning (26.6%). We found no significant differences in the prevalence of impairment in the distinct cognitive domains between older and younger patients with CI. Depression and fatigue were not associated with increased CI among patients in the older age group (p > 0.70). CONCLUSION: There is a remarkably high frequency of CI in older patients with MS. The similar profile of CI between older and younger patients suggests that CI is mostly directly related to MS itself and not to comorbid age-related disorders. DOI: 10.1007/s10072-019-03875-7 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 201 – Multiple Sklerose: Veröffentlichungen April 2019 300. Neurol Sci. 2019 Apr 22. doi: 10.1007/s10072-019-03878-4. [Epub ahead of print] Long-term disability outcomes in relapsing-remitting multiple sclerosis: a 10-year follow-up study. Drulovic J(1)(2), Ivanovic J(3), Mesaros S(4)(3), Martinovic V(4), Kisic-Tepavcevic D(5), Dujmovic I(4)(3), Pekmezovic T(5). Author information: (1)Clinic of Neurology, Clinical Center of Serbia, Dr Subotica 6, Belgrade, 11000, Serbia. [email protected]. (2)Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia. [email protected]. (3)Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, 11000, Serbia. (4)Clinic of Neurology, Clinical Center of Serbia, Dr Subotica 6, Belgrade, 11000, Serbia. (5)Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Visegradska 26A, Belgrade, 11000, Serbia. OBJECTIVE: The aim of this study is to assess the impact of interferon (IFN) beta treatment on the development of worsening disability in relapsing-remitting (RR) multiple sclerosis (MS) patients in the single- center observation cohort. METHOD: This is a prospective study of 236 IFN-beta-treated and 183 untreated RRMS patients recruited consecutively at the Clinic of Neurology in Belgrade (Serbia). Out of this original cohort, 10-year follow-up data were available for 233 IFN-beta-treated and 131 untreated subjects. The median time since recruitment was 9.7 years. RESULTS: IFN-beta treatment significantly delayed (p < 0.001) the time to reach each of the clinical outcomes (secondary progression-SP, EDSS scores 4 and 6) since recruitment. Time from the first visit to SP was reached after 9.7 years for IFN-beta-treated vs. 7.8 years for untreated patients. The delay for the development of EDSS score ≥ 4 from the first visit was 1.6 years (8.7 years for IFN-beta-treated vs. 7.1 years for untreated patients). Time from the first visit to EDSS score of 6 was reached after 9.8 years for IFN-beta-treated vs. 8.8 years for untreated patients. The IFN-beta-treated group showed significant reduction (p < 0.001) in the risk of conversion to SP when compared with untreated patients (HR = 0.22). There was also a significant difference in reaching EDSS scores 4 and 6 (p < 0.001), in favor of the IFN-beta-treated group (HR = 0.40 and HR = 0.27, respectively). CONCLUSION: Comparison of outcomes in our IFN-beta-treated vs. untreated RRMS patients suggests that this treatment may delay development of long-term disability in MS. DOI: 10.1007/s10072-019-03878-4 301. Neurol Sci. 2019 Apr 18. doi: 10.1007/s10072-019-03889-1. [Epub ahead of print] A complex relation between depression and multiple sclerosis: a descriptive review. Corallo F(1), Lo Buono V(1), Genovese R(1), Palmeri R(1), Di Cara M(1), Rifici C(1), Sessa E(1), D'Aleo G(1), Galletti F(2), Bonanno L(1), Marino S(3). Author information: (1)IRCCS Centro Neurolesi "Bonino-Pulejo", S.S. 113 Via Palermo, C.da Casazza, 98124, Messina, Italy. (2)University of Messina, Messina, Italy. (3)IRCCS Centro Neurolesi "Bonino-Pulejo", S.S. 113 Via Palermo, C.da Casazza, 98124, Messina, Italy. [email protected]. BACKGROUND: Multiple sclerosis (MS) is a demyelinating neurodegenerative disease that affects central nervous system (CNS). MS patients are more likely to develop depressive symptoms than patients with other chronic diseases. OBJECTIVE: In this review, we have analysed if there is a correlation between brain lesions (BL), structural damage (SD) and depressive symptoms (DS). METHODS: We Searched on PubMed and Web of Science databases and screening references of included studied and some review article for additional citations. From initial 745 studies, only 9 met the inclusion criteria. All studies conducted research on 389 patients with MS associated with DS and 120 HC (healthy controls). RESULTS: The selected researches highlighted the involvement of limbic system, the role of hippocampus and the impact of brain lesions on the emotional status of MS patients. DISCUSSION: In the genesis of depression are implicated many mechanisms including genetic, biochemical, immunological and psychosocial factors, even if a prominent role in the onset of DS seem to be associated with structural and functional brain alterations. DOI: 10.1007/s10072-019-03889-1 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 202 – Multiple Sklerose: Veröffentlichungen April 2019 302. Neurol Ther. 2019 Apr 12. doi: 10.1007/s40120-019-0136-1. [Epub ahead of print] Exercise in Multiple Sclerosis: Knowing is Not Enough-The Crucial Role of Intention Formation and Intention Realization. Schüler J(1), Wolff W(2)(3), Dettmers C(4). Author information: (1)University of Konstanz, Constance, Baden-Württemberg, Germany. [email protected]. (2)University of Konstanz, Constance, Baden-Württemberg, Germany. (3)University of Bern, Bern, Switzerland. (4)Kliniken Schmieder Konstanz, Constance, Baden-Württemberg, Germany. A large body of evidence supports the notion that patients with multiple sclerosis (MS) benefit from physical exercise. However, this research-based recommendation has been insufficiently translated into practice. In this commentary article, we highlight the psychological evidence for the intention-behaviour gap and discuss evidence-based recommendations for bridging this gap, with the aim to change behaviour in MS patients. It is accepted that psychological research distinguishes intention formation from intention realization and that these processes have to be considered when the aim is to enhance physical activity in MS patients. We suggest that the transtheoretical model of behaviour change is a useful and general framework for examining the process of intention formation and that a MS-specific perspective is more useful for realizing exercise intention. MS patients are faced with severe self-control demands that hinder the realization of sport and exercise goals. Specifically, MS patients experience fatigue, which imposes substantial self-control demands. Here, we suggest implementation intention as an effective tool that aids in counteracting deficits in intention realization (getting started and staying on track). We also note that research knowledge is not sufficiently translated into clinical practice. Based on an interdisciplinary approach we recommend that therapists of MS patients should be more aware of psychological theories of health behaviour change and that they should use these to improve and optimize treatment approaches. DOI: 10.1007/s40120-019-0136-1 303. Neurologia. 2019 Apr 5. pii: S0213-4853(19)30030-1. doi: 10.1016/j.nrl.2018.12.010. [Epub ahead of print] Restless legs syndrome in patients with multiple sclerosis: evaluation of risk factors and clinical impact. [Article in English, Spanish] Lebrato Hernández L(1), Prieto León M(1), Cerdá Fuentes NA(1), Uclés Sánchez AJ(1), Casado Chocán JL(1), Díaz Sánchez M(2). Author information: (1)Departamento de Neurología, Hospital Universitario Virgen del Rocío, Sevilla, España. (2)Departamento de Neurología, Hospital Universitario Virgen del Rocío, Sevilla, España. Electronic address: [email protected]. INTRODUCTION: Restless legs syndrome (RLS) is a disorder characterised by an irresistible urge to move the legs, usually accompanied by unpleasant sensations. It is more frequent in patients with multiple sclerosis (MS) than in the general population. OBJECTIVES: To evaluate the prevalence of RLS, defined according to the 4 essential requirements included in the diagnostic criteria proposed by the International Restless Leg Syndrome Study Group, in a cohort of patients with MS; and to identify potential risk factors and the clinical impact of RLS. RESULTS: The sample included 120 patients with MS, with a mean age of symptom onset of 40 years and an average disease duration of 46 months. The prevalence rate of RLS was 23.3%. MS progression time was significantly shorter in patients with RLS (P = 0.001). A recent relapse, and symptoms of anxiety, depression, and neuropathic pain were significantly associated with risk of RLS (P = 0.001, P < 0.001, P < 0.001, and P = 0.001, respectively). In addition, patients with RLS had a greater risk of poor sleep quality, fatigue, daytime sleepiness, and poor quality of life than those without RLS (P = 0.002, P = 0.017, P = 0.013, and P = 0.009, respectively). CONCLUSIONS: RLS should be considered in the neurological evaluation of patients with MS; early diagnosis and treatment would improve the quality of life of patients with MS presenting RLS. Copyright © 2019 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved. DOI: 10.1016/j.nrl.2018.12.010 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 203 – Multiple Sklerose: Veröffentlichungen April 2019 304. Neurology. 2019 Apr 5. pii: 10.1212/WNL.0000000000007451. doi: 10.1212/WNL.0000000000007451. [Epub ahead of print] Natalizumab-associated progressive multifocal leukoencephalopathy in Germany. Blankenbach K(1), Schwab N(1), Hofner B(1), Adams O(1), Keller-Stanislawski B(1), Warnke C(2). Author information: (1)From the Department Safety of Medicinal Products and Medical Devices (K.B., B.K.- S.), and Section Biostatistics (B.H.), Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen; Clinic of Neurology with Institute of Translational Neurology (N.S.), University Hospital Muenster, University Muenster; Institute for Virology (O.A.), University of Duesseldorf, Medical Faculty, Duesseldorf; and Department of Neurology (C.W.), University Hospital Koeln, Germany. (2)From the Department Safety of Medicinal Products and Medical Devices (K.B., B.K.-S.), and Section Biostatistics (B.H.), Paul-Ehrlich- Institut, Federal Institute for Vaccines and Biomedicines, Langen; Clinic of Neurology with Institute of Translational Neurology (N.S.), University Hospital Muenster, University Muenster; Institute for Virology (O.A.), University of Duesseldorf, Medical Faculty, Duesseldorf; and Department of Neurology (C.W.), University Hospital Koeln, Germany. [email protected]. OBJECTIVE: To evaluate characteristics relevant to diagnosis of JC polyomavirus-associated progressive multifocal leukoencephalopathy (PML), and PML risk stratification in a large national cohort of patients with multiple sclerosis during therapy with natalizumab. METHODS: Analysis of 292 adverse drug reaction forms on suspected cases of PML reported to the German national competent authority until July 2017. Patients not fulfilling PML diagnostic criteria or with insufficient information available were excluded. RESULTS: Of the 142 confirmed patients with PML, 72.3% (95% confidence interval [CI] 64.4%-79.1%) were women, and the median age was 43 years (range 19-69). Of these patients, 7.7% (95% CI 4.3%-13.5%) were clinically asymptomatic at time of PML diagnosis. PML was fatal in 9.1% (95% CI 5.3%-15.1%) of the patients. Infratentorial lesions on imaging were reported in 40% (95% CI 32.0%-48.6%) of the patients. JC polyomavirus DNA in CSF was undetectable at time of first analysis in 23.8% (95% CI 17.3%-31.9%) of the patients. Three patients tested negative for anti-JC polyomavirus antibodies within 6 to 18 months before PML diagnosis, with seroconversion confirmed 5.5 months, 7 months (in a post hoc analysis only), or at time of PML diagnosis. CONCLUSIONS: JC polyomavirus DNA detection in CSF has limited sensitivity in early PML, and clinical and imaging presentation may be atypical. Thus, critical revision of current PML diagnostic criteria is warranted. Negative anti-JC polyomavirus antibodies in sera do not preclude the later development of PML. This emphasizes the need for close and regular serologic, imaging, and clinical monitoring in patients treated with natalizumab. © 2019 American Academy of Neurology. DOI: 10.1212/WNL.0000000000007451 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 204 – Multiple Sklerose: Veröffentlichungen April 2019 305. Neurology. 2019 Apr 30;92(18):e2127-e2135. doi: 10.1212/WNL.0000000000006800. Epub 2019 Apr 3. Total intake of different minerals and the risk of multiple sclerosis. Cortese M(1), Chitnis T(2), Ascherio A(2), Munger KL(2). Author information: (1)From the Departments of Nutrition (M.C., A.A., K.L.M.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Global Public Health and Primary Care (M.C.), University of Bergen, Norway; and Partners Multiple Sclerosis Center (T.C.) and Channing Division of Network Medicine, Department of Medicine (A.A.), Brigham and Women's Hospital, Boston, MA. [email protected]. (2)From the Departments of Nutrition (M.C., A.A., K.L.M.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Global Public Health and Primary Care (M.C.), University of Bergen, Norway; and Partners Multiple Sclerosis Center (T.C.) and Channing Division of Network Medicine, Department of Medicine (A.A.), Brigham and Women's Hospital, Boston, MA. OBJECTIVE: To investigate the association between mineral intake (potassium, magnesium, calcium, phosphorus, iron, zinc, manganese, copper) and multiple sclerosis (MS) risk. METHODS: In a prospective cohort study, we assessed dietary and supplemental mineral intake by a validated food frequency questionnaire administered every 4 years to 80,920 nurses in the Nurses' Health Study (1984-2002) and 94,511 in the Nurses' Health Study II (1991-2007). There were 479 new MS cases during follow-up. We estimated hazard ratios and 95% confidence intervals for the association of energy-adjusted mineral intake with MS risk using Cox regression, adjusting for age, residence latitude at age 15, ancestry, body mass index at age 18, supplemental vitamin D, smoking, and total energy intake. RESULTS: We did not find any association between the minerals and MS risk, either for baseline or cumulative intake during follow-up. The associations were null comparing women with highest to those with lowest intakes in quintiles or deciles and there was no significant trend for higher intakes (p trend across baseline quintiles: potassium 0.35, magnesium 0.13, calcium 0.22, phosphorus 0.97, iron 0.85, zinc 0.67, manganese 0.48, copper 0.59). CONCLUSIONS: Our findings suggest that mineral intake is not an important determinant of MS risk. © 2019 American Academy of Neurology. DOI: 10.1212/WNL.0000000000006800 306. Neurology. 2019 Apr 26. pii: 10.1212/WNL.0000000000007576. doi: 10.1212/WNL.0000000000007576. [Epub ahead of print] Severe transient myopathy in a progressive multiple sclerosis patient with high- dose biotin. Maillart E(1), Mochel F(2), Acquaviva C(2), Maisonobe T(2), Stankoff B(2). Author information: (1)From the Department of Neurology (E.M.), Department of Genetics and Reference Centre for Adult Neurometabolic Diseases (F.M.), and Department of Neurophysiology and Neuropathology (T.M.), AP-HP, Hôpital Pitié-Salpêtrière; Institut du Cerveau et de la Moelle Épinière, UPMC-Paris 6, UMR S 1127 and Inserm U 1127, and CNRS UMR 7225 (F.M., B.S.), Sorbonne Université, Paris, France; Laboratory of Inborn Errors of Metabolism (C.A.), Centre Hospitalier Universitaire de Lyon, France; and Department of Neurology (B.S.), AP-HP, Hôpital Saint-Antoine, Paris, France. [email protected]. (2)From the Department of Neurology (E.M.), Department of Genetics and Reference Centre for Adult Neurometabolic Diseases (F.M.), and Department of Neurophysiology and Neuropathology (T.M.), AP-HP, Hôpital Pitié-Salpêtrière; Institut du Cerveau et de la Moelle Épinière, UPMC-Paris 6, UMR S 1127 and Inserm U 1127, and CNRS UMR 7225 (F.M., B.S.), Sorbonne Université, Paris, France; Laboratory of Inborn Errors of Metabolism (C.A.), Centre Hospitalier Universitaire de Lyon, France; and Department of Neurology (B.S.), AP-HP, Hôpital Saint-Antoine, Paris, France. DOI: 10.1212/WNL.0000000000007576 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 205 – Multiple Sklerose: Veröffentlichungen April 2019 307. Neurology. 2019 Apr 19. pii: 10.1212/WNL.0000000000007447. doi: 10.1212/WNL.0000000000007447. [Epub ahead of print] Temporal lobe epilepsy: Hippocampal pathology modulates connectome topology and controllability. Bernhardt BC(1), Fadaie F(1), Liu M(1), Caldairou B(1), Gu S(1), Jefferies E(1), Smallwood J(1), Bassett DS(1), Bernasconi A(1), Bernasconi N(2). Author information: (1)From the Neuroimaging of Epilepsy Laboratory (B.C.B., F.F., M.L., B.C., A.B., N.B.) and Multimodal Imaging and Connectome Analysis Laboratory (B.C.B.), McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Canada; Department of Bioengineering and Electrical and Systems Engineering (S.G., D.S.B.), University of Pennsylvania, Philadelphia; and York Neuroimaging Center (E.J., J.S.), University of York, UK. (2)From the Neuroimaging of Epilepsy Laboratory (B.C.B., F.F., M.L., B.C., A.B., N.B.) and Multimodal Imaging and Connectome Analysis Laboratory (B.C.B.), McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Canada; Department of Bioengineering and Electrical and Systems Engineering (S.G., D.S.B.), University of Pennsylvania, Philadelphia; and York Neuroimaging Center (E.J., J.S.), University of York, UK. [email protected]. OBJECTIVE: To assess whether hippocampal sclerosis (HS) severity is mirrored at the level of large-scale networks. METHODS: We studied preoperative high-resolution anatomical and diffusion-weighted MRI of 44 temporal lobe epilepsy (TLE) patients with histopathologic diagnosis of HS (n = 25; TLE-HS) and isolated gliosis (n = 19; TLE-G) and 25 healthy controls. Hippocampal measurements included surface-based subfield mapping of atrophy and T2 hyperintensity indexing cell loss and gliosis, respectively. Whole-brain connectomes were generated via diffusion tractography and examined using graph theory along with a novel network control theory paradigm that simulates functional dynamics from structural network data. RESULTS: Compared to controls, we observed markedly increased path length and decreased clustering in TLE-HS compared to controls, indicating lower global and local network efficiency, while TLE-G showed only subtle alterations. Similarly, network controllability was lower in TLE-HS only, suggesting limited range of functional dynamics. Hippocampal imaging markers were positively associated with macroscale network alterations, particularly in ipsilateral CA1-3. Systematic assessment across several networks revealed maximal changes in the hippocampal circuity. Findings were consistent when correcting for cortical thickness, suggesting independence from gray matter atrophy. CONCLUSIONS: Severe HS is associated with marked remodeling of connectome topology and structurally governed functional dynamics in TLE, as opposed to isolated gliosis, which has negligible effects. Cell loss, particularly in CA1-3, may exert a cascading effect on brain- wide connectomes, underlining coupled disease processes across multiple scales. © 2019 American Academy of Neurology. DOI: 10.1212/WNL.0000000000007447 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 206 – Multiple Sklerose: Veröffentlichungen April 2019 308. Neurology. 2019 Apr 19. pii: 10.1212/WNL.0000000000007499. doi: 10.1212/WNL.0000000000007499. [Epub ahead of print] Diagnosing and quantifying a common deficit in multiple sclerosis: Internuclear ophthalmoplegia. Nij Bijvank JA(1), van Rijn LJ(2), Balk LJ(2), Tan HS(2), Uitdehaag BMJ(2), Petzold A(2). Author information: (1)From Amsterdam UMC (J.A.N.B., L.J.B., A.P.), Vrije Universiteit Amsterdam, Department of Neurology, MS Center and Neuro-ophthalmology Expertise Center, Neuroscience Amsterdam; Amsterdam UMC (J.A.N.B., L.J.v.R., H.S.T., A.P.), Vrije Universiteit Amsterdam, Department of Ophthalmology, Neuro-ophthalmology Expertise Center, Neuroscience Amsterdam; Onze Lieve Vrouwe Gasthuis (L.J.v.R., B.M.J.U.), Department of Ophthalmology, Amsterdam, the Netherlands; and Moorfields Eye Hospital and the National Hospital for Neurology and Neurosurgery (A.P.), London, UK. [email protected]. (2)From Amsterdam UMC (J.A.N.B., L.J.B., A.P.), Vrije Universiteit Amsterdam, Department of Neurology, MS Center and Neuro-ophthalmology Expertise Center, Neuroscience Amsterdam; Amsterdam UMC (J.A.N.B., L.J.v.R., H.S.T., A.P.), Vrije Universiteit Amsterdam, Department of Ophthalmology, Neuro-ophthalmology Expertise Center, Neuroscience Amsterdam; Onze Lieve Vrouwe Gasthuis (L.J.v.R., B.M.J.U.), Department of Ophthalmology, Amsterdam, the Netherlands; and Moorfields Eye Hospital and the National Hospital for Neurology and Neurosurgery (A.P.), London, UK. OBJECTIVE: We present an objective and quantitative approach for diagnosing internuclear ophthalmoplegia (INO) in multiple sclerosis (MS). METHODS: A validated standardized infrared oculography protocol (DEMoNS [Demonstrate Eye Movement Networks with Saccades]) was used for quantifying prosaccades in patients with MS and healthy controls (HCs). The versional dysconjugacy index (VDI) was calculated, which describes the ratio between the abducting and adducting eye. The VDI was determined for peak velocity, peak acceleration, peak velocity divided by amplitude, and area under the curve (AUC) of the saccadic trajectory. We calculated the diagnostic accuracy for the several VDI parameters by a receiver operating characteristic analysis comparing HCs and patients with MS. The National Eye Institute Visual Function Questionnaire-25 was used to investigate vision-related quality of life of MS patients with INO. RESULTS: Two hundred ten patients with MS and 58 HCs were included. The highest diagnostic accuracy was achieved by the VDI AUC of 15° horizontal prosaccades. Based on a combined VDI AUC and peak velocity divided by amplitude detection, the prevalence of an INO in MS calculated to 34%. In the INO group, 35.2% of the patients with MS reported any complaints of double vision, compared to 18.4% in the non-INO group (p = 0.010). MS patients with an INO had a lower overall vision-related quality of life (median 89.9, interquartile range 12.8) compared to patients without an INO (median 91.8, interquartile range 9.3, p = 0.011). CONCLUSIONS: This study provides an accurate quantitative and clinically relevant definition of an INO in MS. This infrared oculography-based INO standard will require prospective validation. The high prevalence of INO in MS provides an anatomically well described and accurately quantifiable model for treatment trials in MS. