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1 lhe IFNB MS Stuijy Group, Neurology 1993; 43:655-661. 1 Bayer Pharma AG, Data on file. 'Kappos L et al.; Neurol�y 2016;87:978-987. 'Goodin D et al., Neurology 2012; 78: 1315-1322 Betaferon" 250 Mlkrogramn\lml Pulver und Lösungsmittel zur Herstellung einer lnjektionslösung. Wirkstoff: Interferon beta-1 b ('M\lerschreibung bitte die Fachinformation b�;,,amnnensetz\llg:A1meikdi ,wksiiTJer Bestancteil' 1 ml der gebrauchsferrigen lnjektionslösung emhält 150 Mikrogramm (8,0 Mio. l.E.) rekombinan1es lnlerferon beta-1I1 1 Durch<techflasche en1hal1 JOO Mikrogramm (9,6 Mio. l.EJ rekombinam,s In1erferon beta-111 SonsVgeBestanctei/e: Pulver für lnjektionslösung:Albumin vom Menschen, Mannitol, Lösungsmittel: Natrlumchloridlösung 0,54 % GN. Anwendungsgebiete: Betaferon• ist inclziert zur Behanclung von Patienten mit erstmaligem demyelinisierendem Ereignis mit aktivem entzündichem Prozess, wenn di,ses Ereignis schwer genug ist, um eine intravenöse Konikasteroldtheraple zu rechtfenigen, wenn mögliche Differentialcliagnosen ausgeschlC6sen wurden und wenn bei diE'Sen Patienten der _Beuneilung zufolge ein hohe; Risiko für das Auftreten einer klinisch g,slcherten Multiplen Siclerose besteh� von Patiemen mit schubweise verlaufender Multipler Sicleros� die In den letzten zwei Jahren zwei cxler mehr Schübe curchgemacht haben und von Pattenten mit sekundlr progredient verlaufender Multipler Skleros� die sich in einem akuten Krankheitsstadium befinden, d. h . klinische Schübe erfahren. Gegen1W1zelgen: Beginn der Behandlung V.Ghrend der Schwanc}'rschaft, Überempfindlichkeit gegen natürliches cxler rekombinant,s Interferon beta, Humanalbumin odler einen der sonstigen Be;tandteile in der Anamne;� bEStehende schwere Depressionen und/oder Sulzidneigungen, dekompensiene Lebefinsuffizienz. Warnhinweise: Z)tokin-Gabe bei vorl:J<,;tehender monoklonaler Gammopathie in Zusammenhang mit Entwicklung eines Capillary-Leak-Syndroms mit schoclcähnlichen Symptomen und tödlichem Ausgang. In seltenen Fällen Pankreatitis, oft mit Hypenriglyzeridämie. Vooicht bei vorb,stehenden cder aktuellen depressiven Störungen, insbesondere Sulzidneigung. Depression und SUiziclneigung können bei Multipler Sklerose und lnterferonbehandlung vermehn auftreten. Depression oder Suizidneigung unmittelbar an behandelnden Arzt berichten und engmaschig beoh3chten und behandeln. Gegebenenfalls Abbruch der Betaferon-Behandlung. Vorsicht bei Krampfanfällen in der Anamne;� Amiepileptikabehandlung und Epilepsi� die nicht adäquat mitAntiepileptika kam rolliert ist. Das Präparat enthalt Humanal:Jumin und birgt da her ein Risikoeier ObemagungviralerErkrankungen. Das Risiko für die übenragung der Creutzfeld-Jacob-Krankheit (CJK) kann nicht ausge;chlC6sen werden. Regelmäßige Schilddrüsenfunktlonstests empfohlen bei Funktionsstörung der Schilddrüse oder medizinischer lndikation .. Vor Behanclungsbeginn und regelmäßig während Betaferon-Behandlung großes Blutbild mit drrferentiellen Leukozyten- und lhrombozytenzahlen sowie Labor einschließlich Leberwene (z_ B. AST [SGOT), ALT [SGPT) und y-GT) auch ohne klinische S)mI�orne. Patienten mit Anämie, Thrornbozytopenie und/odler Leukopenie bedarten_möglicherwelse eines intensiveren Monitorings. Selten Berichte über schwere Leberschädigung einschließlich Fälle von Leberversagen. Schwerwlec_Jendste Fälle hauflg in Kombination mit Lebenoxizität assoziierten Substanzen oder bei g�ichzeitigen Erkrankungen. ObeMKhung auf Anzeichen von Leberversagen. Erhöhte Transamlnasensverte engmaschig kontrollieren. Bel slgnilikamer Erhöhung cder Symptomen wie Gelbsucht.Absetzen in E�vägung ziehen. Voolcht bei schwerer Niereninsuffizienz und engmaschige Ober.vachung. Fälle von nephrotischem Syndrom mit unterschiedlichen zugrundeliegenden Nephropathien, einschließlich der kollabierenden fonTI der fokal segmentalen Glornerulosk�rC6e (FSGS), Minimal-Chango-Glomerulonephrltis (MCG), membranoprolrrerativen Glomerulonephritis (MPGN) und mernbranö6en Glomerulopathle (MGN) wurden während der Behandlung mit Interferon-beta Produkten berichtet. Ereignisse wurden zu verschiedenen Zeitpunkten der Behanclung berichtet und können nach mehreren Jahren der Behandlung mit Interferon-beta auftreten. Eine regelmäßige Überprüfung auf frühe Anzeichen oder Synnptom� besonders bei Patienten mit einem erhöhten Risiko von N�enerkrankungen, wird empfohlen. Bne sofortige Behandlung"des nephrotischen Syndroms ist erforderlich und ein Abbruch der Behandlung mit Betaferon sollte in EMlgung gezogen weiden.Vorsicht bei vorbestehenden Herzerkrankungen wie Herzinsuffizien� koronarer Herzkrankheit oder Herzrhythmusstörungen. Dann insbesondere zu Beginn der Behandlung auf Verschlechterung des karrlialen Zustands überwachen. Betaferon besitzt zwar keine bekanme direkte kardiotoxische W1rkung, Gnppe-ähnliche Symptom� die umer Beta-Interferonen auftreten können, können skh für Patienten mit vorbestehender relevanter Herzerkrankung jedoch als belastend er.veisen. Seltene Falle von Kardiomyopathie wurden berichtet. Behandlungsabbruch bei Kardlom)'l!Jathle und Verdacht eines Zusammenhangs mit Betaferon. Berichtete Fälle von thrombotischer Mikroangiopath� (TMA), die sich als thrombotisch-thrombozytopenische Purpura (TTP) oder hämolytlsch-urämlsches Syndrom (HUS) manifestiene. Die Ereignisse wurden zu unterschle<Jichen Zeitpunkten wahrencl der Behandlung gemeldet und können mehrere Wochen bis mehrere Jahre nach Beginn der Behandlung mit Interferon beta auftreten. Bei Diagnose einerTMA ist eine umgehende Behandlung erforderlich und ein sofortiges Absetzen von Betaferon v.;rd empfohlen. Schwere Oberempfindlkhkeitsreaktionen möglich. Bel schweren Reaktionen Behandlungsabbruch und geeignete arztliche Maßnahmen. Berichtete Nekrosen an den lnjektl onsstellen können ausgedehnt sein und zur NarlJenbildung führen. Bei Hautla�on aus der lnjektionsstelle ärztliche Konsultation vor weiterer Behanclung. Bei mehreren Läsionen Unterbrechung bts Abheilung der L.a�on. Nebenwirkungen: Zu Beginn der BehandluncJ sind unerwünschte Wirkungen häufig, diese klingen aber Im Allgemeinen bei weiterer Behanclung ab. Die arn haufigsten beobachteten unerwünschten Wirkungen waren ein grippeahnlicher Symptomen komplex und Reaktionen an der ln]ektionsstelle. Zu Beginn der Behanclung wird eine Auftltrlerung der Dosis empfohlen, um cMe Verträglichkeit von Betaferon zu verbessern. Grippeähnliche Symptome lassen sich außmlern durch Veraireichung eine; nlcht-steroldalen Entzündungshernmers veningem. Die Hauflgkelt von Reaktionen an der lnjektlonsstelle lasst sich durch Anwendung elnesAutolnjektoo vermindern. Liste der unerwünschten Ereignisse: Infektion, Abszess, Lymphopenl� Anämi� lhromboz)topeni� Thrombotische Mikroaajopathle, einschließlich thrombotischer thrombozytopenlscher Purpura/hämolytlschurämlsches Syndrom, Neutropenl� Leukopenie, Lymphadenopathi� Palpitationen, Kardiomyopathie, Tach)1<ardie, Hypothyreos� Hypenhyreose, Schilddrüsenerkrankungen, Diarrho� Verstopfung, Übelkeit, Erbrechen, abdominelle Schmerzen, Pankreatitis, Anstieg der Glutamalpyruvat-, Glutarnatoxalacetattransamlnase, des Bilirubin-Spl«Jels und der Gammaglutamyltransferase, Hepatitis, Leberschaden Onicl. Hepatitis), Leberinsuffizienz, anaph)laktische Reaktion, Kapillarlecksynci'om bei vorbe;tehender monoklonaler Gammopathi� Gewchtsverlus� Gewchtszunahm� Anstieg der Tnglyzende Im Blut, Anorex!� Hypogl)1<amle, Arthralgi� arznelmittelinduzlerter Lupus erythernatode, Hypertonie (Skelettmuskulatur), Muskelschmerzen, Myasthenl� Rückenschmerzen, Schmerzen In einer Extremität, Krampf anfall� Kopfschmerzen, Schv.ndel, Schlaflosigkeit, Migran� Parasthesi� Verwlmhelt, SUlziclversuch, emotionale lnstabilita, Depresslon,An� Menorrhagi� Dysmenorrho� Menstruationsstörungen, Metrorrhagle, lmpoten� Bronchospasmus, pulmonale arterielle Hypenoni� Infektionen der oberen Atemweg� Sinusitls, vermehne; Husten, Dyspnoe, Urtikaria, Pruritus, Alopezie, Hautverfarbung, Hauterkrankungen, Hautausschlag, Konjunktivitis, Sehstörungen, Ohrenschmerzen, Vasodllatation, Hypertoni� Harnverhaltung, pos. Harnprotein, häufige Blasenentleerung, Harninkontlnen� starker Harndrang, nephrotisch,s Syndrom, GlomerulC6klerC6� Reaktionen und Nekrose an der lnjektionsstell� grippeähnliche S�Tiptorn� Rebe\ Schmerzen, lhoraxschmerzef\ penphere ödem� Astheni� SchOttelfros� Schwitzen, Un•,vohlseln. Verschrelbl.ngspflk:htlg. Bayer /lt',, 51368 Leverlmsoo, 0eutsdll1Wld. Ver.;lon: FV4, 0312017 LDE.MKT.SM.04.1018.6349

Literatur-Dauerrecherche | L.DE.MKT.SM.02.2017.5323 Multiple Sklerose: Veröffentlichungen September 2018

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Bayer Vital GmbH, Specialty Medicine http://www.gesundheit.bayer.de http://www.betaferon.de

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Inhaltsverzeichnis

Ghanavatian S(1), Derian A(1). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018-. 2018 Sep 5. ....................................................... 18

Rituximab in systemic autoimmune rheumatic diseases: indications and practical

use. ............................................................................................................ 18

Oxidative stress and neuroinflammation should be both considered in the occurrence of fatigue and depression in multiple sclerosis. ................................ 19

The width of the third ventricle associates with cognition and behaviour in motor neuron disease. ........................................................................................... 20

Hypoxic pre-conditioning suppresses experimental autoimmune encephalomyelitis by modifying multiple properties of blood vessels. ........................................... 21

Changes in peripapillary choroidal thickness in patients with multiple sclerosis. .... 21

Subcutaneous Interferon-β1a Does Not Increase the Risk of Stroke in Patients with Multiple Sclerosis: Analysis of Pooled Clinical Trials and Post-Marketing Surveillance.22

72-Week Safety and Tolerability of Dimethyl Fumarate in Japanese Patients with Relapsing-remitting Multiple Sclerosis: Analysis of the Randomised, Double Blind, Placebo-Controlled, Phase III APEX Study and its Open-Label Extension. ............. 23

Detection of Leukocortical Lesions in Multiple Sclerosis and Their Association with

Physical and Cognitive Impairment: A Comparison of Conventional and Synthetic Phase-Sensitive Inversion Recovery MRI. ........................................................ 24

Longitudinal Persistence of Meningeal Enhancement on Postcontrast 7T 3D-FLAIR

MRI in Multiple Sclerosis. ............................................................................... 25

Automated Integration of Multimodal MRI for the Probabilistic Detection of the Central Vein Sign in White Matter Lesions. ....................................................... 26

Berkey FJ(1), Wiedemer JP(1), Vithalani ND(1). ............................................... 26

An Ancient Fecundability-Associated Polymorphism Creates a GATA2 Binding Site in

a Distal Enhancer of HLA-F. ........................................................................... 27

Minimal mosaicism, maximal phenotype: Discordance between clinical and molecular findings in two patients with tuberous sclerosis. ............................... 27

Gender-Specific Association of Leptin and Adiponectin Genes With Multiple

Sclerosis. .................................................................................................... 28

Co-occurrence of MS and ALS: a clue in favor of common pathophysiological findings? ..................................................................................................... 28

Surface plasmon resonance sensing on naturally derived membranes: A

remyelination-promoting human antibody binds myelin with extraordinary affinity.29

Poststroke emotionalism with dacrystic (Crying) episodes - making a case for risperidone. ................................................................................................. 29

[Suprapubic Nicolau syndrome following subcutaneous injection of glatiramer

acetate]. ..................................................................................................... 30

[Multiple hypochromic or achromic macules in children and risk of tuberous sclerosis]..................................................................................................... 30

Modulating NRF2 in Disease: Timing Is Everything............................................ 31


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Demographical Profile and Spectrum of Multiple Malignancies in Children and Adults with Neurocutaneous Disorders. ..................................................................... 31

The effectiveness of exercise interventions for pain reduction in people with

multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. .......................................................................................................... 32

Brazilian Consensus for the Treatment of Multiple Sclerosis: Brazilian Academy of

Neurology and Brazilian Committee on Treatment and Research in Multiple Sclerosis. .................................................................................................... 33

The Sources of Essential Fatty Acids for Allergic and Cancer Patients; a Connection

with Insight into Mammalian Target of Rapamycin: A Narrative Review ............... 34

The role of dietary sodium on autoimmune diseases: The salty truth. ................. 34

Mir223 restrains autophagy and promotes CNS inflammation by targeting ATG16L1.35

Gut microbiota, cannabinoid system and neuroimmune interactions: New perspectives in multiple sclerosis. ................................................................... 36

Involvement of Mitochondria in Neurodegeneration in Multiple Sclerosis. ............. 36

Association Between Exposure to Heavy Metals and Systemic Sclerosis: the Levels

of Al, Cd, Hg, and Pb in Blood and Urine of Patients. ......................................... 37

Assessment of Biochemical and Densitometric Markers of Calcium-Phosphate Metabolism in the Groups of Patients with Multiple Sclerosis Selected due to the

Serum Level of Vitamin D3. ........................................................................... 37

Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis. ........................................................ 38

Effect of interferon beta-1a subcutaneously three times weekly on clinical and

radiological measures and no evidence of disease activity status in patients with relapsing-remitting multiple sclerosis at year 1. ............................................... 38

The subtleties of cognitive decline in multiple sclerosis: an exploratory study using

hierarchichal cluster analysis of CANTAB results. .............................................. 39

Voluntary stopping of eating and drinking (VSED) as an unknown challenge in a long-term care institution: an embedded single case study. ............................... 40

Neuromyelitis optica spectrum disorder presenting in an octogenarian. ............... 40

Case of colonic mucosal Schwann cell hamartoma and review of literature on

unusual colonic polyps. ................................................................................. 41

Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive

multiple sclerosis. ......................................................................................... 42

Predicting cognitive decline in multiple sclerosis: a 5-year follow-up study. ......... 44

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.45

Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis. ......................................................................................... 47

Mental health among children of mothers with multiple sclerosis: A Danish cohort and register-based study. .............................................................................. 48

Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury. ......................................................................... 49


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Commentary on the 2018 Named Series on blood-brain interfaces: Roles of neuroimmunomodulation in health and disease. ............................................... 50

The relationship between corticospinal tract integrity and lower-extremity strength

is attenuated when controlling for age and sex in multiple sclerosis. ................... 50

Interhermispheric inhibition predicts anxiety levels in multiple sclerosis: A corticospinal excitability study. ....................................................................... 51

S100A8/A9 induces microglia activation and promotes the apoptosis of

oligodendrocyte precursor cells by activating the NF-κB signaling pathway. ......... 52

Gender Differences and Comorbidities in U.S. Adults with Bipolar Disorder. ......... 53

Jack Antel: Canadian Leader in Neurology. ...................................................... 53

Nothing Ventured, Nothing Gained? Navigating Disease-Modifying Treatment in Multiple Sclerosis. ........................................................................................ 53

Trait Mindfulness and Wellness in Multiple Sclerosis. ......................................... 53

A polysaccharide from Eclipta prostrata alleviates experimental autoimmune encephalomyelitis through inhibiting Th17 cells. ............................................... 54

Impairment, disability and fatigue in multiple sclerosis. ..................................... 54

Cross-talks between the kidneys and the central nervous system in multiple

sclerosis. ..................................................................................................... 55

Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis. .................................................................................................... 55

The RNA binding protein Sam68 controls T helper 1 differentiation and anti-mycobacterial response through modulation of miR-29. .................................... 56

Multimodal Enhancement of Remyelination by Exercise with a Pivotal Role for Oligodendroglial PGC1α. ................................................................................ 56

Exploring physicochemical space via a bioisostere of the trifluoromethyl and ethyl groups (BITE): attenuating lipophilicity in fluorinated analogues of Gilenya® for

multiple sclerosis. ......................................................................................... 57

Autonomic symptom burden is an independent contributor to multiple sclerosis related fatigue. ............................................................................................ 57

Euthyroid Graves' disease with spurious hyperthyroidism: a diagnostic challenge. 58

Natalizumab Treatment for Relapsing-Remitting Multiple Sclerosis: The Experience

From Saudi Arabia. ....................................................................................... 58

The relevance of ceramides and their synthesizing enzymes for multiple sclerosis. 59

Correction to: Improvement in Cognitive Function as Measured by NeuroTrax in Patients with Relapsing Multiple Sclerosis Treated with Natalizumab: A 2-Year

Retrospective Analysis. ................................................................................. 59

Ocrelizumab: A Review in Multiple Sclerosis. .................................................... 60

Clinical and Serological Biomarkers of Treatment's Response in Patients Treated Continuously with Interferonβ-1b for More than a Decade. ................................ 60

Vitamin D for the management of multiple sclerosis.......................................... 61

Small Heat Shock Proteins, Amyloid Fibrils, and Nicotine Stimulate a Common Immune Suppressive Pathway with Implications for Future Therapies. ................ 62


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Home-based, square-stepping exercise program among older adults with multiple sclerosis: results of a feasibility randomized controlled study. ............................ 62

Parkinsonism in a Patient with Human T-lymphotropic Virus 1 Myelopathy. .......... 63

Sugars and Sweeteners: Structure, Properties and in silico Modeling. ................. 63

Pediatric Multiple Sclerosis: an Update. ........................................................... 64

Ocrelizumab-induced psoriasiform dermatitis in a patient with multiple sclerosis. . 64

Isolated seizures during the first episode of relapsing myelin oligodendrocyte glycoprotein antibody-associated demyelination in children. .............................. 65

A Brief Questionnaire to Assess Post-Exertional Malaise. ................................... 65

Is there a standard procedure for assessing and providing assistive devices for

people with neuro-disabling conditions in United Kingdom? A nation-wide survey. 66

Psychosocial aspects of the lived experience of multiple sclerosis: personal perspectives. ............................................................................................... 67

Current and Innovative Pharmacological Options to Treat Typical and Atypical

Trigeminal Neuralgia. .................................................................................... 67

Therapeutic Advances and Challenges in the Treatment of Progressive Multiple Sclerosis. .................................................................................................... 68

Tumefactive multiple sclerosis masquerade as a central nervous system tumor: a

case report. ................................................................................................. 68

Injury-induced perivascular niche supports alternative differentiation of adult rodent CNS progenitor cells. .................................................................................... 69

Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity. ............ 69

Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial

division and mitophagy. ................................................................................ 70

Early auto-immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis. ......................................................................................... 70

A Functionally Defined In Vivo Astrocyte Population Identified by c-Fos Activation in

a Mouse Model of Multiple Sclerosis Modulated by S1P Signaling: Immediate-Early Astrocytes (ieAstrocytes)............................................................................... 71

Brain and spinal cord MRI lesions in primary progressive vs. relapsing-remitting multiple sclerosis. ......................................................................................... 71

PON1 DNA methylation and neurobehavior in Mexican-American children with prenatal organophosphate exposure. .............................................................. 72

Titanium implants and silent inflammation in jawbone-a critical interplay of dissolved titanium particles and cytokines TNF-α and RANTES/CCL5 on overall

health? ....................................................................................................... 73

Neuromyelitis optica spectrum disorders and pregnancy: relapse-preventive measures and personalized treatment strategies. ............................................. 74

Dietary Inflammatory Index and clinical course of multiple sclerosis. .................. 75

Prophylactic treatment against GM-CSF, but not IL-17, abolishes relapses in a

chronic murine model of multiple sclerosis. ...................................................... 75

Leveraging technology to identify subclinical deficits in radiologically isolated syndrome. ................................................................................................... 76


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Predicting responsiveness to fampridine in gait-impaired patients with multiple sclerosis. ..................................................................................................... 76

Clinical and magnetic resonance imaging features of children, adolescents, and

adults with a clinically isolated syndrome. ....................................................... 77

Sexual Dysfunction Seems to Trigger Depression in Female Multiple Sclerosis Patients. ..................................................................................................... 78

Repeatability and reproducibility of FreeSurfer, FSL-SIENAX and SPM brain

volumetric measurements and the effect of lesion filling in multiple sclerosis. ...... 79

Childhood multiple sclerosis: clinical features and recent developments on treatment choices and outcomes. ................................................................... 80

Drug discovery and development: Biomarkers of neurotoxicity and

neurodegeneration. ...................................................................................... 80

Pharmacological management of depression in patients with multiple sclerosis. ... 81

A review of the effects of baclofen and of THC:CBD oromucosal spray on spasticity-related walking impairment in multiple sclerosis. .............................................. 81

Immunohistochemical analysis of spinal cord components in mouse model of

experimental autoimmune encephalomyelitis. .................................................. 82

Expression Pattern of Myelin-Related Apolipoprotein D in Human Multiple Sclerosis Lesions. ...................................................................................................... 82

Intracranial Inoculation Is More Potent Than Intranasal Inoculation for Inducing

Optic Neuritis in the Mouse Hepatitis Virus-Induced Model of Multiple Sclerosis. ... 83

Galectin-3-Mediated Glial Crosstalk Drives Oligodendrocyte Differentiation and (Re)myelination. .......................................................................................... 83

Comorbidities and Treatment Strategies in Bullous Pemphigoid: An Appraisal of the

Existing Litterature. ...................................................................................... 84

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases. ................... 84

Identifying and Quantifying Neurological Disability via Smartphone. ................... 84

Restless Legs Syndrome in Chinese Patients With Sporadic Amyotrophic Lateral Sclerosis. .................................................................................................... 85

MRI Markers and Functional Performance in Patients With CIS and MS: A Cross-

Sectional Study. ........................................................................................... 86

A Pilot Study Examining Speed of Processing Training (SPT) to Improve Processing Speed in Persons With Multiple Sclerosis. ........................................................ 87

Occulomotor Neural Integrator Dysfunction in Multiple Sclerosis: Insights From

Neuroimaging. ............................................................................................. 87

Balance Changes in Patients With Relapsing-Remitting Multiple Sclerosis: A Pilot Study Comparing the Dynamics of the Relapse and Remitting Phases. ................ 88

Functional Connectivity Alterations Reveal Complex Mechanisms Based on Clinical

and Radiological Status in Mild Relapsing Remitting Multiple Sclerosis. ................ 89

Dysregulation of Astrocytic HMGB1 Signaling in Amyotrophic Lateral Sclerosis. .... 90

The Role of Oxidative Stress in the Development of Systemic Sclerosis Related Vasculopathy. .............................................................................................. 90


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Human Endogenous Retroviral Envelope Protein Syncytin-1 and Inflammatory Abnormalities in Neuropsychological Diseases. ................................................. 91

How to reprogram microglia toward beneficial functions. ................................... 91

Nav1.5 in astrocytes plays a sex-specific role in clinical outcomes in a mouse model of multiple sclerosis. ..................................................................................... 92

Distinct patterns of glia repair and remyelination in antibody-mediated demyelination models of multiple sclerosis and neuromyelitis optica. .................. 92

The TAM receptor TYRO3 is a critical regulator of myelin thickness in the central

nervous system............................................................................................ 93

Value assessment of disease-modifying therapies for Relapsing-Remitting Multiple Sclerosis: HTA evidence from seven OECD countries. ........................................ 93

The peroxisome: an update on mysteries 2.0. .................................................. 94

Education, and the balance between dynamic and stationary functional connectivity jointly support executive functions in relapsing-remitting multiple sclerosis. ........ 94

Nuclear localization and phosphorylation modulate pathological effects of Alpha-Synuclein. ................................................................................................... 95

HBV vaccine and risk of developing multiple sclerosis: a systematic review and

meta-analysis. ............................................................................................. 96

Impact of sex hormones on immune function and MS development. ................... 96

Improving the job-retention strategies in multiple sclerosis workers: the role of occupational physicians. ................................................................................ 97

Terminalia chebula Retz. Fruit Extracts Inhibit Bacterial Triggers of Some

Autoimmune Diseases and Potentiate the Activity of Tetracycline. ...................... 97

A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future. ............................................................................ 98

Immunoregulatory Effects of Silymarin on Proliferation and Activation of Th1 Cells

Isolated from Newly Diagnosed and IFN-ß1b-Treated MS Patients. ..................... 99

Early P2X7R-dependent activation of microglia during the asymptomatic phase of autoimmune encephalomyelitis. ..................................................................... 99

Polymorphisms in the angiotensin I converting enzyme (ACE) gene are associated

with multiple sclerosis risk and response to Interferon-β treatment. ................. 100

Common DNA Variants Accurately Rank an Individual of Extreme Height. .......... 100

Spatial analyzes of HLA data in Rio Grande do Sul, south Brazil: genetic structure and possible correlation with autoimmune diseases. ....................................... 101

Association of nod-like receptor protein-3 single nucleotide gene polymorphisms

and expression with the susceptibility to relapsing-remitting multiple sclerosis. .. 102

Advancing a Systemic Perspective on Multidisciplinary Teams: A Comparative Case Study of Work Organisation in Four Multiple Sclerosis Hospitals. ...................... 102

Ageing, Cellular Senescence and Neurodegenerative Disease. .......................... 103

Erratum: Treatment of a multiple sclerosis animal model by a novel nanodrop

formulation of a natural antioxidant [Corrigendum]. ....................................... 103

Role of developmental venous anomalies in etiopathogenesis of demyelinating diseases. ................................................................................................... 104


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DIFFERENTIATION OF HEALTH-RELATED QUALITY OF LIFE OUTCOMES BETWEEN FIVE DISEASE AREAS: RESULTS FROM AN INTERNATIONAL SURVEY OF PATIENTS.104

PREFERENCES OF PATIENTS WITH MULTIPLE SCLEROSIS FOR ATTRIBUTES OF

INJECTABLE MULTIPLE SCLEROSIS TREATMENTS IN THE UNITED KINGDOM AND FRANCE. ................................................................................................... 105

Role of Interleukin-37 in Inflammatory and Autoimmune Diseases. .................. 105

Transdifferentiation of human adipose-derived mesenchymal stem cells into

oligodendrocyte progenitor cells. .................................................................. 106

Interferon beta-1b-induced thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) in a patient treated for multiple sclerosis: A case report. .. 106

Thrombotic microangiopathy associated with interferon-beta treatment in patients

with multiple sclerosis. ................................................................................ 106

Evaluating the relationship between emotional intelligence and cognitive disorders in patients with Multiple Sclerosis. ................................................................ 107

Evaluation of the risk of cervical cancer in patients with Multiple Sclerosis treated

with cytotoxic agents: A cohort study. .......................................................... 107