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. DOI: 10.1212/WNL.0000000000007499 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 207 – Multiple Sklerose: Veröffentlichungen April 2019 309. Neurology. 2019 Apr 10. pii: 10.1212/WNL.0000000000007450. doi: 10.1212/WNL.0000000000007450. [Epub ahead of print] Damage of the lateral geniculate nucleus in MS: Assessing the missing node of the visual pathway. Papadopoulou A(1), Gaetano L(2), Pfister A(2), Altermatt A(2), Tsagkas C(2), Morency F(2), Brandt AU(2), Hardmeier M(2), Chakravarty MM(2), Descoteaux M(2), Kappos L(2), Sprenger T(2), Magon S(2). Author information: (1)From the Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, and Biomedical Engineering (A. Papadopoulou, L.G., A. Pfister, C.T., M.H., L.K., T.S., S.M.), and Translational Imaging in Neurology (ThINK) Basel, Department of Medicine and Biomedical Engineering (A. Papadopoulou, L.G., A.A., C.T., S.M.), University Hospital Basel and University of Basel, Switzerland; NeuroCure Clinical Research Center (NCRC) (A. Papadopoulou, A.U.B.), and Experimental and Clinical Research Center (A. Papadopoulou, A.U.B.), Max Delbrück Center for Molecular Medicine, Charité- Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Medical Image Analysis Center (MIAC) (L.G., A.A., C.T., S.M.), Basel, Switzerland; Imeka Solutions (F.M.), Sherbrooke, Canada; Department of Neurology (A.U.B.), University of California Irvine; Cerebral Imaging Centre (M.M.C.), Douglas Mental Health University Institute; Departments of Psychiatry and Biomedical Engineering (M.M.C.), McGill University, Montreal; University of Sherbrooke (M.D.), Canada; and Department of Neurology (T.S.), DKD Helios Klinik Wiesbaden, Germany. The present address for L.G. is F. Hoffmann-La Roche, Basel, Switzerland. [email protected]. (2)From the Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, and Biomedical Engineering (A. Papadopoulou, L.G., A. Pfister, C.T., M.H., L.K., T.S., S.M.), and Translational Imaging in Neurology (ThINK) Basel, Department of Medicine and Biomedical Engineering (A. Papadopoulou, L.G., A.A., C.T., S.M.), University Hospital Basel and University of Basel, Switzerland; NeuroCure Clinical Research Center (NCRC) (A. Papadopoulou, A.U.B.), and Experimental and Clinical Research Center (A. Papadopoulou, A.U.B.), Max Delbrück Center for Molecular Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Medical Image Analysis Center (MIAC) (L.G., A.A., C.T., S.M.), Basel, Switzerland; Imeka Solutions (F.M.), Sherbrooke, Canada; Department of Neurology (A.U.B.), University of California Irvine; Cerebral Imaging Centre (M.M.C.), Douglas Mental Health University Institute; Departments of Psychiatry and Biomedical Engineering (M.M.C.), McGill University, Montreal; University of Sherbrooke (M.D.), Canada; and Department of Neurology (T.S.), DKD Helios Klinik Wiesbaden, Germany. The present address for L.G. is F. Hoffmann-La Roche, Basel, Switzerland. OBJECTIVE: To study if the thalamic lateral geniculate nucleus (LGN) is affected in multiple sclerosis (MS) due to anterograde degeneration from optic neuritis (ON) or retrograde degeneration from optic radiation (OR) pathology, and if this is relevant for visual function. METHODS: In this cross-sectional study, LGN volume of 34 patients with relapsing-remitting MS and 33 matched healthy controls (HC) was assessed on MRI using atlas-based automated segmentation (MAGeT). ON history, thickness of the ganglion cell-inner plexiform layer (GC-IPL), OR lesion volume, and fractional anisotropy (FA) of normal-appearing OR (NAOR- FA) were assessed as measures of afferent visual pathway damage. Visual function was tested, including low-contrast letter acuity (LCLA) and Hardy-Rand-Rittler (HRR) plates for color vision. RESULTS: LGN volume was reduced in patients vs HC (165.5 ± 45.5 vs 191.4 ± 47.7 mm3, B = -25.89, SE = 5.83, p < 0.001). It was associated with GC-IPL thickness (B = 0.95, SE = 0.33, p = 0.006) and correlated with OR lesion volume (Spearman ρ = -0.53, p = 0.001), and these relationships remained after adjustment for normalized brain volume. There was no association between NAOR-FA and LGN volume (B = -133.28, SE = 88.47, p = 0.137). LGN volume was not associated with LCLA (B = 5.5 × 10-5, SE = 0.03, p = 0.998), but it correlated with HRR color vision (ρ = 0.39, p = 0.032). CONCLUSIONS: LGN volume loss in MS indicates structural damage with potential functional relevance. Our results suggest both anterograde degeneration from the retina and retrograde degeneration from the OR lesions as underlying causes. LGN volume is a promising marker reflecting damage of the visual pathway in MS, with the advantage of individual measurement per patient on conventional MRI. © 2019 American Academy of Neurology. DOI: 10.1212/WNL.0000000000007450 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 208 – Multiple Sklerose: Veröffentlichungen April 2019 310. Neurology (ECronicon). 2018 Aug;10(8):761-770. Epub 2018 Jul 27. Longer Duration of Downslope Treadmill Walking Induces Depression of H-Reflexes Measured during Standing and Walking. Hoque MM(1), Ardizzone MA(1), Sabatier M(1), Borich MR(1), Kesar TM(1). Author information: (1)Department of Rehabilitation Medicine, Division of Physical Therapy, Emory University, Atlanta, Georgia, USA. Objectives: The Hoffman-reflex (H-reflex) is an electrophysiological technique used to evaluate the excitability of the monosynaptic spinal reflex arc. In individuals with upper motor neuron lesions who show elevated spinal excitability, a depression of spinal excitability may indicate adaptive spinal plasticity. Downslope walking (DSW), an exercise intervention comprising repetitive eccentric muscle activity, has been shown to induce depression of soleus H-reflex amplitudes while seated, however, the dose-response time- course of H-reflex modulation during DSW has not been characterized. The objectives of this study were twofold: (1) to evaluate DSW-induced soleus H-reflex depression in the standing posture and during walking, and (2) to investigate the effect of walking duration (20 minutes and 40 minutes) of DSW (-15% decline) on soleus H-reflexes, (with level walking (LW) as a control intervention). Methods: Soleus H-reflexes were collected Pre, Post-20 minutes, and Post-40 minutes of walking in the standing position; and H-reflexes were also measured at 4 different time points during the terminal stance phase of walking. Results: Our results showed that soleus H-reflexes evaluated in standing showed a greater % depression after DSW compared to LW, with a statistical trend for greater depression with longer durations (40-minutes). H-reflexes measured during walking showed greater depression after 40 minutes of walking compared to 20- or 30-minutes for both DSW and LW. Conclusions: Longer duration treadmill walking (40-minutes) may induce a greater acute depressive effect on soleus H-reflex excitability compared to shorter durations (20-minutes) of treadmill walking. Future work will investigate the potential for DSW as a gait training intervention in people with upper motor neuron lesions such as multiple sclerosis and stroke. Conflict of interest statement: Statement of Conflicts of Interest The authors have no conflicts of interest to disclose related to this study. 311. Neuropeptides. 2019 Apr 13. pii: S0143-4179(19)30014-9. doi: 10.1016/j.npep.2019.04.001. [Epub ahead of print] Effect of mesenchymal stem cells on glial cells population in cuprizone induced demyelination model. Barati S(1), Kashani IR(2), Tahmasebi F(2), Mehrabi S(3), Joghataei MT(4). Author information: (1)Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. (2)Department of Anatomy, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran. (3)Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. (4)Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address: [email protected]. Mesenchymal stem cells (MSCs) have a notable potential to modulate immune responses and protect the central nervous system (CNS), mostly by secreting factors that affect inflammation. MSCs have the ability to improve several autoimmune diseases in animal models including multiple sclerosis (MS). MS is a disease of the CNS among adult humans and it is characterized by demyelination, neuroinflammation and gliosis. In this study, we first induced chronic demyelination by cuprizone, followed by intraventricular injection of MSC. Our results showed that MSC significantly decreased microgliosis and astrocytosis by secreting cytokines that have neuroprotective activity including TGF-β and CX3CL1. Also, downregulation of IL-1β and TNF-α as inflammatory chemokines was seen along with decreased astrocytes and microglia activation. Finally, these results showed that trophic factors secreted by MSC can increase oligodendrocyte population and remyelination rate by reducing pro-inflammatory factors. These findings demonstrate that MSC could decrease inflammation, gliosis and demyelination with neuroprotective and immunomodulating properties in chronic cuprizone demyelination model. Therefore MSC transplantation can be considered as a suitable approach for enhancing myelination and reducing inflammation in diseases such as MS. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.npep.2019.04.001 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 209 – Multiple Sklerose: Veröffentlichungen April 2019 312. Neurosci Biobehav Rev. 2019 Apr 5. pii: S0149-7634(18)30811-X. doi: 10.1016/j.neubiorev.2019.04.003. [Epub ahead of print] Impact of sex differences and gender specificity on behavioral characteristics and pathophysiology of neurodegenerative disorders. Ullah MF(1), Ahmad A(2), Bhat SH(3), Abu-Duhier FM(3), Barreto GE(4), Ashraf GM(5). Author information: (1)Prince Fahd Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, 71491, Saudi Arabia. Electronic address: [email protected]. (2)Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA. (3)Prince Fahd Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, 71491, Saudi Arabia. (4)Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile. (5)King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: [email protected]. The impact of neurodegenerative disorders in humans has multiple consequences because of the progressive decline in cognitive and physical performances. These disorders have diverse manifestations and are influenced by genetic and lifestyle factors, concurrent health conditions as well as un-modifiable predisposing risk factors, including gender and advanced age. Accumulating evidence indicates a gender- dependent natural bias of neurodegenerative diseases, such as, Alzheimer's disease, Parkinson's disease, Huntington's disease and multiple sclerosis, with the ratio of male to female prevalence as well as the severity of the disease differing significantly between the two sexes. This observation has recently garnered much attention and it is now being realized that understanding the sex as a biological variable in the etiology of the neurodegenerative diseases may advance the status of the pathophysiology and treatment strategies while improving the associated decline in cognitive and functional abilities. This review highlights the influence of gender in neurodegenerative disorders and further discusses the sex-specific pre-determined microenvironments that are critical in predisposing the individuals to such disorders. Copyright © 2019. Published by Elsevier Ltd. DOI: 10.1016/j.neubiorev.2019.04.003 313. Neurosci Lett. 2019 Apr 4;704:116-125. doi: 10.1016/j.neulet.2019.04.007. [Epub ahead of print] Regulation of sirtuin expression in autoimmune neuroinflammation: Induction of SIRT1 in oligodendrocyte progenitor cells. Prozorovski T(1), Ingwersen J(1), Lukas D(1), Göttle P(1), Koop B(1), Graf J(1), Schneider R(1), Franke K(2), Schumacher S(3), Britsch S(3), Hartung HP(1), Küry P(1), Berndt C(1), Aktas O(4). Author information: (1)Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. (2)Department of Dermatology and Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany. (3)Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany. (4)Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: [email protected]. In multiple sclerosis (MS) regeneration of oligodendrocytes following inflammatory demyelination is limited by the compromised ability of progenitors to repopulate lesioned areas and transition to functionally competent oligodendrocytes. Regarding underlying mechanisms, the involvement of epigenetic processes has been suggested, e.g. the contribution of histone deacetylases (HDAC) known to regulate oligodendrocyte progenitor cell (OPC) differentiation. However, their precise expression patterns, particular of redox-sensitive NAD+ HDACs, remains largely unknown. In this study, we determined the expression and activity of sirtuins, members of the HDAC class III family with a specific focus on SIRT1, previously associated with neurodegenerative, inflammatory and demyelinating disorders of the central nervous system (CNS). By investigating mouse experimental autoimmune encephalomyelitis (EAE), a model for MS, we found that transcription of SIRT1, SIRT2 and SIRT6 was significantly increased in the CNS during chronic disease stages. We confirmed this finding for SIRT1 protein expression and were able to localize upregulated SIRT1 in nuclei of NG2+ or PDGFRα+ OPCs in demyelinated brain lesions. In cultured mouse A2B5+ OPCs blockade of SIRT1 activity by the small molecule compound Ex527 enhanced mitotic activity but did not affect the capacity to differentiate. A similar pattern was detectable in OPCs derived from SIRT1-deficient animals. Taken together, our data suggest that SIRT1 inhibition may help to expand the endogenous pool of OPCs without affecting their differentiation. Copyright © 2019. Published by Elsevier B.V. DOI: 10.1016/j.neulet.2019.04.007 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 210 – Multiple Sklerose: Veröffentlichungen April 2019 314. Neurosci Lett. 2019 Apr 17;705:39-45. doi: 10.1016/j.neulet.2019.04.035. [Epub ahead of print] Rapamycin relieves inflammation of experimental autoimmune encephalomyelitis by altering the balance of Treg/Th17 in a mouse model. Li Z(1), Nie L(2), Chen L(3), Sun Y(1), Li G(1). Author information: (1)Department of Neurology, the second Hospital of Hebei Medical University, ShiJiaZhuang, Hebei, 050000, China. (2)Shijiazhuang circular Chemical Industry Park Hospital, ShiJiaZhuang, Hebei, 050000, China. (3)Department of Neurology, the second Hospital of Hebei Medical University, ShiJiaZhuang, Hebei, 050000, China. Electronic address: [email protected]. This study was to observed the different doses of rapamycin on the treatment of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. 63 female C57BL/6 mice (6-8 weeks) was chosen and randomly divided into three groups: control, low-dose rapamycin-treated EAE mice (0.3 mg/kg), and high-dose rapamycin-treated EAE mice (1 mg/kg). The EAE mice recovery of neurological function in different concentrations of rapamycin were assessed by neurological function score; The assessment of neurological function was divided into three periods: initial stage (10-13d), peak phase (17-21d), remission phase (25- 28d), and calculated the score for each period. The inflammatory cell infiltration of mice was assessed by IL- 17 A immunohistochemical staining which produced by Th17 cell and positive cell count. The autoimmune recovery of EAE mice was evaluated by flow cytometry on the expression of CD4+ CD25+ Foxp3+ T cells. The transcription factors of Foxp3+ and RORC (RAR-related orphan receptor C) mRNA expression were evaluated by qRT-PCR in Treg cells and Th17 cells. In the neurological function score, the high-dose group was significantly lower than the other two groups in the peak drug phase and the remission phase (P < 0.05), while there was no significant difference in the initial stage (P > 0.05). The percentage of CD4+CD25+Foxp3+T cells, the number of Th17 cells, and the expression of Foxp3 and RORC mRNA level in the high-dose rapamycin group were greater than those in the vehicle-treated group and the low-dose rapamycin group. High doses of rapamycin (1 mg/kg) have a better relieves inflammation of EAE by altering the balance of Treg/Th17 in a mouse model. Copyright © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/j.neulet.2019.04.035 315. Neurosurgery. 2019 Apr 8. pii: nyz103. doi: 10.1093/neuros/nyz103. [Epub ahead of print] The Effectiveness of Percutaneous Balloon Compression, Thermocoagulation, and Glycerol Rhizolysis for Trigeminal Neuralgia in Multiple Sclerosis. Noorani I(1)(2), Lodge A(1), Vajramani G(1), Sparrow O(1). Author information: (1)Department of Neurosurgery, Wessex Neurological Centre, University Hospital Southampton, Southampton, United Kingdom. (2)Department of Neurosurgery, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom. BACKGROUND: Balloon compression (BC), thermocoagulation (TC), and glycerol rhizolysis (GR) are percutaneous surgical options for trigeminal neuralgia (TN). Whether the outcomes of these procedures in multiple sclerosis -related TN (MS-TN) are as effective as in idiopathic TN (ITN) is unknown. OBJECTIVE: To retrospectively compare pain relief, complications, and durability achieved by these 3 types of procedures in MS-TN and ITN. METHODS: Two hundred and four patients with typical TN were treated percutaneously: 33 had MS-TN (64 procedures) and 171 had ITN (329 procedures). All were performed by 1 of 2 neurosurgeons; interviews enabled long-term data to be gathered by an independent observer. RESULTS: MS-TN patients (53.1%) had Barrow Neurological Institute pain scores of I or II after a percutaneous procedure, compared with 59.3% in the ITN cohort; there was no difference in initial relief between the 2 groups overall (P = .52). There was a trend toward fewer complications in MS-TN compared with ITN (23.4% vs 33.7%, respectively; P = .058). Kaplan-Meier analysis demonstrated no difference in durability of relief in MS-TN (median 23.0 mo) compared with ITN overall (median 24.0 mo; P = .75). Subgroup analysis demonstrated longer relief from BC and TC compared with GR in MS-TN (P = .013). Multivariate analysis confirmed that although the presence of MS does not predict durability of outcome, postoperative numbness (P = .0046) and undergoing a repeat procedure (P = .037) were significant predictors. CONCLUSION: BC and TC are safe and effective in MS-TN. Postoperative numbness is the strongest prognostic factor in MS-TN. Copyright © 2019 by the Congress of Neurological Surgeons. DOI: 10.1093/neuros/nyz103 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 211 – Multiple Sklerose: Veröffentlichungen April 2019 316. Neurotox Res. 2019 Apr 4. doi: 10.1007/s12640-019-00030-0. [Epub ahead of print] Effects of Curcumin on Microglial Cells. Ghasemi F(1), Bagheri H(2), Barreto GE(3)(4), Read MI(5), Sahebkar A(6)(7)(8)(9). Author information: (1)Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran. (2)Department of Biotechnology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran. (3)Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, DC, Colombia. (4)Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile. (5)Department of Pharmacology, School of Medical Sciences, University of Otago, Dunedin, New Zealand. (6)Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. [email protected]. (7)Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. [email protected]. (8)School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. [email protected]. (9)Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, P.O. Box: 91779-48564, Mashhad, Iran. [email protected]. Microglia are innate immune system cells which reside in the central nervous system (CNS). Resting microglia regulate the homeostasis of the CNS via phagocytic activity to clear pathogens and cell debris. Sometimes, however, to protect neurons and fight invading pathogens, resting microglia transform to an activated-form, producing inflammatory mediators, such as cytokines, chemokines, iNOS/NO and cyclooxygenase-2 (COX-2). Excessive inflammation, however, leads to damaged neurons and neurodegenerative diseases (NDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Curcumin is a phytochemical isolated from Curcuma longa. It is widely used in Asia and has many therapeutic properties, including antioxidant, anti-viral, anti-bacterial, anti-mutagenic, anti-amyloidogenic and anti-inflammatory, especially with respect to neuroinflammation and neurological disorders (NDs). Curcumin is a pleiotropic molecule that inhibits microglia transformation, inflammatory mediators and subsequent NDs. In this mini- review, we discuss the effects of curcumin on microglia and explore the underlying mechanisms. DOI: 10.1007/s12640-019-00030-0 317. Noncoding RNA. 2019 Apr 24;5(2). pii: E35. doi: 10.3390/ncrna5020035. MicroRNAs in Neuroinflammation: Implications in Disease Pathogenesis, Biomarker Discovery and Therapeutic Applications. Slota JA(1)(2), Booth SA(3)(4). Author information: (1)Prion Diseases Section, Public Health Agency of Canada, National Microbiology Laboratory, 1015 Arlington St., Winnipeg, MB R3E 3R2, Canada. [email protected]. (2)Department of Medical Microbiology and Infectious Diseases, Faculty of Health Sciences, University of Manitoba, 730 William Ave., Winnipeg, MB R3E 0W3, Canada. [email protected]. (3)Prion Diseases Section, Public Health Agency of Canada, National Microbiology Laboratory, 1015 Arlington St., Winnipeg, MB R3E 3R2, Canada. [email protected]. (4)Department of Medical Microbiology and Infectious Diseases, Faculty of Health Sciences, University of Manitoba, 730 William Ave., Winnipeg, MB R3E 0W3, Canada. [email protected]. The central nervous system can respond to threat via the induction of an inflammatory response. Under normal circumstances this response is tightly controlled, however uncontrolled neuroinflammation is a hallmark of many neurological disorders. MicroRNAs are small non-coding RNA molecules that are important for regulating many cellular processes. The ability of microRNAs to modulate inflammatory signaling is an area of ongoing research, which has gained much attention in recent years. MicroRNAs may either promote or restrict inflammatory signaling, and either exacerbate or ameliorate the pathological consequences of excessive neuroinflammation. The aim of this review is to summarize the mode of regulation for several important and well-studied microRNAs in the context of neuroinflammation, including miR-155, miR-146a, miR-124, miR-21 and let-7. Furthermore, the pathological consequences of miRNA deregulation during disorders that feature neuroinflammation are discussed, including Multiple Sclerosis, Alzheimer's disease, Parkinson's disease, Prion diseases, Japanese encephalitis, Herpes encephalitis, ischemic stroke and traumatic brain injury. There has also been considerable interest in the use of altered microRNA signatures as biomarkers for these disorders. The ability to modulate microRNA expression may even serve as the basis for future therapeutic strategies to help treat pathological neuroinflammation. DOI: 10.3390/ncrna5020035 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 | L.DE.MKT.SM.02.2017.5323 – 212 – Multiple Sklerose: Veröffentlichungen April 2019 318. Obesity (Silver Spring). 