GPR15+ T cells are Th17 like, increased in smokers and associated with multiple sclerosis. ................................................................................................... 108

Prophylactic exposure of human corneal endothelial cells to Rho-associated kinase

inhibitor reduced apoptosis rate after phacoemulsification: Ex vivo study. ......... 109

Changes in cell differentiation and proliferation lead to production of abzymes in EAE mice treated with DNA-Histone complexes. ............................................. 110

A comparative system-level analysis of the neurodegenerative diseases. ........... 111

Benefit of sugammadex in a morbidly obese patient with multiple sclerosis and

severe respiratory dysfunction. .................................................................... 111

The impact of motivational interviewing on self-perceived burden in patients receiving therapeutic plasma exchange. ........................................................ 112

Peripheral Quantitative Computed Tomography: Review of Evidence and

Recommendations for Image Acquisition, Analysis, and Reporting, Among Individuals With Neurological Impairment. ..................................................... 113

CNS resident classical DCs play a critical role in CNS autoimmune disease. ....... 114

Can the Fact That Myelin Proteins Are Old and Break down Explain the Origin of

Multiple Sclerosis in Some People? ............................................................... 114

Aerobic Capacity Is Not Associated with Most Cognitive Domains in Patients with Multiple Sclerosis-A Cross-Sectional Investigation. ......................................... 115

Safe Childbirth after Taking Teriflunomide in a Woman with Multiple Sclerosis. .. 115

The Role of Information Processing Speed in Clinical and Social Support Variables of

Patients with Multiple Sclerosis. ................................................................... 116

Changes in the Multiple Sclerosis Treatment Paradigm. What Do We Do Now and What Were We Doing Before? ..................................................................... 116

Remotely-supervised transcranial direct current stimulation paired with cognitive

training in Parkinson's disease: An open-label study. ...................................... 117

Lessons From Leprosy: Peripheral Neuropathies and Deformities in Chronic Demyelinating Diseases. ............................................................................. 118


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Serum level of interleukin 36 in patients with multiple sclerosis. ...................... 118

[Factors Influencing Psychosocial Well-Being in Family Caregivers of People with Amyotrophic Lateral Sclerosis]. .................................................................... 119

Evaluation of Normal-Appearing White Matter in Multiple Sclerosis Using Direct Visualization of Short Transverse Relaxation Time Component (ViSTa) Myelin Water Imaging and Gradient Echo and Spin Echo (GRASE) Myelin Water Imaging. ....... 119

Characterizing Structural Changes With Devolving Remyelination Following

Experimental Demyelination Using High Angular Resolution Diffusion MRI and Texture Analysis. ........................................................................................ 120

Targeting senescence to delay progression of multiple sclerosis. ...................... 121

Teriflunomide's Effect on Glia in Experimental Demyelinating Disease: A

Neuroimaging and Histologic Study. ............................................................. 121

Multicenter Measurements of T1 Relaxation and Diffusion Tensor Imaging: Intra and Intersite Reproducibility. ............................................................................. 122

B cells from patients with multiple sclerosis have a pathogenic phenotype and

increased LTα and TGFβ1 response. .............................................................. 123

Recurrent optic neuritis - Different patterns in multiple sclerosis, neuromyelitis optica spectrum disorders and MOG-antibody disease. .................................... 123

1,25-Dihydroxyvitamin D3 increases the methionine cycle, CD4+ T cell DNA

methylation and Helios+Foxp3+ T regulatory cells to reverse autoimmune neurodegenerative disease. ......................................................................... 124

Prevalence of anti-aquaporin 4 antibody in a diagnostic cohort of patients being

investigated for possible neuromyelitis optica spectrum disorder in Western Australia. .................................................................................................. 125

Therapeutic potentials of ginger for treatment of Multiple sclerosis: A review with emphasis on its immunomodulatory, anti-inflammatory and anti-oxidative

properties. ................................................................................................ 126

Calcitonin gene-related peptide decreases IL-1beta, IL-6 as well as Ym1, Arg1, CD163 expression in a brain tissue context-dependent manner while ameliorating

experimental autoimmune encephalomyelitis. ................................................ 127

Serum levels of leptin and adiponectin are not associated with disease activity or treatment response in multiple sclerosis. ....................................................... 128

High levels of antibodies against PtpA and PknG secreted by Mycobacterium avium

ssp. paratuberculosis are present in neuromyelitis optica spectrum disorder and multiple sclerosis patients. .......................................................................... 128

Effect of fingolimod action on the release of monocyte-derived microvesicles in

multiple sclerosis patients. .......................................................................... 129

Age-adjusted CSF β2-microglobulin and lactate are increased and ACE is decreased in patients with multiple sclerosis, but only lactate correlates with clinical disease duration and severity. ................................................................................. 129

Genome-wide association study in Guillain-Barré syndrome. ............................ 130

CTLA-4, PD-1 and TIM-3 expression predominantly downregulated in MS patients.130

Granulocyte-macrophage colony-stimulating factor as a mediator of autoimmunity in multiple sclerosis. ................................................................................... 131


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Clinical and radiological characteristics of neuromyelitis optica spectrum disorder in the North Egyptian Nile Delta. ...................................................................... 131

Effects of inflammatory cytokines IFN-γ, TNF-α and IL-6 on the viability and

functionality of human pluripotent stem cell-derived neural cells. ..................... 132

Dysfunctional RNA binding proteins and stress granules in multiple sclerosis. .... 132

Rapamycin and fingolimod modulate Treg/Th17 cells in experimental autoimmune encephalomyelitis by regulating the Akt-mTOR and MAPK/ERK pathways. ......... 133

LncRNAs expression profile in peripheral blood mononuclear cells from multiple

sclerosis patients. ....................................................................................... 134

Inflammatory markers of CHMP2B-mediated frontotemporal dementia. ............. 135

A comparison of brain magnetic resonance imaging lesions in multiple sclerosis by race with reference to disability progression. ................................................. 136

Expression of the neuroprotective protein aryl hydrocarbon receptor nuclear translocator 2 correlates with neuronal stress and disability in models of multiple sclerosis. ................................................................................................... 137

Exome sequencing study in patients with multiple sclerosis reveals variants

associated with disease course. .................................................................... 138

2017 revisions of McDonald criteria shorten the time to diagnosis of multiple sclerosis in clinically isolated syndromes. ....................................................... 139

Targeting phosphocreatine metabolism in relapsing-remitting multiple sclerosis:

evaluation with brain MRI, 1H and 31P MRS, and clinical and cognitive testing. .. 139

No evidence of disease activity (NEDA-3) and disability improvement after alemtuzumab treatment for multiple sclerosis: a 36-month real-world study. .... 140

Identifying barriers to help-seeking for sexual dysfunction in multiple sclerosis. . 141

Efficacy and safety of mycophenolate mofetil in progressive multiple sclerosis

patients. ................................................................................................... 141

The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS): results from the German validation study. ............................................................... 142

Delayed treatment of MS is associated with high CSF levels of IL-6 and IL-8 and

worse future disease course. ....................................................................... 143

X linked Charcot-Marie-Tooth disease and multiple sclerosis: emerging evidence for an association. ........................................................................................... 144

How common is truly benign MS in a UK population? ...................................... 145

Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in

multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme. .................................................................................................... 146

Long-term follow-up for multiple sclerosis patients initially treated with interferon-

beta and glatiramer acetate. ........................................................................ 147

Mobile Universal Lexicon Evaluation System (MULES) in MS: Evaluation of a new visual test of rapid picture naming. ............................................................... 148

Identifying Incidence of and Risk Factors for Fluoroscopy-Guided Lumbar Puncture

and Subsequent Persistent Low-Pressure Syndrome in Patients With Idiopathic Intracranial Hypertension. ........................................................................... 149


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Galectin-4, a Negative Regulator of Oligodendrocyte Differentiation, Is Persistently Present in Axons and Microglia/Macrophages in Multiple Sclerosis Lesions. ........ 149

Motor imagery in multiple sclerosis: exploring applications in therapeutic treatment.150

Depressive Symptoms Are Associated With More Negative Functional Outcomes Than Anxiety Symptoms in Persons With Multiple Sclerosis. ............................. 150

Reduced microglial activity and enhanced glutamate transmission in the basolateral amygdala in early CNS autoimmunity. .......................................................... 151

TRPM2 Exacerbates Central Nervous System Inflammation in Experimental

Autoimmune Encephalomyelitis by Increasing Production of CXCL2 Chemokines.152

A sub-population of Foxj1 expressing, non-myelinating Schwann cells of the peripheral nervous system contribute to Schwann cell remyelination in the central

nervous system.......................................................................................... 153

Validation of a precision tremor measurement system for multiple sclerosis. ...... 154

Correlating new directional measures of myelin and axonal integrity in T2-weighted MRI with quantitative histology in multiple sclerosis. ....................................... 155

Effect of Multiple Sclerosis on Dyadic Adjustment. .......................................... 156

Factors Affecting the Adherence to Disease-Modifying Therapy in Patients With

Multiple Sclerosis. ...................................................................................... 156

Signaling pathways and therapeutic perspectives related to environmental factors associated with multiple sclerosis. ................................................................ 156

Reduced long-term cost and increased patient satisfaction with rechargeable

implantable pulse generators for deep brain stimulation. ................................. 157

Comorbidities of Rare Epilepsies: Results from the Rare Epilepsy Network. ........ 158

Physical behaviour is weakly associated with physical fatigue in persons with multiple sclerosis-related fatigue. ................................................................. 159

A Meta-Analytic and Scoping Study on Strength Training in People with Multiple

Sclerosis. Manca A(1), Dvir Z(2), Deriu F(1). ................................................ 159

Deciding on the Best Multiple Sclerosis Therapy: Tough Choices. ...................... 159

MRI and laboratory features and the performance of international criteria in the diagnosis of multiple sclerosis in children and adolescents: a prospective cohort

study. ....................................................................................................... 160

Paediatric multiple sclerosis: early diagnosis as a first step. ............................. 161

Long-term prognosis after childhood convulsive status epilepticus: a prospective cohort study. ............................................................................................. 161

The hippocampus in multiple sclerosis. .......................................................... 162

The hippocampus and behaviour in multiple sclerosis. ..................................... 162

Myelocortical multiple sclerosis: a new disease subtype? ................................. 162

Relevance of time-dependence for clinically viable diffusion imaging of the spinal cord. ......................................................................................................... 163

Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. ........................ 164

[Demyelinating disorders]. .......................................................................... 164


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Alteration of the cutaneous microbiome in psoriasis and potential role in Th17 polarization. .............................................................................................. 165

Involvement of Midkine in Autoimmune and Autoinflammatory Diseases. .......... 166

Interleukin-33 deficiency exacerbated experimental autoimmune encephalomyelitis with an influence on immune cells and glia cells. ............................................ 167

Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes. ....................................................................................... 168

Olfactory Dysfunction in CNS Neuroimmunological Disorders: a Review. ............ 168

Visualization of the Breakdown of the Axonal Transport Machinery: a Comparative Ultrastructural and Immunohistochemical Approach. ....................................... 169

Integrative Analysis of lncRNAs in Th17 Cell Lineage to Discover New Potential Biomarkers and Therapeutic Targets in Autoimmune Diseases. ........................ 170

Cannabinoid Delivery Systems for Pain and Inflammation Treatment. ............... 170

Smoking and its interaction with genetics in MS etiology. ................................ 171

Autologous hematopoietic stem cell transplantation improves fatigue in multiple sclerosis. ................................................................................................... 171

Mahajan KR(1), Nakamura K(2), Ontaneda D(1). ........................................... 171

Silent lesions on MRI imaging - Shifting goal posts for treatment decisions in

multiple sclerosis. ....................................................................................... 172

Lavorgna L(1), Brigo F(2), Moccia M(3), Leocani L(4), Lanzillo R(5), Clerico M(6), Abbadessa G(1), Schmierer K(7), Solaro C(8), Prosperini L(9), Tedeschi G(1), Giovannoni G(7), Bonavita S(1). .................................................................. 173

Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System. .......................................................... 174

Symptomatology and symptomatic treatment in multiple sclerosis: Results from a nationwide MS registry. ............................................................................... 175

Glutamate-sensitive imaging and evaluation of cognitive impairment in multiple sclerosis. ................................................................................................... 176

Zika virus found in brain tissue of a multiple sclerosis patient undergoing an acute disseminated encephalomyelitis-like episode. ................................................. 177

gMS-Classifier1 does not predict disability progression in multiple sclerosis. ...... 177

Tasks of activities of daily living (ADL) are more valuable than the classical neurological examination to assess upper extremity function and mobility in multiple sclerosis. ....................................................................................... 178

The effect of disease modifying therapies on CD62L expression in multiple sclerosis.178

Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability. .................................. 179

Photophobia in multiple sclerosis. ................................................................. 179

Static postural control disturbances among the different multiple sclerosis phenotypes: A Neurocom Balance Manager® evaluation study. ....................... 180

B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate. ................................................................... 180

Recurrent schilder's disease. ........................................................................ 181


– 12 –



Autoimmune encephalitis with elevated N-type calcium channel antibodies as a multiple sclerosis mimic. ............................................................................. 181

Safety liver profile of teriflunomide versus interferon β in multiple sclerosis:

Systematic review and indirect comparison meta-analysis. .............................. 182

Leptomeningeal inflammation in multiple sclerosis: Insights from animal and human studies. ..................................................................................................... 182

Stress-full life events and multiple sclerosis: A population-based incident case-

control study. ............................................................................................ 183

Multiple sclerosis and fabry Disease, two sides of the coin? The case of an Italian family. ...................................................................................................... 184

How does cognition relate to employment in multiple Sclerosis? A systematic

Review. ..................................................................................................... 184

Pilot investigation of the relationship between hippocampal volume and pattern separation deficits in multiple sclerosis. ......................................................... 185

The Bayesian risk estimate at onset (BREMSO) correlates with cognitive and

physical disability in patients with early multiple sclerosis. ............................... 185

Severe disease exacerbation in a patient with neuromyelitis optica spectrum disorder during treatment with dimethyl fumarate. ......................................... 186

Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A

systematic review....................................................................................... 187

Primary progressive multiple sclerosis in Iran: A consensus recommendation for diagnosis and management. ........................................................................ 188

Considerations for using Natalizumab treatment in patients with a history of

choroidal melanoma. .................................................................................. 188

Recurrent disseminated encephalomyelitis: A case report and literature review. . 189

Herpes simplex virus encephalitis temporally associated with dimethyl fumarate-induced lymphopenia in a multiple sclerosis patient. ....................................... 189

Clinical utility of anti-MOG antibody testing in a Danish cohort. ........................ 190

Serum sickness (Like Reaction) in a patient treated with alemtuzumab for multiple

sclerosis: A case report. .............................................................................. 190

Outcomes and treatment management of a French cohort suffering from multiple sclerosis: A retrospective epidemiological study. ............................................ 191

Modified Functional Walking Categories and participation in people with multiple

sclerosis. ................................................................................................... 191

Alemtuzumab-containing reduced intensity conditioning allogenic hematopoietic stem cell transplantation in a case of primary progressive multiple sclerosis. ..... 192

Low vitamin D-25(OH) level in Indonesian multiple sclerosis and neuromyelitis optic

patients. ................................................................................................... 192

Multiple Sclerosis: kFLC index values related to gender. .................................. 193

Efficacy and safety of monoclonal antibody therapies for relapsing remitting multiple sclerosis: A network meta-analysis. .................................................. 193

Metabolomic profile of insulin resistance in patients with multiple sclerosis is

associated to the severity of the disease. ...................................................... 194


– 13 –



Proton magnetic resonance spectroscopy differentiates tumefactive demyelinating lesions from gliomas. .................................................................................. 194

Exploring the role of physical activity and exercise for managing vascular

comorbidities in people with multiple sclerosis: A scoping review. ..................... 195

Resilience and depression/anxiety symptoms in multiple sclerosis and neuromyelitis optica spectrum disorder. ............................................................................ 196

No association between socioeconomic status and risk of multiple sclerosis: A

population-based incident case-control study in a developing country. .............. 197

Is there an effect of dietary intake on MS-related fatigue? - A systematic literature review. ..................................................................................................... 197

The dilemma of benign multiple sclerosis: Can we predict the risk of losing the

"benign status"? A 12-year follow-up study. .................................................. 198

Peginterferon beta-1a for the treatment of relapsing multiple sclerosis: A case series. ...................................................................................................... 198

Promising effect of rapamycin on multiple sclerosis......................................... 199

Multiple sclerosis and neuromyelitis optica spectrum disorders in Malaysia: A

comparison in different ethnic groups. .......................................................... 200

Therapy in Multiple Sclerosis - Coming of Age. ............................................... 200

Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis. ...... 201

A scalable online tool for quantitative social network assessment reveals potentially modifiable social environmental risks. ........................................................... 202

Male offspring born to mildly ZIKV-infected mice are at risk of developing

neurocognitive disorders in adulthood. .......................................................... 203

Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases. ................................................................................................... 204

Maladaptive cortical hyperactivity upon recovery from experimental autoimmune

encephalomyelitis. ...................................................................................... 204

Deconstructing and targeting the genomic architecture of human neurodegeneration. .................................................................................... 205

The role of brain vasculature in neurodegenerative disorders. .......................... 205

CNS lymphatic drainage and neuroinflammation are regulated by meningeal

lymphatic vasculature. ................................................................................ 206

A new subtype of multiple sclerosis? ............................................................. 206

Neurofilaments as biomarkers in neurological disorders. .................................. 207

A homing system targets therapeutic T cells to brain cancer. ........................... 208

[MOG encephalomyelitis: international recommendations on diagnosis and antibody

testing]. .................................................................................................... 209

[Neuroimmunology and rheumatology: overlap and differential diagnoses]. ....... 210

Cadmium-induced neurotoxicity: still much ado. ............................................ 210

Sequencing of high-efficacy disease-modifying therapies in multiple sclerosis: perspectives and approaches. ...................................................................... 211

Stem cell therapy for neurological disorders: A focus on aging. ........................ 212


– 14 –



The Role of Calpain and Proteasomes in the Degradation of Carbonylated Neuronal Cytoskeletal Proteins in Acute Experimental Autoimmune Encephalomyelitis. ..... 212

Identifying a new subtype of multiple sclerosis. .............................................. 213

The role of optical coherence tomography and infrared oculography in assessing the visual pathway and CNS in multiple sclerosis. ................................................ 213

Naturally occurring change in Multiple Sclerosis Walking Scale-12 scores over time in multiple sclerosis. ................................................................................... 213

Characterization of relapsing-remitting multiple sclerosis patients using support

vector machine classifications of functional and diffusion MRI data. .................. 214

Structural neuroimaging as clinical predictor: A review of machine learning applications. .............................................................................................. 214

Lymphocyte populations and their change during five-year glatiramer acetate

treatment. ................................................................................................. 215

Temporal visual resolution and disease severity in MS. ................................... 215

Identification of MS-specific serum miRNAs in an international multicenter study.216

Immunotherapy-responsive dorsal column myelopathy in a patient with asymptomatic celiac disease. ...................................................................... 216

The direct costs of multiple sclerosis-study in the Czech Republic. .................... 217

Health-related quality of life in clinically isolated syndrome and risk of conversion to multiple sclerosis. ....................................................................................... 218

A randomized double-blind trial of comparative efficacy and safety of Avonex and CinnoVex for treatment of relapsing-remitting multiple sclerosis. ..................... 219

Practical Evidence-Based Recommendations for Patients with Multiple Sclerosis Who Want to Have Children. ............................................................................... 219

Wall-eyed Bilateral Internuclear Ophthalmoplegia (WEBINO) in a Patient With Idiopathic Intracranial Hypertension. ............................................................ 220

Retinal vasculopathy with cerebral leukoencephalopathy (RVCL): A rare mimic of tumefactive MS. ......................................................................................... 220

Pregnancy rates and outcomes in women with and without MS in the United States.221

Relapses and disease-modifying drug treatment in pregnancy and live birth in US women with MS. ........................................................................................ 222

Safety and efficacy of venoplasty in MS: A randomized, double-blind, sham-controlled, phase II trial. ............................................................................. 223

Pregnancy in multiple sclerosis: Data from an administrative claims database. ... 223

Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive

NMOSD. .................................................................................................... 224

Incidence and prevalence of MS in children: A population-based study in Ontario, Canada. .................................................................................................... 225

Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. .................................................................................... 225

The FOXP3 rs3761547 Gene Polymorphism in Multiple Sclerosis as a Male-Specific Risk Factor. ............................................................................................... 226


– 15 –



Re-examining the potential of targeting ABHD6 in multiple sclerosis: Efficacy of systemic and peripherally restricted inhibitors in experimental autoimmune

encephalomyelitis. ...................................................................................... 227

Investigation of ischemic and demyelinating lesions by cerebral vasoreactivity based on transcranial Doppler sonography: a comparative study. ..................... 228

Do eyes with and without optic neuritis in multiple sclerosis age equally? .......... 228

Neurofilament light chain as a biological marker for multiple sclerosis: a meta-

analysis study. ........................................................................................... 229

Integrative CNS Plasticity With Exercise in MS: The PRIMERS (PRocessing, Integration of Multisensory Exercise-Related Stimuli) Conceptual Framework. .... 229

Cognitive-motor interference during gait in patients with Multiple Sclerosis: a mixed

methods Systematic Review. ....................................................................... 230

Effect of voluntary wheel running on neuroactive steroid levels in murine experimental autoimmune encephalomyelitis. ................................................ 230

The Short-Term Effect of Slope Walking on Soleus H-Reflexes in People with

Multiple Sclerosis. ...................................................................................... 231

Preoperative evaluation and surgical management of infants and toddlers with drug-resistant epilepsy. .............................................................................. 232

The Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ-15): Validation

of the Dutch version in patients with multiple sclerosis and spinal cord injury. ... 233

A pilot randomized-controlled trial of the urodynamic efficacy of mirabegron for patients with neurogenic lower urinary tract dysfunction. ................................ 233

Clinical Characteristics, Treatment Outcomes and Predictive Factors in Optic

Neuritis. .................................................................................................... 234

Neuropathic Pain and Pain Interference is Linked to Alpha Band Slowing and Reduced Beta Band MEG Activity within the Dynamic Pain Connectome in Patients

with Multiple Sclerosis. ................................................................................ 234

Adherence to disease-modifying therapies in patients with multiple sclerosis. .... 235

Therapeutic Interferon Interchange in Relapsing Multiple Sclerosis Lowers Health Care and Pharmacy Expenditures with Comparable Safety. .............................. 235

CCSVI, Chlamydia pneumoniae and multiple sclerosis clarification. ................... 236

Chronic cerebrospinal venous insufficiency, chlamydia and multiple sclerosis. .... 236

Threshold-based fall detection using the hybrid of tri-axial accelerometer and

gyroscope. ................................................................................................ 236

Gait pattern changes after six-minute walk test in persons with multiple sclerosis.237

Therapeutic potential of extracellular vesicles derived from human mesenchymal stem cells in a model of progressive multiple sclerosis. ................................... 237

In vivo conversion of astrocytes into oligodendrocyte lineage cells with transcription

factor Sox10; Promise for myelin repair in multiple sclerosis. ........................... 238

Longitudinal study of multiple sclerosis lesions using ultra-high field (7T) multiparametric MR imaging. ....................................................................... 239

New MS diagnostic criteria in practice. .......................................................... 239


– 16 –



Disseminated nocardiosis with cerebral and subcutaneous lesions on low-dose prednisone. ............................................................................................... 240

Functional characterization of reappearing B cells after anti-CD20 treatment of CNS

autoimmune disease. .................................................................................. 240

Engineered DNA plasmid reduces immunity to dystrophin while improving muscle force in a model of gene therapy of Duchenne dystrophy. ............................... 241

Exploring mania-associated white matter injury by comparison with multiple

sclerosis: a diffusion tensor imaging study. ................................................... 242

Probability discounting of treatment decisions in multiple sclerosis: associations with disease knowledge, neuropsychiatric status, and adherence. .................... 243

The Mindful Body: A Phenomenology of the Body With Multiple Sclerosis. .......... 243

The 88-item Multiple Sclerosis Spasticity Scale: a Rasch validation of the Italian

version and suggestions for refinement of the original scale. ........................... 244

Advanced neuroimaging in Balo's concentric sclerosis: MRI, MRS, DTI, and ASL perfusion imaging over 1 year. ..................................................................... 244

Bladder diverticuli following injection of onabotulinum toxin A in a patient with

multiple sclerosis and autosomal dominant polycystic kidney disease. ............... 245

Intermittent superior mesenteric artery syndrome in a patient with multiple sclerosis. ................................................................................................... 245

[Autoimmune reactions and paraneoplastic syndromes]. ................................. 246

High burden of skin sclerosis is associated with severe organ involvement in

patients with systemic sclerosis and systemic sclerosis overlap syndrome. ........ 246

Diagnostic challenges in a patient with calciphylaxia - a case report. ................ 247

Burden for Parents of Patients With Schizophrenia-A Nationwide Comparative Study of Parents of Offspring With Rheumatoid Arthritis, Multiple Sclerosis, Epilepsy, and

Healthy Controls. ....................................................................................... 247

Neuronal microRNA regulation in Experimental Autoimmune Encephalomyelitis. . 248

Identification of Peptide Mimotope Ligands for Natalizumab. ............................ 248

Misfolded SOD1 pathology in sporadic Amyotrophic Lateral Sclerosis. ............... 249

N-Phenylquinazolin-2-amine Yhhu4952 as a novel promotor for oligodendrocyte differentiation and myelination. .................................................................... 250

Objective Evaluation of Multiple Sclerosis Lesion Segmentation using a Data Management and Processing Infrastructure. .................................................. 251

Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis. ................................................................................................... 252

"Augmentative and Alternative Communication (AAC) Will Give You a Voice": Key Practices in AAC Assessment and Intervention as Described by Persons with Amyotrophic Lateral Sclerosis. ..................................................................... 252

Intraspinal calcinosis mimicking intervertebral disc extrusion: A clinical and surgical

case report. ............................................................................................... 253

Neurological complications of immune checkpoint inhibitors: what happens when you 'take the brakes off' the immune system. ................................................ 253


– 17 –



Short-term disability progression in two multiethnic multiple sclerosis centers in the treatment era. ........................................................................................... 254

Comparable efficacy and safety of dimethyl fumarate and teriflunomide treatment

in Relapsing-Remitting Multiple Sclerosis: an Italian real-word multicenter experience. ............................................................................................... 255

Peginterferon β-1a every 2 weeks increased achievement of no evidence of disease

activity over 4 years in the ADVANCE and ATTAIN studies in patients with relapsing-remitting multiple sclerosis. ......................................................................... 256

Long-term outcomes of peginterferon beta-1a in multiple sclerosis: results from the

ADVANCE extension study, ATTAIN. ............................................................. 257

Integration of magnetic resonance imaging and protein and metabolite CSF measurements to enable early diagnosis of secondary progressive multiple

sclerosis. ................................................................................................... 258

Veterinary Neurologic Rehabilitation: The Rationale for a Comprehensive Approach.259

Impacts of Indoxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120. ...................................................................... 260

Assessment of renal deterioration and associated risk factors in patients with

multiple sclerosis. ....................................................................................... 260

Cost Sharing of Disease-Modifying Treatments (DMTs) as Policy Lever to Improve DMTs' Access in Multiple Sclerosis. ............................................................... 261

BK Polyomavirus MicroRNA Levels in Exosomes Are Modulated by Non-Coding Control Region Activity and Down-Regulate Viral Replication When Delivered to

Non-Infected Cells Prior to Infection. ............................................................ 262

[Paroxysmal dyskinesias - disorder categories, their causes and treatment]. ..... 263

Absorption, Disposition and Metabolic Pathway of Amiselimod (MT-1303) in Healthy Volunteers in a Mass Balance Study. Kifuji T(1), Inoue S(1), Furukawa M(1),

Madera BP(2), Goto T(3), Kumagai H(3), Mair SJ(4), Kawaguchi A(1). .............. 263

Sicherheit durch Erfahrung Sicherheit durch Erfahrungdurch Erfahrung

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.

Mehr als 25 Jahre klinische Erfahrung

Mehr als 1,5 Millionen Patientenjahre Erfahrung

Für Kinder ab 12 Jahren einsetzbar

1

2

3

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


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1. Baclofen.

Ghanavatian S(1), Derian A(1). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018-. 2018 Sep 5.