2019 Apr 15. doi: 10.1002/oby.22457. [Epub ahead of print] Glycated Hemoglobin, but not Insulin Sensitivity, is Associated with Memory in Subjects with Obesity. Arnoriaga Rodríguez M(1)(2), Blasco G(3)(4), Coll C(5), Biarnés C(4), Contreras-Rodríguez O(6), Garre- Olmo J(2)(7), Puig J(2)(3)(4), Gich J(2)(8), Ricart W(1)(2), Ramió-Torrentà L(2)(5)(8), Fernández-Real JM(1)(2). Author information: (1)Department of Diabetes, Endocrinology and Nutrition, Girona Biomedical Research Institute, Dr. Josep Trueta University Hospital, Center for Physiopathology of Obesity and Nutrition, Girona, Spain. (2)Faculty of Medicine, Department of Medical Sciences, University of Girona, Girona, Spain. (3)Institute of Diagnostic Imaging-Research Unit, Parc Sanitari Pere Virgili, Barcelona, Spain. (4)Department of Medical Imaging, Girona Biomedical Research Institute, Girona, Spain. (5)Neuroimmunology and Multiple Sclerosis Unit, Department of Neurology, Dr. Josep Trueta University Hospital, Girona, Spain. (6)Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) and Biomedical Research Networking Center for Mental Health (CIBERSAM), L'Hospitalet de Llobregat, Spain. (7)Research Group on Aging, Health and Disability, Girona Biomedical Research Institute, Health Assistance Institute, Girona, Spain. (8)Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute, Girona, Spain. OBJECTIVE: Obesity has been related to later-life dementia. Serum glucose levels and insulin resistance are known to influence cognition in individuals with diabetes. This study aimed to evaluate memory function in middle-aged individuals with obesity in association with glucose metabolism and brain iron content. METHODS: This was a cross-sectional case-control study including 121 participants aged 27.2 to 66.6 years (56 without obesity, 65 with obesity) stratified according to sex and menopausal status. Insulin sensitivity, body composition, brain iron content, and memory function were evaluated by euglycemic hyperinsulinemic clamp, dual-energy x-ray absorptiometry, magnetic resonance relaxometry (R2*), and California Verbal Learning Test, respectively. RESULTS: Women with obesity, but not men, had lower scores in some California Verbal Learning Tests in association with metabolic parameters and increased brain iron content compared with controls. Fasting plasma glucose, glycated hemoglobin (HbA1c; within normal range), and R2* were negatively associated with memory scores, whereas insulin sensitivity showed positive associations. Remarkably, only HbA1c levels and R2* in the right inferior fronto-orbital region remained significant after controlling for age, sex, education, and BMI. CONCLUSIONS: Impairments in memory function in middle-aged women with obesity are associated with HbA1c levels and brain iron content independently of insulin sensitivity. These results may have implications in the design of therapeutic strategies in women with obesity. © 2019 The Obesity Society. DOI: 10.1002/oby.22457 319. Ochsner J. 2019 Spring;19(1):17-25. doi: 10.31486/toj.18.0111. Gadolinium Deposition in Neurology Clinical Practice. Smith TE(1), Steven A(2)(3), Bagert BA(1)(3). Author information: (1)Department of Neurology, Ochsner Clinic Foundation, New Orleans, LA. (2)Department of Radiology, Ochsner Clinic Foundation, New Orleans, LA. (3)The University of Queensland Faculty of Medicine, Ochsner Clinical School, New Orleans, LA. Background: Magnetic resonance imaging (MRI) enhanced with gadolinium-based contrast agents (GBCAs) is an essential tool in the diagnosis and management of many neurologic diseases, including multiple sclerosis, brain tumors, and infections. The clinical utility of GBCAs is evidenced by their widespread use. GBCAs are produced in macrocyclic and linear forms. Since 2014, evidence has suggested that repeated administration of GBCAs can lead to gadolinium deposition in the brain. Methods: We review the literature on gadolinium deposition, including both animal and human studies, as well as the literature on GBCA- associated health outcomes. Additionally, we summarize and discuss the updated medical society recommendations and perspectives on GBCA use in clinical practice. Results: The first publication reporting gadolinium deposition in the human brain was published in 2014. Since that seminal report, multiple studies have demonstrated that exposure to linear GBCAs is associated with gadolinium deposition in the dentate nucleus and globus pallidus as seen on brain MRI. Macrocyclic GBCA exposure has not convincingly been associated with gadolinium deposition evident on brain MRI. Conclusion: Clear evidence demonstrates that GBCAs lead to gadolinium deposition in the brain in a dose-dependent manner; however, only linear GBCAs have been associated with gadolinium deposition visualized on MRI. To date, no evidence links gadolinium deposition with any adverse health outcome. Updated medical society guidelines emphasize the importance of an individualized risk-benefit analysis with each administration of GBCAs. DOI: 10.31486/toj.18.0111 PMCID: PMC6447198 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 213 – Multiple Sklerose: Veröffentlichungen April 2019 320. Ophthalmologe. 2019 Apr 3. doi: 10.1007/s00347-019-0883-5. [Epub ahead of print] [Optical coherence tomography angiography in neuronal diseases : Preliminary findings]. [Article in German] Mardin CY(1), Hosari S(2). Author information: (1)Universitätsaugenklinik Erlangen, FAU Erlangen-Nürnberg, 91054, Erlangen, Deutschland. [email protected]. (2)Universitätsaugenklinik Erlangen, FAU Erlangen- Nürnberg, 91054, Erlangen, Deutschland. BACKGROUND: Optical coherence tomography angiography (OCTA) enables a noninvasive detailed imaging of retinal and choroidal vessels of the fundus. In neuronal diseases changes in retinal structures can be imaged and measured with OCT and OCTA. OBJECTIVE: Can OCTA be used in neuronal diseases? MATERIAL AND METHODS: Evaluation of recent scientific articles and studies extracted from Medline on the topic of OCTA and neuronal diseases. RESULTS: It could be shown that Alzheimer type dementia, Parkinson's disease, multiple sclerosis. cerebral infarction and CADASIL are neuronal diseases with rarification of retinal vessels and atrophy of the retinal layers in the ocular fundus. CONCLUSION: These findings are beyond all changes which can be appreciated with ophthalmoscopy and OCTA parameters could serve in the future as supplementary biomarkers for assessment of the retinal-neurovascular coupling in these diseases. DOI: 10.1007/s00347-019-0883-5 321. Osteoporos Int. 2019 Apr 27. doi: 10.1007/s00198-019-04965-0. [Epub ahead of print] Distal radius and tibia bone microarchitecture impairment in female patients with diffuse systemic sclerosis. Sampaio-Barros MM(1), Alvarenga JC(1), Takayama L(1), Assad APL(1), Sampaio-Barros PD(1), Pereira RMR(2). Author information: (1)Bone Metabolism Laboratory, Rheumatology Division, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo, 455, 3° andar, sala 3193, São Paulo, SP, 01246- 903, Brazil. (2)Bone Metabolism Laboratory, Rheumatology Division, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Av. Dr. Arnaldo, 455, 3° andar, sala 3193, São Paulo, SP, 01246-903, Brazil. [email protected]. Radius and tibia bone microarchitecture, analyzed through a high-resolution peripheral quantitative computed tomography, were significantly impaired in female patients with diffuse systemic sclerosis compared with healthy controls. Acroosteolysis, quality of life-grip strength, hand disability, and disease duration were significantly associated with this bone deterioration.INTRODUCTION: The effect of diffuse systemic sclerosis (dSSc) on the bone is not completely understood. The objective of this study was to analyze the volumetric bone mineral density (vBMD), microarchitecture, and biomechanical parameters at the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT, XtremeCT) in female patients with dSSc and identify clinical and laboratory variables associated with these parameters. METHODS: Thirty-eight women with dSSc and 76 healthy controls were submitted to HR-pQCT at the distal radius and tibia. Clinical and laboratory findings, bone mineral density(BMD), nailfold capillaroscopy (NC), total passive range of motion(ROM), and quality of life (health assessment questionnaire-HAQ) were associated with HR-pQCT (Scanco Medical AG, Brüttisellen, Switzerland) parameters. Multiple linear regression models adjusted for clinical and laboratory variables, ROM and HAQ, were performed. RESULTS: Density, microarchitecture, and biomechanical parameters at the distal radius and tibia were significantly impaired in dSSc patients compared with healthy controls (p < 0.001). Multiple linear regression models showed that lower trabecular density (Tb.vBMD) (radius R2 = 0.561, p = 0.002; and tibia R2 = 0.533, p = 0.005), and lower trabecular number (Tb.N) (tibia R2 = 0.533, p = 0.005) were significantly associated with acroosteolysis. Higher trabecular separation (Tb.Sp) was associated with disease duration and higher HAQ-grip strength (radius R2 = 0.489, p = 0.013), while cortical density (Ct.vBMD) was associated with ROM (radius R2 = 0.294, p = 0.002). CONCLUSION: Bone microarchitecture in patients with dSSc, analyzed through HR-pQCT, showed impairment of trabecular and cortical bone at distal radius and tibia. Variables associated with hand involvement (acroosteolysis, quality of life-grip strength, and ROM) and disease duration may be considered prognostic factors of this bone impairment. DOI: 10.1007/s00198-019-04965-0 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 214 – Multiple Sklerose: Veröffentlichungen April 2019 322. Patient Educ Couns. 2019 Apr 6. pii: S0738-3991(19)30132-6. doi: 10.1016/j.pec.2019.04.007. [Epub ahead of print] Gender differences in information needs and preferences regarding depression among individuals with multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis. Marrie RA(1), Walker JR(2), Graff LA(2), Patten SB(3), Bolton JM(4), Marriott JJ(5), Fisk JD(6), Hitchon C(5), Peschken C(5), Bernstein CN(5); CIHR Team in Defining the Burden and Managing the Effects of Immune- mediated Inflammatory Disease. Author information: (1)Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. Electronic address: [email protected]. (2)Department of Clinical Health Psychology, Max Rady College of Medicine Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. (3)Departments of Community Health Sciences & Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Canada. (4)Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Department of Psychiatry, Max Rady College of Medicine Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. (5)Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. (6)Nova Scotia Health Authority, Departments of Psychiatry, Psychology & Neuroscience, and Medicine, Dalhousie University, Halifax, Canada. OBJECTIVE: We assessed the information needs of persons with any of three immune-mediated inflammatory diseases (multiple sclerosis [MS], inflammatory bowel disease [IBD] and rheumatoid arthritis [RA]) regarding depression, as a first step toward developing patient-relevant information resources, ultimately to facilitate self-management and appropriate care. We also compared information needs across genders. METHODS: We surveyed participants with MS, IBD and RA regarding depression-related information needs including types of treatments, effectiveness, risks, benefits, and perceived helpfulness of treatments. We compared responses between groups using multivariate regression. RESULTS: 328 participants provided complete responses (MS: 141, IBD: 114, RA: 73). Most of the topics queried were perceived as very important, and similarly important for all groups. Women placed higher importance than men on most topics. The most popular formats for receiving information were discussion with a counselor (very preferred: 67.4%) and written information (very preferred: 65.5%); this did not differ between groups. CONCLUSIONS: Persons affected by MS, IBD and RA are interested in receiving information about multiple topics related to depression treatment, from multiple sources. Women desire more information than men. PRACTICE IMPLICATIONS: These findings can be used to design information resources to meet information needs regarding depression in MS, IBD and RA. Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.pec.2019.04.007 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 215 – Multiple Sklerose: Veröffentlichungen April 2019 323. Pediatr Neurol. 2019 Mar 13. pii: S0887-8994(18)31292-X. doi: 10.1016/j.pediatrneurol.2019.03.003. [Epub ahead of print] Tuberous Sclerosis Complex Genotypes and Developmental Phenotype. Farach LS(1), Pearson DA(2), Woodhouse JP(3), Schraw JM(4), Sahin M(5), Krueger DA(6), Wu JY(7), Bebin EM(8), Lupo PJ(3), Au KS(9), Northrup H(9); TACERN Study Group. Collaborators: Sahin M(10), Krueger D(11), Bebin M(8), Wu JY(12), Northrup H(13), Warfield S(10), Peters J(10), Scherrer B(10), Goyal M(8), Filip-Dhima R(10), Dies K(10), Bruns S(11), Hanson E(10), Bing N(11), Kent B(11), O'Kelley S(8), Williams ME(14), Pearson D(13), Cutter G(15), Roberds S(16), Murray DS(17). Author information: (1)Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas. Electronic address: [email protected]. (2)Department of Psychiatry, Division of Child and Adolescent Psychiatry, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas. (3)Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas. (4)Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, Texas. (5)Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. (6)Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. (7)Division of Pediatric Neurology, UCLA Mattel Children's Hospital and David Geffen School of Medicine, Los Angeles, California. (8)University of Alabama at Birmingham, Birmingham, Alabama. (9)Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas. (10)Boston Children's Hospital, Boston, Massachusetts. (11)Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. (12)University of California, Los Angeles, Los Angeles, California. (13)McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas. (14)Keck School of Medicine of USC, University of Southern California, Children's Hospital Los Angeles, Los Angeles, California. (15)University of Alabama at Birmingham, Data Coordinating Center, Birmingham, Alabama. (16)Tuberous Sclerosis Alliance, Silver Spring, Maryland. (17)Autism Speaks, New York, New York. BACKGROUND: Children with tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1/TSC2, are at risk for intellectual disability. TSC2 pathogenic variants appear to increase the risk, compared with TSC1. However, the effect of TSC2 pathogenic variants on early and specific domains of development hasn't been studied. Using an extensively phenotyped group, we aimed to characterize differences in early intellectual development between genotypes. METHODS: The study group (n = 92) included participants with TSC enrolled in a multicenter study involving genetic testing and detailed prospective phenotyping including the Mullen Scales of Early Learning, a validated measure of cognition, language, and motor development in babies and preschool children. Mean T-scores at 24 months for each Mullen Scales of Early Learning domain were calculated for children with, versus without, a TSC2 pathogenic variant. Multivariable linear regression models were used to compare the groups, adjusting for seizures. RESULTS: T-scores on every Mullen Scales of Early Learning domain were significantly worse in the TSC2 group. Below average composite scores were present in three-fourths of the TSC2 group, compared with one-fourth of those without TSC2. Having a TSC2 pathogenic variant was associated with lower composite Mullen Scales of Early Learning scores, even when corrected for seizures. CONCLUSIONS: In a well-characterized patient population with standardized assessment of multiple aspects of development, we found that having a TSC2 pathogenic variant was associated with significantly lower Mullen Scales of Early Learning scores at age 24 months, independent of seizures. These data suggest that a baby identified to have a TSC2 pathogenic variant is at high risk for significant developmental delays by 24 months. Copyright © 2019 Elsevier Inc. All rights reserved. DOI: 10.1016/j.pediatrneurol.2019.03.003 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 216 – Multiple Sklerose: Veröffentlichungen April 2019 324. PeerJ. 2019 Apr 5;7:e6711. doi: 10.7717/peerj.6711. eCollection 2019. HERVs, immunity, and autoimmunity: understanding the connection. Greenig M(1). Author information: (1)Department of Life Sciences, Imperial College London, London, United Kingdom. Since their discovery in the 1960s, further investigation into endogenous retroviruses (ERVs) has challenged the conventional view of viral sequences as exclusively parasitic elements. Once presumed to be a group of passive genetic relics, it is becoming increasingly clear that this view of ERVs, while generally accurate, is incorrect in many specific cases. Research has identified ERV genes that appear to be co-opted by their mammalian hosts, but the biological function of ERV elements in humans remains a controversial subject. One area that has attracted some attention in this domain is the role of co-opted ERV elements in mammalian immune systems. The relationship between ERVs and human autoimmune diseases has also been investigated, but has historically been treated as a separate topic. This review will summarize the current evidence concerning the phenotypic significance of ERVs, both in the healthy immune system and in manifestations of autoimmunity. Furthermore, it will evaluate the relationship between these fields of study, and propose previously-unexplored molecular mechanisms through which human endogenous retroviruses might contribute to certain autoimmune pathologies. Investigation into these novel mechanisms could further our understanding of the molecular basis of autoimmune disease, and may one day provide new targets for treatment. DOI: 10.7717/peerj.6711 PMCID: PMC6452852 Conflict of interest statement: The authors declare they have no competing interests. 325. Phys Med Rehabil Clin N Am. 2019 May;30(2):473-483. doi: 10.1016/j.pmr.2018.12.002. Epub 2019 Mar 5. Telemedicine in Rehabilitation. Galea MD(1). Author information: (1)Department of Spinal Cord Injury and Disorder, Amyotrophic Lateral Sclerosis Program, Multiple Sclerosis Regional Center, The James J Peters VAMC, SCI/D Unit, 130 West Kingsbridge Road, Bronx, NY 10468, USA. Electronic address: [email protected]. Telerehabilitation refers to the virtual delivery of rehabilitation services into the patient's home. This methodology has shown to be advantageous when used to enhance or replace conventional therapy to overcome geographic, physical, and cognitive barriers. The exponential growth of technology has led to the development of new applications that enable health care providers to monitor, educate, treat, and support patients in their own environment. Best practices and well-designed Telerehabilitation studies are needed to build and sustain a strong Telerehabilitation system that is integrated in the current health care structure and is cost-effective. Published by Elsevier Inc. DOI: 10.1016/j.pmr.2018.12.002 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 217 – Multiple Sklerose: Veröffentlichungen April 2019 326. Physiother Res Int. 2019 Apr 22:e1776. doi: 10.1002/pri.1776. [Epub ahead of print] A qualitative study of active participation in sport and exercise for individuals with multiple sclerosis. Smith M(1), Neibling B(1), Williams G(2), Birks M(1), Barker R(1). Author information: (1)College of Healthcare Sciences, James Cook University, Townsville, Queensland, Australia. (2)Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia. OBJECTIVE: The aim of this study was to explore the experience of participation in sport and exercise for individuals with multiple sclerosis (MS) with minimal disability. The objectives were to gain an understanding of key factors that influence participation in sport and exercise and to determine support required by individuals with MS to participate in their choice of sport and exercise for as long as possible. METHODS: A qualitative, descriptive study utilizing three focus groups was conducted. Data were analysed thematically aided by NVivo software. Participants were individuals with MS who had an Expanded Disability Status Scale score of 0-4, indicating full ambulation. All participants were living in northern Queensland, Australia. RESULTS: Sixteen individuals participated; 63% of whom regularly participated in sport or exercise. All participants viewed sport and exercise positively and identified inherent benefits of exercise. Five key themes emerged to describe the experience of participating in sport and exercise: "personally engaging with exercise," "influencing barriers and enablers of exercise," "sustaining independence," "integrating exercise into lifestyle," and "getting the balance right." Most participants felt that advice and guidance from health professionals about the optimum mode and dose (how much and how often) of exercise was lacking. CONCLUSIONS: Participation in sport and exercise was valued by individuals with MS with minimal disability for sustaining independence and an active lifestyle. Personalized exercise advice from health professionals was the key support identified by participants to assist them to maintain an active lifestyle for as long as possible. © 2019 John Wiley & Sons, Ltd. DOI: 10.1002/pri.1776 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 218 – Multiple Sklerose: Veröffentlichungen April 2019 327. PLoS One. 2019 Apr 26;14(4):e0215981. doi: 10.1371/journal.pone.0215981. eCollection 2019. Activation of aryl hydrocarbon receptor signaling by a novel agonist ameliorates autoimmune encephalomyelitis. Abdullah A(1), Maged M(2)(3), Hairul-Islam M I(1), Osama I A(4), Maha H(5), Manal A(1), Hamza H(1)(6)(7). Author information: (1)Biological Sciences Department, College of Science, King Faisal University, Hofuf, Saudi Arabia. (2)Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Hofuf, Saudi Arabia. (3)Department of Pharmacognosy, Faculty of Pharmacy, University of Zagazig, Zagazig, Egypt. (4)Department of Pharmaceutical Sciences, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. (5)College of Pharmacy, Aqaba University of Technology, Aqaba, Jordan. (6)Department of Biological Sciences, College of Science, Al-Hussein Bin Talal University, Ma'an, Jordan. (7)Department of Medical Analysis, Aisha Bint Al-Hussein College for Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma'an, Jordan. BACKGROUND: Multiple sclerosis (MS) is a widespread neurological autoimmune disease that includes episodes of demyelination in the central nervous system (CNS). The accumulated evidence has suggested that aryl hydrocarbon receptor (Ahr), a ligand-activated transcription factor, is a promising treatment target for MS. Thus, the current study aimed to identify a novel Ahr ligand with anti-inflammatory potential in experimental autoimmune encephalomyelitis (EAE). METHODS: An in silico analysis was carried out to predict interactions between Ahr and potential natural ligands. The effects of a predicted interaction were examined in vitro using CD4+ T cells under T helper17 (Th17) cell-polarizing conditions and lipopolysaccharide (LPS)-stimulated macrophages. Silencing Ahr and microRNA (miR)-132 was achieved by electroporation. Myelin oligodendrocyte glycoprotein (MOG)35-55 and the adoptive transfer of encephalitogenic CD4+ T cells were used to induce EAE. RESULTS: Molecular docking analysis and in vitro data identified gallic acid (GA) as a novel Ahr ligand with potent activation potential. GA induced the expression of Ahr downstream genes, including cytochrome P450 family 1 subfamily A member 1 (Cyp1a1) and the miR-212/132 cluster, and promoted the formation of the Ahr/Ahr nuclear translocator (Arnt) complex. In vivo, GA-treated mice were resistant to EAE and exhibited reduced levels of proinflammatory cytokines and increased levels of transforming growth factor-β (TGF-β). Furthermore, GA reduced infiltration of CD4+CD45+ T cells and monocytes into the CNS. The anti-inflammatory effects of GA were concomitant with miR-132-potentiated cholinergic anti-inflammation and the regulation of the pathogenic potential of astrocytes and microglia. Inducing EAE by adoptive transfer revealed that CD4+ T cells were not entirely responsible for the ameliorative effects of GA. CONCLUSION: Our findings identify GA as a novel Ahr ligand and provide molecular mechanisms elucidating the ameliorative effects of GA on EAE, suggesting that GA is a potential therapeutic agent to control inflammation in autoimmune diseases such as MS. DOI: 10.1371/journal.pone.0215981 Conflict of interest statement: The authors have declared that no competing interests exist. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 219 – Multiple Sklerose: Veröffentlichungen April 2019 328. PLoS One. 2019 Apr 15;14(4):e0215410. doi: 10.1371/journal.pone.0215410. eCollection 2019. The clinical significance of single or double bands in cerebrospinal fluid isoelectric focusing. A retrospective study and systematic review. Hegen H(1), Zinganell A(1), Auer M(1), Deisenhammer F(1). Author information: (1)Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. B KG UND The presence of ≥3 oligoclonal bands ( B) in the cerebrospinal fluid (CSF) without corresponding bands in serum represents a definite pathological pattern, whereas the clinical significance of 1-2 CSF bands (borderline pattern) is poorly investigated. METHODS: We screened 1986 consecutive CSF and serum samples which were collected over a four-year time period and had results of isoelectric focusing (IEF) available. Of patients with borderline OCB we reviewed individual medical charts for assessment of clinical diagnoses. Where feasible, IEF was replicated and results of follow-up samples were obtained. IEF was performed using polyacrylamide gel followed by immunoblotting and IgG-specific antibody staining. Additionally, we performed a systematic literature review of the diagnostic specificity of OCB using different cut-offs for CSF-restricted bands. RESULTS: Out of 253 patients with borderline OCB, 21.7% had an inflammatory neurological disease (IND) of the central nervous system, comprising 4% multiple sclerosis patients, and 14.2% had a peripheral IND, whereas the remaining 64.1% of patients showed non- inflammatory diseases. Frequency of one or two CSF bands without corresponding serum bands did not differ between the disease groups. In a subgroup of 100 patients IEF was repeated. Of those, 73% were OCB negative, while no sample was positive. In 26 patients IEF results were available of a follow-up sample collected after a median of 27 months. Of those, 4 (15.4%) turned positive. Systematic literature review revealed a diagnostic specificity of OCB of 97% and 92% using a cut-off ≥3 and ≥ SF bands in patients with mainly non-inflammatory neurological diseases. CONCLUSION: The clinical significance of one or two CSF-restricted bands is moderate and, hence, indicates a possible but not reliable proof of intrathecal B-cell activity. Sample re-testing, introduction of an additional diagnostic category, e.g. "possible intrathecal IgG synthesis", and follow-up lumbar puncture might be possible options to address this scenario. DOI: 10.1371/journal.pone.0215410 Conflict of interest statement: The authors have declared that no competing interests exist. 329. PLoS One. 2019 Apr 10;14(4):e0214469. doi: 10.1371/journal.pone.0214469. eCollection 2019. PP2A activation alone and in combination with cisplatin decreases cell growth and tumor formation in human HuH6 hepatoblastoma cells. Stafman LL(1), Williams AP(1), Marayati R(1), Aye JM(2), Stewart JE(1), Mroczek-Musulman E(3), Beierle EA(1). Author information: (1)Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, United States of America. (2)Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama, Birmingham, Birmingham, AL, United States of America. (3)Department of Pathology, University of Alabama, Birmingham, Birmingham, AL, United States of America. Despite an increase in incidence, treatments for hepatoblastoma remain virtually unchanged for the past 20 years, emphasizing the need for novel therapeutics. FTY720 (fingolimod) is an immunomodulator approved for use in multiple sclerosis in children that has been demonstrated to have anti-cancer properties in multiple cancer types. We have demonstrated that FTY720 activates PP2A in hepatoblastoma, but does not do so via inhibition of the endogenous inhibitors, CIP2A and I2PP2A, as previously observed in other cancers. PP2A activation in hepatoblastoma decreased cell viability, proliferation, and motility and induced apoptosis. In a subcutaneous xenograft model, FTY720 decreased tumor growth. FTY720 in combination with the standard chemotherapeutic, cisplatin, decreased proliferation in a synergistic manner. Finally, animals bearing subcutaneous hepatoblastoma xenografts treated with FTY720 and cisplatin in combination had significantly decreased tumor growth compared to those treated with either drug alone. These findings show that targeting PP2A with FTY70 shows promise in the treatment of hepatoblastoma and that combining FTY720 with cisplatin may be a novel and effective strategy to better treat this devastating pediatric liver tumor. DOI: 10.1371/journal.pone.0214469 Conflict of interest statement: The authors have declared that no competing interests exist. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 220 – Multiple Sklerose: Veröffentlichungen April 2019 330. PLoS One. 2019 Apr 9;14(4):e0214738. doi: 10.1371/journal.pone.0214738. eCollection 2019. Epidemiology of multiple sclerosis in Iran: A systematic review and meta-analysis. Azami M(1), YektaKooshali MH(2), Shohani M(3), Khorshidi A(4), Mahmudi L(5). Author information: (1)Student Research Committee, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran. (2)Student Research Committee, School of Nursing, Midwifery and Paramedicine, Guilan University of Medical Sciences, Rasht, Iran. (3)Department of Nursing, Faculty of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran. (4)Department of Epidemiology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran. (5)Faculty of Medicine, Dezful University of Medical Sciences, Dezful, Iran. BACKGROUND: Multiple sclerosis (MS) is one of the most common neurological disorders and is one of the main causes of disability. The prevalence and incidence of MS in Iran is reported to range from 5.3 to 89/ 100,000and 7 to 148.1/ 100,000, respectively. There are no systematic and meta-analysis studies on MS in Iran. Therefore, this study was conducted to investigate the prevalence and incidence of MS in Iran using meta-analysis. METHOD: A systematic review of the present study focused on MS epidemiology in Iran based on PRISMA guidelines for systematic review and meta-analysis. We searched eight international databases including Scopus, PubMed, Science Direct, Cochrane Library, Web of Science, EMBASE, PsycINFO, Google Scholar search engine and six Persian databases for peer-reviewed studies published without time limit until May 2018. Data were analyzed using Comprehensive meta-analysis ver. 2 software. The review protocol has been registered in PROSPERO with ID: CRD42018114491. RESULTS: According to searching on different databases, 39 (15%) articles finalized. The prevalence of MS in Iran was estimated 29.3/ 100,000 (95%CI: 25.6-33.5) based on random effects model. The prevalence of MS in men and women was estimated to be 16.5/ 100,000 (95%CI: 13.7-23.4) and 44.8/ 100,000 (95%CI: 36.3-61.6), respectively. The incidence of MS in Iran was estimated to be 3.4/ 100,000 (95%CI: 1.8-6.2) based on random effects model. The incidence of MS in men was estimated to be 16.5/ 100,000 (95%CI: 13.7-23.4) and the incidence of MS in women was 44.8/ 100,000 (95%CI: 36.3-61.6). The meta-regression model for prevalence and incidence of MS was significantly higher in terms of year of study (p<0.001). CONCLUSIONS: The results of this study can provide a general picture of MS epidemiology in Iran. The current meta-analysis showed that the prevalence and incidence of MS in Iran is high and is rising over time. DOI: 10.1371/journal.pone.0214738 Conflict of interest statement: The authors have declared that no competing interests exist. 331. PLoS One. 2019 Apr 4;14(4):e0214662. doi: 10.1371/journal.pone.0214662. eCollection 2019. A computer-aided diagnosis of multiple sclerosis based on mfVEP recordings. de Santiago L(1), Sánchez Morla EM(2)(3), Ortiz M(1), López E(1), Amo Usanos C(1), Alonso-Rodríguez MC(4), Barea R(1), Cavaliere-Ballesta C(1), Fernández A(1), Boquete L(1)(5). Author information: (1)Grupo de Ingeniería Biomédica, Departamento de Electrónica, Universidad de Alcalá, Alcalá de Henares, Spain. (2)Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain. (3)Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain. (4)Departamento de Física y Matemáticas, Universidad de Alcalá, Alcalá de Henares, Spain. (5)RETICS: Red Temática de Investigación Cooperativa Sanitaria en Enfermedades Oculares Oftared, Madrid, Spain. INTRODUCTION: The aim of this study is to develop a computer-aided diagnosis system to identify subjects at differing stages of development of multiple sclerosis (MS) using multifocal visual-evoked potentials (mfVEPs). Using an automatic classifier, diagnosis is performed first on the eyes and then on the subjects. PATIENTS: MfVEP signals were obtained from patients with Radiologically Isolated Syndrome (RIS) (n = 30 eyes), patients with Clinically Isolated Syndrome (CIS) (n = 62 eyes), patients with definite MS (n = 56 eyes) and 22 control subjects (n = 44 eyes). The CIS and MS groups were divided into two subgroups: those with eyes affected by optic neuritis (ON) and those without (non-ON). METHODS: For individual eye diagnosis, a feature vector was formed with information about the intensity, latency and singular values of the mfVEP signals. A flat multiclass classifier (FMC) and a hierarchical classifier (HC) were tested and both were implemented using the k-Nearest Neighbour (k-NN) algorithm. The output of the best eye classifier was used to classify the subjects. In the event of divergence, the eye with the best mfVEP recording was selected. RESULTS: In the eye classifier, the HC performed better than the FMC (accuracy = 0.74 and extended Matthew Correlation Coefficient (MCC) = 0.68). In the subject classification, accuracy = 0.95 and MCC = 0.93, confirming that it may be a promising tool for MS diagnosis. CONCLUSION: In addition to amplitude (axonal loss) and latency (demyelination), it has shown that the singular values of the mfVEP signals provide discriminatory information that may be used to identify subjects with differing degrees of the disease. DOI: 10.1371/journal.pone.0214662 PMCID: PMC6449069 Conflict of interest statement: The authors have declared that no competing interests exist. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 221 – Multiple Sklerose: Veröffentlichungen April 2019 332. PLoS One. 2019 Apr 1;14(4):e0210375. doi: 10.1371/journal.pone.0210375. eCollection 2019. Symptoms of fatigue and depression is reflected in altered default mode network connectivity in multiple sclerosis. Høgestøl EA(1), Nygaard GO(2), Alnæs D(3), Beyer MK(4), Westlye LT(3)(5), Harbo HF(1)(2). Author information: (1)Department of Neurology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (2)Department of Neurology, Oslo University Hospital, Oslo, Norway. (3)NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (4)Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway. (5)Department of Psychology, University of Oslo, Oslo, Norway. BACKGROUND: Fatigue and depression are frequent and often co-occurring symptoms in multiple sclerosis (MS). Resting-state functional magnetic resonance imaging (rs-fMRI) represents a promising tool for disentangling differential associations between depression and fatigue and brain network function and connectivity. In this study we tested for associations between symptoms of fatigue and depression and DMN connectivity in patients with MS. MATERIALS AND METHODS: Seventy-four MS patients were included on average 14 months after diagnosis. They underwent MRI scanning of the brain including rs-fMRI, and symptoms of fatigue and depression were assessed with Fatigue Severity Scale (FSS) and Beck Depression Inventory II (BDI). A principal component analysis (PCA) on FSS and BDI scores was performed, and the component scores were analysed using linear regression models to test for associations with default mode network (DMN) connectivity. RESULTS: We observed higher DMN connectivity with higher scores on the primary principal component reflecting common symptom burden for fatigue and depression (Cohen's f2 = 0.075, t = 2.17, p = 0.03). The secondary principal component reflecting a pattern of low fatigue scores with high scores of depression was associated with lower DMN connectivity (Cohen's f2 = 0.067, t = -2.1, p = 0.04). Using continuous mean scores of FSS we also observed higher DMN connectivity with higher symptom burden (t = 3.1, p = 0.003), but no significant associations between continuous sum scores of BDI and DMN connectivity (t = 0.8, p = 0.4). CONCLUSION: Multivariate decomposition of FSS and BDI data supported both overlapping and unique manifestation of fatigue and depression in MS patients. Rs-fMRI analyses showed that symptoms of fatigue and depression were reflected in altered DMN connectivity, and that higher DMN activity was seen in MS patients with fatigue even with low depression scores. DOI: 10.1371/journal.pone.0210375 PMCID: PMC6443168 Conflict of interest statement: The authors have declared that no competing interests exist. 333. Proc (Bayl Univ Med Cent). 2018 Oct 26;31(4):530-531. doi: 10.1080/08998280.2018.1499318. eCollection 2018 Oct. Anesthetic management for cesarean section and tubal ligation in a patient with Marfan syndrome, multiple sclerosis, and multiple postdural puncture headaches. Hofkamp MP(1), Galvan JM(2). Author information: (1)Department of Anesthesiology, Scott & White Medical Center - TempleTempleTexas. (2)Department of Anesthesiology, University of Illinois at ChicagoChicagoIllinois. We report a 29-year-old woman with Marfan syndrome, multiple sclerosis, and multiple postdural puncture headaches who presented for a scheduled repeat cesarean delivery with bilateral tubal ligation at 37 weeks gestation. During an outpatient preoperative visit, a general anesthetic plan was ultimately selected through a shared decision-making process. The patient had an uneventful general anesthetic that included a rapid sequence induction with direct laryngoscopy. Neonatal Apgar scores were 8 at 1 minute and 9 at 5 minutes. Prior to emergence, fentanyl, acetaminophen, and ketorolac were administered intravenously and a transversus abdominus plane block was performed. On the first postoperative day, the patient expressed satisfaction with the anesthetic plan and, in particular, the avoidance of a neuraxial technique and postdural puncture headache. The patient was discharged on the second postoperative day with no apparent sequelae. A neuraxial anesthetic technique is usually preferred in patients undergoing cesarean delivery, and it is safe to perform this technique in patients with either Marfan syndrome or multiple sclerosis. We formulated an anesthetic plan that honored our patient's autonomy and produced a good maternal and neonatal outcome. DOI: 10.1080/08998280.2018.1499318 PMCID: PMC6413975 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 222 – Multiple Sklerose: Veröffentlichungen April 2019 334. Proc Natl Acad Sci U S A. 2019 Apr 23. pii: 201818042. doi: 10.1073/pnas.1818042116. [Epub ahead of print] Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease. Ferrari Bardile C(1), Garcia-Miralles M(1), Caron NS(2), Rayan NA(3), Langley SR(4)(5), Harmston N(4), Rondelli AM(6), Teo RTY(1), Waltl S(2), Anderson LM(2), Bae HG(7)(8), Jung S(7)(9), Williams A(6), Prabhakar S(3), Petretto E(4), Hayden MR(1)(2)(10), Pouladi MA(11)(9)(10). Author information: (1)Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Immunos, 138648 Singapore. (2)Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver BC V5Z 4H4, Canada. (3)Computational and Systems Biology, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 138672 Singapore. (4)Centre for Computational Biology, Duke-NUS Medical School, 169857 Singapore. (5)Lee Kong Chian School of Medicine, Nanyang Technological University, 636921 Singapore. (6)The Medical Research Council Centre for Regenerative Medicine and Multiple Sclerosis Society Edinburgh Centre, Edinburgh bioQuarter, The University of Edinburgh, Edinburgh EH16 4UU, United Kingdom. (7)Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), 138667 Singapore. (8)Department of Life Sciences, Yeungnam University, Gyeongsan, Gyeongsangbuk-do 38541, South Korea. (9)Department of Physiology, National University of Singapore, 117597 Singapore. (10)Department of Medicine, National University of Singapore, 117597 Singapore. (11)Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Immunos, 138648 Singapore; [email protected]. White matter abnormalities are a nearly universal pathological feature of neurodegenerative disorders including Huntington disease (HD). A long-held assumption is that this white matter pathology is simply a secondary outcome of the progressive neuronal loss that manifests with advancing disease. Using a mouse model of HD, here we show that white matter and myelination abnormalities are an early disease feature appearing before the manifestation of any behavioral abnormalities or neuronal loss. We further show that selective inactivation of mutant huntingtin (mHTT) in the NG2+ oligodendrocyte progenitor cell population prevented myelin abnormalities and certain behavioral deficits in HD mice. Strikingly, the improvements in behavioral outcomes were seen despite the continued expression of mHTT in nonoligodendroglial cells including neurons, astrocytes, and microglia. Using RNA-seq and ChIP-seq analyses, we implicate a pathogenic mechanism that involves enhancement of polycomb repressive complex 2 (PRC2) activity by mHTT in the intrinsic oligodendroglial dysfunction and myelination deficits observed in HD. Our findings challenge the long-held dogma regarding the etiology of white matter pathology in HD and highlight the contribution of epigenetic mechanisms to the observed intrinsic oligodendroglial dysfunction. Our results further suggest that ameliorating white matter pathology and oligodendroglial dysfunction may be beneficial for HD. DOI: 10.1073/pnas.1818042116 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 | L.DE.MKT.SM.02.2017.5323 – 223 – Multiple Sklerose: Veröffentlichungen April 2019 335. Proc Natl Acad Sci U S A. 2019 Apr 23;116(17):8131-8136. doi: 10.1073/pnas.1814131116. Epub 2019 Apr 11. Structural basis for ligand modulation of the CCR2 conformational landscape. Taylor BC(1), Lee CT(2), Amaro RE(3). Author information: (1)Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093. (2)Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093. (3)Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093 [email protected]. CC chemokine receptor 2 (CCR2) is a part of the chemokine receptor family, an important class of therapeutic targets. These class A G-protein coupled receptors (GPCRs) are involved in mammalian signaling pathways and control cell migration toward endogenous CC chemokine ligands, named for the adjacent cysteine motif on their N terminus. Chemokine receptors and their associated ligands are involved in a wide range of diseases and thus have become important drug targets. CCR2, in particular, promotes the metastasis of cancer cells and is also implicated in autoimmunity-driven type-1 diabetes, diabetic nephropathy, multiple sclerosis, asthma, atherosclerosis, neuropathic pain, and rheumatoid arthritis. Although promising, CCR2 antagonists have been largely unsuccessful to date. Here, we investigate the effect of an orthosteric and an allosteric antagonist on CCR2 dynamics by coupling long-timescale molecular dynamics simulations with Markov-state model theory. We find that the antagonists shift CCR2 into several stable inactive conformations that are distinct from the crystal structure conformation and disrupt a continuous internal water and sodium ion pathway, preventing transitions to an active-like state. Several metastable conformations present a cryptic drug-binding pocket near the allosteric site that may be amenable to targeting with small molecules. Without antagonists, the apo dynamics reveal intermediate conformations along the activation pathway that provide insight into the basal dynamics of CCR2 and may also be useful for future drug design. DOI: 10.1073/pnas.1814131116 Conflict of interest statement: Conflict of interest statement: R.E.A. has equity interest in, and is a cofounder and on the scientific advisory board of Actavalon, Inc. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 224 – Multiple Sklerose: Veröffentlichungen April 2019 336. Proc Natl Acad Sci U S A. 2019 Apr 23;116(17):8463-8470. doi: 10.1073/pnas.1820039116. Epub 2019 Apr 8. Immune tolerance in multiple sclerosis and neuromyelitis optica with peptide- loaded tolerogenic dendritic cells in a phase 1b trial. Zubizarreta I(1), Flórez-Grau G(2), Vila G(1), Cabezón R(2), España C(2), Andorra M(1), Saiz A(1)(3), Llufriu S(1)(3), Sepulveda M(1)(3), Sola-Valls N(1)(3), Martinez-Lapiscina EH(1)(3), Pulido-Valdeolivas I(1), Casanova B(4), Martinez Gines M(5), Tellez N(6), Oreja-Guevara C(7), Español M(2), Trias E(8)(9), Cid J(10), Juan M(2), Lozano M(10), Blanco Y(1)(3), Steinman L(11), Benitez-Ribas D(2), Villoslada P(12). Author information: (1)Center of Neuroimmunology, Institut d'Investigacions Biomediques August Pi Sunyer, 08036 Barcelona, Spain. (2)Department of Immunology, Hospital Clinic, 08036 Barcelona, Spain. (3)Service of Neurology, Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain. (4)Department of Neurology, Hospital La Fe, 46009 Valencia, Spain. (5)Department of Neurology, Hospital Gregorio Marañon, 28009 Madrid, Spain. (6)Department of Neurology, Hospital de Valladolid, 47005 Valladolid, Spain. (7)Department of Neurology, Hospital Clinico San Carlos, 28040 Madrid, Spain. (8)Advanced Therapies Unit, Hospital Clinic, 08036 Barcelona, Spain. (9)Banc de Sang i Teixits, 08005 Barcelona, Spain. (10)Apheresis Unit, Department of Hemotherapy and Hemostasis, Hospital Clinic, 08036 Barcelona, Spain. (11)Department of Neurology, Stanford University, Stanford, CA 94305 [email protected] [email protected]. (12)Center of Neuroimmunology, Institut d'Investigacions Biomediques August Pi Sunyer, 08036 Barcelona, Spain; [email protected] [email protected]. There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide- specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials. Copyright © 2019 the Author(s). Published by PNAS. DOI: 10.1073/pnas.1820039116 Conflict of interest statement: Conflict of interest statement: E.F. and L.S. published an obituary on two leaders in MS [Kildebeck EJ, et al. (2017) The emergence of neuroepidemiology, neurovirology and neuroimmunology: The legacies of John F. Kurtz e and ichard “Dic ” T. Johnson. J Neurol 64 817–828]. I.Z. has received travel reimbursement from Genzyme, Biogen, and Merck for national and international meetings over the last 3 y. E.H.M.-L. has received speaker honoraria from Biogen, Roche, Novartis, and Sanofi and a travel reimbursement from Biogen, Roche, Novartis, and Sanofi. E.H.M.-L. has participated in advisory boards for Roche and Sanofi. A.S. has received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd., Roche, and Novartis. S.L. has received speaker honoraria and travel reimbursement from Biogen, Merck, Novartis, and Teva. I.P.-V. has received travel reimbursement from Roche Spain and Genzyme- Sanofi, European Academy of Neurology, and the European Committee for Treatment and Research in Multiple Sclerosis for international and national meetings over the last 3 y; I.P.-V. holds a patent for an affordable eye-tracking system to measure eye movement in neurologic diseases and holds stock in Aura Innovative Robotics. N.S.-V. received compensation for consulting services and speaker honoraria from Genzyme-Sanofi, Biogen idec, Merck-Serono, and Bayer-Schering. P.V. holds stocks and has received compensation from Bionure Farma SL; Health Engineering SL; Spiral Therapeutics, Inc.; and QMenta SL. L.S. received compensation from Novartis, Celgene, Bionure, Tolerion, Katexco, Atreca, and TG Therapeutics. All other 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 | L.DE.MKT.SM.02.2017.5323 – 225 – Multiple Sklerose: Veröffentlichungen April 2019 337. Proc Natl Acad Sci U S A. 2019 Apr 19. pii: 201903796. doi: 10.1073/pnas.1903796116. [Epub ahead of print] New age for progressive multiple sclerosis. Imitola J(1). Author information: (1)Laboratory for Neural Stem Cells and Functional Neurogenetics, Progressive Multiple Sclerosis Clinic and Translational Research Program, Division of Neuroimmunology and Multiple Sclerosis, Department of Neurology, The Ohio State University Neurological Institute, The Ohio State University, Columbus, OH 43221 [email protected]. DOI: 10.1073/pnas.1903796116 Conflict of interest statement: The author declares 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 | L.DE.MKT.SM.02.2017.5323 – 226 – Multiple Sklerose: Veröffentlichungen April 2019 338. Proc Natl Acad Sci U S A. 2019 Apr 19. pii: 201818347. doi: 10.1073/pnas.1818347116. [Epub ahead of print] MAPK pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis. Kotelnikova E(1)(2)(3), Kiani NA(4)(5), Messinis D(6), Pertsovskaya I(1), Pliaka V(6)(7), Bernardo-Faura M(8), Rinas M(9), Vila G(1), Zubizarreta I(1), Pulido-Valdeolivas I(1), Sakellaropoulos T(7), Faigle W(10), Silberberg G(4)(5), Masso M(11), Stridh P(12), Behrens J(13)(14), Olsson T(12), Martin R(10), Paul F(13)(14)(15), Alexopoulos LG(6)(7), Saez-Rodriguez J(8)(9)(16)(17), Tegner J(4)(5)(18)(19)(20), Villoslada P(21). Author information: (1)Center of Neuroimmunology, Institut d'Investigacions Biomèdiques August Pi Sunyer, Barcelona 08036, Spain. (2)Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow 127051, Russia. (3)Clarivate Analytics, Barcelona 08025, Spain. (4)Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, Solna, Stockholm SE-171 76, Sweden. (5)Center for Molecular Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden. (6)ProtatOnce, Athens 15343, Greece. (7)Department of Mechanical Engineering, National Technical University of Athens, Athens 15780, Greece. (8)European Bioinformatics Institute, European Molecular Biology Laboratory, Hinxton CB10 1SD, United Kingdom. (9)Joint Research Centre for Computational Biomedicine, Rheinisch-Westfälische Technische Hochschule - Aachen University Hospital, Aachen 52074, Germany. (10)Department of Neurology, University of Zurich, Zurich 8091, Switzerland. (11)Bionure Farma SL, Barcelona 08028, Spain. (12)Department of Neurology, Karolinska University Hospital, Stockholm SE- 171 77, Sweden. (13)NeuroCure Clinical Research Center, Charité University Universitätsmedizin Berlin, Berlin 13125, Germany. (14)Department of Neurology, Charité University Universitätsmedizin Berlin, Berlin 13125, Germany. (15)Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, Berlin 13125, Germany. (16)Institute of Computational Biomedicine BioQuant, Faculty of Medicine, Heidelberg University, Heidelberg 69120, Germany. (17)Heidelberg University Hospital, Heidelberg University, Heidelberg 69120, Germany. (18)Science for Life Laboratory, Solna SE-171 65, Sweden. (19)Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia. (20)Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal 23955, Saudi Arabia. (21)Center of Neuroimmunology, Institut d'Investigacions Biomèdiques August Pi Sunyer, Barcelona 08036, Spain; [email protected]. Dysregulation of signaling pathways in multiple sclerosis (MS) can be analyzed by phosphoproteomics in peripheral blood mononuclear cells (PBMCs). We performed in vitro kinetic assays on PBMCs in 195 MS patients and 60 matched controls and quantified the phosphorylation of 17 kinases using xMAP assays. Phosphoprotein levels were tested for association with genetic susceptibility by typing 112 single-nucleotide polymorphisms (SNPs) associated with MS susceptibility. We found increased phosphorylation of MP2K1 in MS patients relative to the controls. Moreover, we identified one SNP located in the PHDGH gene and another on IRF8 gene that were associated with MP2K1 phosphorylation levels, providing a first clue on how this MS risk gene may act. The analyses in patients treated with disease-modifying drugs identified the phosphorylation of each receptor's downstream kinases. Finally, using flow cytometry, we detected in MS patients increased STAT1, STAT3, TF65, and HSPB1 phosphorylation in CD19+ cells. These findings indicate the activation of cell survival and proliferation (MAPK), and proinflammatory (STAT) pathways in the immune cells of MS patients, primarily in B cells. The changes in the activation of these kinases suggest that these pathways may represent therapeutic targets for modulation by kinase inhibitors. DOI: 10.1073/pnas.1818347116 Conflict of interest statement: Conflict of interest statement: D.M. is an employee of ProtATonce; T.O. received honoraria for lectures and/or participation on advisory boards, as well as unrestricted multiple sclerosis research grants from Allmiral, Astrazeneca, Biogen, Genzyme, Merck, and Novartis; R.M. received grants and personal fees from Biogen Idec, personal fees from Genzyme Sanofi Aventis, grants and personal fees from Novartis, and personal fees from Merck Serono, Bionamics, all for work unrelated to that submitted; R.M. received honoraria for lectures and/or participation on advisory boards, as well as unrestricted multiple sclerosis research grants from Biogen, Genzyme, Merck, Celgene, Roche, Novartis, Neuway, and CellProtect, all for work unrelated to that submitted; F.P. received research grants and personal compensation from Alexion, Bayer, Chugai, Novartis, Merck, Teva, Sanofi, Genzyme, Biogen, and MedImmune; L.G.A is the founder and shareholder at ProtATonce; P.V. holds stock in and has received consultancy payments from Bionure Farma SL, QMenta Inc, Health Engineering SL, Spire Therapeutics Inc, and Spire Bioventures Inc. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 227 – Multiple Sklerose: Veröffentlichungen April 2019 339. Proc Natl Acad Sci U S A. 2019 Apr 15. pii: 201822013. doi: 10.1073/pnas.1822013116. [Epub ahead of print] DNA threads released by activated CD4+ T lymphocytes provide autocrine costimulation. Costanza M(1), Poliani PL(2), Portararo P(3), Cappetti B(3), Musio S(4), Pagani F(2), Steinman L(5), Colombo MP(3), Pedotti R(4), Sangaletti S(3). Author information: (1)Department of Clinical Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; [email protected] [email protected]. (2)Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, 25121 Brescia, Italy. (3)Department of Research, Molecular Immunology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy. (4)Department of Clinical Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy. (5)Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305 [email protected] [email protected]. The extrusion of DNA traps contributes to a key mechanism in which innate immune cells clear pathogens or induce sterile inflammation. Here we provide evidence that CD4+ T cells, a critical regulator of adaptive immunity, release extracellular threads of DNA on activation. These DNA extrusions convey autocrine costimulatory signals to T lymphocytes and can be detected in lymph nodes isolated during the priming phase of experimental autoimmune encephalomyelitis (EAE), a CD4+ T cell-driven mouse model of multiple sclerosis. Pharmacologic inhibition of mitochondrial reactive oxygen species (mtROS) abolishes the extrusion of DNA by CD4+ T cells, reducing cytokine production in vitro and T cell priming against myelin in vivo. Moreover, mtROS blockade during established EAE markedly ameliorates disease severity, dampening autoimmune inflammation of the central nervous system. Taken together, these experimental results elucidate a mechanism of intrinsic immune costimulation mediated by DNA threads released by activated T helper cells, and identify a potential therapeutic target for such disorders as multiple sclerosis, neuromyelitis optica, and CD4+ T cell-mediated disorders. DOI: 10.1073/pnas.1822013116 Conflict of interest statement: The authors declare no conflict of interest. 340. Prog Brain Res. 2019;245:119-144. doi: 10.1016/bs.pbr.2019.03.013. Epub 2019 Apr 2. Oligodendrocyte precursor cells as a therapeutic target for demyelinating diseases. Skaper SD(1). Author information: (1)Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy. Electronic address: [email protected]. The mechanisms regulating differentiation of multipotent oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs) are critical to our understanding of myelination and remyelination. Following acute demyelination in the central nervous system, adult OPCs migrate to the injury site, differentiate into OLs and generate new myelin sheaths. A common feature of regenerative processes is the fact that remyelination efficiency declines with aging and, accounts for the observation that chronic demyelinating diseases like multiple sclerosis (MS) are characterized by an ineffective remyelination. Without doubt, impairment of OPC differentiation is an essential determinant of the aging effects in remyelination. However, spontaneous remyelination is limited in demyelinating diseases such as MS, owing in part to the failure of adult OPCs to differentiate into myelinating OLs. The inability to restore myelin after injury compromises axon integrity and renders them vulnerable to degeneration. Although the genes that regulate the proliferation and differentiation of OPCs during development have been intensively studied, relatively little is known about the molecular signals that regulate the function of adult OPCs after demyelination. Elucidating the mechanisms regulating OPC differentiation are key to identifying pharmacological targets for remyelination-enhancing therapy. This review will discuss OPC biology, myelination, and possible pharmacological targets for promoting the differentiation of OPCs as a strategy to enhance remyelination, including the potential for nanoscale delivery. © 2019 Elsevier B.V. All rights reserved. DOI: 10.1016/bs.pbr.2019.03.013 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 228 – Multiple Sklerose: Veröffentlichungen April 2019 341. Prog Retin Eye Res. 2019 Apr 15. pii: S1350-9462(18)30080-6. doi: 10.1016/j.preteyeres.2019.04.001. [Epub ahead of print] Retinal oximetry: Metabolic imaging for diseases of the retina and brain. Stefánsson E(1), Olafsdottir OB(2), Eliasdottir TS(2), Wehmeijer W(3), Einarsdottir AB(4), Bek T(5), Torp TL(6), Grauslund J(6), Eysteinsson T(2), Karlsson RA(7), Van Keer K(8), Stalmans I(8), Vandewalle E(8), Todorova MG(9), Hammer (10), Garhöfer G(11), Schmetterer L(1 ), Šín (13), Hardarson SH(14). Author information: (1)University of Iceland, Reykjavik, Iceland; Landspitali, University Hospital, Reykjavik, Iceland; Oxymap ehf, Reykjavik, Iceland. Electronic address: [email protected]. (2)University of Iceland, Reykjavik, Iceland; Landspitali, University Hospital, Reykjavik, Iceland. (3)Leiden University, Leiden, the Netherlands. (4)University of Iceland, Reykjavik, Iceland; Odense University Hospital, Odense, Denmark; University of Southern Denmark, Odense, Denmark. (5)Aarhus University Hospital, Aarhus, Denmark. (6)Odense University Hospital, Odense, Denmark; University of Southern Denmark, Odense, Denmark. (7)University of Iceland, Reykjavik, Iceland; Oxymap ehf, Reykjavik, Iceland. (8)University of Leuven, Leuven, Belgium. (9)University of Basel, Department of Ophthalmology, Basel, Switzerland; Cantonal Hospital St.Gallen, Department of Ophthalmology, St. Gallen, Switzerland. (10)Universitätsklinikum Jena, Germany. (11)Department of Clinical Pharmacology, Medical University of Vienna, Austria. (12)Singapore Eye Research Institute, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore; Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Austria. (13)Department of Ophthalmology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. (14)University of Iceland, Reykjavik, Iceland. Retinal oximetry imaging of retinal blood vessels measures oxygen saturation of hemoglobin. The imaging technology is non-invasive and reproducible with remarkably low variability on test-retest studies and in healthy cohorts. Pathophysiological principles and novel biomarkers in several retinal diseases have been discovered, as well as possible applications for systemic and brain disease. In diabetic retinopathy, retinal venous oxygen saturation is elevated and arteriovenous difference progressively reduced in advanced stages of retinopathy compared with healthy persons. This correlates with pathophysiology of diabetic retinopathy where hypoxia stimulates VEGF production. Laser treatment and vitrectomy both improve retinal oximetry values, which correlate with clinical outcome. The oximetry biomarker may allow automatic measurement of severity of diabetic retinopathy and predict its response to treatment. Central retinal vein occlusion is characterized by retinal hypoxia, which is evident in retinal oximetry. The retinal hypoxia seen on oximetry correlates with the extent of peripheral ischemia, visual acuity and thickness of macular edema. This biomarker may help diagnose and measure severity of vein occlusion and degree of retinal ischemia. Glaucomatous retinal atrophy is associated with reduced oxygen consumption resulting in reduced arteriovenous difference and higher retinal venous saturation. The oximetry findings correlate with worse visual field, thinner nerve fiber layer and smaller optic disc rim. This provides an objective biomarker for glaucomatous damage. In retinitis pigmentosa, an association exists between advanced atrophy, worse visual field and higher retinal venous oxygen saturation, lower arteriovenous difference. This biomarker may allow measurement of severity and progression of retinitis pigmentosa and other atrophic retinal diseases. Retinal oximetry offers visible light imaging of systemic and central nervous system vessels. It senses hypoxia in cardiac and pulmonary diseases. Oximetry biomarkers have been discovered in Alzheimer's disease and multiple sclerosis and oxygen levels in the retina correspond well with brain. Copyright © 2019. Published by Elsevier Ltd. DOI: 10.1016/j.preteyeres.2019.04.001 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 229 – Multiple Sklerose: Veröffentlichungen April 2019 342. Psychiatr Danub. 2019 Mar;31(Suppl 1):118-125. Quality of life and health of patients in early stages of Multiple sclerosis. Du a Glavor K(1), Titlić , uletic G. Author information: (1)Department of Neurology, General Hospital Zadar, Boze Pericica 5, 23000 Zadar, Croatia, [email protected]. BACKGROUND: Multiple sclerosis is a chronic neurologic condition with a variety of symptoms which have a great impact on quality of life even in the early stages. The aim of this study was to investigate, and to compare overall subjective quality of life with self-perceived health in patients with early stages of MS. SUBJECTS AND METHODS: Thirty patients with MS (22 women, 8 men; mean age 37.3±9.7years; relapsing-remitting MS; EDSS<2.5; all on immunomodulatory therapy: IFN, GA) were enrolled in the study. The QOL was assessed using the Personal well-being index (PWI) and health was measured by the Short Form 36-Item Health Survey (SF-36) questionnaire. RESULTS: Results indicate that MS patients in early stage experience similar health and quality of life, comparing to the general adult population. Analysis of self- reported change in health by categories showed that 50% patients access their health about the same as a year before, 9 rate their health as worse as one year before and 5 rate their health even better. Correlation analysis revealed that SF-36 domain Mental health correlates with most PWI domains. CONCLUSION: This study demonstrates that MS patients in early stage experience similar quality of life as general adult population. Also, it was revealed that health domain Mental health is correlated with various quality of life domains, suggesting that mental health is of great significance for subjective quality of life perception. However, it is important to emphasize the distinction between the health and quality of life, due to the fact that one can perceive his/hers own health as impaired, but at the same time can have satisfactory quality of life. 343. Psychol Health Med. 2019 Apr 29:1-11. doi: 10.1080/13548506.2019.1612082. [Epub ahead of print] Factors associated with disease self-efficacy in individuals aging with a disability. Amtmann D(1), Bamer AM(1), Nery-Hurwit MB(1), Liljenquist KS(1), Yorkston K(1). Author information: (1)a Department of Rehabilitation Medicine , University of Washington , Seattle , WA , USA. Self-management of a disability consists of treatment adherence, obtaining information about the disease and treatment options, caring for oneself, participating in decisions, and maintaining social relationships and emotional balance. Understanding and measuring an individual's beliefs about their ability to successfully self-manage and live well with a disability allows researchers and clinicians to better target interventions aimed at increasing disability management self-efficacy (DMSE). The purpose of this study was to examine the associations between demographic and clinical indicators, and self-efficacy for DMSE in individuals with chronic physical conditions. Adults (N = 815) with muscular dystrophy, multiple sclerosis, spinal cord injury, or post-polio syndrome completed a self-report mailed survey assessing DMSE, perceived social support, depression symptoms, resilience, fatigue, pain interference, satisfaction with participation in social roles, physical function, and demographics. A cross-sectional regression model was used to examine the associations between the clinical and demographic factors, and DMSE. The model explained 67% of the variance in DMSE. Satisfaction with participation in social roles, resilience, pain interference, social support, and fatigue were statistically significant. Better social functioning, more resilience, and less pain and fatigue were most strongly associated with DMSE. Interventions aimed at increasing DMSE should include strategies for improving social participation. DOI: 10.1080/13548506.2019.1612082 344. Radiology. 2019 Apr 9:190398. doi: 10.1148/radiol.2019190398. [Epub ahead of print] Cortical Lesions on 7-T MRI in Multiple Sclerosis: A Window into Pathogenetic Mechanisms? Filippi M(1), Rocca MA(1). Author information: (1)From the Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy. Comment on Radiology. 