Author information: (1)Mayo Clinic Baclofen was originally designed in 1960 to treat epilepsy. However, the result was not satisfactory. Baclofen was then reintroduced in 1971 when it was found to treat muscle spasticity and has been widely used since. Baclofen is FDA-approved for the management of reversible spasticity, particularly for the relief of flexor spasms, clonus, and concomitant pain, common sequelae of spinal cord lesions and multiple sclerosis. However, for patients who experience intolerable adverse effects or who fail to respond to the oral therapy, intrathecal baclofen might be considered.[1] Intrathecal baclofen administration is FDA-approved for the management of spasticity of cerebral origins, such as traumatic brain injury or severe spasticity of spinal cord origin that is unresponsive to treatment with maximum doses of oral baclofen, tizanidine, and/or dantrolene.

2. Acta Clin Belg. 2018 Sep 26:1-8. doi: 10.1080/17843286.2018.1521904. [Epub ahead of print]

Rituximab in systemic autoimmune rheumatic diseases: indications and practical use.

Berghen N(1)(2), Vulsteke JB(1), Westhovens R(1)(2), Lenaerts J(1), De Langhe E(1)(2). Author information: (1)a Department of Rheumatology , University Hospitals Leuven , Leuven , Belgium. (2)b Department of Development and Regeneration , Skeletal Biology and Engineering Research Center , KU Leuven , Belgium. OBJECTIVES: To review the therapeutic option of Rituximab, a chimeric anti-CD20 antibody, in systemic autoimmune rheumatic diseases (SARDs) such as systemic lupus erythematosus, systemic sclerosis, primary Sjögren syndrome and idiopathic inflammatory myopathy. METHODS: A non-systematic review was conducted. RESULTS: The specific role and indication of rituximab in SARDs has been the subject of multiple trials in recent years. Evidence supports the use of rituximab in moderate-to-severe refractory systemic lupus erythematosus, diffuse skin involvement in systemic sclerosis and systemic involvement in primary Sjögren syndrome. Several guidelines have adopted these indications. In addition, there is a consensus about the use of rituximab in refractory myositis. The role of rituximab in interstitial lung disease associated with these SARDs needs to be further explored. CONCLUSION: Rituximab is a treatment option in several SARDs. Upcoming trials, use in daily practice and the safety profile are elaborated on. DOI: 10.1080/17843286.2018.1521904


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3. Acta Neurol Belg. 2018 Sep 4. doi: 10.1007/s13760-018-1015-8. [Epub ahead of print]

Oxidative stress and neuroinflammation should be both considered in the occurrence of fatigue and depression in multiple sclerosis.

Katarina V(1)(2), Gordana T(3)(4), Svetlana MD(3)(4), Milica B(5)(6). Author information: (1)Faculty of Medical Sciences, Department of Neurology, University of Kragujevac, 69 Svetozara Markovica St., 34000, Kragujevac, Serbia. [email protected]. (2)Clinic of Neurology, Clinical Center Kragujevac, 30 Zmaj Jovina St., 34000, Kragujevac, Serbia. [email protected]. (3)Faculty of Medical Sciences, Department of Neurology, University of Kragujevac, 69 Svetozara Markovica St., 34000, Kragujevac, Serbia. (4)Clinic of Neurology, Clinical Center Kragujevac, 30 Zmaj Jovina St., 34000, Kragujevac, Serbia. (5)Psychiatric Clinic, Clinical Centre Kragujevac, 30 Zmaj Jovina St., 34000, Kragujevac, Serbia. (6)Faculty of Medical Sciences, Department of Psychiatry, University of Kragujevac, Kragujevac, Serbia. Oxidative stress and neuroinflammation have a role in the pathogenesis of multiple sclerosis (MS) and in depression. Fatigue is the most disabling symptom in patients with MS and could also be a part of depressive symptomatology. In this study, we measured the serum levels of uric acid (UA) as a marker of oxidative stress and C-reactive protein (CRP) as an inflammatory marker, in 98 patients with MS in relapse and remitting phase of illness and 35 healthy subjects. Degree of depressive symptomatology and fatigue were assessed with Beck's Depression Inventory (BDI) and Fatigue Severity Scale (FSS). Further, we examined the possible correlation of these biomarkers with symptoms of depression and fatigue. Relapse and remitting MS had a lower serum UA levels than controls (236.97 ± 9.25 µmol/L vs. 268.27 ± 0.09 µmol/L vs. 314.82 ± 11.02 µmol/L; p = 0.000), while sera levels of CRP were higher in relapse than remitting patients (4.46 ± 0.40 mg/L vs. 1.01 ± 0.38 mg/L; p = 0.000). Patients in relapse had higher BDI scores (15.68 ± 16.62 vs. 8.36 ± 7.10; p = 0.045). Decreased UA levels showed weak negative correlation with the presence of sadness and disturbed daily activities, higher CRP levels positively correlated with severe depression and the correlation between depression and fatigue was also observed (p < 0.05). It is possible that decreased UA levels lead to sadness, disturbed daily activities and severe disability. Every attack of CRP elevation in relapse could additionally precipitate the depression onset. The clinicians must pay special attention to early detection of fatigue because it could precede depression and improve further treatment. DOI: 10.1007/s13760-018-1015-8


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4. Acta Neurol Scand. 2018 Sep 5. doi: 10.1111/ane.13022. [Epub ahead of print]

The width of the third ventricle associates with cognition and behaviour in motor neuron disease.

Vázquez-Costa JF(1)(2)(3), Carratalà-Boscà S(4)(5), Tembl JI(6), Fornés-Ferrer V(7), Pérez-Tur J(8)(9)(10), Martí-Bonmatí L(4), Sevilla T(1)(2)(3)(11). Author information: (1)Neuromuscular Research Unit, Instituto de Investigación Sanitaria la Fe (IIS La Fe), Valencia, Spain. (2)ALS Unit, Department of Neurology, Hospital Universitario y Politécnico La Fe, Valencia, Spain. (3)Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain. (4)Department of Radiology and Biomedical Imaging Research Group GIBI230, Hospital Universitario y Politécnico La Fe and Instituto de Investigación Sanitaria la Fe, Valencia, Spain. (5)Multiple Sclerosis and Neural Regeneration Research Group, Hospital Universitario y Politécnico La Fe, Valencia, Spain. (6)Neurosonology Laboratory, Department of Neurology, Hospital Universitario y Politécnico La Fe, Valencia, Spain. (7)Biostatistics Unit, Instituto de Investigación Sanitaria la Fe (IIS La Fe), Valencia, Spain. (8)Laboratory of Molecular Genetics, Institut de Biomedicina de València-CSIC, Valencia, Spain. (9)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain. (10)Unidad mixta de Neurología y Genética, Instituto de Investigación Sanitaria la Fe (IIS La Fe), Valencia, Spain. (11)Department of Medicine, University of Valencia, Valencia, Spain. OBJECTIVES: An enlarged width of the third ventricle (WTV) has been described in amyotrophic lateral sclerosis (ALS) patients, although its clinical meaning is unknown. The aims of this study were to evaluate the contribution of demographical, clinical and genetic factors to the WTV in different motor neuron disease (MND) phenotypes and to assess its brain structural correlates. MATERIALS AND METHODS: The WTV was measured by transcranial ultrasound in 107 MND patients (82 diagnosed with classical ALS, 16 with progressive muscular atrophy and 9 with primary lateral sclerosis) and 25 controls. Genetic analysis, and neurological and neuropsychological examinations were performed in patients. Brain volumetric analysis of MR images was obtained in 85 patients. The association of WTV with demographical, clinical, genetic and neuropsychological variables as well as with brain volumes was assessed by multivariable models. RESULTS: Eighteen patients were diagnosed with genetic MND and 42.3% of patients showed executive or behavioural impairment (EBI). MND patients showed larger WTV than controls. The WTV was significantly associated with age, spinal onset and the presence of EBI, but not with the genetic background, the phenotype or disability. Greater WTV was also associated with reduced subcortical grey matter volume, but not with the cortical or the white matter volume. CONCLUSIONS: The enlargement of the WTV found in the different MND phenotypes is attributable to the subcortical grey matter atrophy and is associated with cognitive and behavioural impairment. Larger longitudinal studies are needed to determine its role as biomarker in MND patients with frontotemporal dementia. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. DOI: 10.1111/ane.13022


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5. Acta Neuropathol Commun. 2018 Sep 3;6(1):86. doi: 10.1186/s40478-018-0590-5.

Hypoxic pre-conditioning suppresses experimental autoimmune encephalomyelitis by modifying multiple properties of blood vessels.

Halder SK(1), Kant R(1), Milner R(2). Author information: (1)Department of Molecular Medicine, MEM-151, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA. (2)Department of Molecular Medicine, MEM-151, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA. [email protected]. While hypoxic pre-conditioning protects against neurological disease the underlying mechanisms have yet to be fully defined. As chronic mild hypoxia (CMH, 10% O2) triggers profound vascular remodeling in the central nervous system (CNS), the goal of this study was to examine the protective potential of hypoxic pre-conditioning in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS) and then determine how CMH influences vascular integrity and the underlying cellular and molecular mechanisms during EAE. We found that mice exposed to CMH at the same time as EAE induction were strongly protected against the development of EAE progression, as assessed both at the clinical level and at the histopathological level by reduced levels of inflammatory leukocyte infiltration, vascular breakdown and demyelination. Mechanistically, our studies indicate that CMH protects, at least in part, by enhancing several properties of blood vessels that contribute to vascular integrity, including reduced expression of the endothelial activation molecules VCAM-1 and ICAM-1, maintained expression of endothelial tight junction proteins ZO-1 and occludin, and upregulated expression of the leukocyte inhibitory protein laminin-111 in the vascular basement membrane. Taken together, these data suggest that optimization of BBB integrity is an important mechanism underlying the protective effect of hypoxic pre-conditioning. DOI: 10.1186/s40478-018-0590-5 PMCID: PMC6122733

6. Acta Ophthalmol. 2018 Sep 21. doi: 10.1111/aos.13807. [Epub ahead of print]

Changes in peripapillary choroidal thickness in patients with multiple sclerosis.

Garcia-Martin E(1)(2), Jarauta L(2)(3), Pablo LE(1)(2), Bambo MP(1)(2), Ara JR(2)(3), Martin J(2)(3), Polo V(1)(2), Larrosa JM(1)(2), Vilades E(1)(2), Ramirez T(2)(4), Satue M(1)(2). Author information: (1)Ophthalmology Department, Miguel Servet University Hospital, Zaragoza, Spain. (2)Aragon Institute for Health Research (IIS Aragón), University of Zaragoza, Zaragoza, Spain. (3)Neurology Department, Miguel Servet University Hospital, Zaragoza, Spain. (4)Anatomic Pathology Department, Lozano Blesa University Hospital, Zaragoza, Spain. PURPOSE: To study peripapillary choroidal thickness (PPCT) around the optic disc and establish zones using a new swept source optical coherence tomography (SS-OCT) device. To evaluate PPCT differences between patients with multiple sclerosis (MS) and age- and sex-matched healthy controls. METHODS: A total of 102 healthy subjects and 51 patients with MS were consecutively recruited. Healthy subjects were divided into teaching (n = 51, used to establish choroidal zones) and validating (n = 51, used to compare measurements with MS patients) populations. An optic disc 6.0 × 6.0-mm three-dimensional scan was obtained using SS-OCT Triton. A 26 × 26 cube-grid centred on the optic disc was generated automatically to measure PPCT. Four choroidal zones were established and used to compare PPCT between healthy controls and patients with MS. RESULTS: Peripapillary choroidal thickness (PPCT) was significantly thinner in patients in all concentric zones (p ≤ 0.0001): 134.02 ± 16.59 μm in MS group versus 171.56 ± 12.43 μm in the control group in zone 2; 182.23 ± 20.52 versus 219.03 ± 17.99 μm, respectively, in zone 3; and 223.52 ± 10.70 versus 259.99 ± 10.29 μm, respectively, in zone 4. The choroidal thinning in the MS group tended to decrease as we distanced from the optic nerve head. Peripapillary choroidal thickness (PPCT) had a similar pattern in controls and MS; it was thicker in the superior region, followed by temporal, nasal and inferior regions. CONCLUSION: Patients with MS showed peripapillary choroidal thinning when compared with healthy subjects in all zones around the optic disc. Peripapillary choroidal tissue shows a concentric pattern, increasing in thickness when increasing the distance from the optic nerve. The new SS-OCT could be useful for evaluating choroidal thinning in clinical practice. © 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd. DOI: 10.1111/aos.13807


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7. Adv Ther. 2018 Sep 25. doi: 10.1007/s12325-018-0790-1. [Epub ahead of print]

Subcutaneous Interferon-β1a Does Not Increase the Risk of Stroke in Patients with Multiple Sclerosis: Analysis of Pooled Clinical Trials and Post-Marketing Surveillance.

Sabidó M(1), Venkatesh S(2), Hayward B(3), Aldridge J(3), Gillett A(4). Author information: (1)Merck KGaA, Darmstadt, Germany. [email protected]. (2)EMD Serono Inc., Rockland, MA, USA. (3)EMD Serono Inc., Billerica, MA, USA. (4)EMD Serono Inc., Mississauga, ON, Canada. INTRODUCTION: Previous studies suggest that multiple sclerosis (MS) patients have a greater stroke risk than the general population but there is limited evidence of stroke risk in patients receiving disease-modifying treatment. We assessed stroke risk in MS patients treated with subcutaneous interferon-β1a (sc IFN-β1a) using pooled data from clinical trials and post-marketing surveillance. METHODS: Seventeen phase II-IV Merck KGaA-sponsored trials of sc IFN-β1a were assessed to estimate the stroke incidence rate (IR) and IR ratio (IRR) per 100 patient-years (PY), and associated 95% confidence intervals (CI). The association of treatment duration with stroke was assessed through a Cox model. IR, IRR, and hazard ratio (HR) were adjusted by age, sex, presence of any comorbidity, and MS duration. Individual case safety reports were retrieved from the Global Patient Safety Database. The reporting rates of stroke were calculated and classified as medically confirmed or non-medically confirmed according to the source of each report. RESULTS: In 17 clinical trials, 4412 patients were treated with sc IFN-β1a for a total of 10,622 PY and 1055 patients with placebo for 2005 PY. The IR/100 PY (95% CI) of stroke was 0.025 (0.004, 0.150) in sc IFN-β1a patients and 0.051 (0.008, 0.349) in placebo patients. The IRR for sc IFN-β1a vs placebo was 0.486 (0.238, 0.995) and the HR was 0.496 (0.235, 1.043) for time to stroke-related event for sc IFN-β1a treatment at any dose compared with placebo. Among sc IFN-β1a patients, the IRR in those treated for < 2 years was 0.602 (0.159, 2.277) and for ≥ 2 years 0.469 (0.196, 1.124). Analysis of the safety database showed that the overall reporting rate for stroke was 13.286/10,000 PY. CONCLUSION: Safety data from both clinical trial and post-marketing settings indicate that treatment with sc IFN-β1a does not increase stroke risk in patients with MS. FUNDING: Merck KGaA, Darmstadt, Germany. DOI: 10.1007/s12325-018-0790-1


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8. Adv Ther. 2018 Sep 11. doi: 10.1007/s12325-018-0788-8. [Epub ahead of print]

72-Week Safety and Tolerability of Dimethyl Fumarate in Japanese Patients with Relapsing-remitting Multiple Sclerosis: Analysis of the Randomised, Double Blind, Placebo-Controlled, Phase III APEX Study and its Open-Label Extension.

Ochi H(1), Niino M(2), Onizuka Y(3), Hiramatsu K(3), Hase M(3), Yun J(4), Matta A(4), Torii S(3). Author information: (1)Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Ehime, Japan. [email protected]. (2)Department of Clinical Research, Hokkaido Medical Center, Sapporo, Japan. (3)Biogen Japan Ltd., Tokyo, Japan. (4)Biogen Inc., Cambridge, USA. INTRODUCTION: The long-term safety of dimethyl fumarate (DMF) in patients with relapsing-remitting multiple sclerosis (RRMS) has been studied in mainly Caucasian patients. The present interim analysis aimed to evaluate the 72-week safety of DMF in Japanese patients with RRMS. METHODS: Safety data of Japanese subjects enrolled in the 24-week randomised, double-blind, placebo-controlled APEX study (Part I) and its following open-label extension (Part II) were analysed at 72 weeks from the beginning of Part I. In Part I, subjects were randomised to DMF treatment or matching placebo while all subjects received DMF treatment during Part II. Adverse events (AEs) reported throughout the study period were recorded. RESULTS: Overall, 109 Japanese subjects completed 72 weeks of treatment. The incidence of AEs and serious AEs was 95% and 19%, respectively, in the DMF group compared with 84% and 18%, respectively, in the placebo group at 24 weeks. Common AEs (at least 5%) reported with treatment included nasopharyngitis, flushing, hot flush, gastrointestinal events, pruritus, rash, headache, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AEs led to discontinuation of DMF in 5% of patients and included MS relapse, flushing, abdominal pain, liver disorder and increased ALT/AST. After an initial decrease from baseline of 17% in the DMF group at week 24, the mean lymphocyte counts stabilised and were maintained until week 72. No opportunistic/serious infections nor malignancies were reported with DMF treatment. The incidences of AEs, serious AEs, and discontinuation due to AEs were similar between the DMF and the placebo groups. CONCLUSION: The 72-week safety profile of DMF in Japanese patients with RRMS was consistent with previous studies that enrolled mostly Caucasian patients, with a lower incidence of flushing and related symptoms and a lower reduction in the lymphocyte count compared with previous reports. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01838668. FUNDING: Biogen Japan Ltd. DOI: 10.1007/s12325-018-0788-8


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9. AJNR Am J Neuroradiol. 2018 Sep 27. doi: 10.3174/ajnr.A5815. [Epub ahead of print]

Detection of Leukocortical Lesions in Multiple Sclerosis and Their Association with Physical and Cognitive Impairment: A Comparison of Conventional and Synthetic Phase-Sensitive Inversion Recovery MRI.

Forslin Y(1)(2), Bergendal Å(3), Hashim F(3)(2), Martola J(3)(2), Shams S(3)(2), Wiberg MK(3)(2), Fredrikson S(4)(5), Granberg T(3)(2). Author information: (1)From the Departments of Clinical Science, Intervention and Technology (Y.F., Å.B., F.H., J.M., S.S., M.K.W., T.G.) [email protected]. (2)Departments of Radiology (Y.F., F.H., J.M., S.S., M.K.W., T.G.). (3)From the Departments of Clinical Science, Intervention and Technology (Y.F., Å.B., F.H., J.M., S.S., M.K.W., T.G.). (4)Clinical Neuroscience (S.F.), Karolinska Institutet, Stockholm, Sweden. (5)Neurology (S.F.), Karolinska University Hospital, Stockholm, Sweden. BACKGROUND AND PURPOSE: Cortical lesions are common in multiple sclerosis and are included in the latest diagnostic criteria. The limited sensitivity of cortical MS lesions on conventional MR imaging can be improved by phase-sensitive inversion recovery. Synthetic MR imaging could provide phase-sensitive inversion recovery without additional scanning, but the use of synthetic phase-sensitive inversion recovery remains to be validated. We aimed to compare the ability and clinical value of detecting leukocortical lesions with conventional and synthetic phase-sensitive inversion recovery in MS. MATERIALS AND METHODS: Twenty-one patients with MS prospectively underwent conventional and synthetic phase-sensitive inversion recovery, 3D T1-weighted, and T2 FLAIR imaging. Two neuroradiologists independently performed blinded phase-sensitive inversion recovery lesion assessments; a consensus rating with all sequences was considered the criterion standard. Lesion volumes were segmented. All participants underwent standardized cognitive and physical examinations and Fatigue Severity Scale assessment. Results were analyzed with multiple linear regressions. RESULTS: Interrater and criterion standard agreement for leukocortical lesions was excellent for both conventional and synthetic phase-sensitive inversion recovery (intraclass correlation coefficient = 0.79-0.97). Leukocortical lesion volumes for both sequences were associated with lower information-processing speed (P ≤ .01) and verbal fluency (P ≤ .02). Both phase-sensitive inversion recovery sequences showed a positive effect on the association when combining volumes of leukocortical lesions and white matter lesions with information-processing speed (P ≤ .005) and verbal fluency (P ≤ .03). No associations were found between leukocortical lesion volumes and physical disability or fatigue. CONCLUSIONS: Synthetic and conventional phase-sensitive inversion recovery have a sensitivity similar to that of leukocortical MS lesions. The detected leukocortical lesions are associated with cognitive dysfunction and thus provide clinically relevant information, which encourages assessment of cortical MS involvement at conventional field strengths. © 2018 by American Journal of Neuroradiology. DOI: 10.3174/ajnr.A5815


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Longitudinal Persistence of Meningeal Enhancement on Postcontrast 7T 3D-FLAIR MRI in Multiple Sclerosis.

Jonas SN(1), Izbudak I(2), Frazier AA(3), Harrison DM(4). Author information: (1)From the Department of Radiology (S.N.J., A.A.F.), University of Maryland Medical Center, Baltimore, Maryland [email protected]. (2)Department of Radiology/Neuroradiology (I.I), Johns Hopkins University, Baltimore, Maryland. (3)From the Department of Radiology (S.N.J., A.A.F.), University of Maryland Medical Center, Baltimore, Maryland. (4)Department of Neurology, University of Maryland School of Medicine (D.M.H.), Baltimore, Maryland. BACKGROUND AND PURPOSE: Preliminary research has demonstrated that postgadolinium 3D-FLAIR MR imaging at 7T may be a valuable tool for detecting abnormal meningeal enhancement and inflammation in MS; however, researchers have not systematically investigated its longitudinal persistence. We hypothesized that persistence of meningeal enhancement in MS varies on the basis of pattern of enhancement as well as demographic and clinical factors such as treatment status, disease phenotype, and disability score. MATERIALS AND METHODS: Thirty-one subjects with MS were prospectively scanned before and after intravenous contrast administration at 2 time points, approximately 1 year apart. Fifteen subjects in the cohort were scanned at another time approximately 1 year later. Foci of enhancement were categorized into 4 subtypes: subarachnoid spread/fill, subarachnoid nodular, vessel wall, and dural foci. We reviewed follow-up scans to determine whether foci changed between time points and then compared persistence with demographic and clinical variables. RESULTS: Persistence ranged from 71% to 100% at 1 year and 73% to 100% at 2 years, depending on the enhancement pattern. Subarachnoid spread/fill and subarachnoid nodular subtypes persisted less often than vessel wall and dural foci. Persistence was not significantly different between those on/off treatment and those with progressive/nonprogressive disease phenotypes. The number of persisting foci was significantly different in subjects with/without increasing Expanded Disability Status Scale scores (median, 12 versus 7.5, P = .04). CONCLUSIONS: Longitudinal persistence of meningeal enhancement on 3D-FLAIR at 7T in MS varies by pattern of enhancement and correlates with worsening disability; however, it is not significantly different in those on/off treatment or in those with progressive/nonprogressive disease phenotypes. © 2018 by American Journal of Neuroradiology. DOI: 10.3174/ajnr.A5796


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Automated Integration of Multimodal MRI for the Probabilistic Detection of the Central Vein Sign in White Matter Lesions.

Dworkin JD(1), Sati P(2), Solomon A(3), Pham DL(4), Watts R(5), Martin ML(6), Ontaneda D(7), Schindler MK(2), Reich DS(2)(8), Shinohara RT(6). Author information: (1)From the Department of Biostatistics, Epidemiology, and Informatics (J.D.D., M.L.M., R.T.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania [email protected]. (2)Translational Neuroradiology Section (P.S., M.K.S., D.S.R.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. (3)Departments of Neurological Sciences (A.S.). (4)Center for Neuroscience and Regenerative Medicine (D.L.P.), Henry M. Jackson Foundation, Bethesda, Maryland. (5)Radiology (R.W.), Larner College of Medicine at the University of Vermont, Burlington, Vermont. (6)From the Department of Biostatistics, Epidemiology, and Informatics (J.D.D., M.L.M., R.T.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. (7)Mellen Center for Multiple Sclerosis Treatment and Research (D.O.), Cleveland Clinic, Cleveland, Ohio. (8)Department of Neurology (D.S.R.), Johns Hopkins University School of Medicine, Baltimore, Maryland. BACKGROUND AND PURPOSE: The central vein sign is a promising MR imaging diagnostic biomarker for multiple sclerosis. Recent studies have demonstrated that patients with MS have higher proportions of white matter lesions with the central vein sign compared with those with diseases that mimic MS on MR imaging. However, the clinical application of the central vein sign as a biomarker is limited by interrater differences in the adjudication of the central vein sign as well as the time burden required for the determination of the central vein sign for each lesion in a patient's full MR imaging scan. In this study, we present an automated technique for the detection of the central vein sign in white matter lesions. MATERIALS AND METHODS: Using multimodal MR imaging, the proposed method derives a central vein sign probability, πij, for each lesion, as well as a patient-level central vein sign biomarker, ψi. The method is probabilistic in nature, allows site-specific lesion segmentation methods, and is potentially robust to intersite variability. The proposed algorithm was tested on imaging acquired at the University of Vermont in 16 participants who have MS and 15 participants who do not. RESULTS: By means of the proposed automated technique, participants with MS were found to have significantly higher values of ψ than those without MS (ψMS = 0.55 ± 0.18; ψnon-MS = 0.31 ± 0.12; P <.001). The algorithm was also found to show strong discriminative ability between patients with and without MS, with an area under the curve of 0.88. CONCLUSIONS: The current study presents the first fully automated method for detecting the central vein sign in white matter lesions and demonstrates promising performance in a sample of patients with and without MS. © 2018 by American Journal of Neuroradiology. DOI: 10.3174/ajnr.A5765

12. Am Fam Physician. 2018 Jul 15;98(2):99-104. Delivering Bad or Life-Altering News.

Berkey FJ(1), Wiedemer JP(1), Vithalani ND(1).

Author information: (1)Penn State Health Family and Community Medicine Residency at Mount Nittany Medical Center, State College, PA, USA. Delivering serious, bad, or life-altering news to a patient is one of the most difficult tasks physicians encounter. Broadly defined as information that may alter a patient's view of his or her future, bad news may include information related to a chronic disease (e.g., diabetes mellitus), a life-altering illness (e.g., multiple sclerosis), or an injury leading to significant change (e.g., a season-ending knee injury). Patients prefer to receive such news in person, with the physician's full attention, and in clear, easy-to-understand language with adequate time for questions. Most patients prefer to know their diagnosis, but the amount of desired details varies among different cultures and by education level, age, and sex. The physician should respect the patient's unique preferences for receiving bad news. Physicians may experience stress related to providing bad news that extends beyond the actual conversation. For example, physicians are afraid of eliciting an emotional reaction, being blamed for the bad news, and expressing their emotions during the process. Physicians often withhold information or are overly optimistic regarding prognosis, but this can lead to confusion for patients regarding their condition. There are several algorithms available to help guide the physician in the delivery of bad news, including the SPIKES protocol (setting, perception, invitation, knowledge, emotion, and strategy and summary). Skillful delivery of bad news can provide comfort for the patient and family.


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13. Am J Hum Genet. 2018 Sep 13. pii: S0002-9297(18)30275-1. doi: 10.1016/j.ajhg.2018.08.009. [Epub ahead of print]

An Ancient Fecundability-Associated Polymorphism Creates a GATA2 Binding Site in a Distal Enhancer of HLA-F.

Mika KM(1), Li X(2), DeMayo FJ(2), Lynch VJ(3). Author information: (1)Department of Human Genetics, The University of Chicago, 920 East 58(th) Street, CLSC 319C, Chicago, IL 60637, USA. (2)National Institute of Environmental Health Sciences, Department Reproductive & Developmental Biology Laboratory, 111 TW Alexander Drive, Research Triangle Park, Durham, NC 27709, USA. (3)Department of Human Genetics, The University of Chicago, 920 East 58(th) Street, CLSC 319C, Chicago, IL 60637, USA. Electronic address: [email protected]. Variation in female reproductive traits, such as fertility, fecundity, and fecundability, are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits have been challenging. Here, we explore the functional significance and evolutionary history of a G/A polymorphism at SNP rs2523393, which is an eQTL for HLA-F and is significantly associated with fecundability (the probability of being pregnant within a single menstrual cycle). We replicated the association between the rs2523393 genotype and HLA-F expression by using GTEx data and demonstrate that HLA-F is upregulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells. Next, we show that the rs2523393 A allele creates a GATA2 binding site in a progesterone-responsive distal enhancer that loops to the HLA-F promoter. Remarkably, we found that the A allele is derived in the human lineage and that the G/A polymorphism arose before the divergence of modern and archaic humans and segregates at intermediate to high frequencies across human populations. Remarkably, the derived A allele is has also been identified in a GWAS as a risk allele for multiple sclerosis. These data suggest that the polymorphism is maintained by antagonistic pleiotropy and a reproduction-health tradeoff in human evolution. Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.ajhg.2018.08.009

14. Am J Med Genet C Semin Med Genet. 2018 Sep 27. doi: 10.1002/ajmg.c.31656. [Epub ahead of print]

Minimal mosaicism, maximal phenotype: Discordance between clinical and molecular findings in two patients with tuberous sclerosis.