2019 Apr 9;:181719. DOI: 10.1148/radiol.2019190398 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 230 – Multiple Sklerose: Veröffentlichungen April 2019 345. Radiology. 2019 Apr 9:181719. doi: 10.1148/radiol.2019181719. [Epub ahead of print] Longitudinal Characterization of Cortical Lesion Development and Evolution in Multiple Sclerosis with 7.0-T MRI. Treaba CA(1), Granberg TE(1), Sormani MP(1), Herranz E(1), Ouellette RA(1), Louapre C(1), Sloane JA(1), Kinkel RP(1), Mainero C(1). Author information: (1)From the A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Bldg 149, 13th St, Charleston, MA 02129 (C.A.T., T.E.G., E.H., R.A.O., C.L., C.M.); Harvard Medical School, Boston, MA (C.A.T., T.E.G., E.H., C.L., C.M.); Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (T.E.G.); Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy (M.P.S.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (J.A.S.); and Department of Neurosciences, University of California San Diego, San Diego, CA (R.P.K.). Comment in Radiology. 2019 Apr 9;:190398. Background Cortical lesions develop early in multiple sclerosis (MS) and play a major role in disease progression. MRI at 7.0 T shows high sensitivity for detection of cortical lesions as well as better spatial resolution and signal-to-noise ratio compared with lower field strengths. Purpose To longitudinally characterize (a) the development and evolution of cortical lesions in multiple sclerosis across the cortical width, sulci, and gyri; (b) their relation with white matter lesion accrual; and (c) the contribution of 7.0-T cortical and white matter lesion load and cortical thickness to neurologic disability. Materials and Methods Twenty participants with relapsing-remitting MS and 13 with secondary progressive MS, along with 10 age- matched healthy controls, were prospectively recruited from 2010 to 2016 to acquire, in two imaging sessions (mean interval, 1.5 years), 7.0-T MRI T2*-weighted gradient-echo images (0.33 × 0.33 × 1.0 mm3) for cortical and white matter lesion segmentation and 3.0-T T1-weighted images for cortical surface reconstruction and cortical thickness estimation. Cortical lesions were sampled through the cortex to quantify cortical lesion distribution. The Expanded Disability Status Scale (EDSS) was used to assess neurologic disability. Nonparametric statistics assessed differences between and within groups in MRI metrics of cortical and white matter lesion burden; regression analysis explored associations of disability with MRI metrics. Results Twenty-five of 31 (81%) participants developed new cortical lesions per year (intracortical, 1.3 ± 1.7 vs leukocortical, 0.7 ± 1.9; P = .04), surpassing white matter lesion accrual (cortical, 2.0 ± 2.8 vs white matter, 0.7 ± 0.6; P = .01). In contrast to white matter lesions, cortical lesion accrual was greater in participants with secondary progressive MS than with relapsing-remitting MS (3.6 lesions/year ± 4.2 vs 1.1 lesions/year ± 0.9, respectively; P = .03) and preferentially localized in sulci. Total cortical lesion volume independently predicted baseline EDSS (β = 1.5, P < .001) and EDSS changes at follow-up (β = 0.5, P = .003). Conclusion Cortical lesions predominantly develop intracortically and within sulci, suggesting an inflammatory cerebrospinal fluid-mediated lesion pathogenesis. Cortical lesion accumulation was prominent at 7.0 T and independently predicted neurologic disability progression. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Filippi and Rocca in this issue. DOI: 10.1148/radiol.2019181719 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 231 – Multiple Sklerose: Veröffentlichungen April 2019 346. Res Pharm Sci. 2019 Feb;14(1):36-45. doi: 10.4103/1735-5362.251851. Regulatory effects of hemp seed/evening primrose oil supplement in comparison with rapamycin on the expression of the mammalian target of rapamycin-complex 2 and interleukin-10 genes in experimental autoimmune encephalomyelitis. Rezapour-Firouzi S(1), Kheradmand F(2), Shahabi S(1), Tehrani AA(3), Mazloomi E(1), Mohammadzadeh A(4). Author information: (1)Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, I.R. Iran. (2)Solid Tumor Research Center, Urmia University of Medical sciences, Urmia, I.R. Iran. (3)Department of Pathobiology, Faculty of Veterinary Medicine, Urmia University, Urmia, I.R. Iran. (4)Departement of Immunology and Genetics, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, I.R. Iran. The mammalian target of rapamycin (mTOR) signaling plays a critical role in lipid synthesis and immune responses. The T regulatory cells (Treg) as suppressor of T cells, are a subset of T cells that modulate the immune system, maintain tolerance, and prevent autoimmune diseases.. The interleukin (IL) -10 derived from the Treg and T helper (Th) 2 is an anti-inflammatory cytokine in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Due to the exclusive roles of rapamycin (RAPA) in mTOR inhibition, we evaluated the regulatory effect of the hemp seed oil/evening primrose oil (HSO/EPO) supplement in comparison with RAPA in EAE. EAE was induced by using myelin oligodendrocyte glycoprotein peptide and complete freund's adjuvant (CFA) in C57BL/6 mice, total mRNA was extracted from local lymph nodes and real-time polymerase chain reaction was used to evaluate the expression level of the rapamycin-insensitive companion of mTOR complex 2 (RICTOR) and IL-10 genes. The expression of IL-10 and RICTOR genes were significantly increased in HSO/EPO group. In contrast with RAPA groups, histological findings have shown that the HSO/EPO treated group remarkably reduced cell infiltration and promoted remyelination. The EPO/HSO has beneficial effects on the repair of myelin, which was confirmed by immunological and histological findings. DOI: 10.4103/1735-5362.251851 PMCID: PMC6407336 347. Res Pharm Sci. 2019 Feb;14(1):20-26. doi: 10.4103/1735-5362.251849. Design and molecular dynamic simulation of a new double-epitope tolerogenic protein as a potential vaccine for multiple sclerosis disease. Banisharif-Dehkordi F(1), Mobini-Dehkordi M(1), Shakhsi-Niaei M(1)(2), Mahnam K(3)(2). Author information: (1)Department of Genetics, Faculty of Science, Shahrekord University, Shahrekord, I.R. Iran. (2)Nanotechnology Research Center, Shahrekord University, Shahrekord, I.R. Iran. (3)Department of Biology, Faculty of Science, Shahrekord University, Shahrekord, I.R. Iran. One of the debilitating diseases affecting the central nervous system is multiple sclerosis (MS). As there is no definitive treatment for MS, researchers have mainly consented with optimization of strategies which slows down the progression of the disease such as specific auto-antigens tolerance induction. In this regard, the aim of this study was design of a new double-epitope protective vaccine based on interleukin (IL)-16- neuroantigens fusion proteins. First, we selected highly antigenic epitopes of myelin basic protein (MBP) (aa 84-104) and myelin oligodendrocyte glycoprotein (MOG) (aa 99-107) from available literature and our bioinformatics analysis. The correct cleavage of our constructs and major histocompatibility complex class II binding affinities of cleaved epitopes were checked and evaluated using Pepcleave and IEDB servers, respectively. Then, different combination of MOG and MBP epitopes with or without fusion to C-terminal active part of IL-16 were designed as constructs. Afterward, Modeller and Gromacs softwares used for the investigation of the MBP, and MOG epitopes antigenicity in these constructs. The results of molecular dynamics simulations showed that IL-16 in MOG + linker + MBP + IL-16 construct does not interfere with final epitopes antigenicity of MOG + linker + MBP construct. To sum up, the construct with IL-16 is suggested as a new double-epitope tolerogenic vaccine for prevention and amelioration of MS in human. DOI: 10.4103/1735-5362.251849 PMCID: PMC6407332 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 232 – Multiple Sklerose: Veröffentlichungen April 2019 348. Rev Med Liege. 2019 Apr;74(4):179-184. [Extended optic neuropathy with myelin oligodendrocyte glycoprotein antibodies]. [Article in French; Abstract available in French from the publisher] Gillard F(1), Andris C(2), Lommers E(3). Author information: (1)Service d'Ophtalmologie, CHU Liège, Belgique. (2)Service de Neuro-Ophtalmologie, CHU Liège, Belgique. (3)Service de Neurologie, CHU Liège, Belgique. The discovery of autoantibodies targeting aquaporin-4 (AQP4) of astrocytes has improved the understanding and management of Neuromyelitis Optica Syndrome Disorders (NMO-SD), previously considered as a variant of multiple sclerosis. Later, the detection of MOG IgG1 antibodies, directed against an oligodendrocyte myelin glycoprotein, made it possible to distinguish pathologies with different clinical and prognostic particularities, then helping the clinician in his diagnostic and therapeutic approach. This clinical case aims to feature the clinical differences, prognosis and therapeutic solutions of these pathologies. Publisher La découverte d’auto-anticorps ciblant l’aquaporine-4 (AQP4) des astrocytes a permis d’avancer dans la compréhension et la prise en charge du spectre des maladies de la neuromyélite optique (NMO-SD), antérieurement considérée comme une variante proche de la sclérose en plaques. Plus tard, la mise en évidence des anticorps MOG IgG1, dirigés contre une protéine de la myéline oligodendrocytaire, a permis de distinguer des pathologies avec des particularités cliniques et pronostiques différentes, pouvant aider le clinicien dans sa démarche diagnostique et thérapeutique. Ce cas clinique permet de détailler les différences cliniques et pronostiques ainsi que les solutions thérapeutiques de ces pathologies. 349. Rev Neurol. 2019 May 1;68(9):384-388. doi: 10.33588/rn.6809.2018354. [Epilepsy surgery for refractory neurocysticercosis-related epilepsy]. [Article in Spanish; Abstract available in Spanish from the publisher] Suller-Marti A(1), Escalaya AL(2), Burneo JG(1). Author information: (1)Western University, London, Ontario, Canada. (2)Universidad Peruana Cayetano Heredia, San Martin de Porres, Lima, Peru. INTRODUCTION: Neurocysticercosis is one of the most frequent causes of epilepsy worldwide, with some cases going into refractoriness. For that reason, surgical treatment should be considered, particularly lesionectomy, with or without temporal lobectomy. CASE REPORTS: From our series of patients with drug- resistant epilepsy from 2008 to 2018, we selected all cases with one or more lesions suggestive of neurocysticercosis who underwent epilepsy surgery. Three patients fulfilled the inclusion criteria, with an average age of 39.33 year-old, two were female, epilepsy onset was at a mean age of 17.33 years. One case had multiple neurocysticercosis lesions and mesial temporal sclerosis, the other two cases had single neurocysticercosis lesions in the temporal region. In all cases, the epileptogenic zone was located in the temporal lobe. One patient underwent a temporal lobectomy, while the other two underwent lesionectomy. Pathology confirmed neurocysticercosis granuloma. All three cases remain seizure free. CONCLUSION: Evaluation of patients with neurocysticercosis-related refractory epilepsy for potential surgery is indicated, as this procedure can be quite successful. Publisher: Cirugia en epilepsia refractaria debida a neurocisticercosis.Introduccion. La neurocisticercosis es una causa frecuente de crisis epileptica en el mundo, y en algunos casos puede llegar a ser farmacorresistente, por lo cual las opciones quirurgicas deben estar presentes y la lesionectomia, con o sin lobectomia temporal, es la cirugia de eleccion. Casos clinicos. De la serie de pacientes con epilepsia farmacorresistente entre los años 2008 a 2018, se seleccionaron los que tenian una o varias lesiones sugerentes de neurocisticercosis y que se sometieron a cirugia de la epilepsia. Tres pacientes cumplian los criterios de seleccion, dos de ellos mujeres, con una edad media de 39,33 años. La edad media de inicio de la epilepsia fue a los 17,33 años, con diagnostico de cisticercosis confirmado a la edad de 30. Uno de los casos tenia multiples lesiones de neurocisticercosis junto con esclerosis mesial temporal, y los otros dos, lesiones unicas en el lobulo temporal. En todos los pacientes, la zona epileptogena se localizo en el lobulo temporal correspondiente. Por lo tanto, en dos casos se realizo una lesionectomia, y en el otro, con multiples lesiones, una lobectomia temporal. La patologia de las lesiones sugiere estadios cronicos de neurocisticercosis. Todos los pacientes estan libres de crisis en el momento actual. Conclusion. La evaluacion para cirugia de la epilepsia en pacientes con epilepsia refractaria debida a neurocisticercosis esta recomendada y puede ser eficaz en el control y tratamiento de las crisis. DOI: 10.33588/rn.6809.2018354 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 233 – Multiple Sklerose: Veröffentlichungen April 2019 350. Rev Neurol. 2019 May 1;68(9):357-368. doi: 10.33588/rn.6809.2018350. [Efficacy of virtual reality on balance and gait in multiple sclerosis. Systematic review of randomized controlled trials]. [Article in Spanish; Abstract available in Spanish from the publisher] Moreno-Verdu M(1), Ferreira-Sanchez MR(1), Cano-de-la-Cuerda R(2), Jimenez-Antona C(2). Author information: (1)Asociacion Parkinson Madrid, Madrid, Espana. (2)Universidad Rey Juan Carlos, 28922 Alcorcon, Espana. INTRODUCTION: Multiple sclerosis (MS) is a neurodegenerative disease that causes gait abnormalities and a deficit in balance control in the vast majority of people affected by it. Virtual reality has been proposed as a complementary approach to conventional physiotherapeutic treatment as a way of improving these variables. AIM: To assess the real efficacy of this approach compared to other neurorehabilitation therapies, or no intervention, in MS. PATIENTS AND METHODS: A systematic review of randomized controlled trials was conducted. Studies of the last five years that compare virtual reality with conventional treatment or no intervention, on balance and/or gait, in adults with MS, were included. PEDro scale was used to assess methodological quality and the Oxford scale to determine the level of evidence and grades of recommendations. RESULTS: Eight studies met the eligibility criteria. For balance, the efficacy of virtual reality is, at least, comparable as conventional training. For gait, virtual reality seems not to be superior in improving the speed, compared with the other types of interventions assessed. Methodological quality of studies was low-moderate. CONCLUSIONS: Virtual reality is as effective as conventional training for improving balance in people with MS. No data suggests that virtual reality is superior to other interventions in improving gait speed. For other gait parameters, virtual reality's efficacy remains unknown. Publisher: Eficacia de la realidad virtual sobre el equilibrio y la marcha en esclerosis multiple. Revision sistematica de ensayos controlados aleatorizados.Introduccion. La esclerosis multiple (EM) es una enfermedad neurodegenerativa que produce alteraciones en el equilibrio y la marcha en la mayoria de los pacientes. La realidad virtual se ha propuesto como un abordaje complementario al tratamiento rehabilitador convencional como medio para mejorar dichas alteraciones. Objetivo. Evaluar la eficacia del abordaje mediante realidad virtual, en comparacion con otras intervenciones de neurorrehabilitacion o la no intervencion, en la EM. Pacientes y metodos. Se realiza una revision sistematica de ensayos controlados aleatorizados. Se incluyeron estudios de los ultimos cinco años que comparasen la intervencion de realidad virtual frente al tratamiento convencional o la no intervencion sobre el equilibrio y la marcha en personas adultas con EM. Se utilizo la escala PEDro para evaluar la calidad metodologica de los estudios incluidos y la escala de Oxford para evaluar el nivel de evidencia y el grado de recomendacion. Resultados. Ocho estudios cumplieron los criterios de elegibilidad. Para el equilibrio, la eficacia de la realidad virtual es, al menos, comparable a la del entrenamiento convencional. Para la marcha, la realidad virtual parece no ser superior en el parametro velocidad, en comparacion con el resto de intervenciones evaluadas. La calidad metodologica de los estudios fue moderada-baja. Conclusiones. La realidad virtual es igual de eficaz que el entrenamiento rehabilitador convencional para mejorar el equilibrio en personas con EM. No se han hallado datos que sugieran que la realidad virtual sea superior a otras intervenciones en la mejora de la velocidad de la marcha, y su eficacia sobre otros parametros de la marcha es aun incierta. DOI: 10.33588/rn.6809.2018350 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 234 – Multiple Sklerose: Veröffentlichungen April 2019 351. Rev Neurol (Paris). 2019 Apr 23. pii: S0035-3787(17)30802-0. doi: 10.1016/j.neurol.2018.12.006. [Epub ahead of print] Impact of astrocyte and lymphocyte interactions on the blood-brain barrier in multiple sclerosis. Yan XB(1), Zhao YF(2), Yang YM(2), Wang N(2), He BZ(3), Qiu XT(2). Author information: (1)Department of Neurology, The Second Clinical Hospital of Harbin Medical University, 150086 Harbin, China. Electronic address: [email protected]. (2)Department of Neurology, The Second Clinical Hospital of Harbin Medical University, 150086 Harbin, China. (3)The University of New South Wales, 2033 Kensington, Australia. OBJECTIVE: This study was designed to investigate the impact of astrocyte and lymphocyte (LC) interactions in the blood-brain barrier (BBB) on the pathogenesis of multiple sclerosis (MS). METHODS: Primary rat brain microvascular endothelial cells (rBMECs) and astrocytes isolated from Sprague-Dawley rats were used to establish in vitro BBB models. Transendothelial electrical resistance (TEER) and permeability were compared between rBMEC monocultures and rBMEC/astrocyte co-cultures to evaluate the validity of each as a BBB cell model. rBMEC/LC co-cultures and rBMEC/astrocyte/LC tri-cultures were established to evaluate inflammatory responses in MS by measuring the gene expression levels of nerve growth factor (NGF), matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), interleukin 17 (IL-17), interferon γ (IFN-γ), and forkhead box P3 (Foxp3). RESULTS: The rBMEC/astrocyte co-cultures exhibited higher TEER values and lower lymphocyte permeabilities than those of rBMEC monocultures. Compared to the rBMEC mono-cultures, the rBMEC/astrocyte/LC tri-cultures showed significantly decreased NGF, IL-17, and IFN-γ and increased MMP-2 and Foxp3 expression. Furthermore, the tri-cultures exhibited decreased NGF, IL-17, and IFN-γ expression compared to the rBMEC/astrocyte co-cultures, and increased MMP-2 expression compared to that shown by the rBMEC/LC co-cultures. MMP-9 expression did not vary significantly between the four established BBB cell models. CONCLUSION: These results suggest that the synergistic effect between astrocytes and LCs may increase the expression of MMP-2 and decrease that of IL-17 and IFN-γ at the BBB. Furthermore, the use of rBMEC/astrocytes/LC tri-cultures enabled us to test the synergistic effect between astrocytes and LCs and their roles in MS pathogenesis. Copyright © 2019. Published by Elsevier Masson SAS. DOI: 10.1016/j.neurol.2018.12.006 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 235 – Multiple Sklerose: Veröffentlichungen April 2019 352. Rev Neurol (Paris). 2019 Apr 1. pii: S0035-3787(17)30801-9. doi: 10.1016/j.neurol.2018.07.011. [Epub ahead of print] Dronabinol use in France between 2004 and 2017. Lejczak S(1), Rousselot H(2), Di Patrizio P(3), Debouverie M(4). Author information: (1)Department of neurology, hôpital Central, Nancy university hospital, CHRU, 29, avenue du Maréchal-de-Lattre-de-Tassigny CO n(o)34, 54035 Nancy cedex, France; Service interdiciplinaire de soins de support aux patients en oncologie (SISSPO), institute of oncology of Lorraine « Alexis Vautrin », 6, avenue de Bourgogne, 54519 andœuvre-les-Nancy cedex, France. Electronic address: [email protected]. (2)Service interdiciplinaire de soins de support aux patients en oncologie (SISSPO), institute of oncology of Lorraine « Alexis Vautrin », 6, avenue de Bourgogne, 54519 andœuvre- les-Nancy cedex, France. (3)Department of general practice at the university of Lorraine, 9, avenue de la Forêt de Haye, BP 0199, 54505 andœuvre-les-Nancy cedex, France. (4)Department of neurology, hôpital Central, Nancy university hospital, CHRU, 29, avenue du Maréchal-de-Lattre-de-Tassigny CO n(o)34, 54035 Nancy cedex, France; EA 4360 Apemac, université de Lorraine, 54000 Nancy, France. OBJECTIVES: To investigate prescription practices for dronabinol, a pure extract of delta-9- tetrahydrocannabinol, prescribed for refractory chronic pain in France since 2004. DESIGN: A descriptive study based on answers to a questionnaire sent to dronabinol prescribers throughout metropolitan France between June and July 2017. MAIN OUTCOMES MEASURES: We assessed the type of prescribers including place of work (hospital, clinic or private practice) and their specialty. We also collected information about the patient profiles, diseases or symptoms initiating dronabinol prescription, its efficacy and side effects. RESULTS: We received completed questionnaires from 26 prescribers in 17 different areas throughout 12 regions. This represented a total of 191 patients of the 377 indexed since 1st January 2006: the sex ratio was 1:1, with an average age of 51 years for men and of 45 for women. The reason for dronabinol prescription was: multiple sclerosis (49.7%); central neuropathic pain from other causes (36.6%); peripheral neuropathic pain (8%); Parkinson's disease (2.9%); and other causes (around 1%). The duration of dronabinol treatment ranged from 1 month to 6 years and the dose from 2.5mg to 30mg per day (in one or several intakes). 59% of the patients declared experiencing a 30 to 50% reduction in pain. CONCLUSION: This first investigation into dronabinol in France underlines the need to further investigate prescription practices and efficacy so as to define conditions of good use and the place of dronabinol in pain management. Copyright © 2019. Published by Elsevier Masson SAS. DOI: 10.1016/j.neurol.2018.07.011 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 236 – Multiple Sklerose: Veröffentlichungen April 2019 353. Rev Neurosci. 2019 Apr 26. pii: /j/revneuro.ahead-of-print/revneuro-2018-0057/revneuro-2018- 0057.xml. doi: 10.1515/revneuro-2018-0057. [Epub ahead of print] The potentials of umbilical cord-derived mesenchymal stem cells in the treatment of multiple sclerosis. Mehdipour A(1), Ebrahimi A(2), Shiri-Shahsavar MR(3), Soleimani-Rad J(4), Roshangar L(4)(5), Samiei M(6), Ebrahimi-Kalan A(7)(8). Author information: (1)Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. (2)Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Haliç University, Istanbul, Turkey. (3)Department of Nutrition, School of Health, Qazvin University of Medical Sciences, Qazvin, Iran. (4)Department of Anatomical Sciences, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. (5)Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. (6)Endodontics Department of Dental Faculty, Tabriz University of Medical Sciences, Tabriz, Iran. (7)Department of Neurosciences and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. (8)Department of Radiology, School of Paramedicine, Tabriz University of Medical Sciences, Tabriz, Iran, Email:[email protected]. Stem cell therapy has indicated a promising treatment capacity for tissue regeneration. Multiple sclerosis is an autoimmune-based chronic disease, in which the myelin sheath of the central nervous system is destructed. Scientists have not discovered any cure for multiple sclerosis, and most of the treatments are rather palliative. The pursuit of a versatile treatment option, therefore, seems essential. The immunoregulatory and non-chronic rejection characteristics of mesenchymal stem cells, as well as their homing properties, recommend them as a prospective treatment option for multiple sclerosis. Different sources of mesenchymal stem cells have distinct characteristics and functional properties; in this regard, choosing the most suitable cell therapy approach seems to be challenging. In this review, we will discuss umbilical cord/blood-derived mesenchymal stem cells, their identified exclusive properties compared to another adult mesenchymal stem cells, and the expectations of their potential roles in the treatment of multiple sclerosis. DOI: 10.1515/revneuro-2018-0057 354. Saudi Med J. 2019 Apr;40(4):372-378. doi: 10.15537/smj.2019.4.24010. Association of acute stress with multiple sclerosis onset and relapse in Saudi Arabia. AlZahrani AS(1), Alshamrani FJ, Al-Khamis FA, Al-Sulaiman AA, Al Ghamdi WS, Al Ghamdi OA, Mohammad MY, Alshayea MS, Alhazmi RA, Alkhaja MA. Author information: (1)Imam Abdulrahman bin Faisal University, King Fahad Hospital of the University, Al Khobar, Kingdom of Saudi Arabia. E-mail. [email protected]. OBJECTIVES: To determine if there is a relationship between acute stress and either the onset or relapse of multiple sclerosis (MS) and to discover how different types of acute stressors may be involved. Methods: This study was carried out in Saudi Arabia between September 2017 and June 2018 and involved King Fahad University Hospital in Eastern province, Arfa Multiple Sclerosis Society in the Central and Western province of Saudi Arabia. A cross-sectional descriptive study was performed using an Arabic self-constructed questionnaire consisted of 4 sections: 1) demographic data and time of diagnosis; 2) emotional/psychological stressors; 3) environmental/physical stressors; and 4) 4 specific stressors measuring their effect on the severity and recurrence of attacks. Results: A total of 370 patients participated in the study. Almost half of patients reported no effect of family problems on their disease, whereas the other reported that family problems have an impact on the onset or relapse of the disease. Majority of patients reported that work and social life stressors affect the recurrence of attacks. Cold weather showed no effect on MS; however, hot weather and physical activity increased the number of attacks. Continuous thinking about social stress and problems, mood swings, and sleep deprivation showed an impact on the severity and recurrence of attacks. Financial problems showed no effect. Conclusion: Study indicates that an association exists between acute stress and relapse in MS but not the disease onset. DOI: 10.15537/smj.2019.4.24010 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 237 – Multiple Sklerose: Veröffentlichungen April 2019 355. Sci Immunol. 2019 Apr 5;4(34). pii: eaax3917. doi: 10.1126/sciimmunol.aax3917. Luring T cells into a gray area. Alsufyani F(1), Pillai S(1). Author information: (1)Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Department of Medicine, Harvard University, Cambridge, MA 02139, USA. King Fahd Specialist Hospital-Dammam, Al Muraikabat, Dammam, Saudi Arabia. Email: [email protected]. T cells that target β-synuclein induce damage to the gray matter of the brain in multiple sclerosis and contribute to neurodegeneration. Copyright © 2019, American Association for the Advancement of Science. DOI: 10.1126/sciimmunol.aax3917 356. Sci Rep. 2019 Apr 5;9(1):5690. doi: 10.1038/s41598-019-42201-1. An ecological measure to screen executive functioning in MS: the Picture Interpretation Test (PIT) 360°. Realdon O(1), Serino S(2)(3), Savazzi F(4), Rossetto F(4), Cipresso P(2)(3), Parsons TD(5), Cappellini G(6), Mantovani F(1), Mendozzi L(7), Nemni R(8)(9), Riva G(2)(3), Baglio F(10). Author information: (1)Università degli Studi di Milano-Bicocca, Department of Human Sciences for Education, Piazza Ateneo Nuovo 1, 20126, Milan, Italy. (2)Università Cattolica del Sacro Cuore, Department of Psychology, Largo Gemelli 1, 20123, Milan, Italy. (3)IRCCS Istituto Auxologico Italiano, Applied Technology for Neuro-Psychology LAB, via Magnasco 2, 20149, Milan, Italy. (4)IRCCS, Fondazione Don Carlo Gnocchi, Neurorehabilitation Unit and Imaging in Rehabilitation LAB, Via Capecelatro, 66, 20148, Milan, Italy. (5)University of North Texas, Computational Neuropsychology and Simulation Laboratory, 1155 Union Circle #311280, Denton, Texas, 76203-5017, USA. (6)National Research Council of Italy, Institute for the Dynamics of Environmental Processes, Piazza della Scienza, 1, 20126, Milan, Italy. (7)IRCCS, Fondazione Don Carlo Gnocchi, Multiple Sclerosis Unit, Via Capecelatro, 66, 20148, Milan, Italy. (8)IRCCS, Fondazione Don Carlo Gnocchi, Neurorehabilitation Unit, Via Capecelatro, 66, 20148, Milan, Italy. (9)Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Via Francesco Sforza 35, 20122, Milan, Italy. (10)IRCCS, Fondazione Don Carlo Gnocchi, Neurorehabilitation Unit and Imaging in Rehabilitation LAB, Via Capecelatro, 66, 20148, Milan, Italy. [email protected]. Executive functions are crucial for performance of everyday activities. In Multiple Sclerosis (MS), executive dysfunctions can be apparent from the early onset of the disease. Technology-based time-efficient and resource-saving tools for early evaluation of executive functions using an ecological approach are needed to assess functional performance in real-life. The aim was to compare the efficiency of the Picture Interpretation Test 360° (PIT 360°) with traditional measures on executive dysfunction in Persons with Multiple Sclerosis (PwMS) and Healthy Controls (HC). Participants were 31 patients with Relapsing- Remitting MS (mean age = 44.323 ± 13.149; mean Expanded Disability Status Scale = 2) and 39 HC (mean age = 39.538 ± 15.728). All were tested with standard neuropsychological tests of executive functions, PIT 360°, and measures of user experience. While standard neuropsychological tests failed to differentiate between PwMS and HC group, the PIT 360° was successful in detecting executive dysfunction in PwMS. All participants reported the PIT 360° to be an engaging tool and endorsed positive reactions to their experience. Overall, the PIT 360° is a quick, sensitive, and ecological tool that captures real-world executive dysfunction in PwMS. This engaging measure is sensitive for the detection of executive deficits since the early phases of the disease. DOI: 10.1038/s41598-019-42201-1 PMCID: PMC6450934 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 238 – Multiple Sklerose: Veröffentlichungen April 2019 357. Stroke. 2019 May;50(5):1224-1231. doi: 10.1161/STROKEAHA.118.023667. Siponimod (BAF312) Treatment Reduces Brain Infiltration but Not Lesion Volume in Middle-Aged Mice in Experimental Stroke. Vogelgesang A(1), Domanska G(2), Ruhnau J(1), Dressel A(1)(3), Kirsch M(4), Schulze J(1). Author information: (1)From the Department of Neurology (A.V., J.R., A.D., J.S.), University Medicine, Greifswald, Germany. (2)Department of Immunology (G.D.), University Medicine, Greifswald, Germany. (3)Department of Neurology, Carl-Thiem-Klinikum, Cottbus, Germany (A.D.). (4)Department of Diagnostic Radiology and Neuroradiology (M.K.), University Medicine, Greifswald, Germany. Background and Purpose- The contribution of neuroinflammation and, in particular, the infiltration of the brain by lymphocytes is increasingly recognized as a substantial pathophysiological mechanism after stroke. The interaction of lymphocytes with endothelial cells and platelets, termed thromboinflammation, fosters microvascular dysfunction and secondary infarct growth. Siponimod is an S1PR (sphingosine-1-phosphate receptor) modulator, which blocks the egress of lymphocytes from lymphoid organs and has demonstrated beneficial effects in multiple sclerosis treatment. We investigated the effect of treatment with siponimod on stroke outcome in a mouse model of cerebral ischemia. Methods- Transient middle cerebral artery occlusion was induced in middle-aged wild-type mice. Animals were either treated with siponimod (3 mg/kg; intraperitoneal) or vehicle for 6 days. Stroke outcome was assessed by magnetic resonance imaging (spleen volume: prestroke, day 3, and day 7; infarct volume: days 1, 3, and 7) and behavioral tests (prestroke, day 2, and day 6). Immune cells of the peripheral blood and brain-infiltrating cells ipsilateral and contralateral were analyzed by VETScan and by flow cytometry. Results- Siponimod significantly induced lymphopenia on day 7 after transient middle cerebral artery occlusion and reduced T-lymphocyte accumulation in the central nervous system. No effect was detected for lesion size. Conclusions- For siponimod administered at 3 mg/kg in transient middle cerebral artery occlusion mouse model, our findings do not provide preclinical evidence for the use of S1PR1/5 modulators as neuroprotectant in stroke therapy. DOI: 10.1161/STROKEAHA.118.023667 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 239 – Multiple Sklerose: Veröffentlichungen April 2019 358. Ther Adv Neurol Disord. 2019 Apr 1;12:1756286419836571. doi: 10.1177/1756286419836571. eCollection 2019. Risks and risk management in modern multiple sclerosis immunotherapeutic treatment. Klotz L(1), Havla J(2), Schwab N(3), Hohlfeld R(4), Barnett M(5), Reddel S(5), Wiendl H(1). Author information: (1)Department of Neurology with Institute of Translational Neurology, University of Münster, Building A1, Albert Schweitzer Campus 1, 48149 Münster, Germany. (2)Institute of Clinical Neuroimmunology, University Hospital; Data Integration for Future Medicine consortium (DIFUTURE), Ludwig-Maximilians University, Munich, Germany. (3)Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany. (4)Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians University, Munich, Germany Munich Cluster for Systems Neurology, Ludwig- Maximilians University, Munich, Germany. (5)Brain and Mind Centre, University of Sydney, NSW, Australia. In recent years, there has been a paradigm shift in the treatment of multiple sclerosis (MS) owing to the approval of a number of new drugs with very distinct mechanisms of action. All approved disease-modifying drugs primarily work directly on the immune system. However, the identification of an 'optimal choice' for individual patients with regard to treatment efficacy, treatment adherence and side-effect profile has become increasingly complex including conceptual as well as practical considerations. Similarly, there are peculiarities and specific requirements with regard to treatment monitoring, especially in relation to immunosuppression, the development of secondary immune-related complications, as well as the existence of drug-specific on- and off-target effects. Both classical immunosuppression and selective immune interventions generate a spectrum of potential therapy-related complications. This article provides a comprehensive overview of available immunotherapeutics for MS and their risks, detailing individual mechanisms of action and side-effect profiles. Furthermore, practical recommendations for patients treated with modern MS immunotherapeutics are provided. DOI: 10.1177/1756286419836571 PMCID: PMC6444778 Conflict of interest statement: Conflict of interest statement: LK reports personal fees and non-financial support from Genzyme, Novartis and Roche, personal fees from Merck Serono, Teva, and CSL Behring, as well as grants from Novartis and Biogen outside the submitted work. JH reports grants from Friedrich-Baur- Stiftung, personal fees and non-financial support from Merck, Novartis, Roche, Bayer Healthcare, Santhera, Biogen, Sanofi-Genzyme, and non-financial support from Guthy-Jackson Charitable Foundation, all outside the submitted work. NS reports non-financial support from Sanofi-Genzyme and Novartis outside the submitted work. RH reports personal fees from Novartis, Actelion, Roche, Sanofi-Genzyme, Merck, and Teva outside the submitted work. SR reports funds including but not limited to travel support, honoraria, trial payments, research and clinical support to the neurology department of which he is a member, from NHMRC, MGANSW, MGAQLD, MAA, Lambert Initiative, Beeren foundation and from Baxter, Bayer Schering, Biogen Idec, CSL, Genzyme, Grifols, Octapharma, Merck, Novartis, Roche, Sanofi Aventis Genzyme, Servier, TEVA outside the submitted work. This includes participating in the CARE MS1 and 2 RCTs and the long term Lemtrada PASS study. He is Co-founder / shareholder of Medical Safety Systems trading as RxMx (grant and contracts with Genzyme > $25000 AUD with Novartis, Roche, Janssen, potential application to multiple drugs). National IVIG Governance Advisory Council & Specialist Working Group Australia (Neurology) (paid), Australian Medical Services Advisory Committee ad-hoc sub-committee on IVIG (paid), Australian Technical Advisory Group on Immunisation Varicella Zoster working party (unpaid), Nerve Research Foundation board member (unpaid). Furthermore he is public Salary as a staff specialist neurologist from Concord Hospital Sydney Local Health District (paid), private billings from patients and medicare Australia reimbursement as a private practice neurologist (paid), medical advisor (unpaid) to various patient and advocacy groups. MB reports grants from Biogen, Novartis Pharmaceuticals, Sanofi- Genzyme, and Merck outside the submitted work. Dr Barnett is a Consultant to Medical Safety Systems and Research Director at the Sydney Neuroimaging Analysis Centre. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 240 – Multiple Sklerose: Veröffentlichungen April 2019 359. Ther Adv Neurol Disord. 2019 Mar 29;12:1756286419837809. doi: 10.1177/1756286419837809. eCollection 2019. Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis. Prosperini L(1), Kinkel RP(2), Miravalle AA(3), Iaffaldano P(4), Fantaccini S(5). Author information: (1)Department of Neurosciences, S. Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87, 00152 Rome, Italy. (2)Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. (3)Advanced Neurology of Colorado, MS Center of the Rockies, University of Colorado Denver, Aurora, CO, USA. (4)Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy. (5)Biogen Italia S.r.l., Milan, Italy. Background: Natalizumab (NTZ) is sometimes discontinued in patients with multiple sclerosis, mainly due to concerns about the risk of progressive multifocal leukoencephalopathy. However, NTZ interruption may result in recrudescence of disease activity. Objective: The objective of this study was to summarize the available evidence about NTZ discontinuation and to identify which patients will experience post-NTZ disease reactivation through meta-analysis of existing literature data. Methods: PubMed was searched for articles reporting the effects of NTZ withdrawal in adult patients (⩾18 years) with relapsing-remitting multiple sclerosis (RRMS). Definition of disease activity following NTZ discontinuation, proportion of patients who experienced post-NTZ disease reactivation, and timing to NTZ discontinuation to disease reactivation were systematically reviewed. A generic inverse variance with random effect was used to calculate the weighted effect of patients' clinical characteristics on the risk of post-NTZ disease reactivation, defined as the occurrence of at least one relapse. Results: The original search identified 205 publications. Thirty-five articles were included in the systematic review. We found a high level of heterogeneity across studies in terms of sample size (10 to 1866 patients), baseline patient characteristics, follow up (1-24 months), outcome measures (clinical and/or radiological), and definition of post-NTZ disease reactivation or rebound. Clinical relapses were observed in 9-80% of patients and peaked at 4-7 months, whereas radiological disease activity was observed in 7-87% of patients starting at 6 weeks following NTZ discontinuation. The meta- analysis of six articles, yielding a total of 1183 patients, revealed that younger age, higher number of relapses and gadolinium-enhanced lesions before treatment start, and fewer NTZ infusions were associated with increased risk for post-NTZ disease reactivation (p ⩽ 0.05). Conclusions: Results from the present review and meta-analysis can help to profile patients who are at greater risk of post-NTZ disease reactivation. However, potential reporting bias and variability in selected studies should be taken into account when interpreting our data. DOI: 10.1177/1756286419837809 PMCID: PMC6444403 Conflict of interest statement: Conflict of interest statement: LP has received research grant from Genzyme and Italian MS Society (Associazione Italiana Sclerosi Multipla); consulting fees from Biogen, Genzyme, and Novartis; speaking honoraria from Almirall, Biogen, Genzyme, Merck Serono, Novartis, Roche and Teva; and travel grants from Biogen, Genzyme, and Teva. He is also a member of the steering committee AIFA (Italian Medicine Agency) on natalizumab. RPK has been a scientific consultant for CorTech, Genentech, ImStem, and Novoron and has received speaking honoraria from Acorda, Biogen, Genentech, and Genzyme. AAM has received consulting fees from Bayer, Biogen, the Consortium of MS Centers, Genentech, Genzyme, Questcor/Mallinckrodt, and the Rocky Mountain MS Center. PI has received consulting fees from Bayer-Schering, Biogen, and Genzyme; speaking honoraria from Biogen, Genzyme, Merck Serono, Novartis, and Teva; and travel grants from Biogen, Genzyme, Merck Serono, Novartis, and Teva. SF had equity interests in Biogen and was employeed by Biogen at the time of manuscript development. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 241 – Multiple Sklerose: Veröffentlichungen April 2019 360. Ther Adv Neurol Disord. 2019 Mar 29;12:1756286419835652. doi: 10.1177/1756286419835652. eCollection 2019. Prediction of conversion to multiple sclerosis using the 2017 McDonald and 2016 MAGNIMS criteria in patients with clinically isolated syndrome: a retrospective single-centre study. Miclea A(1), Salmen A(2), Wiest R(3), Zoehner G(2), Wagner F(3), Hoepner A(4), Schrewe L(2), Evangelopoulos ME(5), Kamber N(2), Chan A(2), Hoepner R(2). Author information: (1)Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Freiburgstrasse, CH-3010 Bern, Switzerland. (2)Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. (3)Department of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. (4)Banking & Finance Group, Michael Smurfit, Graduate Business School & UCD Lochlann Quinn School of Business, University College Dublin, Dublin, Ireland. (5)Department of Neurology, Eginition University Hospital, National and Kapodistrian University of Athens, Athens, Greece. DOI: 10.1177/1756286419835652 PMCID: PMC6444400 Conflict of interest statement: Conflict of Interest Statement: The authors declare no conflict of interest in preparing this article. 361. Ther Adv Neurol Disord. 2019 Mar 28;12:1756286419836913. doi: 10.1177/1756286419836913. eCollection 2019. Pulsed immune reconstitution therapy in multiple sclerosis. Sorensen PS(1), Sellebjerg F(2). Author information: (1)Department of Neurology 2082, Danish Multiple Sclerosis Center, University of Copenhagen, Rigshospitalet, 9, Blegdamsvej, DK-2100 Copenhagen, Denmark. (2)Department of Neurology, Danish Multiple Sclerosis Center, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. Whereas drugs used for maintenance/escalation therapy do not maintain their beneficial effect after cessation of therapy, some new highly effective therapies can show prolonged treatment effects after a short treatment course. Such therapies have been named pulsed immune reconstitution therapies or pulsed immunosuppressive therapies, and typical representatives are alemtuzumab and cladribine. Autologous haematopoietic stem cell transplantation could be considered as the strongest immune reconstitution therapy. Both alemtuzumab and cladribine induce depletion of lymphocytes, and a common mechanism of action is preferential depletion of class-switched and unswitched memory B-cells. Whereas CD-19+ B- lymphocytes repopulate within 6 months, CD4+ T-cells repopulate at a slower rate, taking 1-2 years to reach the lower level of normal. In general, the depletion of lymphocytes is more profound and the repletion of T- cells is slower after alemtuzumab than after cladribine treatment. Both drugs have a strong effect on relapses and magnetic resonance imaging (MRI) activity, and reduce disability worsening. The therapeutic effect is maintained beyond the period of active treatment in a large proportion of patients, which is best documented for alemtuzumab. Adverse effects include reactivation of latent infections such as tuberculosis and risk of herpes zoster. The main disadvantage in alemtuzumab-treated patients is the risk of secondary immune-mediated disorders. Pulsed immune reconstitution therapy is an option as initial therapy in relapsing-remitting multiple sclerosis patients with high disease activity and in patients on treatment with another disease-modifying therapy with significant relapse and/or MRI activity. DOI: 10.1177/1756286419836913 PMCID: PMC6440030 Conflict of interest statement: Conflict of interest statement: PSS has received personal compensation for serving on scientific advisory boards, steering committees or independent data monitoring boards for Biogen, Merck, Novartis, TEVA, GlaxoSmithKline, MedDay Pharmaceuticals, Genzyme, Celgene and Forward Pharma, and has received speaker honoraria from Biogen, Merck, Teva, Genzyme and Novartis. FS has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria or received research support for his laboratory from Biogen, EMD Serono, Merck, Novartis, Roche and Sanofi Genzyme. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 242 – Multiple Sklerose: Veröffentlichungen April 2019 362. Ther Adv Neurol Disord. 2019 Mar 27;12:1756286419835077. doi: 10.1177/1756286419835077. eCollection 2019. Real-life outcomes of teriflunomide treatment in patients with relapsing multiple sclerosis: TAURUS-MS observational study. Kallmann BA(1), Tiel-Wilck K(2), Kullmann JS(3), Engelmann U(4), Chan A(5). Author information: (1)Multiple-Sclerosis-Center Bamberg, Bamberg, Germany. (2)Neurologisches Facharztzentrum Berlin, Berlin, Germany, for the NeuroTransData Study Group. (3)Medical Management MS, Medical Affairs, Sanofi-Aventis Deutschland GmbH, Siemensstraße 5b, 63263 Neu-Isenburg, Germany. (4)Medical Affairs, Sanofi-Aventis Deutschland GmbH, Neu-Isenburg, Germany. (5)Department of Neurology, Bern University Hospital, University of Bern, Switzerland. Background: Teriflunomide is a once-daily oral immunomodulatory agent approved for the treatment of relapsing-remitting multiple sclerosis (MS). We aimed to obtain data on the effectiveness, tolerability, and subject satisfaction with teriflunomide (Aubagio®) under clinical practice conditions in unselected MS patients. Methods: This work was a non-interventional, prospective, longitudinal, observational study in 307 sites in Germany. Results: A total of 1128 patients were eligible for the efficacy analysis [67.5% female; mean age (± standard deviation) 44.9 ± 9.7 years, range 20-73 years]. Time since first MS symptoms was 10.6 ± 8.2 years, and time since MS diagnosis was 8.9 ± 7.6 years. Expanded Disability Status Scale (EDSS) score at inclusion was 2.3 ± 1.5 (70.4% with score < 3.5). The mean observation period was 16.3 ± 9.1 months. A total of 75.2% had received previous disease-modifying therapies (DMTs) at any time. Of these patients, 504 (44.7%) received no DMT within 6 months of study entry, 593 patients (52.6%) had DMT discontinued prior to study entry [glatiramer acetate in 10.6%, subcutaneous interferon-beta 1a (IFNβ-1a) in 9.3%, intramuscular IFNβ-1a or IFNβ-1b in 6.6% each, azathioprine oral in 0.4%, other in 7.3%, last medication not known in 12.0%]. The mean annualized relapse rate decreased from 0.87 in the 24 months prior to study entry to 0.35 in the 24 months after study entry (n = 468; p ⩽ 0.001). EDSS and Fatigue Severity Scale remained stable. In patients who received previous MS treatments, Treatment Satisfaction Questionnaire (TSQM-9) values (maximum = 100), for the observation at 24 months improved by 8.1 points for effectiveness, 17.0 points for convenience, and 15.3 points for global satisfaction (p ⩽ 0.001 each, compared with study entry). In the safety cohort (n = 1139), the proportion of patients with adverse events (AEs) of any severity was 35.8%, and with serious events 13.0%. The most frequently reported AEs were diarrhea (n = 55), followed by MS relapse (n = 48), hair thinning (n = 38), and viral upper respiratory tract infection (n = 31). Conclusions: Relapse rate was halved during the observation period in comparison with the same time period before study entry. Patient satisfaction with teriflunomide was high in this real-world observation of patients, the majority of whom switched from other DMTs. The safety and tolerability profile of teriflunomide was similar to that reported in previous clinical trials. DOI: 10.1177/1756286419835077 PMCID: PMC6437319 Conflict of interest statement: Conflict of interest statement: BAK has received compensation for activities with Bayer, Biogen, Sanofi Genzyme, Merck, Novartis, Roche, and Teva. KTW has received honoraria for lectures, studies, and consultancy from Almirall, Bayer, Biogen, Genzyme, Ipsen, Merck Serono, Merz Pharma, Novartis, Roche, Sanofi, and Teva. AC has received compensation for activities with Actelion, Almirall, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Roche, and Teva for use of university research funds. He receives research support from UCB, and from Sanofi for basic research on drug transport mechanisms relevant to teriflunomide. UE and JK are full-time employees of Sanofi-Aventis Deutschland GmbH. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 243 – Multiple Sklerose: Veröffentlichungen April 2019 363. Transl Neurosci. 2019 Mar 26;10:1-9. doi: 10.1515/tnsci-2019-0001. eCollection 2019. Nox2-dependent Neuroinflammation in An EAE Model of Multiple Sclerosis. Ravelli KG(1), Santos GD(1), Dos Santos NB(2), Munhoz CD(2), Azzi-Nogueira D(1), Campos AC(3), Pagano RL(3), Britto LR(1), Hernandes MS(4). Author information: (1)Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil. (2)Department of Pharmacology, University of São Paulo, São Paulo, Brazil. (3)Laboratory of Neuroscience, Hospital Sirio-Libanes, Sao Paulo, SP, Brazil. (4)Division of Cardiology, Department of Medicine Emory University, Atlanta, GA, United States. Background: Multiple sclerosis (MS) is an inflammatory disease of the CNS, characterized by demyelination, focal inflammatory infiltrates and axonal damage. Oxidative stress has been linked to MS pathology. Previous studies have suggested the involvement of NADPH oxidase 2 (Nox2), an enzyme that catalyzes the reduction of oxygen to produce reactive oxygen species, in the MS pathogenesis. The mechanisms of Nox2 activation on MS are unknown. The purpose of this study was to investigate the effect of Nox2 deletion on experimental autoimmune encephalomyelitis (EAE) onset and severity, on astrocyte activation as well as on pro-inflammatory and anti-inflammatory cytokine induction in striatum and motor cortex. Methodology: Subcutaneous injection of MOG35-55 emulsified with complete Freund's adjuvant was used to evaluate the effect of Nox2 depletion on EAE-induced encephalopathy. Striatum and motor cortices were isolated and evaluated by immunoblotting and RT-PCR. Results: Nox2 deletion resulted in clinical improvement of the disease and prevented astrocyte activation following EAE induction. Nox2 deletion prevented EAE-induced induction of pro-inflammatory cytokines and stimulated the expression of the anti-inflammatory cytokines IL-4 and IL-10. Conclusions: Our data suggest that Nox2 is involved on the EAE pathogenesis. IL-4 and IL-10 are likely to be involved on the protective mechanism observed following Nox2 deletion. DOI: 10.1515/tnsci-2019-0001 PMCID: PMC6455010 Conflict of interest statement: Conflict of interest The author has no conflicts of interest related to this work. 364. Trends Neurosci. 2019 Apr 17. pii: S0166-2236(19)30044-X. doi: 10.1016/j.tins.2019.03.010. [Epub ahead of print] Fifty Shades of Microglia. Brioschi S(1), Peng V(1), Colonna M(2). Author information: (1)Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA. (2)Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: [email protected]. In a recent study, Masuda and colleagues (Nature 2019;566:388-392) used single-cell RNA-sequencing (scRNA-seq) to profile microglia across different anatomical compartments, developmental stages, and types of brain pathology in mice. Moreover, the authors performed a novel transcriptomic characterization of microglia from multiple sclerosis patients and identified phenotypically conserved microglial subsets between species. These findings, together with seminal prior results from various groups, provide valuable insights into the spatiotemporal heterogeneity of microglia during brain development and disease. Copyright © 2019 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.tins.2019.03.010 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 244 – Multiple Sklerose: Veröffentlichungen April 2019 365. Trials. 2019 Apr 16;20(1):223. doi: 10.1186/s13063-019-3275-x. Uro-Vaxom® versus placebo for the prevention of recurrent symptomatic urinary tract infections in participants with chronic neurogenic bladder dysfunction: a randomised controlled feasibility study. Wade D(1), Cooper J(2), Derry F(3), Taylor J(3)(4)(5)(6). Author information: (1)Oxford Institute of Nursing, Midwifery and Allied Health Research (OxINMAHR), Faculty of Health & Life Sciences, Gipsy Lane Campus, Oxford, OX3 0BP,, UK. (2)National Spinal Injuries Centre, Stoke Mandeville Hospital, Buckinghamshire Healthcare NHS Trust, Aylesbury, HP21 8AL, UK. [email protected]. (3)National Spinal Injuries Centre, Stoke Mandeville Hospital, Buckinghamshire Healthcare NHS Trust, Aylesbury, HP21 8AL, UK. (4)Stoke Mandeville Spinal Research, National Spinal Injuries Centre, Aylesbury, HP218 AL, UK. (5)Harris Manchester College, University of Oxford, Oxford, OX1 3TD, UK. (6)Sensorimotor Function Group, Hospital Nacional de Parapléjicos, SESCAM, Finca 'La Peraleda', 45071, Toledo, Spain. BACKGROUND: Patients with lower neurogenic bladder dysfunction are at an increased risk of suffering from recurrent urinary tract infections. Recurrent symptomatic urinary tract infection is occasionally treated with antibiotics as a prophylactic prevention strategy. This risks increasing the frequency of antibiotic resistance. National healthcare policymakers have requested further research into alternative preventive measures for pathologies that require antibiotic treatment. METHODS: This study protocol describes a two- centre, randomised, double-blinded, placebo-controlled study to evaluate the prevention of recurrent urinary tract infections with the commercial immunotherapy agent Uro-Vaxom®, based on Escherichia coli pathogen-associated molecular patterns. Eligible participants are recruited by the direct healthcare team and randomised to receive Uro-Vaxom® in the form of an oral capsule, or a matching placebo. Participants will receive the study treatment daily for 3 months and followed up for an additional 3 months so that the number of symptomatic urinary tract infection episodes and individual signs and symptoms per episode can be recorded using participant study diaries. Primary outcome measures are: number of symptomatic urinary tract infections experienced over 3 months, number of symptomatic urinary tract infections experienced over 6 months, time from the start of treatment to the first urinary tract infection, and the presence of asymptomatic bacteriuria at 3 and 6 months. Secondary outcome measures are: individually recorded symptoms normally associated with recurrent urinary tract infection and consistency of reported symptoms during the symptomatic urinary tract infection experienced during the study, compliance with study protocol and study medication, and adverse events. DISCUSSION: Healthcare policymakers recommend that alternative preventative strategies are identified for symptomatic urinary tract infections that require antibiotic treatment. If Uro-Vaxom® is shown to be effective, this feasibility study would warrant a larger, statistically powered, multicentre study to investigate whether this immunotherapy strategy is an effective preventative measure for recurrent symptomatic urinary tract infection for people with spinal cord injuries and neurological pathologies. TRIAL REGISTRATION: ISRTCN. Registered on 30 October 2015. ClinicalTrials.gov, ID: NCT0251901 . Registered on 30 October 2015. URL of trial registry record: Ethics Ref: 15-LO-2069. IRAS Number: 185760. Sponsor Number: RXQ/648. NIHR Funding Reference: PB-PG-1013- 32017. DOI: 10.1186/s13063-019-3275-x PMCID: PMC6469220 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 245 – Multiple Sklerose: Veröffentlichungen April 2019 366. Turk J Med Sci. 2019 Apr 26;49(3). doi: 10.3906/sag-1811-50. [Epub ahead of print] Validation and reliability study of the Turkish version of the Neuroquality of Life (Neuro-QoL)-Stigma Scale for neurological disorders Karşıdağ S, Çınar N, Şahin Ş, Kotevoğlu N, teş F. Background/aim: Stigma can be defined as a negative perception of chronically ill patients by their relatives or by society, or a similar self-perception by the patients themselves. We aimed to validate the Turkish version of the Neuroquality of Life (Neuro-QoL)-Stigma Scale for neurologic diseases. Materials and methods: Forms were filled out by a total of 152 randomized patients under regular follow-up in the outpatient clinic (29 polyneuropathy, 25 epilepsy, 23 stroke, 24 tension-type headache, 28 multiple sclerosis, 27 Parkinson disease). The forms consisted of the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), WHOQOL-BREF quality of life scale, the Multidimensional Scale of Perceived Social Support (MSPSS), the General Self-Efficacy (GSE) scale, and the Neuro-QoL-Stigma scale. Results: The internal consistency of the Neuro-QoL-Stigma scale showed ronbach’s α coefficients of 0.95 for all groups. The mean scores of the stigma scales were 33.42 ± 13.91 (min–max: 24–87). There were strong negative correlations between high stigma scores and GSE-T, MSPSS-T, and WHOQOL-BREF, and a positive correlation with the BDI and BAI. Conclusion: The Turkish version of Neuro-QoL-Stigma has satisfactory content validity and high internal consistency. Neuro-QoLStigma is suitable for understanding stigmatization in different neurological disorders in the Turkish population. The scale is available for use at http://www.healthmeasures.net/explore-measurement-systems/neuro-qol. DOI: 10.3906/sag-1811-50 367. Value Health. 2019 Apr;22(4):453-466. doi: 10.1016/j.jval.2018.11.007. Epub 2019 Feb 21. Development and Validation of the FSIQ-RMS: A New Patient-Reported Questionnaire to Assess Symptoms and Impacts of Fatigue in Relapsing Multiple Sclerosis. Hudgens S(1), Schüler R(2), Stokes J(3), Eremenco S(4), Hunsche E(5), Leist TP(6). Author information: (1)Clinical Outcomes Solutions, Tucson, AZ, USA. Electronic address: [email protected]. (2)Global Market Access & Pricing, Actelion, Singapore. (3)Patient- Centered Outcomes, Adelphi Values, Boston, MA, USA. (4)Outcomes Research, Evidera, Bethesda, MD, USA. (5)Global Market Access & Pricing, Actelion, Allschwil, Switzerland. (6)Comprehensive Multiple Sclerosis Center, Thomas Jefferson University, Philadelphia, PA, USA. OBJECTIVES: A new patient-reported outcome (PRO) instrument to measure fatigue symptoms and impacts in relapsing multiple sclerosis (RMS) was developed in a qualitative stage, followed by psychometric validation and migration from paper to an electronic format. METHODS: Adult patients with relapsing- remitting multiple sclerosis (RRMS) were interviewed to elicit fatigue-related symptoms and impacts. A draft questionnaire was debriefed in cognitive interviews with further RRMS patients, and revised. Content confirmation interviews were conducted with patients with progressive-relapsing multiple sclerosis (PRMS) and relapsing secondary-progressive multiple sclerosis (RSPMS). Psychometric analyses used data from adult patients with different RMS subtypes and matched non-RMS controls in a multicenter, observational study. After item reduction, the final instrument was migrated to a smartphone (eDiary) and usability was confirmed in interviews with additional adult RMS patients. RESULTS: The qualitative stage included 37 RRMS, 5 PRMS, and 5 RSPMS patients. Saturation of concepts was reached during concept elicitation. Cognitive interviews confirmed that participants understood the instructions, items, and response options of the instrument-named FSIQ-RMS-as intended. Psychometric validation included 164 RMS and 74 control patients. Internal consistency and test-retest reliability were demonstrated. The symptoms domain discriminated along the RMS symptom-severity continuum and between patients and controls. Patients were able to attribute fatigue-related symptoms to RMS. Usability and conceptual equivalence of the eDiary were confirmed (n = 10 participants). CONCLUSIONS: With 7 symptom items and 13 impact items (in 3 impacts subdomains: physical, cognitive and emotional, and coping) after item reduction, the FSIQ-RMS is a comprehensive, valid, and reliable measure of fatigue-related symptoms and impacts in RMS patients. Copyright © 2018 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.jval.2018.11.007 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 246 – Multiple Sklerose: Veröffentlichungen April 2019 368. Virol Sin. 2019 Apr 23. doi: 10.1007/s12250-019-00116-1. [Epub ahead of print] The Saffold Virus-Penang 2B and 3C Proteins, but not the L Protein, Induce Apoptosis in HEp-2 and Vero Cells. Xu Y(1)(2), Victorio CBL(1)(2), Meng T(1)(3), Jia Q(1), Tan YJ(4)(5), Chua KB(6). Author information: (1)Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore, 117604, Singapore. (2)Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, 117545, Singapore. (3)Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore. (4)Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, 117545, Singapore. [email protected]. (5)Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, 138673, Singapore. [email protected]. (6)Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore, 117604, Singapore. [email protected]. Our previous work has shown that Saffold virus (SAFV) induced several rodent and primate cell lines to undergo apoptosis (Xu et al. in Emerg Microb Infect 3:1-8, 2014), but the essential viral proteins of SAFV involved in apoptotic activity lack study. In this study, we individually transfected the viral proteins of SAFV into HEp-2 and Vero cells to assess their ability to induce apoptosis, and found that the 2B and 3C proteins are proapoptotic. Further investigation indicated the transmembrane domain of the 2B protein is essential for the apoptotic activity and tetramer formation of the 2B protein. Our research provides clues for the possible mechanisms of apoptosis induced by SAFV in different cell lines. It also opens up new directions to study viral proteins (the 2B, 3C protein), and sets the stage for future exploration of any possible link between SAFV, inclusive of its related uncultivable genotypes, and multiple sclerosis. DOI: 10.1007/s12250-019-00116-1 Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 – 247 – Multiple Sklerose: Veröffentlichungen April 2019 369. Zdr Varst. 2019 Mar 26;58(2):54-61. doi: 10.2478/sjph-2019-0007. eCollection 2019 Mar. Influence of Cognitive and Motor Abilities on the Level of Current Functioning in People with Multiple Sclerosis. Slavkovic S(1), Golubovic S(1), Vojnovic M(2), Nadj C(3). Author information: (1)University of Novi Sad, Faculty of Medicine, Department for Special Rehabilitation and Education, Hajduk Veljkova 3, 21000 Novi Sad, Serbia. (2)University of Novi Sad, Faculty of Medicine, Department of General Medicine, Hajduk Veljkova 3, 21000 Novi Sad, Serbia. (3)University of Novi Sad, Faculty of Medicine, Department of Neurology, Hajduk Veljkova 3, 21000 Novi Sad, Serbia. Introduction: Multiple sclerosis (MS) results in a wide range of disabilities. The effects of cognitive and motor dysfunctions are significant and affect level of functioning in people with MS. Objective: The aim of the research was to determine the common contribution of neurological, motor and cognitive status to the overall functioning of MS patients. Method: The sample consisted of 108 subjects with RRMS. The instruments used in the research included: The General Questionnaire, the World Health Organization Disability Assessment Schedule, the Audio Recorded Cognitive Screen, Paced Auditory Serial Addition Test, the Nine Hole Peg Test, the 25 Foot Walk Test, and the Expanded Disability Status Scale. Results: Subjects with a mild neurological deficit had a higher level of current functioning in all domains (a lower WHODAS 2.0 score) than subjects with a moderate neurological deficit (r=0.43, p<0.001). We found a positive correlation between the level of cognitive impairment and motor deficits of both upper and lower extremities and the level of neurological deficit (p<0.001). Subjects with lower neurological deficits had significantly lower WHODAS 2.0. scores, i.e. better motor abilities of both upper and lower extremities than subjects with moderate neurological deficits (p<0.001). The greatest contribution to explaining the overall level of current functioning of people with MS had subjects' age, cognitive abilities and motor abilities of the upper extremities. Conclusion: Inverse relationship of neurological, motor and cognitive status affects the overall daily functioning of people with MS, requiring planning of comprehensive programs in the rehabilitation of people with MS. Publisher ultipla s leroza ( S) se aže v širo em naboru nezmožnosti. Učin i ognitivnih in motoričnih nezmožnosti so znatni in vplivajo na stopnjo delovanja pri osebah z S. ilj razis ave je določiti pogost doprinos nevrološ ega, motoričnega in ognitivnega statusa splošnemu delovanju bolni ov z S. zorec je v ljučeval 108 oseb z S. rodja, i so bila uporabljena v razis avi, so naslednja Splošni vprašalni (General Questionnaire), Lestvica ocenjevanja zmanjšanih zmožnosti (WH D S), presejalni test udio Recorded Cognitive Screen ( S), test Paced uditory Serial ddition Test (P S T), Test devetih zatičev (Nine Hole Peg Test), test časovno omejene hoje 5 Foot Wal Test in azširjena lestvica stopnje prizadetosti (Expanded Disability Status Scale, EDSS).Osebe z blago obli o nevrološ e pomanj ljivosti so po azale višjo stopnjo trenutnega delovanja na vseh področjih (nižji rezultat WHODAS 2.0) kot osebe z zmerno nevrološ o pomanj ljivostjo (r = 0,43, p < 0,001). ed stopnjami ognitivne prizadetosti in motorične pomanj ljivosti obeh zgornjih in spodnjih o ončin ter stopnjo nevrološ e pomanj ljivosti smo od rili pozitivno korelacijo (p < 0,001). sebe z nižjo nevrološ o pomanj ljivostjo so imele občutno nižje rezultate vprašalni a WH D S .0, tj. boljše motorične sposobnosti obeh zgornjih in spodnjih o ončin ot osebe z zmerno nevrološ o pomanj ljivostjo (p < 0,001). Največji doprinos pojasnjevanju splošne stopnje trenutnega delovanja oseb z MS so imele starost oseb, njihove ognitivne sposobnosti in motorične sposobnosti zgornjih o ončin.Inverzni odnos nevrološ ega, motoričnega in ognitivnega statusa splošno vpliva na vsa odnevno delovanje oseb z S, zahteva načrtovanje celostnih programov pri rehabilitaciji oseb z MS. DOI: 10.2478/sjph-2019-0007 PMCID: PMC6455014 Conflict of interest statement: Conflict of interest Conflicts of interest: The authors report no conflicts of interest. Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de http://www.ms-gateway.de MS ® MIT BETAPLUS Gut betreut von den BETAPLUS®-Schwestern und dem Serviceteam Langjährige Erfahrung bei der Betreuung von Betaferon®-Patienten Therapieunterstützung mit Infomaterialien und Injektionshilfen L.DE.MKT.SM.10.2016.5036 BETAPLUS®-Serviceteam Tel.: 0800-2 38 23 37 (gebührenfrei) E-Mail: [email protected] Internet: www.ms-gateway.de