Byers HM(1), Jensen DM(2), Glass IA(3), Bennett JT(2)(3). Author information: (1)Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, California. (2)Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington. (3)Department of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine, Seattle, Washington. Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by hamartomatous growths in the brain, kidneys, lungs, skin, heart, and retina. TSC is caused by loss of function mutations in one of two tumor suppressor genes, TSC1 or TSC2. Two-thirds of individuals with TSC have de novo mutations, and individuals with postzygotic pathogenic variants in both TSC1 and TSC2 have been reported. The development of sensitive molecular methods, such as next generation sequencing, has led to an increased ability to detect low-level mosaic variants, which are typically thought to have milder phenotypes because a smaller fraction of cells in the body harbor the mutation. Here, we describe two patients with TSC who had severe phenotypic involvement, but only low-level mosaicism in TSC2. Given this apparent discrepancy and concern about a missed constitutional variant, we sampled multiple tissues in both cases to confirm these mosaic mutations. Sampling of multiple tissues can be crucial in molecular diagnosis of mosaic TSC. These cases highlight, in general, challenges in molecular diagnosis of genetic conditions due to postzygotic mutations. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/ajmg.c.31656


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15. Am J Med Sci. 2018 Aug;356(2):159-167. doi: 10.1016/j.amjms.2018.03.008. Epub 2018 Mar 6.

Gender-Specific Association of Leptin and Adiponectin Genes With Multiple Sclerosis.

Yousefian M(1), Nemati R(1), Daryabor G(2), Gholijani N(3), Nikseresht A(4), Borhani-Haghighi A(4), Kamali-Sarvestani E(5). Author information: (1)Neurology Department, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran. (2)Department of Immunology, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran. (3)Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. (4)Neurology Department, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran. (5)Neurology Department, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Immunology, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: [email protected]. BACKGROUND: Adipocytokines such as leptin (LEP) and adiponectin (ADIPOQ) represent a link between metabolism, nutritional status and immune responses. The present study aimed to determine the possible association between single nucleotide polymorphisms of LEP and ADIPOQ genes with multiple sclerosis (MS). MATERIALS AND METHODS: Single nucleotide polymorphisms in LEP (rs2167270 or 19G > A and rs7799039 or -2,548G > A) and ADIPOQ (rs1501299 or +276G > T and rs266729 or -11,377C > G) were genotyped in 305 patients and 255 healthy individuals using polymerase chain reaction-restriction fragment length polymorphism. Sera levels of leptin and adiponectin were measured using enzyme-linked immunosorbent assay. RESULTS: The frequencies of low leptin producer rs2167270GG genotype and rs2167270G allele were significantly lower in patients with MS compared to those of controls (for GG genotype: 39.7% and 49.8%, respectively; P = 0.01; for G allele: 63.3% and 68.8%, respectively; P = 0.05). Both polymorphisms in ADIPOQ did not show any significant association with disease susceptibility, though after gender categorization the frequency of high adiponectin producer rs1501299TT genotype and rs1501299T allele were significantly higher in male controls compared to male patients (TT genotype: P = 0.006; T allele: P = 0.006). Additionally, rs1501299TT genotype in ADIPOQ was associated with susceptibility to primary progressive multiple sclerosis (PP-MS) (P = 0.02). Moreover, while the sera levels of leptin were only different between male patients and controls (P = 0.05), adiponectin levels were significantly higher in total and female healthy controls (P < 0.001, P = 0.002, respectively). CONCLUSIONS: Our findings provide evidence to support the hypothesis that functional ADIPOQ and LEP gene polymorphisms are associated with susceptibility to MS and its clinical forms. Copyright © 2018. Published by Elsevier Inc. DOI: 10.1016/j.amjms.2018.03.008

16. Amyotroph Lateral Scler Frontotemporal Degener. 2018 Sep 3:1-6. doi: 10.1080/21678421.2018.1476547. [Epub ahead of print]

Co-occurrence of MS and ALS: a clue in favor of common pathophysiological findings?

Guennoc AM(1), Pallix-Guyot M(2), Le Page E(3), Le Port D(3), Daryabin M(4), Hergesheimer R(1), Beltran S(1)(5), Tourbah A(6), Edan G(3), Corcia P(1)(5). Author information: (1)a Neurology Department , University Hospital Center of Tours , Tours , France. (2)b Neurology Department , Regional Hospital Center of Orléans , Orléans , France. (3)c Neurology Department , University Hospital Center of Rennes , Rennes , France. (4)d Neurology Department , Hospital Center of Angoulême , Angoulême , France. (5)e ALS Center, University Hospital Center of Tours , Tours , France , and. (6)f Neurology Department , University Hospital Center of Reims , Reims , France. Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are two neurological disorders that seem, theoretically, completely divergent according to epidemiological, clinical, pathophysiological, and therapeutic data. However, some reports that have mentioned the occurrence of both conditions within the same patient underpin the suggestion that this co-occurrence might not be random. We report six co-occurrences of ALS and MS cases, focusing on epidemiological and clinical diseases findings. We then compare our cohort to those in the literature. Our cohort was composed of five females and one male. The age of onset for MS ranged from 27 to 54 years with either primary or secondary prominence while all being progressive. Both diseases occurred sequentially in all but one the cases. Concerning ALS, the age of onset ranged from 51 to 60 years and the site of onset was the legs in 5/6 cases. The disease lasted from four to 29 months. Although infrequent, this co-occurrence supports the hypothesis of common, pathophysiological mechanisms between ALS and MS. We discuss some arguments favoring a potential link between both conditions. DOI: 10.1080/21678421.2018.1476547


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17. Anal Chem. 2018 Sep 19. doi: 10.1021/acs.analchem.8b02664. [Epub ahead of print]

Surface plasmon resonance sensing on naturally derived membranes: A remyelination-promoting human antibody binds myelin with extraordinary affinity.

Vala M, Jordan LR, Warrington AE, Maher Iii LJ, Rodriguez M, Wittenberg NJ, Oh SH. rHIgM22 is a recombinant human monoclonal IgM designed to promote remyelination, and it is currently in Phase I clinical trials in patients with multiple sclerosis (MS). In animal models of demyelination, a single low dose of rHIgM22 stimulates oligodendrocyte maturation, induces remyelination, preserves axons, and slows the decline of locomotor deficits. Natural autoantibodies like rHIgM22 typically bind to multiple antigens with weak affinity. rHIgM22 binds to oligodendrocytes and myelin. Because the antigen(s) for rHIgM22 is prevalent within and exclusive to central nervous system (CNS) myelin, we used CNS myelin particles in combination with surface plasmon resonance to determine the kinetic and affinity constants for the interaction of rHIgM22 to myelin. We found that both the serum and recombinant forms of the antibody bind to myelin with very small dissociation constants in the 100 pM range, which is highly unusual for natural autoantibodies. The extraordinary affinity between rHIgM22 and myelin may explain why such a low effective dose can stimulate CNS repair in animal models of demyelination and underlie the accumulation of rHIgM22 in the CSF in treated MS patients by targeting myelin. DOI: 10.1021/acs.analchem.8b02664

18. Ann Afr Med. 2018 Jul-Sep;17(3):156-158. doi: 10.4103/aam.aam_24_17.

Poststroke emotionalism with dacrystic (Crying) episodes - making a case for risperidone.

Imarhiagbe FA(1), Abidakun OA(1). Author information: (1)Department of Medicine, Neurology Unit, University of Benin Teaching Hospital, Benin City, Nigeria. Emotionalism is the abnormal expression of emotions like crying and laughing and could follow stroke, traumatic brain injury, multiple sclerosis and amyotrophic lateral sclerosis. Emotionalism has been known to respond therapeutically to different classes of drugs including tricyclic antidepressants like imipramine, Selective Serotonin Reuptake Inhibitors (SSRI) like sertraline and citalopram, anticonvulsants like lamotrigine, dopamine precursors like levodopa and NMDA receptor antagonists like dextromethorphan. Classical antipsychotics are hardly prescribed for emotionalism alone without psychotic features. In this case report, an eighty year old woman with a dominant fronto-temporal infarctive stroke with right faciohemiparesis presented with frequent crying (dacrystic) episodes after a month of onset of stroke and who did not satisfy DSM IV criteria for depression nor had other psychotic features. Serial trial of SSRIs and dextromethorphan/quinidine could not help until risperidone, an antipsychotic was introduced with resolution of crying episodes. The response to risperidone after trial of SSRIs and dextromethorphan/quinidine which are considered the gold standard for post-stroke emotionalism (PSE), could be another therapeutic dimension in the management of emotionalism in general and PSE in particular. Publisher: Résumé L'émotivité est l'expression anormale d'émotions comme les pleurs et les rires et pourrait suivre un accident vasculaire cérébral, une lésion cérébrale traumatique, la sclérose en plaques et la sclérose latérale amyotrophique. L'émotionnisme a été connu pour répondre thérapeutiquement à différentes classes de médicaments incluant les antidépresseurs tricycliques comme l'imipramine, les inhibiteurs sélectifs du recaptage de la sérotonine (ISRS) comme la sertraline et le citalopram, les anticonvulsivants comme la lamotrigine, les précurseurs de la dopamine comme la lévodopa et les antagonistes des récepteurs NMDA comme le dextrométhorphane. Les antipsychotiques classiques ne sont guère prescrits pour l'émotivité seule sans caractéristiques psychotiques. Dans ce cas, une femme de quatre-vingts ans avec un infarctus fronto-temporal dominant avec faciohemiparesis droite a présenté des épisodes pleurs fréquents (dacrystiques) après un mois d'apparition de l'accident vasculaire cérébral et qui ne répondaient pas aux critères du DSM IV. fonctionnalités. Essai en série des ISRS et dextrométhorphane / quinidine n'a pas pu aider jusqu'à risperidone, un antipsychotique a été introduit avec la résolution des épisodes de pleurs. La réponse à la rispéridone après essai des ISRS et de la dextrométhorphane / quinidine, considérés comme l'étalon-or de l'émotivité post-AVC, pourrait constituer une autre dimension thérapeutique dans la gestion de l'émotivité en général et des EPS en particulier. DOI: 10.4103/aam.aam_24_17 PMCID: PMC6126052 Conflict of interest statement: There are no conflicts of interest


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19. Ann Dermatol Venereol. 2018 Sep 11. pii: S0151-9638(18)30506-4. doi: 10.1016/j.annder.2018.04.012. [Epub ahead of print]

[Suprapubic Nicolau syndrome following subcutaneous injection of glatiramer acetate].

[Article in French] Blind A(1), Lenormand C(2), Schissler C(2), Cribier B(2), Lipsker D(2). Author information: (1)Clinique de dermatologie, hôpital Civil de Strasbourg, 1, place de l'Hôpital, 67091 Strasbourg, France. Electronic address: [email protected]. (2)Clinique de dermatologie, hôpital Civil de Strasbourg, 1, place de l'Hôpital, 67091 Strasbourg, France. BACKGROUND: Subcutaneous glatiramer acetate, commercialized under the name of Copaxone®, is licensed for the treatment of relapsing multiple sclerosis. Its major adverse effects are skin reactions at the injection site. Nicolau syndrome is a rare but serious iatrogenic accident. Herein we report a case seen in a setting of change of dosage and administration rate of Copaxone®. PATIENTS AND METHODS: A 64-year-old woman, treated since 2010 with daily sub-cutaneous injections of Copaxone® 20mg/L, reported the appearance of a painful, indurated and erythematous plaque in the suprapubic area following changeover to 40mg/mL injections three times weekly. The suprapubic injections were continued and ugly greyish spots with stellate purpuric borders appeared. Fournier gangrene was ruled out by means of a soft tissue scan. DISCUSSION: We report this latest case of Nicolau syndrome to alert readers to the non-exceptional nature of this complication associated with use of glatiramer acetate, particularly at a dosage of 40mg/L injections three times weekly. In our case, onset of Nicolau syndrome appears to have been favored by continued injection in areas already showing inflammation. Re-injection of the drug in these areas should thus be proscribed. Copyright © 2018 Elsevier Masson SAS. All rights reserved. DOI: 10.1016/j.annder.2018.04.012

20. Ann Dermatol Venereol. 2018 Sep 11. pii: S0151-9638(18)30473-3. doi: 10.1016/j.annder.2018.07.005. [Epub ahead of print]

[Multiple hypochromic or achromic macules in children and risk of tuberous sclerosis].

[Article in French] Battini M(1), Casassa E(2), Maza A(2), Dreyfus I(2), Mazereeuw-Hautier J(2). Author information: (1)Service de dermatologie, CHU de Toulouse, centre de référence des maladies rares de la peau, hôpital Larrey, 24, chemin Pouvourville, 31400 Toulouse, France. Electronic address: [email protected]. (2)Service de dermatologie, CHU de Toulouse, centre de référence des maladies rares de la peau, hôpital Larrey, 24, chemin Pouvourville, 31400 Toulouse, France. AIM: To describe in a large paediatric cohort the characteristics of hypopigmented and depigmented (hypochromatic and achromic) macules with no clear diagnosis but potentially evocative of tuberous sclerosis (TS). PATIENTS AND METHODS: This was a retrospective multicentre study performed between 2010 and 2017 at a reference centre for rare skin diseases; it included all children consulting for hypochromic and achromic macules. A descriptive analysis was made of the characteristics of macules with no clear diagnosis, enabling them to be classified in three secondary groups: TS certain, TS ruled out, TS uncertain. RESULTS: Of the 3300 children seen during this 7-year period 7,265 were consulting for hypochromic or achromic macules, with no clear diagnosis in 18 cases: 7 girls and 11 boys of median age at 7.21 years (range: 4 months to 16 years and 7 months). The lesions were congenital in 7 cases. The number of macules varied, with over 20 in some cases. The majority were in the form of ash-leaf spots, followed by the oval form. Two children were diagnosed at clinical examination, and 16 underwent it is not examinations, resulting in a diagnosis of certain ST in 6 of these cases. No particular characteristics of the macules appeared to guide the clinical examination towards ST or isolated lesions. Café-au-lait spots were more frequent in the group in which ST was ruled out than in the other two groups: 67% vs. 33% and 33%. Neurologic involvement was more common in children with certain or uncertain ST than in children in whom ST was ruled out (83% and 67% vs. 11%). CONCLUSION: No identified characteristics of stains enabled the clinical examination to confirm or rule out tuberous sclerosis. Screening for acute any signs of ST is essential. Diagnostic efficacy is enhanced by additional exams. Copyright © 2018 Elsevier Masson SAS. All rights reserved. DOI: 10.1016/j.annder.2018.07.005


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21. Annu Rev Pharmacol Toxicol. 2018 Sep 26. doi: 10.1146/annurev-pharmtox-010818-021856. [Epub ahead of print]

Modulating NRF2 in Disease: Timing Is Everything.

Dodson M(1), de la Vega MR(1), Cholanians AB(1), Schmidlin CJ(1), Chapman E(1), Zhang DD(1)(2). Author information: (1)Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721, USA; email: [email protected]. (2)Arizona Cancer Center, University of Arizona, Tuscon, Arizona 85724, USA. The transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) is a central regulator of redox, metabolic, and protein homeostasis that intersects with many other signaling cascades. Although the understanding of the complex nature of NRF2 signaling continues to grow, there is only one therapeutic targeting NRF2 for clinical use, dimethyl fumarate, used for the treatment of multiple sclerosis. The discovery of new therapies is confounded by the fact that NRF2 levels vary significantly depending on physiological and pathological context. Thus, properly timed and targeted manipulation of the NRF2 pathway is critical in creating effective therapeutic regimens. In this review, we summarize the regulation and downstream targets of NRF2. Furthermore, we discuss the role of NRF2 in cancer, neurodegeneration, and diabetes as well as cardiovascular, kidney, and liver disease, with a special emphasis on NRF2-based therapeutics, including those that have made it into clinical trials. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. DOI: 10.1146/annurev-pharmtox-010818-021856

22. Anticancer Res. 2018 Sep;38(9):5453-5457. doi: 10.21873/anticanres.12877.

Demographical Profile and Spectrum of Multiple Malignancies in Children and Adults with Neurocutaneous Disorders.

Marjanska A(1), Jatczak-Gaca A(1), Wojtkiewicz A(1), Wysocki M(1), Styczynski J(2). Author information: (1)Department of Pediatric Hematology and Oncology, Nicolaus Copernicus University Torun, Jurasz University Hospital, Collegium Medicum, Bydgoszcz, Poland. (2)Department of Pediatric Hematology and Oncology, Nicolaus Copernicus University Torun, Jurasz University Hospital, Collegium Medicum, Bydgoszcz, Poland [email protected]. BACKGROUND/AIM: Neurocutaneous disorders, also referred as phacomatoses, are congenital disorders manifesting at different ages with central nervous system and cutaneous abnormalities. Analysis of the demographic and clinical profile of patients with phacomatoses in the context of the incidence and spectrum of malignancy. MATERIALS AND METHODS: This is a retrospective analysis of 20 years of data in a single-center study in Poland. RESULTS: Phacomatoses were diagnosed in 45.6% (913/2,003) of referred patients, including 61.4% children. The distribution of phacomatoses included: neurofibromatosis type 1 (NF1) in 92.4%, tuberous sclerosis complex (TSC) 3.9%, neurofibromatosis type 2 (NF2) 2.0%, Klippel-Trenaunay syndrome 0.5%, Von Hippel-Lindau syndrome 0.5%, and other sporadic diseases 0.7%. Non-phacomatosis patients were diagnosed mainly for cafe-au-lait-macules (42.8%). The frequency of malignancy was 9.4% (86/913), including 9.1% in patients with NF1; 27.8% in NF2; and 8.3% in TSC. Multiple malignancies were diagnosed in 0.7% and 7% of all phacomatosis and malignancy-diagnosed patients, respectively. CONCLUSION: The risk of malignancy in patients with phacomatoses was 21.3-fold higher than in the general population. The risk of secondary malignancy was 7%. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. DOI: 10.21873/anticanres.12877


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23. Arch Phys Med Rehabil. 2018 Sep 18. pii: S0003-9993(18)31191-2. doi: 10.1016/j.apmr.2018.08.178. [Epub ahead of print]

The effectiveness of exercise interventions for pain reduction in people with multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials.

Demaneuf T(1), Aitken Z(2), Karahalios A(3), Leong TI(1), De Livera AM(4), Jelinek GA(1), Weiland TJ(1), Marck CH(5). Author information: (1)Neuroepidemiology Unit, The Melbourne School of Population and Global Health, The University of Melbourne. (2)Disability and Health, The Melbourne School of Population and Global Health, The University of Melbourne. (3)Biostatistics Unit, The Melbourne School of Population and Global Health, The University of Melbourne. (4)Neuroepidemiology Unit, The Melbourne School of Population and Global Health, The University of Melbourne; Biostatistics Unit, The Melbourne School of Population and Global Health, The University of Melbourne. (5)Neuroepidemiology Unit, The Melbourne School of Population and Global Health, The University of Melbourne; Disability and Health, The Melbourne School of Population and Global Health, The University of Melbourne. Electronic address: [email protected]. OBJECTIVE: To systematically review the evidence of the effect of exercise compared to passive control on pain in people with multiple sclerosis. DATA SOURCE AND STUDY SELECTION: Five electronic databases were searched for randomized controlled trials published up to March 2017 that recruited people with multiple sclerosis where exercise was the intervention and pain was an outcome. (PROSPERO registration number CRD42017060489). STATISTICAL ANALYSIS: A random-effects meta-analysis was conducted to estimate the standardized mean difference of the effect of exercise on pain between treatment and control groups. We assessed risk of bias, fitted meta-regression models to explore heterogeneity between studies, and assessed small study effects. DATA SYNTHESIS: Ten studies met the inclusion criteria (total sample size = 389) and all studies were at high risk of bias. We found that exercise intervention was associated with less pain compared to passive control groups (standardized mean difference = -0.46; 95% CI: -0.92, 0.00). There was high between study heterogeneity (I2 = 77.0%), which was not explained by the pre-specified study characteristics. There was also some evidence of small study effects. CONCLUSION: This is the first systematic review of the effect of exercise interventions on pain in people with multiple sclerosis, a chronic neurological disorder that affects 2.5 million people. We found some evidence that exercise compared to passive control alleviates pain in this population, but there were limitations in reporting and study quality with high risk of bias of individual studies and heterogeneity between studies. Copyright © 2018. Published by Elsevier Inc. DOI: 10.1016/j.apmr.2018.08.178


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24. Arq Neuropsiquiatr. 2018 Aug;76(8):539-554. doi: 10.1590/0004-282X20180078.

Brazilian Consensus for the Treatment of Multiple Sclerosis: Brazilian Academy of Neurology and Brazilian Committee on Treatment and Research in Multiple Sclerosis.

Marques VD(1), Passos GRD(2), Mendes MF(3), Callegaro D(3), Lana-Peixoto MA(4), Comini-Frota ER(5), Vasconcelos CCF(6), Sato DK(2), Ferreira MLB(7), Parolin MKF(8), Damasceno A(9), Grzesiuk AK(10), Muniz A(11), Matta APDC(12), Oliveira BES(13), Tauil CB(14)(15), Maciel DRK(16), Diniz DS(17), Corrêa EC(18), Coronetti F(19), Jorge FMH(3), Sato HK(20), Gonçalves MVM(21), Sousa NAC(22), Nascimento OJM(12), Gama PDD(23), Domingues R(24)(25)(26), Simm RF(3), Thomaz RB(27), Morales RR(28), Dias RM(29), Apóstolos-Pereira SD(3), Machado SCN(30), Junqueira TF(31), Becker J(2)(12). Author information: (1)Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Hospital das Clínicas de Ribeirão Preto, Ribeirão Preto SP, Brasil. (2)Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre RS, Brasil. (3)Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo SP, Brasil. (4)Universidade Federal de Minas Gerais, Centro de Investigação em Esclerose Múltipla de Minas Gerais, Belo Horizonte MG, Brasil. (5)Universidade José do Rosário Vellano, Belo Horizonte MG, Brasil. (6)Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro RJ, Brasil. (7)Hospital da Restauração, Recife PE, Brasil. (8)Clínica Gonçalves Dias, Curitiba PR, Brasil. (9)Universidade de Campinas, Campinas SP, Brasil. (10)Clínica Privada, Cuiabá MT, Brasil. (11)Hospital São Rafael, Salvador BA, Brasil. (12)Universidade Federal Fluminense, Niterói RJ, Brasil. (13)Fundação Centro Integrado de Apoio ao Portador de Deficiência, João Pessoa PB, Brazil. (14)Universidade de Brasília, Brasília DF, Brasil. (15)Universidade Católica de Brasília, Brasília DF, Brasil. (16)Santa Casa de Misericórdia de Londrina, Londrina PR, Brasil. (17)Faculdade de Medicina da Universidade Federal de Goiás, Goiânia GO, Brasil. (18)Clínica de Neurologia e Endocrinologia, Brasília DF, Brasil. (19)Universidade Estadual Paulista, São Paulo SP, Brasil. (20)Instituto de Neurologia de Curitiba, Curitiba PR, Brasil. (21)Universidade da Região de Joinville, Joinville SC, Brasil. (22)Universidade Federal do Amazonas, Hospital Universitário Getúlio Vargas, Manaus AM, Brazil. (23)Pontifícia Universidade Católica de São Paulo, Sorocaba SP, Brasil. (24)Senne Líquor Diagnóstico, São Paulo SP, Brasil. (25)Hospital Cruz Azul, São Paulo SP, Brasil. (26)Faculdade São Leopoldo Mandic, Campinas SP, Brasil. (27)Hospital Israelita Albert Einstein, São Paulo SP, Brasil. (28)Universidade Federal de Uberlândia, Uberlândia MG, Brasil. (29)Hospital de Base do Distrito Federal, Brasília DF, Brasil. (30)Imperial Hospital de Caridade, Florianópolis SC, Brasil. (31)Escola Bahiana de Medicina e Saúde Pública, Salvador BA, Brasil. The expanding therapeutic arsenal in multiple sclerosis (MS) has allowed for more effective and personalized treatment, but the choice and management of disease-modifying therapies (DMTs) is becoming increasingly complex. In this context, experts from the Brazilian Committee on Treatment and Research in Multiple Sclerosis and the Neuroimmunology Scientific Department of the Brazilian Academy of Neurology have convened to establish this Brazilian Consensus for the Treatment of MS, based on their understanding that neurologists should be able to prescribe MS DMTs according to what is better for each patient, based on up-to-date evidence and practice. We herein propose practical recommendations for the treatment of MS, with the main focus on the choice and management of DMTs, as well as present a review of the scientific rationale supporting therapeutic strategies in MS. DOI: 10.1590/0004-282X20180078


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25. Asian Pac J Cancer Prev. 2018 Sep 26;19(9):2391-2401.

The Sources of Essential Fatty Acids for Allergic and Cancer Patients; a Connection with Insight into Mammalian Target of Rapamycin: A Narrative Review

Arshad Z(1), Rezapour-Firouzi S, Mohammadian M, Ebrahimifar. Author information: (1)Department of Pathology of Anatomy, School of Medicine, Baku University of Medical Sciences, Baku, Azerbaijan. Email: [email protected], [email protected] Background: Disturbance in essential fatty acids (EFA) metabolism plays a key role in autoimmune diseases, but EFA supplementation with sources of borage, evening primrose, hemp seed and fish oils was not effective in atopic and cancer diseases, as that seen in the case of multiple sclerosis. It seems that two complexes of the mammalian target of rapamycin (mTOR) signaling, mTORC1 and mTORC2, are congruent with the two bases of the Traditional Iranian Medicine (TIM) therapy, Cold and Hot nature, which are essential for the efficacy of functional oils for controlling immune responses in autoimmune diseases. Methods: We searched PubMed database, Web of Science (WOS), Google Scholar, Scopus and selected studies by predefined eligibility criteria. We then assessed their quality and extracted data. Results: The oils controlled by Cold or Hot nature may be helpful in maintaining homeostasis and preventing autoimmune diseases. In summary, studies of randomized controlled trials for allergy and cancer patients found no improvement in the signs or response to tests, despite a remarkable change in EFA fractions in the blood by supplementation with sources of borage, evening primrose, hemp seed and fish oils. In contrast, portulaca oleracea oil exhibited protective effects by anti-inflammatory properties via the PI3K/Akt/mTORC2 pathway with a deviation immune response to Th1 to treat atopic diseases and cancer. Conclusions: According to the concept of Traditional Iranian Medicine therapy, in contrast to Cold-nature oils, EFA supplementation with the sources of Hot-nature oilsis not suitable for the treatment of atopic and cancerous diseases. Creative Commons Attribution License DOI: 10.22034/APJCP.2018.19.9.2391

26. Autoimmun Rev. 2018 Sep 11. pii: S1568-9972(18)30204-0. doi: 10.1016/j.autrev.2018.05.007. [Epub ahead of print]

The role of dietary sodium on autoimmune diseases: The salty truth.

Sharif K(1), Amital H(1), Shoenfeld Y(2). Author information: (1)Department of Medicine 'B',, Sheba Medical Center, Tel-Hashomer, Israel; Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. (2)Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel. Electronic address: [email protected]. Autoimmune diseases are a group of heterogeneous condition that occur secondary to the intrinsic loss of tolerance to self- antigens. In genetically susceptible individuals, the complex interplay of environmental factors and epigenetic deregulations have been proposed to drive disease etiopathogenesis. Various environmental variables have been identified including viral infections, exposure to pollutants, stress and dietary factors. Sodium, a major constituent of salt is essential for mammalian physiology. However, high salt intake may play a role in the development of autoimmune diseases. Several lines of evidence point toward the role of high sodium intake in reversing the suppressive effects of Regulatory T cells (Tregs) and instead promoting cellular shift toward T-helper (Th)-1 and Th17 pro-inflammatory phenotypes. These effects have been attributed to cascade of events that ultimately results in downstream activation of serum glucocorticoid kinase 1 (Sgk1). In vivo, various autoimmune animal models have confirmed the role of high sodium diet in the emergence and the exacerbation of autoimmune conditions including for instance Experimental Autoimmune Encephalomyelitis model for multiple sclerosis, MRL/lpr mouse model for lupus nephritis, collagen induced arthritis model for rheumatoid arthritis, and dextran sulfate sodium induced colitis, and TNBS-induced colitis models for Crohn's disease. Clinical epidemiological studies are scarce. High sodium intake was associated with increased risk of rheumatoid arthritis disease emergence. In multiple sclerosis, some studies suggest a relation to clinical exacerbation rates however other studies did not corroborate these results. Taken together, high dietary salt intake plays a role in the spectrum of autoimmune disease etiology. Further research is warranted to better characterize such relationship and assist in identifying individuals that would benefit from dietary salt restriction. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.autrev.2018.05.007


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27. Autophagy. 2018 Sep 13:1-15. doi: 10.1080/15548627.2018.1522467. [Epub ahead of print]

Mir223 restrains autophagy and promotes CNS inflammation by targeting ATG16L1.

Li Y(1), Zhou D(1), Ren Y(2), Zhang Z(1), Guo X(1), Ma M(1)(3), Xue Z(1), Lv J(1)(4), Liu H(1), Xi Q(1), Jia L(1), Zhang L(1), Liu Y(1), Zhang Q(5), Yan J(6), Da Y(1), Gao F(7), Yue J(8), Yao Z(1), Zhang R(1)(9). Author information: (1)a Laboratory of Immunology and Inflammation, Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Hormones and Development (Ministry of Health) , Tianjin Medical University , Tianjin , China. (2)b Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute , Tianjin Medical University General Hospital , Tianjin , China. (3)c Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin , China. (4)d Hexi Women & Children Healthcare and Family Planning Service Center , Tianjin , China. (5)e Institute of Integrative Medicines for Acute Abdominal Diseases , Nankai Hospital , Tianjin , China. (6)f Tianjin Institute of Animal husbandry and veterinary , Tianjin , China. (7)g State Key Laboratory of Reproductive Biology, Institute of Zoology , Chinese Academy of Sciences , Beijing , China. (8)h Department of Biomedical Sciences , City University of Hong Kong , Hong Kong , China. (9)i Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics , Guangdong Pharmaceutical University , Guangzhou , China. Microglia are innate immune cells in the central nervous system (CNS), that supplies neurons with key factors for executing autophagosomal/lysosomal functions. Macroautophagy/autophagy is a cellular catabolic process that maintains cell balance in response to stress-related stimulation. Abnormal autophagy occurs with many pathologies, such as cancer, and autoimmune and neurodegenerative diseases. Hence, clarification of the mechanisms of autophagy regulation is of utmost importance. Recently, researchers presented microRNAs (miRNAs) as novel and potent modulators of autophagic activity. Here, we found that Mir223 deficiency significantly ameliorated CNS inflammation, demyelination and the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) and increased resting microglia and autophagy in brain microglial cells. In contrast, the autophagy inhibitor 3-methylademine (3-MA) aggravated the clinical symptoms of EAE in wild-type (WT) and Mir223-deficienct mice. Furthermore, it was confirmed that Mir223 deficiency in mice increased the protein expression of ATG16L1 (autophagy related 16-like 1 [S. cerevisiae]) and LC3-II in bone marrow-derived macrophage cells compared with cells from WT mice. Indeed, the cellular level of Atg16l1 was decreased in BV2 cells upon Mir223 overexpression and increased following the introduction of antagomirs. We also showed that the 3' UTR of Atg16l1 contained functional Mir223-responsive sequences and that overexpression of ATG16L1 returned autophagy to normal levels even in the presence of Mir223 mimics. Collectively, these data indicate that Mir223 is a novel and important regulator of autophagy and that Atg16l1 is a Mir223 target in this process, which may have implications for improving our understanding of the neuroinflammatory process of EAE.ABBREVIATIONS: 3-MA: 3-methylademine; ACTB/β-actin: actin, beta; ATG: autophagy related; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CNR2: cannabinoid receptor 2 (macrophage); CNS: central nervous system; CQ: chloroquine; EAE: experimental autoimmune encephalomyelitis; FOXO3: forkhead box O3; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; H&E: hematoxylin and eosin; ITGAM: integrin alpha M; LPS: lipoplysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; miRNAs: microRNAs; MS: multiple sclerosis; PPARG: peroxisome proliferator activated receptor gamma; PTPRC: protein tyrosine phosphatase, receptor type, C; RA: rheumatoid arthritis; SQSTM1: sequestosome 1; TB: tuberculosis; TIMM23: translocase of inner mitochondrial membrane 23; TLR: toll-like receptor. DOI: 10.1080/15548627.2018.1522467


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28. Biochem Pharmacol. 2018 Aug 30. pii: S0006-2952(18)30363-0. doi: 10.1016/j.bcp.2018.08.037. [Epub ahead of print]

Gut microbiota, cannabinoid system and neuroimmune interactions: New perspectives in multiple sclerosis.

Mestre L(1), Carrillo-Salinas FJ(2), Mecha M(1), Feliú A(1), Guaza C(3). Author information: (1)Grupo de Neuroinmunología, Departamento de Neurobiología Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid, Spain; Red Española de Esclerosis Múltiple (REEM), Spain. (2)Grupo de Neuroinmunología, Departamento de Neurobiología Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid, Spain. (3)Grupo de Neuroinmunología, Departamento de Neurobiología Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid, Spain; Red Española de Esclerosis Múltiple (REEM), Spain. Electronic address: [email protected]. The gut microbiota plays a fundamental role on the education and function of the host immune system. Immunological dysregulation is the cause of numerous human disorders such as autoimmune diseases and metabolic disorders frequently associated with inflammatory processes therefore is critical to explore novel mechanisms involved in maintaining the immune system homeostasis. The cannabinoid system and related bioactive lipids participate in multiple central and peripheral physiological processes that affect metabolic, gastrointestinal and neuroimmune regulatory mechanisms displaying a modulatory role and contributing to the maintenance of the organism's homeostasis. In this review, we gather the knowledge on the gut microbiota-endocannabinoids interactions and their impact on autoimmune disorders such as inflammatory bowel disease, rheumatoid arthritis and particularly, multiple sclerosis (MS) as the best example of a CNS autoimmune disorder. Furthermore, we contribute to this field with new data on changes in many elements of the cannabinoid system in a viral model of MS after gut microbiota manipulation by both antibiotics and probiotics. Finally, we highlight new therapeutic opportunities, under an integrative view, targeting the eCBS and the commensal microbiota in the context of neuroinflammation and MS. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.bcp.2018.08.037

29. Biochemistry (Mosc). 2018 Jul;83(7):813-830. doi: 10.1134/S0006297918070052.

Involvement of Mitochondria in Neurodegeneration in Multiple Sclerosis.

Kozin MS(1)(2), Kulakova OG(3)(2), Favorova OO(4)(2). Author information: (1)Pirogov Russian National Research Medical University, Moscow, 117997, Russia. [email protected]. (2)National Medical Research Center of Cardiology, Moscow, 121552, Russia. (3)Pirogov Russian National Research Medical University, Moscow, 117997, Russia. [email protected]. (4)Pirogov Russian National Research Medical University, Moscow, 117997, Russia. Functional disruption and neuronal loss followed by progressive dysfunction of the nervous system underlies the pathogenesis of numerous disorders defined as "neurodegenerative diseases". Multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system resulting in serious neurological dysfunctions and disability, is one of the most common neurodegenerative diseases. Recent studies suggest that disturbances in mitochondrial functioning are key factors leading to neurodegeneration. In this review, we consider data on mitochondrial dysfunctions in multiple sclerosis, which were obtained both with patients and with animal models. The contemporary data indicate that the axonal degeneration in multiple sclerosis largely results from the activation of Ca2+-dependent proteases and from misbalance of ion homeostasis caused by energy deficiency. The genetic studies analyzing association of mitochondrial DNA polymorphic variants in multiple sclerosis suggest the participation of mitochondrial genome variability in the development of this disease, although questions of the involvement of individual genomic variants are far from being resolved. DOI: 10.1134/S0006297918070052


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30. Biol Trace Elem Res. 2018 Sep 13. doi: 10.1007/s12011-018-1509-5. [Epub ahead of print]

Association Between Exposure to Heavy Metals and Systemic Sclerosis: the Levels of Al, Cd, Hg, and Pb in Blood and Urine of Patients.

Forte G(1), Fadda C(2), Bocca B(3), Erre GL(4), Passiu G(5), Madeddu R(2)(6). Author information: (1)Italian National Institute for Health, Environment and Health Department, Viale Regina Elena, 299, 00161, Rome, Italy. (2)Department of Biomedical Sciences - Histology, University of Sassari, Sassari, Italy. (3)Italian National Institute for Health, Environment and Health Department, Viale Regina Elena, 299, 00161, Rome, Italy. [email protected]. (4)University Hospital Unit of Sassari, Sassari, Italy. (5)Department of Medical, Surgery and Experimental Sciences, University of Sassari, Sassari, Italy. (6)National Institute of Biostructures and Biosystems, Rome, Italy. Systemic sclerosis (SSc) is a multisystem connective tissue disease; exogenous factors-including heavy metals-may have a role in the disease pathogenesis. In this context, a study on the quantification of Al, Cd, Hg, and Pb in blood and urine of 27 SSc patients and 30 controls was carried out. Main findings were that Al was significantly depleted in blood and increased in urine of SSc patients respect to controls; and Pb was found slightly increased in blood and significantly decreased in SSc group. In addition, higher Hg levels in urine were found in SSc subjects with the higher severity of the disease. Females showed the most marked differences in the levels of blood Al, blood Pb, and urine Cd between patients and controls. Smoking, hobby, ingestion of contaminated food, job exposure may contribute to the bodily levels of Al, Hg, Pb in SSc patients. The results indicated that low, chronic, and multiple exposures to heavy metals-also through habits, diet, and environment-may influence the risk for SSc. DOI: 10.1007/s12011-018-1509-5

31. Biomed Res Int. 2018 Aug 23;2018:9329123. doi: 10.1155/2018/9329123. eCollection 2018.

Assessment of Biochemical and Densitometric Markers of Calcium-Phosphate Metabolism in the Groups of Patients with Multiple Sclerosis Selected due to the Serum Level of Vitamin D3.

Niedziela N(1), Pierzchała K(1), Zalejska-Fiolka J(2), Niedziela JT(3), Romuk E(2), Torbus-Paluszczak M(1), Adamczyk-Sowa M(1). Author information: (1)Department of Neurology, SMDZ in Zabrze, Medical University of Silesia in Katowice, ul. 3-go Maja 13-15, 41-800 Zabrze, Poland. (2)Department of Biochemistry, SMDZ in Zabrze, Medical University of Silesia in Katowice, ul. Jordana 19, 41-808 Zabrze, Poland. (3)3rd Department of Cardiology, SMDZ in Zabrze, Medical University of Silesia, Katowice, Silesian Centre for Heart Disease, Zabrze, Poland. Background: In addition to the widely known effect of vitamin D3 (vitD3) on the skeleton, its role in the regulation of the immune response was also confirmed. Aim: The assessment of biochemical and densitometric markers of calcium-phosphate metabolism in the groups of patients with relapsing-remitting multiple sclerosis (RRMS) selected due to the serum level of vitamin D3. Methods: The concentrations of biochemical markers and indices of lumbar spine bone densitometry (DXA) were determined in 82 patients divided into vitamin D3 deficiency (VitDd), insufficiency (VitDi), and normal vitamin D3 level (VitDn) subgroups. Results: The highest level of the parathyroid hormone (PTH) and the highest prevalence of hypophosphatemia and osteopenia were demonstrated in VitDd group compared to VitDi and VitDn. However, in VitDd, VitDi, and VitDn subgroups no significant differences were observed in the levels of alkaline phosphatase (ALP) and ionized calcium (Ca2+) and in DXA indices. A negative correlation was observed between the level of vitamin D3 and the Expanded Disability Status Scale (EDSS) in the whole MS group. The subgroups were significantly different with respect to the EDSS scores and the frequency of complaints related to walking according to the EQ-5D. Conclusions: It is necessary to assess calcium-phosphate metabolism and supplementation of vitamin D3 in RRMS patients. The higher the clinical stage of the disease assessed with the EDSS, the lower the level of vitamin D3 in blood serum. Subjectively reported complaints related to difficulties with walking were reflected in the EDSS in VitDd patients. DOI: 10.1155/2018/9329123 PMCID: PMC6126066


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32. Bioorg Med Chem Lett. 2018 Sep 5. pii: S0960-894X(18)30732-7. doi: 10.1016/j.bmcl.2018.09.001. [Epub ahead of print]

Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis.

Islam I(1), Yuan S(2), West CW(2), Adler M(3), Bothe U(4), Bryant J(2), Chang Z(2), Chu K(5), Emayan K(2), Gualtieri G(2), Ho E(6), Light D(7), Mallari C(6), Morser J(8), Phillips G(2), Schaefer C(6), Sukovich D(5), Whitlow M(3), Chen D(2), Buckman BO(2). Author information: (1)Medical Core Facility and Research Platforms, King Abdullah International Medical Research Center/King Saud Bin, Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia; Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. Electronic address: [email protected]. (2)Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. (3)Department of Biophysics, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. (4)Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States; Research and Development Pharmaceutical, Bayer AG, 13342 Berlin, Germany. (5)Department of Molecular Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. (6)Department of Animal Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. (7)Department of Antibody Technology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. (8)Cardiovascular Department, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.bmcl.2018.09.001

33. BMC Neurol. 2018 Sep 14;18(1):143. doi: 10.1186/s12883-018-1145-x.

Effect of interferon beta-1a subcutaneously three times weekly on clinical and radiological measures and no evidence of disease activity status in patients with relapsing-remitting multiple sclerosis at year 1.

Traboulsee A(1), Li DKB(2), Cascione M(3), Fang J(4), Dangond F(5), Miller A(6). Author information: (1)University of British Columbia, S113-2211 Wesbrook Mall, Vancouver, BC, V6T 1Z7, Canada. [email protected]. (2)University of British Columbia, S113-2211 Wesbrook Mall, Vancouver, BC, V6T 1Z7, Canada. (3)Tampa Neurology Associates, South Tampa Multiple Sclerosis Center, 2919 W. Swann Avenue, Suite 401, South Tampa, FL, 33609, USA. (4)EMD Serono, Inc., One Technology Place, Rockland, MA, 02370, USA. (5)EMD Serono, Inc, 45A Middlesex Tpke, Billerica, MA, 01821, USA. (6)Mount Sinai Hospital, 5 East 98th Street, 1st Floor, New York, NY, 10029, USA. BACKGROUND: In the PRISMS study, interferon beta-1a subcutaneously (IFN β-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing-remitting multiple sclerosis. The study aimed to characterize efficacy of IFN β-1a SC 44 μg and 22 μg three times weekly (tiw) at Year 1. METHODS: Exploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was < 6.0 [0.5-point if baseline was ≥6.0]), active T2 lesions, and no evidence of disease activity (NEDA; defined as no relapses [subanalyzed by relapse severity], 3-month confirmed progression, or active T2 lesions). Effect of IFN β-1a SC in prespecified patient subgroups was also assessed. RESULTS: Patients were randomized to IFN β-1a 22 μg (n = 189), 44 μg (n = 184), or placebo (n = 187). At 1 year, IFN β-1a SC tiw reduced ARR (p < 0.001), risk of disability progression (p ≤ 0.029), and mean number of active T2 lesions per patients per scan (p < 0.001) versus placebo. Clinical and radiological benefits were seen as early as Month 2 and 3. Outcomes in subgroups were consistent with those in the overall population. More patients treated with IFN β-1a SC tiw achieved NEDA status, versus placebo, regardless of relapse severity (p ≤ 0.006). CONCLUSION: Clinical, radiological, and NEDA outcomes at Year 1 were consistent with Year 2 results. Treatment efficacy was consistent in pre-specified patient subgroups. DOI: 10.1186/s12883-018-1145-x PMCID: PMC6137887


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34. BMC Neurol. 2018 Sep 10;18(1):140. doi: 10.1186/s12883-018-1141-1.

The subtleties of cognitive decline in multiple sclerosis: an exploratory study using hierarchichal cluster analysis of CANTAB results.

Cabeça HLS(1), Rocha LC(2), Sabbá AF(2), Tomás AM(2), Bento-Torres NVO(2)(3), Anthony DC(4), Diniz CWP(5). Author information: (1)Departamento de Neurologia, Hospital Ophir Loyola, Belém, PA, Brazil. (2)Laboratório de Investigações em Neurodegeneração e Infecção, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Instituto de Ciências Biológicas, Belém, PA, Brazil. (3)Faculdade de Fisioterapia e Terapia Ocupacional, Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém, PA, Brazil. (4)Laboratory of Experimental Neuropathology, Department of Pharmacology, University of Oxford, Oxford, UK. (5)Laboratório de Investigações em Neurodegeneração e Infecção, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Instituto de Ciências Biológicas, Belém, PA, Brazil. [email protected]. BACKGROUND: It is essential to investigate cognitive deficits in multiple sclerosis (MS) to develop evidence-based cognitive rehabilitation strategies. Here we refined cognitive decline assessment using the automated tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB) and hierarchical cluster analysis. METHODS: We searched for groups of distinct cognitive profiles in 35 relapsing-remitting MS outpatients and 32 healthy controls. All individuals participated in an automated assessment (CANTAB) and in a pencil and paper general neuropsychological evaluation. RESULTS: Hierarchical cluster analysis of the CANTAB results revealed two distinct groups of patients based mainly on the Simple Reaction Time (RTI) and on the Mean Latency of Rapid Visual Processing (RVP). The general neuropsychological assessment did not show any statistically significant differences between the cluster groups. Compared to the healthy control group, all MS outpatients had lower scores for RTI, RVP, paired associate learning, and delayed matching to sample. We also analyzed the associations between CANTAB results and age, education, sex, pharmacological treatment, physical activity, employment status, and the Expanded Disability Status Scale (EDSS). Although limited by the small number of observations, our findings suggest a weak correlation between performance on the CANTAB and age, education, and EDSS scores. CONCLUSIONS: We suggest that the use of selected large-scale automated visuospatial tests from the CANTAB in combination with multivariate statistical analyses may reveal subtle and earlier changes in information processing speed and cognition. This may expand our ability to define the limits between normal and impaired cognition in patients with Multiple Sclerosis. DOI: 10.1186/s12883-018-1141-1 PMCID: PMC6131879


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35. BMC Nurs. 2018 Sep 1;17:39. doi: 10.1186/s12912-018-0309-8. eCollection 2018.

Voluntary stopping of eating and drinking (VSED) as an unknown challenge in a long-term care institution: an embedded single case study.

Saladin N(1), Schnepp W(2), Fringer A(3). Author information: (1)Institute of Applied Nursing Science IPW-FHS, FHS St.Gallen, University of Applied Sciences, Rosenbergstrasse 59, 9001 St. Gallen, Switzerland. (2)2Faculty of Health, Department of Nursing Science, Chair of Family Oriented and Community Based Care, Witten/Herdecke University, Stockumer Strasse 12, 58453 Witten, Germany. (3)3Institute of Nursing, School of Health Professions, ZHAW Zurich University of Applied Sciences, Technikumstr. 81, CH-8400 Winterthur, Switzerland. Background: Chronically ill persons experience conditions of life that can become unbearable, resulting in the wish to end their life prematurely. Relatives confronted with this wish experience ambivalence between loyalty to the person's desire to die and the fear of losing this person. Caring for a person during the premature dying process can be morally challenging for nurses. One way to end one's life prematurely is Voluntary Stopping of Eating and Drinking (VSED). Methods: This embedded single case study explored the experiences of registered nurses (embedded units of analysis: ward manager, nursing manager, nursing expert) and relatives who accompanied a 49-year-old woman suffering from multiple sclerosis during VSED in a Swiss long-term care institution (main unit of analysis). By means of a within-analysis, we performed an in-depth analysis of every embedded unit of analysis and elaborated a central phenomenon for each unit. Afterwards, we searched for common patterns in a cross-analysis of the embedded units of analysis in order to develop a central model. Results: The following central concept emerged from cross-analysis of the embedded units of analysis: As a way of ending one's life prematurely, VSED represents an unfamiliar challenge to nurses and relatives in the field of tension between one's personal attitude and the agents' concerns, fears and uncertainties. Particularly significant is the personal attitude, influenced on the one hand by one's own experiences, prior knowledge, role and faith, on the other hand by the VSED-performing person's age, disease and deliberate communication of the decision. Depending on the intention of VSED as either suicide or natural dying, an accepting or dismissing attitude evolves on an institutional and personal level. Conclusions: To deal professionally with VSED in an institution, it is necessary to develop an attitude on the institutional and personal level. Educational measures and quality controls are required to ensure that VSED systematically becomes an option to hasten death. As VSED is a complex phenomenon, it is necessary to include palliative care in practice development early on and comprehensively. There is a high need of further research on this topic. Particularly, qualitative studies and hypothesis-testing approaches are required. DOI: 10.1186/s12912-018-0309-8 PMCID: PMC6119585 Conflict of interest statement: The ethics committee of the canton St. Gallen approved this study (EKSG16/016). All participants gave their written informed consent.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

36. BMJ Case Rep. 2018 Sep 8;2018. pii: bcr-2018-225601. doi: 10.1136/bcr-2018-225601.

Neuromyelitis optica spectrum disorder presenting in an octogenarian.

Campbell A(1), Ogundipe OA(1). Author information: (1)Medicine of the Elderly Department, Royal Infirmary of Edinburgh, Edinburgh, UK. This case describes an 81-year-old woman with a history of Sjögren's syndrome presenting with recurrent falls and poor balance. She subsequently developed new and rapidly evolving neurology including hyperaesthesia, spastic paraplegia and sphincteric dysfunction. Following serial clinical reviews and detailed investigations, MRI (brainstem and cervicothoracic spine) and a seropositive result for aquaporin 4 IgG, a diagnosis of neuromyelitis optica spectrum disorder (NMOSD) was made. This case describes the clinical course of this index patient with an unusual late age of onset. The report also includes a discussion on NMOSD. We review aspects of terminology, brief epidemiology, pathogenesis, notable autoimmune associations, variance in clinical presentation and current diagnostic criteria. We also review the importance of distinguishing NMOSD from multiple sclerosis in view of the significant implications for treatment and prognosis. © BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/bcr-2018-225601 Conflict of interest statement: Competing interests: None declared.


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37. BMJ Case Rep. 2018 Sep 21;2018. pii: bcr-2018-224931. doi: 10.1136/bcr-2018-224931.

Case of colonic mucosal Schwann cell hamartoma and review of literature on unusual colonic polyps.

Chintanaboina J(1), Clarke K(1). Author information: (1)Penn State Milton S Hershey Medical Center, Hershey, Pennsylvania, USA. Mucosal Schwann cell hamartomas (MSCH) are benign mesenchymal tumours rarely seen in the gastrointestinal tract. They occasionally present as incidental sessile polyps during colonoscopy. A 55-year-old asymptomatic female patient with a medical history of multiple sclerosis presented for a screening colonoscopy. A 5 mm low-risk tubular adenoma was noted in the caecum, and a second 5 mm polyp was found in the ascending colon. Histopathology of the ascending colon polyp showed proliferation of spindle cells without ganglion cells in the lamina propria. Immunohistochemical findings are compatible with an MSCH. Surveillance colonoscopy was scheduled in 5 years based on the presence of a single low-risk tubular adenoma. © BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/bcr-2018-224931 Conflict of interest statement: Competing interests: None declared.


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38. BMJ Open. 2018 Aug 30;8(8):e021944. doi: 10.1136/bmjopen-2018-021944.

Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis.

Connick P(1), De Angelis F(2), Parker RA(3), Plantone D(2), Doshi A(2), John N(2), Stutters J(2), MacManus D(2), Prados Carrasco F(2)(4), Barkhof F(2)(5), Ourselin S(4), Braisher M(2), Ross M(3), Cranswick G(3), Pavitt SH(6), Giovannoni G(7), Gandini Wheeler-Kingshott CA(2)(8), Hawkins C(9), Sharrack B(10), Bastow R(11), Weir CJ(3), Stallard N(12), Chandran S(1), Chataway J(2); UK Multiple Sclerosis Society Clinical Trials Network. Collaborators: Chataway J, Wheeler-Kingshott CG, Angelis F, Plantone D, Doshi A, John N, Williams T, Chandran S, Connick P, Cameron J, Mollison D, Dhillon B, Weir CJ, Parker R, Giovannoni G, Gnanapavan S, Nicholas R, Rashid W, Aram J, Ford H, Overell J, Young C, Duddy M, Guadagno J, Evangelou N, Craner M, Palace J, Hobart J, Sharrack B, Paling D, Hawkins C, Kalra S, Mclean B. Author information: (1)Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. (2)Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK. (3)Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK. (4)Department of Medical Physics and Biomedical Engineering, Translational Imaging Group (TIG), Centre for Medical Image Computing (CMIC), UCL, London, UK. (5)Department of Radiology and Nuclear Medicine, VU University Medical Centre, Amsterdam, The Netherlands. (6)Dental Translational and Clinical Research Unit (part of the NIHR Leeds CRF), University of Leeds, Leeds, UK. (7)Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. (8)Brain MRI 3T Research Center, IRCCS Mondino Foundation, Pavia, Italy. (9)Keele Medical School and Institute for Science and Technology in Medicine, Keele University, Keele, UK. (10)Department of Neuroscience, Royal Hallamshire Hospital, Sheffield, UK. (11)MS Society Patient Representative, London, UK. (12)Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK. INTRODUCTION: The major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist). METHODS AND ANALYSIS: Patients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland. ETHICS AND DISSEMINATION: MS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: NCT01910259; 2012-005394-31; ISRCTN28440672. © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/bmjopen-2018-021944 PMCID: PMC6119433


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Conflict of interest statement: Competing interests: PC, FDA, DP, AD, NJ, JS, SHP, CH, CJW, RAP, NS, SC, GC, RB, DMCM, MR declare no conflict of interests with respect to this work. MB has received funding from the UK Multiple Sclerosis Society and NIHR Local Clinical Research Network. FP receives a Guarantors of Brain fellowship. SO receives funding from the EPSRC (EP/H046410/1, EP/J020990/1, EP/K005278), the MRC (MR/J01107X/1), the EU-FP7 (FP7-ICT-2011-9-601055) and NIHR UCLH BRC (BW.mn.BRC10269). FB serves on the editorial boards of Brain, European Radiology, Journal of Neurology, Neurosurgery & Psychiatry, Neurology, Multiple Sclerosis and Neuroradiology, and serves as consultant for Bayer Shering Pharma, Sanofi-Aventis, Biogen-Idec, TEVA Pharmaceuticals, Genzyme, Merck-Serono, Novartis, Roche, Synthon, Jansen Research and Lundbeck. CGKW receives research grants (PI and co-applicant) from Spinal Research, Craig H. Neilsen Foundation, EPSRC, Wings for Life, UK MS Society, Horizon2020, NIHR/MRC. JC has received support from the Efficacy and Mechanism Evaluation Programme and Health Technology Assessment Programme (NIHR); UK Multiple Sclerosis Society and National Multiple Sclerosis Society. In the last 3 years, he has been a local principal investigator for trials in multiple sclerosis funded by: Receptos, Novartis, Roche and Biogen-Idec, and has received an investigator grant from Novartis outside this work. He has taken part in Advisory Boards/consultancy for Roche, Merck, MedDay, Biogen and Apitope. BS has received funding from NIHR and the UK MS Society, has been a principal investigator for trials in multiple sclerosis funded by: Receptos, Novartis, Biogen, Merck, Genzyme, Roche and Teva. GG is a steering committee member on the daclizumab trials for AbbVie, the BG12 and daclizumab trials for Biogen-Idec, the fingolimod and siponimod trials for Novartis, the laquinimod trials for Teva and the ocrelizumab trials for Roche. He has also received consultancy fees for advisory board meetings for oral cladribine trials for Merck-Serono, Genzyme-Sanofi and in relation to DSMB activities for Synthon BV, as well as honoraria for speaking at the Physicians’ summit and several medical education meetings. He is also the co-chief editor of Multiple Sclerosis and Related Disorders (Elsevier).


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39. Brain. 2018 Sep 1;141(9):2605-2618. doi: 10.1093/brain/awy202.

Predicting cognitive decline in multiple sclerosis: a 5-year follow-up study.

Eijlers AJC(1), van Geest Q(1), Dekker I(2)(3), Steenwijk MD(1), Meijer KA(1), Hulst HE(1), Barkhof F(2)(4), Uitdehaag BMJ(3), Schoonheim MM(1), Geurts JJG(1). Author information: (1)Department of Anatomy and Neurosciences, Amsterdam Neuroscience, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. (2)Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. (3)Department of Neurology, Amsterdam Neuroscience, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. (4)Institutes of Neurology and Healthcare Engineering, UCL, London, UK. Cognitive decline is common in multiple sclerosis and strongly affects overall quality of life. Despite the identification of cross-sectional MRI correlates of cognitive impairment, predictors of future cognitive decline remain unclear. The objective of this study was to identify which MRI measures of structural damage, demographic and/or clinical measures at baseline best predict cognitive decline, during a 5-year follow-up period. A total of 234 patients with clinically definite multiple sclerosis and 60 healthy control subjects were examined twice, with a 5-year interval (mean = 4.9 years, standard deviation = 0.9). An extensive neuropsychological evaluation was performed at both time points and the reliable change index was computed to evaluate cognitive decline. Both whole-brain and regional MRI (3 T) measures were assessed at baseline, including white matter lesion volume, diffusion-based white matter integrity, cortical and deep grey matter volume. Logistic regression analyses were performed to determine which baseline measures best predicted cognitive decline in the entire sample as well as in early relapsing-remitting (symptom duration <10 years), late relapsing-remitting (symptom duration ≥10 years) and progressive phenotypes. At baseline, patients with multiple sclerosis had a mean disease duration of 14.8 (standard deviation = 8.4) years and 96/234 patients (41%) were classified as cognitively impaired. A total of 66/234 patients (28%) demonstrated cognitive decline during follow-up, with higher frequencies in progressive compared to relapsing-remitting patients: 18/33 secondary progressive patients (55%), 10/19 primary progressive patients (53%) and 38/182 relapsing-remitting patients (21%). A prediction model that included only whole-brain MRI measures (Nagelkerke R2 = 0.22, P < 0.001) showed cortical grey matter volume as the only significant MRI predictor of cognitive decline, while a prediction model that assessed regional MRI measures (Nagelkerke R2 = 0.35, P < 0.001) indicated integrity loss of the anterior thalamic radiation, lesions in the superior longitudinal fasciculus and temporal atrophy as significant MRI predictors for cognitive decline. Disease stage specific regressions showed that cognitive decline in early relapsing-remitting multiple sclerosis was predicted by white matter integrity damage, while cognitive decline in late relapsing-remitting and progressive multiple sclerosis was predicted by cortical atrophy. These results indicate that patients with more severe structural damage at baseline, and especially cortical atrophy, are more prone to suffer from cognitive decline. New studies now need to further elucidate the underlying mechanisms leading to cortical atrophy, evaluate the value of including cortical atrophy as a possible outcome marker in clinical trials as well as study its potential use in individual patient management. DOI: 10.1093/brain/awy202


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40. Brain. 2018 Oct 1;141(10):2895-2907. doi: 10.1093/brain/awy238.

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.

Zhang M(1)(2)(3), Ferrari R(4), Tartaglia MC(3)(5)(6), Keith J(7), Surace EI(8), Wolf U(9), Sato C(3), Grinberg M(3), Liang Y(3), Xi Z(3), Dupont K(3), McGoldrick P(3), Weichert A(3), McKeever PM(3), Schneider R(3)(6)(7), McCorkindale MD(4), Manzoni C(10), Rademakers R(11), Graff-Radford NR(12), Dickson DW(11), Parisi JE(13), Boeve BF(14), Petersen RC(14), Miller BL(15), Seeley WW(16), van Swieten JC(17), van Rooij J(17), Pijnenburg Y(18), van der Zee J(19)(20), Van Broeckhoven C(19)(20), Le Ber I(21)(22), Van Deerlin V(23), Suh E(23), Rohrer JD(24), Mead S(25), Graff C(26)(27), Öijerstedt L(26)(27), Pickering-Brown S(28), Rollinson S(28), Rossi G(29), Tagliavini F(30), Brooks WS(31), Dobson-Stone C(32)(33), Halliday GM(32), Hodges JR(32)(34), Piguet O(34)(35), Binetti G(36), Benussi L(37), Ghidoni R(37), Nacmias B(38), Sorbi S(38)(39), Bruni AC(40), Galimberti D(41), Scarpini E(41), Rainero I(42), Rubino E(42), Clarimon J(43)(44), Lleó A(43)(44), Ruiz A(45), Hernández I(45), Pastor P(46)(47), Diez-Fairen M(46)(47), Borroni B(48), Pasquier F(49), Deramecourt V(49), Lebouvier T(49), Perneczky R(50)(51)(52), Diehl-Schmid J(50), Grafman J(53)(54), Huey ED(55), Mayeux R(55)(56), Nalls MA(57), Hernandez D(57), Singleton A(57), Momeni P(58), Zeng Z(59), Hardy J(4), Robertson J(3), Zinman L(6)(7), Rogaeva E(3)(6); International FTD-Genomics Consortium (IFGC). Collaborators: Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Albani D, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Wald Ouml ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsiung GR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Van Broeckhoven C, Cappa SF, Leber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Grazia Spillantini M, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Elena Conidi M, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebouvier T, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P.


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Author information: (1)Shanghai First Rehabilitation Hospital, School of Medicine, Tongji University, Shanghai, China. (2)Institute for Advanced Study, Tongji University, Shanghai, China. (3)Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada. (4)Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK. (5)Krembil Neuroscience Center, University Health Network Memory clinic, Toronto Western Hospital, Toronto, ON, Canada. (6)Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada. (7)Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. (8)Laboratorio de Biología Molecular, Departamento de Neuropatología, Instituto de Investigaciones Neurológicas Dr. Raúl Carrea (FLENI), Buenos Aires, Argentina. (9)Baycrest Health Science, Department of Psychiatry, University of Toronto, Toronto, ON, Canada. (10)School of Pharmacy, University of Reading, Whiteknights, Reading, UK. (11)Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. (12)Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. (13)Department of Laboratory Medicine and Pathology and Department of Neurology, Mayo Clinic, Rochester, MN, USA. (14)Department of Neurology, Mayo Clinic, Rochester, MN, USA. (15)Department of Neurology, University of California San Francisco Memory and Aging Center, San Francisco, CA, USA. (16)Department of Neurology and Department of Pathology, University of California San Francisco Memory and Aging Center, San Francisco, CA, USA. (17)Department of Neurology, Erasmus MC, Rotterdam, The Netherlands. (18)Alzheimer Center, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands. (19)Neurodegenerative Brain Diseases, Center of Molecular Neurology, VIB, Antwerp, Belgium. (20)Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. (21)Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et la Moelle épinière (ICM), Paris, France. (22)Reference Center for Rare and Young Dementias, Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Hopital Pitié-Salpêtrière, Paris, France. (23)Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (24)Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. (25)MRC Prion Unit at UCL, Institute of Prion Diseases, London, UK. (26)Division of Neurogeriatrics, Alzheimer Research Center, Karolinska Institutet, Solna, Sweden. (27)Genetics Unit, Theme Aging, Karolinska University Hospital, Stockholm, Sweden. (28)Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, University of Manchester, UK. (29)Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. (30)Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. (31)Neuroscience Research Australia and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia. (32)Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia. (33)School of Medical Sciences, University of New South Wales, Sydney, Australia. (34)Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, Australia. (35)School of Psychology and Brain and Mind Centre, University of Sydney, Sydney, Australia. (36)MAC Memory Center, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. (37)Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. (38)Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy. (39)IRCCS Don Gnocchi, Florence, Italy. (40)Regional Neurogenetic Centre, Lamezia Terme, Azienda Sanitaria Provinciale Catanzaro, Italy. (41)Neurodegenerative Disease Unit, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy. (42)Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy. (43)IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain. (44)Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain. (45)Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain. (46)Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain. (47)Fundació per la Recerca Biomèdica i Social Mútua de Terrassa, Terrassa, Barcelona, Spain. (48)Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. (49)National Reference Center for Young Onset Dementia, Neurology Department, Centre Hospitalier Régional Universitaire de Lille, University Hospital, Inserm U1171, DistAlz, Lille, France. (50)Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany. (51)Department of Psychiatry and Psychotherapy, Division of Mental Health in Older Adults and Alzheimer Therapy and Research Center, Ludwig-Maximilians-Universität München, Munich, Germany. (52)Imperial College London, School of Public Health, Neuroepidemiology and Ageing Research Unit, London, UK. (53)Cognitive Neurology and Alzheimer's Center, Department of Psychiatry, Feinberg School of Medicine Chicago, IL, USA. (54)Department of Psychology, Weinberg College of Arts and Sciences Northwestern University Chicago, IL, USA. (55)The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA. (56)The Gertrude H. Sergievsky Center,


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The Departments of Neurology, Psychiatry, Epidemiology, School of Public Health, Columbia University, New York, NY, USA. (57)Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. (58)Rona Holdings, Silicon Valley, CA, USA. (59)Merck & Co., Inc, Kenilworth, NJ, USA. The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis. DOI: 10.1093/brain/awy238

41. Brain. 2018 Oct 1;141(10):2834-2847. doi: 10.1093/brain/awy239.

Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis.

Baker D(1), Pryce G(1), Amor S(1)(2), Giovannoni G(1)(3), Schmierer K(1)(3). Author information: (1)BartsMS, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. (2)Pathology Department, Free University Amsterdam, 1081 HV Amsterdam, The Netherlands. (3)Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK. Although many suspected autoimmune diseases are thought to be T cell-mediated, the response to therapy indicates that depletion of B cells consistently inhibits disease activity. In multiple sclerosis, it appears that disease suppression is associated with the long-term reduction of memory B cells, which serves as a biomarker for disease activity in many other CD20+ B cell depletion-sensitive, autoimmune diseases. Following B cell depletion, the rapid repopulation by transitional (immature) and naïve (mature) B cells from the bone marrow masks the marked depletion and slow repopulation of lymphoid tissue-derived, memory B cells. This can provide long-term protection from a short treatment cycle. It seems that memory B cells, possibly via T cell stimulation, drive relapsing disease. However, their sequestration in ectopic follicles and the chronic activity of B cells and plasma cells in the central nervous system may drive progressive neurodegeneration directly via antigen-specific mechanisms or indirectly via glial-dependent mechanisms. While unproven, Epstein-Barr virus may be an aetiological trigger of multiple sclerosis. This infects mature B cells, drives the production of memory B cells and possibly provides co-stimulatory signals promoting T cell-independent activation that breaks immune tolerance to generate autoreactivity. Thus, a memory B cell centric mechanism can integrate: potential aetiology, genetics, pathology and response to therapy in multiple sclerosis and other autoimmune conditions with ectopic B cell activation that are responsive to memory B cell-depleting strategies. DOI: 10.1093/brain/awy239


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42. Brain Behav. 2018 Sep 21:e1098. doi: 10.1002/brb3.1098. [Epub ahead of print]

Mental health among children of mothers with multiple sclerosis: A Danish cohort and register-based study.

Andersen JB(1), Moberg JY(1), Niclasen J(2), Laursen B(3), Magyari M(1)(4). Author information: (1)Danish Multiple Sclerosis Registry, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. (2)Independent Psychologist. (3)National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark. (4)Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. BACKGROUND: Multiple sclerosis is associated with an increased risk of developing physical, cognitive, and mental health problems. Current studies have demonstrated variating outcomes of parental multiple sclerosis mental health problems and their children's mental health development. OBJECTIVE: The purpose of this study was to investigate whether maternal multiple sclerosis is associated with the mental health status of their child. METHODS: Data from the Danish National Birth Cohort (DNBC) were merged with information from the Danish Multiple Sclerosis Registry. Two proxies, total difficulties score and prediction of any psychiatric diagnosis based on the strengths and difficulties questionnaire, were used to measure the mental health status of the children. The two groups were compared using Mann-Whitney and logistic regression analyses. RESULTS: For the total difficulties score the control and exposed group consisted of respectively n = 42,016 and n = 40, and for the prediction of any psychiatric diagnosis respectively n = 16,829 and n = 17. We found no statistically significant association between maternal multiple sclerosis and mental health status on neither of the proxies. CONCLUSION: Maternal multiple sclerosis did not show any association with the mental health status of their children at age eleven. On the contrary, other studies conclude that there is an association between maternal multiple sclerosis and the child's mental health status, one especially mediated by the maternal mental health status. © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. DOI: 10.1002/brb3.1098


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43. Brain Behav Immun. 2018 Sep 12. pii: S0889-1591(18)30295-2. doi: 10.1016/j.bbi.2018.09.017. [Epub ahead of print]

Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury.

Rangon CM(1), Schang AL(2), Van Steenwinckel J(1), Schwendimann L(1), Lebon S(1), Fu T(3), Chen L(3), Beneton V(4), Journiac N(1), Young-Ten P(1), Bourgeois T(1), Maze J(1), Matrot B(1), Baburamani AA(5), Supramaniam V(5), Mallard C(6), Trottet L(4), Edwards AD(5), Hagberg H(7), Fleiss B(8), Li J(9), Chuang TT(9), Gressens P(10). Author information: (1)PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, F-75019 Paris, France; PremUP, F-75006 Paris, France. (2)PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, F-75019 Paris, France; PremUP, F-75006 Paris, France; UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, F-75006 Paris, France. (3)Platform Technologies and Science, GlaxoSmithKline R&D, Shanghai 201203, China; Platform Technologies and Science, GlaxoSmithKline R&D, Stevenage, SG1 2NY, UK. (4)Flexible Discovery Unit, Les Ulis, France. (5)Centre for the Developing Brain, School of Biomedical Engineering & Imaging Sciences, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom. (6)Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. (7)Centre for the Developing Brain, School of Biomedical Engineering & Imaging Sciences, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom; Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Clinical Sciences, Sahlgrenska Academy/East Hospital, 416 85 Gothenburg, Sweden. (8)PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, F-75019 Paris, France; PremUP, F-75006 Paris, France; Centre for the Developing Brain, School of Biomedical Engineering & Imaging Sciences, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom; School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia. Electronic address: [email protected]. (9)Regenerative Medicine DPU, GlaxoSmithKline, Shanghai 201023, China; Regenerative Medicine DPU, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. (10)PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, F-75019 Paris, France; PremUP, F-75006 Paris, France; Centre for the Developing Brain, School of Biomedical Engineering & Imaging Sciences, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom. Fifteen million babies are born preterm every year and a significant number suffer from permanent neurological injuries linked to white matter injury (WMI). A chief cause of preterm birth itself and predictor of the severity of WMI is exposure to maternal-fetal infection-inflammation such as chorioamnionitis. There are no neurotherapeutics for this WMI. To affect this healthcare need, the repurposing of drugs with efficacy in other white matter injury models is an attractive strategy. As such, we tested the efficacy of GSK247246, an H3R antagonist/inverse agonist, in a model of inflammation-mediated WMI of the preterm born infant recapitulating the main clinical hallmarks of human brain injury, which are oligodendrocyte maturation arrest, microglial reactivity, and hypomyelination. WMI is induced by mimicking the effects of maternal-fetal infection-inflammation and setting up neuroinflammation. We induce this process at the time in the mouse when brain development is equivalent to the human third trimester; postnatal day (P)1 through to P5 with i.p. interleukin-1β (IL-1β) injections. We initiated GSK247246 treatment (i.p at 7 mg/kg or 20 mg/kg) after neuroinflammation was well established (on P6) and it was administered twice daily through to P10. Outcomes were assessed at P10 and P30 with gene and protein analysis. A low dose of GSK247246 (7 mg/kg) lead to a recovery in protein expression of markers of myelin (density of Myelin Basic Protein, MBP & Proteolipid Proteins, PLP) and a reduction in macro- and microgliosis (density of ionising adaptor protein, IBA1 & glial fibrillary acid protein, GFAP). Our results confirm the neurotherapeutic efficacy of targeting the H3R for WMI seen in a cuprizone model of multiple sclerosis and a recently reported clinical trial in relapsing-remitting multiple sclerosis patients. Further work is needed to develop a slow release strategy for this agent and test its efficacy in large animal models of preterm infant WMI. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.bbi.2018.09.017


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44. Brain Behav Immun. 2018 Aug 30. pii: S0889-1591(18)30503-8. doi: 10.1016/j.bbi.2018.08.016. [Epub ahead of print]

Commentary on the 2018 Named Series on blood-brain interfaces: Roles of neuroimmunomodulation in health and disease.

Erickson MA(1), Nicolazzo JA(2), Banks WA(3). Author information: (1)VA Puget Sound Healthcare System, Seattle, WA, USA; Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, USA. (2)Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. (3)VA Puget Sound Healthcare System, Seattle, WA, USA; Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, USA. Electronic address: [email protected]. This year's 2018 Named Series on blood-brain interfaces highlights the importance of brain barriers as mediators of neuroimmune communication and regulators of neurological function. The term "brain interfaces" reflects our growing understanding that brain barriers such as the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) are not only gatekeepers, but facilitators of bidirectional communication between the brain and periphery. There is also an emerging appreciation that CNS sites that are exposed to blood-borne immune molecules and cells, such as the leptomeninges and circumventricular organs, may also be considered brain interfaces with important homeostatic and pathological functions. The work featured in this Series covers novel aspects of brain interface functions that focus on mechanisms regulating barrier integrity and transporter activities, downstream consequences of neurovascular injury, peripheral organ infection/injury, and clearance of pathogenic proteins. Results of these studies have emphasized new mechanisms by which brain interface dysfunction could contribute to neuroinflammation and CNS damage in eclampsia, fetal and adult hypoxic/ischemic injury, traumatic brain injury, Helicobacter infections, acute lung injury, multiple sclerosis, and Alzheimer's disease. This body of work emphasizes that brain interfaces may themselves be important therapeutic targets for a variety of CNS diseases that are associated with immune dyshomeostasis. Future works are warranted to further investigate brain interface functions in health and disease. Published by Elsevier Inc. DOI: 10.1016/j.bbi.2018.08.016

45. Brain Res. 2018 Sep 10. pii: S0006-8993(18)30470-0. doi: 10.1016/j.brainres.2018.09.013. [Epub ahead of print]

The relationship between corticospinal tract integrity and lower-extremity strength is attenuated when controlling for age and sex in multiple sclerosis.

Baird JF(1), Hubbard EA(2), Sutton BP(3), Motl RW(4). Author information: (1)Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: [email protected]. (2)Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, USA. (3)Bioengineering and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA. (4)Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, USA. Muscle weakness, particularly in the lower-extremities, is common in multiple sclerosis (MS) and seemingly results from damage along white matter pathways in the central nervous system including the corticospinal tract (CST). This study examined CST structural integrity indicated by diffusion tensor imaging (DTI) related metrics (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], and axial diffusivity [AD]) as correlates of knee flexor (KF) and knee extensor (KE) muscle strength in MS. We included 36 persons with MS who underwent MRI and measurements of peak KE and KF strength using an isokinetic dynamometer. We examined associations using bivariate Spearman (rs) and partial Spearman correlation (prs) analyses controlling for age and sex. Peak KF strength was significantly associated with FA (rs = 0.42) and RD (rs = -0.36) and peak KE strength was significantly associated with MD (rs = -0.47) and RD (rs = -0.36). The correlations were attenuated after controlling for age and sex, but the relationship between KF strength and FA demonstrated a trend towards significance (prs = 0.33, p = .056). We provide evidence that the anatomical integrity of the CST may be associated with lower-extremity strength in MS. The attenuated correlations when controlling for age and sex suggest these factors, rather than MS per se, may be important contributors toward an association between CST DTI-metrics and KF and KE strength. Future rehabilitation trials of resistance training should consider including CST integrity as an outcome and/or predictor of strength adaptations. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.brainres.2018.09.013


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46. Brain Res. 2018 Aug 30. pii: S0006-8993(18)30451-7. doi: 10.1016/j.brainres.2018.08.029. [Epub ahead of print]

Interhermispheric inhibition predicts anxiety levels in multiple sclerosis: A corticospinal excitability study.

Chalah MA(1), Palm U(2), Lefaucheur JP(1), Créange A(3), Ayache SS(4). Author information: (1)EA 4391, Excitabilité Nerveuse et Thérapeutique, Université Paris-Est-Créteil, Créteil, France; Service de Physiologie - Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, France. (2)Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Nussbaumstr, 7, 80336, Munich, Germany. (3)EA 4391, Excitabilité Nerveuse et Thérapeutique, Université Paris-Est-Créteil, Créteil, France; Service de Neurologie, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, France. (4)EA 4391, Excitabilité Nerveuse et Thérapeutique, Université Paris-Est-Créteil, Créteil, France; Service de Physiologie - Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, France; Neurology Division, Lebanese American University Medical Center Rizk Hospital, Beirut, Lebanon. Electronic address: [email protected]. BACKGROUND: Depression and anxiety stand among the most frequent and debilitating complaints in multiple sclerosis (MS) patients. Understanding their neurophysiological correlates might improve their management. To date, no single study has addressed this issue. METHOD: Patients completed the Hospital Anxiety and Depression Scale (HADS). Transcranial magnetic stimulation (TMS) was performed to obtain the following corticospinal excitability measures: resting motor threshold, short interval intracortical inhibition and facilitation, cortical silent period and interhemispheric inhibition. Anxiety and depression scores were the primary outcomes in the univariate analysis. When obtaining significant associations between anxiety/depression and TMS measures, a multivariate analysis was performed using stepwise linear regression with anxiety and depression scores employed separately as dependent variables and TMS measures, clinical and sociodemographic data as independent variables. Due to the small sample size and the large number of studied variables, only variables with p values less than 0.05 in the univariate analysis were included in the multivariate analysis. RESULTS: Fifty patients completed the study (n=24 women). Their mean age was 51.82 ± 12.72 years. Mean depression score was 6.08 ± 3.66. Mean anxiety score was 5.82 ± 3.42. A significant association was found between anxiety and interhemispheric inhibition (p<0.05), fatigue (p<0.05), depression (p<0.05), and female gender (p<0.05). Stepwise linear regression analysis was performed and interhemispheric inhibition (IHI) values explained 9.10 % of variance in anxiety levels (standardized β: 0.31; p<0.01) when controlling for remaining variables. As for depression, it did not significantly correlate with any TMS measures. CONCLUSION: The results highlight the relationship between anxiety and callosal transfer as reflected by IHI values. The current findings are consistent with previous works assessing healthy participants and patients with social anxiety disorders. Compared to MS patients with aberrant callosal transfer (suggested by low IHI values) those exhibiting a relatively more efficient one (reflected by high IHI values) seem to have higher anxiety scores, a finding that merits further assessment. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.brainres.2018.08.029


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47. Brain Res Bull. 2018 Sep 25. pii: S0361-9230(18)30413-1. doi: 10.1016/j.brainresbull.2018.09.014. [Epub ahead of print]

S100A8/A9 induces microglia activation and promotes the apoptosis of oligodendrocyte precursor cells by activating the NF-κB signaling pathway.

Wu M(1), Xu L(1), Wang Y(1), Zhou N(1), Zhen F(1), Zhang Y(1), Qu X(1), Fan H(2), Liu S(3), Chen Y(4), Yao R(5). Author information: (1)Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221009, PR China. (2)Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221009, PR China; Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, PR China. (3)Department of Rehabilitation, The First People's Hospital of Changzhou, Jiangsu, 213000, PR China. (4)Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221009, PR China. Electronic address: [email protected]. (5)Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221009, PR China. Electronic address: [email protected]. S100A8/A9, a heterodimer complex composed of calcium-binding proteins S100A8 and S100A9, is significantly increased in the serum of multiple sclerosis (MS) patients. Relevant reports have revealed that MS pathology is commonly associated with the activation of microglial cells and the damage of oligodendrocyte precursor cells (OPCs). Moreover, microglia activation following stimulation increases the expression of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), which further exacerbate the damage to OPCs. In this study, we were the first to confirm that S100A8/A9 treatment induced the activation, proliferation and migration of the murine microglia cell line BV-2; moreover, this treatment caused the cells to switch from an anti-inflammatory activated (M2) phenotype to a pro-inflammatory activated (M1) phenotype. Meanwhile, the level of the phosphorylated nuclear factor-κB (p-NF-κB) P65 protein was remarkably elevated, and the production of pro-inflammatory factors (IL-1β, TNF-α, MMP-9) and chemokines (CCL2, CCL3, CXCL10) was also increased in the S100A8/A9-treated BV-2 microglial cells. Inhibition of NF-κB P65 phosphorylation reversed the effects of S100A8/A9 on the production of pro-inflammatory factors and chemokines. We also explored the effects of S100A8/A9 and S100A8/A9-activated BV-2 microglial cells on the viability of OPCs. The results showed that both the S100A8/A9 complex and the conditioned medium (CM) of the S100A8/A9-activated BV-2 microglial cells resulted in OPC apoptosis, which was more pronounced in the case of the CM treatment. However, OPC apoptosis in the CM group was obviously decreased through the inhibition of NF-κB p65 phosphorylation. This study indicates that S100A8/A9 induces the activation of BV-2 microglial cells and promotes the production of pro-inflammatory factors by activating the NF-κB signaling pathway, which further exacerbates OPC damage. Copyright © 2018. Published by Elsevier Inc. DOI: 10.1016/j.brainresbull.2018.09.014


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48. Brain Sci. 2018 Sep 1;8(9). pii: E168. doi: 10.3390/brainsci8090168.

Gender Differences and Comorbidities in U.S. Adults with Bipolar Disorder.

Patel RS(1), Virani S(2), Saeed H(3), Nimmagadda S(4), Talukdar J(5), Youssef NA(6). Author information: (1)Department of Psychiatry, Griffin Memorial Hospital, 900 E Main St, Norman, OK 73071, USA. [email protected]. (2)Department of Psychiatry, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA. [email protected]. (3)Baqai Medical University, 51, Deh Tor, Gadap Road, Super Highway, Karachi 74600, Pakistan. [email protected]. (4)University of Illinois College of Medicine, 1 Illini Dr, Peoria, IL 61605, USA. [email protected]. (5)Gauhati Medical College and Hospital, GMCH Rd, Bhangagarh, Guwahati, Assam 781032, India. [email protected]. (6)Medical College of Georgia, Augusta University, 997 St. Sebastian Way, Augusta, GA 30912, USA. [email protected]. BACKGROUND: Past studies have evaluated the association of various comorbidities with bipolar disorder. This study analyzes differences in the prevalence and association of medical and psychiatric comorbidities in bipolar patients by gender. METHODS: A retrospective analysis was conducted using the Nationwide

Inpatient Sample (2010⁻2014). Using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes, we narrowed the study population to comprise those with a primary diagnosis of bipolar disorder and then obtained information about comorbidities. The differences in comorbidities by gender were quantified using chi-square tests and the logistic regression model (odds ratio (OR)). RESULTS: Hypertension (20.5%), asthma (12.5%) and hypothyroidism (8.1%) were the top medical comorbidities found in bipolar patients. Migraine and hypothyroidism were seen three times higher in females (OR = 3.074 and OR = 3.001; respectively). Females with bipolar disorder had higher odds of comorbid inflammatory disorders like asthma (OR = 1.755), Crohn's disease (OR = 1.197) and multiple sclerosis (OR = 2.440) compared to males. Females had a two-fold higher likelihood of comorbid post-traumatic stress disorder (PTSD) (OR = 2.253) followed by personality disorders (OR = 1.692) and anxiety disorders (OR = 1.663) compared to males. CONCLUSION: Women with bipolar disorder have a much higher medical comorbidity burden than men and may highly benefit from an integrated team of physicians to manage their condition and improve their health-related quality of life. DOI: 10.3390/brainsci8090168

49. Can J Neurol Sci. 2018 Sep 28:1-2. doi: 10.1017/cjn.2018.327. [Epub ahead of print]

Jack Antel: Canadian Leader in Neurology.

Harroud A. DOI: 10.1017/cjn.2018.327

50. Can J Neurol Sci. 2018 Sep;45(5):487-488. doi: 10.1017/cjn.2018.317.

Nothing Ventured, Nothing Gained? Navigating Disease-Modifying Treatment in Multiple Sclerosis.

Burton JM(1), Traboulsee A(2). Author information: (1)1Department of Clinical NeurosciencesHotchkiss Brain Institute,University of Calgary,CalgaryAlbertaCanada. (2)2Department of Medicine,Division of NeurologyUniversity of British Columbia,Vancouver,Canada. DOI: 10.1017/cjn.2018.317

51. Can J Neurol Sci. 2018 Sep;45(5):580-582. doi: 10.1017/cjn.2018.51.

Trait Mindfulness and Wellness in Multiple Sclerosis.

Mioduszewski O(1), MacLean H(2), Poulin PA(1), Smith AM(1), Walker LAS(1). Author information: (1)1School of Psychology,The University of Ottawa,Ottawa,Ontario,Canada. (2)2Department of Medicine,The Ottawa Hospital,Ottawa, Ontario,Canada. Multiple sclerosis (MS) is a chronic, progressive, autoimmune, neurodegenerative disorder that can interfere with physical and psychological functioning, negatively affecting health-related quality of life (HRQoL). Fostering mindfulness may mitigate the negative consequences of MS on HRQoL. The relationship between mindfulness, mood and MS-related quality of life was investigated. In total, 52 individuals with MS completed questionnaires to examine the relationship between trait mindfulness and wellness. Higher levels of trait mindfulness were associated with better HRQoL, lower depression and anxiety, lower fatigue impact and fewer perceived cognitive deficits. Mindfulness interventions have the potential to enhance wellness in those living with MS. DOI: 10.1017/cjn.2018.51


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52. Carbohydr Polym. 2018 Dec 1;201:608-614. doi: 10.1016/j.carbpol.2018.08.113. Epub 2018 Aug 28.

A polysaccharide from Eclipta prostrata alleviates experimental autoimmune encephalomyelitis through inhibiting Th17 cells.

Li N(1), Shi S(1), Yang F(1), Wang H(1), Su J(1), Huang F(1), Wu H(1), Wu X(2), Wang S(3). Author information: (1)The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China. (2)The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China. Electronic address: [email protected]. (3)The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China. Electronic address: [email protected]. Eclipta prostrata has long been used as a medicinal herb in China. EAP20-1, a homogeneous polysaccharide with anti-complementary activity had been obtained from E. prostrate by using anion-exchange and size-exclusion chromatography. In this study, we found that EAP20-1 could inhibit in vitro lymphocyte proliferation stimulated by concanavalin-A or anti-CD3/anti-CD28 antibodies. Furthermore, in experimental autoimmune encephalomyelitis (EAE) mice, EAP20-1 treatment relieved the clinical symptoms, accompanied by reduced neuroinflammation and demyelination in spinal cords. Mechanistically, EAP20-1 reduced the mRNA expression of interleukin (IL)-17, IL-22, and RAR-related orphan receptor gamma t (RORγt) in the spleen; inhibited auto-reactive T cell proliferation and decreased the percentage of Th17 cells in response to myelin oligodendrocyte glycoprotein (MOG35-55) ex vivo. Moreover, EAP20-1 directly inhibited naïve CD4 + T cells differentiate into Th17 cells in vitro. These results indicating EAP20-1 could benefit EAE through inhibiting Th17 cell differentiation and suggesting a therapeutic potential of EAP20-1 in MS. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.carbpol.2018.08.113

53. Caspian J Intern Med. 2018 Summer;9(3):244-251. doi: 10.22088/cjim.9.3.244.

Impairment, disability and fatigue in multiple sclerosis.

Shahrbanian S(1)(2)(3), Duquette P(4), E Mayo N(1)(5). Author information: (1)School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Canada. (2)Faculty of Sport Science, Bu-Ali Sina University, Hamedan, Iran. (3)Department of Physical Education, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran. (4)Notre-Dame Hospital (CHUM), University of Montreal, Montreal, Canada. (5)Division of Clinical Epidemiology, McGill University Health Center, Royal Victoria Hospital, Montreal, Canada. Background: Identifying the predictors of pain is important for both health professionals and researchers, because pain has repeatedly been found to be a strong predictor of activity limitations and participation restrictions. The objective of this study was to determine the predictors of pain presence and severity in a large, well-designed sample of community dwelling individuals with multiple sclerosis (MS). Methods: This was a cross-sectional study. A center-stratified random sample including 188 persons with MS were recruited from three major MS clinics in the Greater Montreal, Canada. Main outcomes included pain prevalence and severity. Predictor variables included depression, anxiety, perceived health status, fatigue, sleep problems, and perceived cognitive deficits. Participants completed three questionnaires: the first asked about the socio-demographic and clinical information of the subjects, the second assessed the pain characteristics of the subjects, and the third covered the predictor variables. Results: The prevalence of pain in our sample was 42%. MS- related disability was found to be in the main predictor for both pain presence and intensity. Fatigue also was a main contributor to pain presence. The results of this study also showed that pain was associated with higher levels of depression, anxiety, sleep problems, and perceived cognitive deficits, and diminished perceived health status. Conclusions: The results of this study indicated that pain is a common symptom among people with MS. Pain presence was predicted by MS-related disability and fatigue, while pain intensity was only predicted by MS severity. DOI: 10.22088/cjim.9.3.244 PMCID: PMC6121335 Conflict of interest statement: The authors declare that there is no conflict of interest.


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54. Caspian J Intern Med. 2018 Summer;9(3):206-210. doi: 10.22088/cjim.9.3.206.

Cross-talks between the kidneys and the central nervous system in multiple sclerosis.

Rostami S(1), Emami-Aleagha MS(1), Ghasemi-Kasman M(2), Allameh A(1). Author information: (1)Department of Clinical Biochemistry, Faculty of Medicine, Tarbiat Modarres University, Tehran, Iran. (2)Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran. Multiple sclerosis (MS) is an inflammatory demyelinating disease, which is considered as a common autoimmune disorder in young adults. A growing number of evidences indicated that the impairment in non-neural tissues plays a significant role in pathology of MS disease. There are bidirectional relationship, metabolic activities and functional similarity between central nervous system (CNS) and kidneys which suggest that kidney tissue may exert remarkable effects on some aspects of MS disorder and CNS impairment in these patients compels the kidney to respond to central inflammation. Recently, it has been well documented that hormonal secretion possesses the important role on CNS abnormalities. In this regard, due to the functional similarity and significant hormonal and non-hormonal relationship between CNS and kidneys, we hypothesized that kidneys exert significant effect on initiation, progression or amelioration of MS disease which might be regarded as potential therapeutic approach in the treatment of MS patients in the future. DOI: 10.22088/cjim.9.3.206 PMCID: PMC6121345

55. Cell. 2018 Sep 20;175(1):85-100.e23. doi: 10.1016/j.cell.2018.08.011. Epub 2018 Aug 30.

Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis.

Jelcic I(1), Al Nimer F(2), Wang J(1), Lentsch V(1), Planas R(1), Jelcic I(1), Madjovski A(1), Ruhrmann S(3), Faigle W(1), Frauenknecht K(4), Pinilla C(5), Santos R(6), Hammer C(7), Ortiz Y(1), Opitz L(8), Grönlund H(9), Rogler G(10), Boyman O(11), Reynolds R(12), Lutterotti A(1), Khademi M(3), Olsson T(3), Piehl F(3), Sospedra M(1), Martin R(13). Author information: (1)Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. (2)Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland; Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden. (3)Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden. (4)Institute of Neuropathology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. (5)Torrey Pines Institute for Molecular Studies (TPIMS), San Diego, CA, USA. (6)Torrey Pines Institute for Molecular Studies (TPIMS), Port St. Lucie, FL, USA. (7)School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland. (8)Functional Genomics Center Zurich, Swiss Federal Institute of Technology and University of Zurich, 8057 Zurich, Switzerland. (9)Therapeutic Immune Design Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden. (10)Department of Gastroenterology and Hepatology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. (11)Department of Immunology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. (12)Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK. (13)Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. Electronic address: [email protected]. Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as "autoproliferation" of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.cell.2018.08.011


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56. Cell Death Differ. 2018 Sep 26. doi: 10.1038/s41418-018-0201-9. [Epub ahead of print]

The RNA binding protein Sam68 controls T helper 1 differentiation and anti-mycobacterial response through modulation of miR-29.

Volpe E(1), Cesari E(2)(3), Mercatelli N(4)(5), Cicconi R(6), De Bardi M(7), Capone A(7)(8), Bonvissuto D(3), Fraziano M(9), Mattei M(6)(9), Battistini L(7), Paronetto MP(4)(5), Sette C(10)(11). Author information: (1)Laboratory of Neuroimmunology, Fondazione Santa Lucia, Rome, Italy. [email protected]. (2)Laboratory of Neuroembriology, Fondazione Santa Lucia, Rome, Italy. (3)Institute of Human Anatomy and Cell Biology, Università Cattolica del Sacro Cuore, Rome, Italy. (4)Laboratory of Cellular and Molecular Neurobiology, Fondazione Santa Lucia, Rome, Italy. (5)Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy. (6)Interdepartmental Service Centre-Station for Animal Technology (STA), University of Rome "Tor Vergata", Rome, Italy. (7)Laboratory of Neuroimmunology, Fondazione Santa Lucia, Rome, Italy. (8)Department of Biology and Biotechnology Charles Darwin, Sapienza University, Rome, Italy. (9)Department of Biology, University of Rome "Tor Vergata", Rome, Italy. (10)Laboratory of Neuroembriology, Fondazione Santa Lucia, Rome, Italy. [email protected]. (11)Institute of Human Anatomy and Cell Biology, Università Cattolica del Sacro Cuore, Rome, Italy. [email protected]. Polarization of naive T cells into interferon (IFN)-γ-producing T helper 1 (Th1) cells is an essential event in the inflammatory response to pathogens. Herein, we identify the RNA binding protein Sam68 as a specific modulator of Th1 differentiation. Sam68-knockout (ko) naive T cells are strongly defective in IL-12-mediated Th1 polarization and express low levels of T-bet and Eomes. Consequently, Sam68-ko Th1 cells are significantly impaired in IFN-γ production. Moreover, we found that Sam68 is required for the induction of an inflammatory Th1 response during Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection, thus limiting bacterial dissemination in the lungs. Mechanistically, Sam68 directly binds to the microRNA miR-29, a negative regulator of Th1 response, and inhibits its expression during BCG infection. These findings uncover a novel post-transcriptional mechanism required for the Th1-mediated defense against intracellular pathogens and identify a new function for Sam68 in the regulation of the immune response. DOI: 10.1038/s41418-018-0201-9

57. Cell Rep. 2018 Sep 18;24(12):3167-3179. doi: 10.1016/j.celrep.2018.08.060.

Multimodal Enhancement of Remyelination by Exercise with a Pivotal Role for Oligodendroglial PGC1α.

Jensen SK(1), Michaels NJ(1), Ilyntskyy S(2), Keough MB(1), Kovalchuk O(2), Yong VW(3). Author information: (1)Hotchkiss Brain Institute and the Department of Clinical Neurosciences University of Calgary, Calgary, AB, Canada. (2)Department of Biology, University of Lethbridge, Lethbridge, AB, Canada. (3)Hotchkiss Brain Institute and the Department of Clinical Neurosciences University of Calgary, Calgary, AB, Canada. Electronic address: [email protected]. Remyelination is a multistep regenerative process that results in the reformation of myelin sheaths around demyelinated axons and is a critical therapeutic target. Here we show that immediate access to a running wheel following toxin-induced demyelination in mice enhances oligodendrogenesis, the rate of remyelination, and the proportion of remyelinated axons. RNA sequencing suggests broad activation of pro-remyelination pathways including phagocytosis by exercise and highlights peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1α) activation. By immunohistochemistry and cell type-specific conditional deletion, we confirmed PGC1α within oligodendrocytes as a transiently expressed factor required for the rate of myelin thickening by exercise. We validated the exercise-enhanced clearance of inhibitory lipid debris from lesions. Finally, exercise works in parallel with the remyelinating medication clemastine to produce complete remyelination of lesions. Our study demonstrates physical activity as an integrative means to enhance remyelination and details a multimodal mechanism including the pivotal PGC1α-dependent enhancement of myelin thickness. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.celrep.2018.08.060


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58. Chem Commun (Camb). 2018 Sep 17. doi: 10.1039/c8cc05643a. [Epub ahead of print]

Exploring physicochemical space via a bioisostere of the trifluoromethyl and ethyl groups (BITE): attenuating lipophilicity in fluorinated analogues of Gilenya® for multiple sclerosis.

Erdeljac N(1), Kehr G(1), Ahlqvist M(2), Knerr L(3), Gilmour R(4). Author information: (1)Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany. [email protected]. (2)Drug Metabolism and Pharmacokinetics, Cardiovascular, Renal and Metabolism IMED Biotech Unit, Astrazeneca, Gothenburg, Sweden. (3)Medicinal Chemistry, Cardiovascular, Renal and Metabolism IMED Biotech Unit, Astrazeneca, Gothenburg, Sweden. [email protected]. (4)Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany. [email protected] and Excellence Cluster EXC 1003, Cells in Motion Westfälische Wilhems-Universität Münster, Münster, Germany. The direct, catalytic vicinal difluorination of terminal alkenes via an I(i)/I(iii) manifold was exploited to install a chiral, hybrid bioisostere of the CF3 and Et groups (BITE) in Gilenya®; the first orally available drug for the clinical management of Multiple Sclerosis (MS). This subtle fluorination pattern allows lipophilicity (log D) to be tempered compared to the corresponding CF3 and Et derivatives (CH2CH3 > CH2CF3 > CHFCH2F). DOI: 10.1039/c8cc05643a

59. Clin Auton Res. 2018 Sep 12. doi: 10.1007/s10286-018-0563-6. [Epub ahead of print]

Autonomic symptom burden is an independent contributor to multiple sclerosis related fatigue.

Krbot Skorić M(1)(2), Crnošija L(1), Adamec I(1), Barun B(1)(3), Gabelić T(1)(3), Smoljo T(3), Stanić I(3), Pavičić T(3), Pavlović I(3), Drulović J(4), Pekmezović T(5), Habek M(6)(7). Author information: (1)Department of Neurology, Referral Center for Autonomic Nervous System Disorders, University Hospital Center Zagreb, Kišpatićeva 12, 10000, Zagreb, Croatia. (2)Faculty of Electrical Engineering and Computing, University of Zagreb, Zagreb, Croatia. (3)School of Medicine, University of Zagreb, Zagreb, Croatia. (4)Clinic of Neurology, CCS, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. (5)Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. (6)Department of Neurology, Referral Center for Autonomic Nervous System Disorders, University Hospital Center Zagreb, Kišpatićeva 12, 10000, Zagreb, Croatia. [email protected]. (7)School of Medicine, University of Zagreb, Zagreb, Croatia. [email protected]. OBJECTIVES: To investigate a possible association between autonomic dysfunction and fatigue in people with multiple sclerosis. METHODS: In 70 people with multiple sclerosis early in the disease course (51 females, mean age 33.8 ± 9.1), quantitative sudomotor axon reflex tests, cardiovascular reflex tests (heart rate and blood pressure responses to the Valsalva maneuver and heart rate response to deep breathing), and the tilt table test were performed. Participants completed the Composite Autonomic Symptom Score 31, the Modified Fatigue Impact Scale, and the Epworth Sleepiness Scale, as well as the Beck Depression Inventory. Cutoff scores of ≥ 38 or ≥ 45 on the Modified Fatigue Impact Scale were used to stratify patients into a fatigued subgroup (N = 17 or N = 9, respectively). RESULTS: We found clear associations between fatigue and scores in subjective tests of the autonomic nervous system: fatigued patients scored significantly worse on Composite Autonomic Symptom Score 31, and there was a strong correlation between the Modified Fatigue Impact Scale and the Composite Autonomic Symptom Score 31 (rs = 0.607, p < 0.001). On the other hand, we found only modest associations between fatigue and scores in objective tests of the autonomic nervous system: there was a clear trend for lower sweating outputs at all measured sites, which reached statistical significance for the distal leg and foot. We found weak correlations between the Modified Fatigue Impact Scale and the Valsalva ratio (rs = - 0.306, p = 0.011), as well as between the Modified Fatigue Impact Scale and quantitative sudomotor axon reflex tests of the forearm, proximal, and distal lower leg (rs = - 0.379, p = 0.003; rs = - 0.356, p = 0.005; and rs = - 0.345, p = 0.006, respectively). A multiple regression model showed that the Composite Autonomic Symptom Score 31, Beck Depression Inventory, and Epworth Sleepiness Scale were independent predictors of fatigue (p = 0.005, p = 0.019, and p = 0.010, respectively). CONCLUSION: These results suggest that-even early in the course of the disease-people with multiple sclerosis suffer from objective and subjective impairments of the autonomic nervous system. The results also point to an association between autonomic nervous system impairment and multiple sclerosis related fatigue. DOI: 10.1007/s10286-018-0563-6


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60. Clin Chem Lab Med. 2018 Sep 11. pii: /j/cclm.ahead-of-print/cclm-2018-0759/cclm-2018-0759.xml. doi: 10.1515/cclm-2018-0759. [Epub ahead of print]

Euthyroid Graves' disease with spurious hyperthyroidism: a diagnostic challenge.

Giovanella L(1), Imperiali M(2), Kasapic D(3), Ceriani L(1), Trimboli P(1). Author information: (1)Clinic for Nuclear Medicine and Molecular Imaging, Competence Centre for Thyroid Diseases EOC, Bellinzona, Switzerland. (2)Ritsch Laboratory Medicine, Lugano, Switzerland. (3)Roche Diagnostics International, Medical and Scientific Affairs Department, Rotkreuz, Switzerland. DOI: 10.1515/cclm-2018-0759

61. Clin Neuropharmacol. 2018 Sep 18. doi: 10.1097/WNF.0000000000000305. [Epub ahead of print]

Natalizumab Treatment for Relapsing-Remitting Multiple Sclerosis: The Experience From Saudi Arabia.

Algahtani H, Shirah B, Abobaker H(1), Alghanaim N(1), Kamel F(2). Author information: (1)King Saud bin Abdulaziz University for Health Sciences. (2)Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. BACKGROUND: Natalizumab is the first targeted humanized monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Natalizumab appears to be more effective than current first-line disease-modifying therapies. In our study, we aimed to evaluate the outcome of Saudi patients with active RRMS treated with natalizumab and compare the results with other outcomes in the Gulf and international trials. METHODS: We conducted a retrospective single-center observational study involving 32 patients with RRMS at King Abdulaziz Medical City in Jeddah, Saudi Arabia. The inclusion criteria included all patients diagnosed with RRMS according to the revised McDonald criteria who are currently receiving or received natalizumab treatment in the past for a minimum of 6 months. RESULTS: The mean baseline Expanded Disability Status Scale score was 4.50 ± 1.80 (range, 1.5-6; median, 5), whereas the mean Expanded Disability Status Scale at the follow-up was 4.02 ± 2.08 (range, 1-6; median, 4.25) (P = 0.3274). The mean annualized relapse rate was significantly reduced from 2.41 ± 2.48 at baseline to 0.16 ± 0.37 at the last follow-up (P < 0.0001). Twenty-seven patients (84.4%) had no relapses since the treatment with natalizumab was started, whereas 5 patients (15.6%) had only 1 relapse. In addition to clinically measurable improvement, radiological improvement was observed through magnetic resonance imaging. Magnetic resonance imaging activity was significantly improved at follow-up magnetic resonance imaging studies when compared with baseline. CONCLUSIONS: Our single-center study in Saudi Arabia provides further support for the efficacy of natalizumab in the clinical practice setting. The sharp decrease in relapse rate and progression of disability following the initiation of natalizumab treatment was similar to other observational studies conducted in different countries across the globe. Natalizumab was a satisfactory therapy for the management of our MS population, both from the patients' and the physicians' perspectives. DOI: 10.1097/WNF.0000000000000305


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62. Clin Sci (Lond). 2018 Aug 17;132(17):1963-1976. doi: 10.1042/CS20180506. Print 2018 Sep 14.

The relevance of ceramides and their synthesizing enzymes for multiple sclerosis.

Kurz J(1), Brunkhorst R(2), Foerch C(2), Blum L(3), Henke M(1), Gabriel L(1), Ulshöfer T(1), Ferreirós N(3), Parnham MJ(1), Geisslinger G(3), Schiffmann S(4). Author information: (1)Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany. (2)Department of Neurology, Goethe-University Frankfurt, Schleusenweg 2-16, 60528 Frankfurt/Main, Germany. (3)Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. (4)Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany [email protected]. Ceramide synthases (CerS) synthesize chain length specific ceramides (Cer), which mediate cellular processes in a chain length-dependent manner. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed that the genetic deletion of CerS2 suppresses EAE pathology by interaction with granulocyte-colony stimulating factor (G-CSF) signaling and CXC motif chemokine receptor 2 (CXCR2) expression, leading to impaired neutrophil migration. In the present study, we investigated the importance of Cers and their synthesizing/metabolizing enzymes in MS. For this purpose, a longitudinal study with 72 MS patients and 25 healthy volunteers was performed. Blood samples were collected from healthy controls and MS patients over 1- or 3-year periods, respectively. Immune cells were counted using flow cytometry, ceramide levels were determined using liquid chromatography-tandem mass spectrometry, and mRNA expression was analyzed using quantitative PCR. In white blood cells, C16-LacCer and C24-Cer were down-regulated in MS patients in comparison with healthy controls. In plasma, C16-Cer, C24:1-Cer, C16-GluCer, and C24:1-GluCer were up-regulated and C16-LacCer was down-regulated in MS patients in comparison with healthy controls. Blood samples from MS patients were characterized by an increased B-cell number. However, there was no correlation between B-cell number and Cer levels. mRNA expression of Cer metabolizing enzymes and G-CSF signaling enzymes was significantly increased in MS patients. Interestingly, G-CSF receptor (G-CSFR) and CXCR2 mRNA expression correlated with CerS2 and UDP-glucose Cer glucosyltransferase (UGCG) mRNA expression. In conclusion, our results indicate that Cer metabolism is linked to G-CSF signaling in MS. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. DOI: 10.1042/CS20180506

63. CNS Drugs. 2018 Sep 22. doi: 10.1007/s40263-018-0574-9. [Epub ahead of print]

Correction to: Improvement in Cognitive Function as Measured by NeuroTrax in Patients with Relapsing Multiple Sclerosis Treated with Natalizumab: A 2-Year Retrospective Analysis.

Gudesblatt M(1), Wissemann K(1), Zarif M(1), Bumstead B(1), Fafard L(1), Wilken J(2), Blitz K(1), Buhse M(1), Santra S(3), Hotermans C(3), Lee L(4). Author information: (1)South Shore Neurologic Associates, Patchogue, NY, USA. (2)Washington Neuropsychology Research Group LLC, Fairfax, VA, USA. (3)Biogen, 225 Binney Street, Cambridge, MA, 02142, USA. (4)Biogen, 225 Binney Street, Cambridge, MA, 02142, USA. [email protected]. Erratum for CNS Drugs. 2018 Aug 24;:. An Online First version of this article was made available online at http://link.springer.com/journal/40263/onlineFirst/page/1 on 24 August 2018. An error was subsequently identified in the article, and the following correction should be noted. DOI: 10.1007/s40263-018-0574-9


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64. CNS Drugs. 2018 Sep;32(9):883-890. doi: 10.1007/s40263-018-0568-7.

Ocrelizumab: A Review in Multiple Sclerosis.

Syed YY(1). Author information: (1)Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand. [email protected]. Ocrelizumab (Ocrevus®) is a humanized anti-CD20 monoclonal antibody approved for the treatment of adults with relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). In the two identically designed, 96-week OPERA I and II trials in patients with RMS, ocrelizumab significantly reduced annualized relapse rates versus interferon β-1a. In the ≥ 120-week ORATORIO trial in patients with PPMS, ocrelizumab significantly reduced the risk of ≥ 12-week confirmed disability progression relative to placebo. These primary endpoint results were supported by a number of secondary outcomes, including disease activity in the brain assessed by magnetic resonance imaging. Ocrelizumab was generally well tolerated in these studies, with infusion-related reactions and infections being the most common adverse events, which were mostly mild to moderate in severity. In summary, ocrelizumab is a novel high-efficacy disease-modifying therapy for RMS that is more effective than interferon β-1a and also a valuable new treatment option for delaying progression in early PPMS. It offers a convenient once every 6 months treatment regimen, with no need for routine monitoring. DOI: 10.1007/s40263-018-0568-7

65. CNS Neurol Disord Drug Targets. 2018 Sep 16. doi: 10.2174/1871527317666180917095256. [Epub ahead of print]

Clinical and Serological Biomarkers of Treatment's Response in Patients Treated Continuously with Interferonβ-1b for More than a Decade.

Iulia BL(1), Andreea R(2), Smaranda M(1), Zoltan B(1), Anca M(1), Adina H(3), Iunius S(1), Sebastian A(2), Rodica B(1). Author information: (1)University of Medicine and Pharmacy, Targu Mures. Romania. (2)First Department of Neurology, Emergency Clinical County Hospital, Targu Mures. Romania. (3)Center of Advanced Medical and Pharmaceutical Research, University of Medicine and Pharmacy Targu Mures. Romania. Introduction We evaluated the peripheral immune panel of multiple sclerosis (MS) patients treated for more than 10 years with interferon-beta1b (IFNβ-1b) and aimed to identify possible biomarkers of treatment response. Material and Methods Serum samples from 70 MS patients treated with IFNβ-1b more than a decade were analysed for 15 cytokines, that were correlated with the disability score, annual relapse ratio (ARR): the total number of relapses-ARR_0, relapses on treatment-ARR_1 and demographic data. Two groups were defined based on the levels of disability, calculated using the Expanded Disability Status Scale (EDSS): G1 - recurrent-remissive and G2 - secondary-progressive. Furthermore, we split the patients based on gender (G1_f, G1_m, G2_f, G2_m). Results The ARR was reduced after treatment was instituted. We found positive correlations between IL_25 and EDSS in G1_f and G2_f, tumor necrosis factor α (TNFα) and ARR_1 and ARR_0 in G1, and IL_17F with ARR_1. Negative correlations were for IL_25 and ARR_0 and ARR_1. SCD40L intensely positively correlated with IL_31 in G1 and G2. Conclusion After more than a decade of treatment, IFNβ-1b offers good results by reducing relapses and slowing disability progression. Several biomarkers can be used to assess the patient's response. High levels of IL_17 and TNFα will indicate a more active form of the disease. IL-25 may exert a positive influence in male MS patients and should be considered for future studies, together with the co-modulation between sCD40L and IL_31. Our method allowed us to screen the peripheral immune panel and can be used for assessing the peripheral levels of above-mentioned cytokines. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]. DOI: 10.2174/1871527317666180917095256


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66. Cochrane Database Syst Rev. 2018 Sep 24;9:CD008422. doi: 10.1002/14651858.CD008422.pub3. [Epub ahead of print]

Vitamin D for the management of multiple sclerosis.

Jagannath VA(1), Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, Robinson SA. Author information: (1)Department of Paediatrics, American Mission Hospital, Manama, Manama, Bahrain, PO Box 1. BACKGROUND: This review is an update of a previously published review, "Vitamin D for the management of multiple sclerosis" (published in the Cochrane Library; 2010, Issue 12). Multiple sclerosis (MS) is characterised by inflammation, demyelination, axonal or neuronal loss, and astrocytic gliosis in the central nervous system (CNS), which can result in varying levels of disability. Some studies have provided evidence showing an association of MS with low levels of vitamin D and benefit derived from its supplementation. OBJECTIVES: To evaluate the benefit and safety of vitamin D supplementation for reducing disease activity in people with MS. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Specialized Register up to 2 October 2017 through contact with the Information Specialist with search terms relevant to this review. We included references identified from comprehensive electronic database searches and from handsearches of relevant journals and abstract books from conferences. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared vitamin D versus placebo, routine care, or low doses of vitamin D in patients with MS. Vitamin D was administered as monotherapy or in combination with calcium. Concomitant interventions were allowed if they were used equally in all trial intervention groups. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the methodological quality of studies, while another review author sorted any disagreements. We expressed treatment effects as mean differences (MDs) for continuous outcomes (Expanded Disability Status Scale and number of magnetic resonance imaging (MRI) gadolinium-enhancing T1 lesions), as standardised MDs for health-related quality of life, as rate differences for annualised relapse rates, and as risk differences (RDs) for serious adverse events and minor adverse events, together with 95% confidence intervals (CIs). MAIN RESULTS: We identified 12 RCTs enrolling 933 participants with MS; 464 were randomised to the vitamin D group, and 469 to the comparator group.

Eleven trials tested vitamin D₃, and one trial tested vitamin D₂. Vitamin D₃ had no effect on the annualised relapse rate at 52 weeks' follow-up (rate difference -0.05, 95% CI -0.17 to 0.07; I² = 38%; five trials; 417 participants; very low-quality evidence according to the GRADE instrument); on the Expanded Disability Status Scale at 52 weeks' follow-up (MD -0.25, 95% CI -0.61 to 0.10; I² = 35%; five trials; 221 participants; very low-quality evidence according to GRADE); and on MRI gadolinium-enhancing T1 lesions at 52 weeks' follow-up (MD 0.02, 95% CI -0.45 to 0.48; I² = 12%; two trials; 256 participants; very low-quality evidence

according to GRADE). Vitamin D₃ did not increase the risk of serious adverse effects within a range of 26 to 52 weeks' follow-up (RD 0.01, 95% CI -0.03 to 0.04; I² = 35%; eight trials; 621 participants; low-quality evidence according to GRADE) or minor adverse effects within a range of 26 to 96 weeks' follow-up (RD 0.02, 95% CI -0.02 to 0.06; I² = 20%; eight trials; 701 participants; low-quality evidence according to GRADE). Three studies reported health-related quality of life (HRQOL) using different HRQOL scales. One study reported that vitamin D improved ratings on the psychological and social components of the HRQOL scale but had no effects on the physical components. The other two studies found no effect of vitamin D on HRQOL. Two studies reported fatigue using different scales. One study (158 participants) reported that

vitamin D₃ reduced fatigue compared with placebo at 26 weeks' follow-up. The other study (71 participants) found no effect on fatigue at 96 weeks' follow-up. Seven studies reported on cytokine levels, four on T-lymphocyte proliferation, and one on matrix metalloproteinase levels, with no consistent pattern of change in these immunological outcomes. The randomised trials included in this review provided no data on time to first treated relapse, number of participants requiring hospitalisation owing to progression of the disease, proportion of participants who remained relapse-free, cognitive function, or psychological symptoms. AUTHORS' CONCLUSIONS: To date, very low-quality evidence suggests no benefit of vitamin D for patient-important outcomes among people with MS. Vitamin D appears to have no effect on recurrence of relapse, worsening of disability measured by the Expanded Disability Status Scale (EDSS), and MRI lesions. Effects on health-related quality of life and fatigue are unclear. Vitamin D₃ at the doses and treatment durations used in the included trials appears to be safe, although available data are limited. Seven ongoing studies will likely provide further evidence that can be included in a future update of this review. DOI: 10.1002/14651858.CD008422.pub3


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67. Cold Spring Harb Perspect Med. 2018 Sep 24. pii: a034223. doi: 10.1101/cshperspect.a034223. [Epub ahead of print]

Small Heat Shock Proteins, Amyloid Fibrils, and Nicotine Stimulate a Common Immune Suppressive Pathway with Implications for Future Therapies.

Rothbard JB(1), Kurnellas MP(2), Ousman SS(3), Brownell S(4), Rothbard JJ(1), Steinman L(1). Author information: (1)Department of Neurology, Stanford University School of Medicine, Stanford, California 94305-5316. (2)Alector, South San Francisco, California 94080. (3)Department of Clinical Neurosciences, University of Calgary, Alberta T2N 1N4, Canada. (4)School of Life Sciences, Arizona State University, Tempe, Arizona 85281. The α7 nicotinic acetylcholine receptor (α7nAChR) is central to the anti-inflammatory function of the vagus nerve in a physiological mechanism termed the inflammatory reflex. Studies on the inflammatory reflex have been instrumental for the current development of the field of bioelectronic medicine. An independent investigation of the biological role of αB-crystallin (HspB5), the most abundant gene transcript present in active multiple sclerosis lesions in human brains, also led to α7nAChR. Induction of experimental autoimmune encephalomyelitis (EAE) in HspB5-/- mice results in greater paralytic signs, increased levels of proinflammatory cytokines, and T-lymphocyte activation relative to wild-type animals. Administration of HspB5 was therapeutic in animal models of multiple sclerosis, retinal and cardiac ischemia, and stroke. Structure-activity studies established that residues 73-92 were as potent as the parent protein, but only when it formed amyloid fibrils. Amyloid fibrils and small heat shock proteins (sHsps) selectively bound α7nAChR on peritoneal macrophages (MΦs) and B lymphocytes, converting the MΦs to an immune suppressive phenotype and mobilizing the migration of both cell types from the peritoneum to secondary lymph organs. Here, we review multiple aspects of this work, which may be of interest for developing future therapeutic approaches for multiple sclerosis and other disorders. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved. DOI: 10.1101/cshperspect.a034223

68. Contemp Clin Trials. 2018 Sep 19;73:136-144. doi: 10.1016/j.cct.2018.09.008. [Epub ahead of print]

Home-based, square-stepping exercise program among older adults with multiple sclerosis: results of a feasibility randomized controlled study.

Sebastião E(1), McAuley E(2), Shigematsu R(3), Adamson BC(2), Bollaert RE(4), Motl RW(5). Author information: (1)Department of Kinesiology and Physical Education, Northern Illinois University, DeKalb, United States. Electronic address: [email protected]. (2)Department of Kinesiology and Community Health, University of Illinois, Urbana, United States. (3)Faculty of Education, Mie University, Tsu, Japan. (4)Department of Physical Therapy, Marquette University, Milwaukee, United States. (5)Department of Physical Therapy, University of Alabama, Birmingham, United States. There is very little known about exercise rehabilitation approaches for older adults with multiple sclerosis (MS), yet this growing segment of the MS population experiences declines in cognition and mobility associated with disease progression and aging. We conducted a RCT examining the feasibility of a 12-week, home-based Square-Stepping Exercise (SSE) program in older adults with MS. Older adults with MS (N = 26) with mild-to-moderate levels of disability were recruited and randomized into the intervention (i.e., SSE) or a minimal activity, attention-control conditions. Participants in the SSE condition received a mat for home-based practice of the step patterns, an instruction manual, and a logbook along with a pedometer for monitoring compliance. Both conditions received weekly Skype™ calls and had biweekly meetings with an exercise trainer. Feasibility was assessed based on process, resource, management and scientific outcomes. Regarding scientific outcomes, participants in both conditions completed in-lab assessments before and after the 12-week period. Twenty-five participants completed the study (96%) and the total cost of the study was $13,387.00 USD. Pedometer data demonstrated good compliance with the SSE intervention condition. Effect sizes calculated for all treatment outcomes ranged from small-to-moderate for both mobility and cognitive variables between the intervention and attention-control conditions, thereby providing preliminary evidence that participation in the SSE program may improve cognition and mobility function. The results support the feasibility, acceptability, and possible efficacy of a home-based SSE intervention for older adults with MS. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.cct.2018.09.008


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69. Cureus. 2018 Jul 7;10(7):e2940. doi: 10.7759/cureus.2940.

Parkinsonism in a Patient with Human T-lymphotropic Virus 1 Myelopathy.

Afzal H(1), Kadakia S(2), Lev S(3). Author information: (1)Resident Physician Psychiatry, Nassau University Medical Center, East Meadow, USA. (2)Chairman Department of Neurology, Nassau University Medical Center, East Meadow, USA. (3)Director of Neuroradiology, Nassau University Medical Center, East Meadow, USA. Human T-lymphotropic virus 1 (HTLV-1) infection is commonly associated with neurological conditions like chronic progressive myelopathy and tropical spastic paraparesis (TSP) but rarely also reported with polymyositis, multiple sclerosis, and parkinsonism. It is important to recognize that HTLV-1 infection increases the risk of these neurological conditions. We present a case of 71-year-old female with HTLV-1 associated chronic progressive myelopathy with parkinsonism which signifies that it is under-recognized and not frequently reported due to lack of expert neurological assessment in these chronically debilitated patients. DOI: 10.7759/cureus.2940 PMCID: PMC6128598 Conflict of interest statement: The authors have declared that no competing interests exist.

70. Curr Med Chem. 2018 Sep 26. doi: 10.2174/0929867325666180926144401. [Epub ahead of print]

Sugars and Sweeteners: Structure, Properties and in silico Modeling.

Janezic D(1), Jantschi L(2), Bolboaca SD(3). Author information: (1)Natural Sciences and Information Technologies, Faculty of Mathematics, University of Primorska, Koper. Slovenia. (2)Department of Physics and Chemistry, Technical University of Cluj-Napoca, Cluj-Napoca. Romania. (3)Department of Medical Informatics and Biostatistics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca. Romania. Several studies report the effects of excessive use of sugars and sweeteners in the diet. These include obesity, cardiac diseases, diabetes, and even lymphomas, leukemias, cancers of the bladder and brain, chronic fatigue syndrome, Parkinson's disease, Alzheimer's disease, multiple sclerosis, autism, and systemic lupus. On the other hand, each sugar and sweetener has a distinct metabolic assimilation process, and its chemical structure plays an important role in this process. Several scientific papers present the biological effects of the sugars and sweeteners in relation to their chemical structure. One important issue dealing with the sugars is the degree of similarity in their structures, focusing mostly on optical isomerism. Finding and developing new sugars and sweeteners with desired properties is an emerging research area, in which in silico approaches play an important role. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]. DOI: 10.2174/0929867325666180926144401


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71. Curr Neurol Neurosci Rep. 2018 Sep 18;18(11):76. doi: 10.1007/s11910-018-0886-7.

Pediatric Multiple Sclerosis: an Update.

Otallah S(1), Banwell B(2)(3). Author information: (1)Pediatric Multiple Sclerosis and Demyelinating Disorders Clinic, Division of Pediatric Neurology, Department of Neurology, Wake Forest University/Brenner Children's Hospital, Medical Center Boulevard, JT9, Winston Salem, NC, 27157, USA. [email protected]. (2)Children's Hospital of Philadelphia, Philadelphia, PA, USA. (3)Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. PURPOSE OF REVIEW: Diagnostic criteria for pediatric-onset multiple sclerosis (POMS) and related demyelinating disorders have been updated, neuroimaging studies have revealed new insights, biological assays identify patients with specific antibodies that influence both diagnosis and treatment, clinical trials are informing on treatment efficacy and safety, and longitudinal studies of neurological, cognitive and quality of life outcomes are informing on the impact of these diseases. We provide updates to assist providers caring for these children. RECENT FINDINGS: The recent 2017 McDonald Criteria for MS provide a simplified means to confirm diagnosis at onset and over time, and have been shown to be equally applicable for POMS. MRI analyses demonstrate that brain volume is reduced at onset, and that both volumetric and tissue integrity measures decline over time, indicating that POMS shares the degenerative aspects that also characterize adult-onset disease. The presence of myelin oligodendrocyte glycoprotein (MOG) antibodies at onset is detected in more than 50% of children with acute disseminated encephalomyelitis. When persistent over time, they are associated with relapsing disease. The first randomized clinical trials of disease supports superiority of fingolimod over subcutaneous interferon beta 1a, and demonstrated a favorable safety profile. Finally, while Expanded Disability Status Scale (EDSS) scores remain low in the first 10 years post-onset, POMS is associated with high rates of patient-reported fatigue and reduced engagement in exercise and carries a risk for cognitive impairment. The past 15 years have borne witness to a marked expansion in recognition and research in POMS. There are now more specific diagnostic criteria, antibodies to CNS proteins appear to define diagnostically distinct disorders, clinical trials have successfully launched and one has completed, and we are gaining increasing appreciation of the impact of MS and related disorders on the lived experience of children and adolescents. DOI: 10.1007/s11910-018-0886-7

72. Dermatol Online J. 2018 Jul 15;24(7). pii: 13030/qt220859qb.

Ocrelizumab-induced psoriasiform dermatitis in a patient with multiple sclerosis.

Darwin E, Romanelli P, Lev-Tov H(1). Author information: (1)Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida. [email protected]. Multiple Sclerosis (MS) is a chronic autoimmune disease that presents with a wide variety of sensory and motor deficiencies. New medications targeting B cells have been approved to treat MS, but the side effect profile has not been widely explored. Herein, we report a case of drug-induced psoriasiform dermatitis following ocrelizumab treatment. Physicians should be cognizant of this possible side effect in patients receiving treatment for MS.


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73. Dev Med Child Neurol. 2018 Sep 17. doi: 10.1111/dmcn.14032. [Epub ahead of print]

Isolated seizures during the first episode of relapsing myelin oligodendrocyte glycoprotein antibody-associated demyelination in children.

Ramanathan S(1)(2), O'grady GL(3), Malone S(4), Spooner CG(3), Brown DA(5)(6), Gill D(7)(8), Brilot F(1)(9)(10), Dale RC(1)(7)(8)(9). Author information: (1)Brain Autoimmunity Group, Kids Neuroscience Centre at the Children's Hospital at Westmead, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. (2)Department of Neurology, Westmead Hospital, Sydney, NSW, Australia. (3)Paediatric Neuroservices, Starship Children's Health, Auckland District Health Board, Auckland, New Zealand. (4)Department of Neurosciences, Lady Cilento Children's Hospital, South Brisbane, QLD, Australia. (5)New South Wales Health Pathology, ICPMR, Westmead, NSW, Australia. (6)Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia. (7)TY Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Sydney, NSW, Australia. (8)Epilepsy and Movement Disorders Group, Kids Neuroscience Centre, Children's Hospital at Westmead, Sydney, NSW, Australia. (9)Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia. (10)Applied Medical Sciences, University of Sydney, Sydney, Australia. Myelin oligodendrocyte glycoprotein (MOG) antibodies have a strong association with acute disseminated encephalomyelitis (ADEM) in children, and bilateral and recurrent optic neuritis in children and adults. Recent reports suggest that seizures and encephalopathy may occur in children and adults with MOG antibody-associated disease. We describe the clinical, laboratory, and radiological course of four MOG antibody-positive children who first presented with isolated seizures without fulfilling clinical or radiological criteria for ADEM or other central nervous system demyelination syndromes, who months to years later developed more typical demyelination. This case series highlights a novel observation that isolated seizures in the absence of ADEM may be the index presentation for MOG antibody-associated disease, which should therefore be considered a form of autoimmune epilepsy. It would be reasonable to test for MOG antibodies in children with seizures accompanied by subtle inflammatory changes on magnetic resonance imaging or cerebrospinal fluid analyses, particularly if followed by demyelination, given the clinical and therapeutic implications of an expedited diagnosis in minimizing long-term disability.WHAT THIS PAPER ADDS: Isolated seizures in the absence of acute disseminated encephalomyelitis may be the index presentation for myelin oligodendrocyte glycoprotein antibody-associated demyelination. © 2018 Mac Keith Press. DOI: 10.1111/dmcn.14032

74. Diagnostics (Basel). 2018 Sep 11;8(3). pii: E66. doi: 10.3390/diagnostics8030066.

A Brief Questionnaire to Assess Post-Exertional Malaise.

Cotler J(1), Holtzman C(2), Dudun C(3), Jason LA(4). Author information: (1)Center for Community Research, Department of Psychology, DePaul University, Chicago, IL 60604, USA. [email protected]. (2)Center for Community Research, Department of Psychology, DePaul University, Chicago, IL 60604, USA. [email protected]. (3)Center for Community Research, Department of Psychology, DePaul University, Chicago, IL 60604, USA. [email protected]. (4)Center for Community Research, Department of Psychology, DePaul University, Chicago, IL 60604, USA. [email protected]. Post-exertional malaise (PEM) is a key symptom of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Currently, five PEM-items from the DePaul Symptom Questionnaire (DSQ) were recommended as a first step in measuring this symptom for patients with ME and CFS by the National Institutes of Health/Centers for Disease Control and Prevention (NIH/CDC) Common Data Elements' (CDE) working group. The second step in this process, as recommended by the NIH/CDC CDE working group, involves assembling information from various sources to confirm the presence of PEM. There have not been any efforts, to date, to standardize this second-step process in the assessment of PEM. The current study examined whether five supplementary items on the DSQ could be used to operationalize the second step of the recommendations made by the NIH/CDC CDE working group. The five supplementary DSQ PEM duration items correctly categorized patients with ME or CFS 81.7% of the time, while incorrectly categorizing multiple sclerosis (MS) and post-polio syndrome (PPS) as ME or CFS only 16.6% of the time. The findings suggested that a PEM second-step process could be operationalized using supplementary DSQ items. DOI: 10.3390/diagnostics8030066


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75. Disabil Health J. 2018 Aug 11. pii: S1936-6574(18)30146-8. doi: 10.1016/j.dhjo.2018.08.003. [Epub ahead of print]

Is there a standard procedure for assessing and providing assistive devices for people with neuro-disabling conditions in United Kingdom? A nation-wide survey.

Tedesco Triccas L(1), McLening B(2), Hendrie W(3), Peryer G(4). Author information: (1)School of Health Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom; Department of Rehabilitation Sciences, KU Leuven, Tervuursevest 101, Heverlee, 3001, Belgium. Electronic address: [email protected]. (2)Norfolk Community Health and Care NHS Trust, Norfolk, United Kingdom. (3)MS Therapy Centre, 5 Hurricane Way, Norwich NR6 6EZ, United Kingdom. (4)School of Health Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom. BACKGROUND: Assistive devices are currently provided to people with neuro-disabling conditions to promote or maintain independence in activities of daily living. However, it is unclear whether assessment procedures performed by health care professionals to guide the provision of assistive devices are standardized. OBJECTIVE: To explore the assessment and service-delivery processes of assistive devices for people with multiple sclerosis, cerebrovascular disease and Parkinson's disease experiencing physical disability by health care professionals in the United Kingdom. METHODS: A survey was conducted among UK health care professionals working with people with neuro-disabling conditions. Descriptive and content analyses were used to code survey data. RESULTS: In total, 231 health care professionals completed the survey: 93 occupational therapists, 136 physiotherapists and 2 assistant practitioners. Less than half of the respondents (46%) reported use of local, national, or combined guidelines when assessing a service user's suitability or need for assistive devices. When guidelines were used, they were not consistent and not specifically for assistive devices. The respondents stated that when users were allocated small and portable assistive devices, they were supplied within four weeks. This period increased for large equipment, major home adaptions or if external specialist services and/or funding was needed. CONCLUSIONS: Standardized operating procedures for assistive device provision are not being carried out within the UK. Variable access to assistive devices supplied by the state indicates inequity across regions. Future research should explore potential benefits of developing standardized assessment procedures for the provision of assistive devices and devise methods to reduce current variability in service delivery. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.dhjo.2018.08.003


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76. Disabil Rehabil. 2018 Sep 27:1-11. doi: 10.1080/09638288.2018.1498545. [Epub ahead of print]

Psychosocial aspects of the lived experience of multiple sclerosis: personal perspectives.

Cowan CK(1), Pierson JM(2), Leggat SG(2). Author information: (1)a Royal Melbourne Hospital , Royal Park Campus: Rehabilitation Unit , Victoria , Australia. (2)b Department of Public Health, School of Psychology and Public Health , La Trobe University , Melbourne , Australia. PURPOSE: To explore participants' personal perspectives: on psychosocial aspects of living with multiple sclerosis (MS) following inpatient rehabilitation; and on experiences of the rehabilitation hospital stay and discharge to home. METHODS: One-on-one, semi-structured in-depth interviews, were conducted with 15 people with various forms of MS, post discharge from a rehabilitation hospital. Thematic analysis of the data was undertaken. RESULTS: The emergent themes were: Fatigue, Independence and Dependence, Loss, Provision of Care, and Perceptions of Care. The first three themes shared a focus on the lived experience of MS and are the subject of this paper. Each of the two remaining themes were essentially independent of the other themes, with one being centred on experiences of the rehabilitation hospital stay, and the other on aspects of general medical care. CONCLUSIONS: Personal perspectives on living with MS following inpatient rehabilitation focussed on: the negative impacts of physical and mental fatigue; the desire to maximise independence in activities of daily living and to minimise reliance on others; and perceptions of loss. These findings shed new light on psychosocial aspects of the lived experience of MS and, as such, have potential applications in rehabilitation for those with MS. Implications for Rehabilitation Physical and mental fatigue is central to the lived experience of multiple sclerosis, as it has an all pervading negative influence on most aspects of life, and can be considerably debilitating. The severe and debilitating effects of multiple sclerosis-related fatigue mandate an explicit focus, of rehabilitation, on fatigue, and, in particular, on the fostering of the development of strategies that serve to minimise the multitude of negative impacts of fatigue. For those with multiple sclerosis, considerable importance is placed on maintaining or regaining independence in activities of daily living, and in daily personal care activities, in particular, partly because a need to rely on an intimate partner or other family member for support with such activities can be problematic. The high importance of independence in activities of daily living, and in daily personal care activities in particular, is indicative of the need for multiple sclerosis rehabilitation to have an explicit focus on this domain, in terms of interventions that aim to maximise independence in such activities. DOI: 10.1080/09638288.2018.1498545

77. Drugs. 2018 Sep 3. doi: 10.1007/s40265-018-0964-9. [Epub ahead of print]

Current and Innovative Pharmacological Options to Treat Typical and Atypical Trigeminal Neuralgia.

Di Stefano G(1), Truini A(1), Cruccu G(2). Author information: (1)Department of Human Neuroscience, Sapienza University, viale Università 30, 00185, Rome, Italy. (2)Department of Human Neuroscience, Sapienza University, viale Università 30, 00185, Rome, Italy. [email protected]. Trigeminal neuralgia is a representative neuropathic facial pain condition, characterised by unilateral paroxysmal pain in the distribution territory of one or more divisions of the trigeminal nerve, triggered by innocuous stimuli. A subgroup of patients with trigeminal neuralgia [TN (previously defined as atypical TN)] also suffer from concomitant continuous pain, i.e. a background pain between the paroxysmal attacks. The aim of this review is to provide current, evidence-based, knowledge about the pharmacological treatment of typical and atypical TN, with a specific focus on drugs in development. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials database (ClinicalTrials.gov), taking into account publications up to February 2018. Two authors independently selected studies for inclusions, data extraction, and bias assessment. Carbamazepine and oxcarbazepine are the first-choice drugs for paroxysmal pain. When sodium channel blockers cannot reach full dosage because of side effects, an add-on treatment with lamotrigine or baclofen should be considered. In patients with atypical TN, both gabapentin and antidepressants are expected to be efficacious and should be tried as an add-on to oxcarbazepine or carbamazepine. Although carbamazepine and oxcarbazepine are effective in virtually the totality of patients, they are responsible for side effects causing withdrawal from treatment in an important percentage of cases. A new, better tolerated, Nav1.7 selective state-dependent, sodium channel blocker (vixotrigine) is under development. Future trials testing the effect of combination therapy in patients with TN are needed, especially in patients with concomitant continuous pain and in TN secondary to multiple sclerosis. DOI: 10.1007/s40265-018-0964-9


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78. Drugs. 2018 Sep 25. doi: 10.1007/s40265-018-0984-5. [Epub ahead of print]

Therapeutic Advances and Challenges in the Treatment of Progressive Multiple Sclerosis.

Baldassari LE(1), Fox RJ(2). Author information: (1)Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, U-10, Cleveland, OH, 44195, USA. (2)Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, U-10, Cleveland, OH, 44195, USA. [email protected]. Despite the fact that majority of patients with multiple sclerosis (MS) have relapsing-remitting disease, many transition to secondary progressive disease (SPMS) over time. This transition is thought to be related to neurodegenerative processes increasingly predominating over inflammatory processes as the driving forces of disability. However, some patients initially present with primary progressive disease (PPMS) that is characterized by a gradual accumulation of neurological symptoms and subsequent disability accumulation. The treatment of both PPMS and SPMS, collectively referred to as progressive MS, has proven quite challenging due to the multifactorial and poorly understood pathophysiology of multiple sclerosis in general, specifically that of progressive disease. The purpose of this article is to discuss important clinical and pathophysiologic differences between relapsing and progressive forms of MS, review previous notable trials of drugs in progressive MS, examine current literature regarding recent and promising progressive MS treatments, and discuss future considerations for progressive MS therapeutics and management. Specifically, the current evidence regarding treatment of progressive MS with ocrelizumab, simvastatin, ibudilast, alpha-lipoic acid, high-dose biotin, siponimod, and cell-based therapies are discussed. DOI: 10.1007/s40265-018-0984-5

79. Electron Physician. 2018 Aug 25;10(8):7180-7184. doi: 10.19082/7180. eCollection 2018 Aug.

Tumefactive multiple sclerosis masquerade as a central nervous system tumor: a case report.

Turkistani AN(1), Alshamrani FJ(2), Shareefi GF(1), Alsulaiman A(2). Author information: (1)College of Medicine, Imam Abdulrahman bin Faisal University, Khobar, Saudi Arabia. (2)Assistant Professor, Consultant Neurologist, Department of Neurology, King Fahd Hospital of the University, Imam Abdulrahman bin Faisal University, Khobar, Saudi Arabia. Introduction: Tumefactive multiple sclerosis is a demyelinating disorder that appears tumor-like on MRI. To most physicians, diagnosing tumefactive MS by applying clinical, radiological, or laboratory examination like Cerebrospinal fluid (CSF) analysis, can be challenging and ultimately biopsy is necessary to confirm the diagnosis. Case presentation: This paper reports a case of a 37-year-old woman who presented with progressive headache and a strong family history of cancer and was misdiagnosed as having a CNS glioma. After considering the MRI features, CSF analysis results and observing improvement with IV steroids, the diagnosis of tumefactive MS was made. The patient refused biopsy to rule out the possibility of tumor or abscess. Nine months later, she presented with another relapse and an injectable disease modifying treatment (DMT) was initiated, and her course has been stable in follow up. Take-away lesson: The overall clinical importance of this case report is to highlight the real possibility of being forced to decide between Tumefactive demyelinating lesions (TDLs) and brain tumors in clinical practice, in order to avoid unnecessary biopsy. DOI: 10.19082/7180 PMCID: PMC6122873 Conflict of interest statement: Conflict of Interest: There is no conflict of interest to be declared.


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80. Elife. 2018 Sep 17;7. pii: e30325. doi: 10.7554/eLife.30325.

Injury-induced perivascular niche supports alternative differentiation of adult rodent CNS progenitor cells.

Ulanska-Poutanen J(1), Mieczkowski J(1), Zhao C(2)(3), Konarzewska K(1), Kaza B(1), Pohl HB(4), Bugajski L(5), Kaminska B(1), Franklin RJ(2)(3), Zawadzka M(1). Author information: (1)Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. (2)Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom. (3)Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom. (4)Department of Biology, Institute of Molecular Health Sciences, Zurich, Switzerland. (5)Laboratory of Cytometry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. Following CNS demyelination, oligodendrocyte progenitor cells (OPCs) are able to differentiate into either remyelinating oligodendrocytes (OLs) or remyelinating Schwann cells (SCs). However, the signals that determine which type of remyelinating cell is generated and the underlying mechanisms involved have not been identified. Here, we show that distinctive microenvironments created in discrete niches within demyelinated white matter determine fate decisions of adult OPCs. By comparative transcriptome profiling we demonstrate that an ectopic, injury-induced perivascular niche is enriched with secreted ligands of the BMP and Wnt signalling pathways, produced by activated OPCs and endothelium, whereas reactive astrocyte within non-vascular area express the dual BMP/Wnt antagonist Sostdc1. The balance of BMP/Wnt signalling network is instructive for OPCs to undertake fate decision shortly after their activation: disruption of the OPCs homeostasis during demyelination results in BMP4 upregulation, which, in the absence of Socstdc1, favours SCs differentiation. © 2018, Ulanska-Poutanen et al. DOI: 10.7554/eLife.30325 PMCID: PMC6141235 Conflict of interest statement: JU, JM, CZ, KK, BK, HP, LB, BK, RF, MZ No competing interests declared

81. Elife. 2018 Sep 11;7. pii: e36428. doi: 10.7554/eLife.36428. [Epub ahead of print]

Oligodendrocyte-encoded Kir4.1 function is required for axonal integrity.

Schirmer L(1), Möbius W(2), Zhao C(3), Cruz-Herranz A(4), Ben Haim L(1), Cordano C(4), Shiow LR(1), Kelley KW(1), Sadowski B(2), Timmons G(4), Pröbstel AK(4), Wright JN(1), Sin JH(4), Devereux M(4), Morrison DE(3), Chang SM(1), Sabeur K(1), Green A(4), Nave KA(2), Franklin RJ(3), Rowitch DH(3). Author information: (1)Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States. (2)Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany. (3)Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom. (4)Department of Neurology, University of California, San Francisco, San Francisco, United States. Glial support is critical for normal axon function and can become dysregulated in white matter (WM) disease. In humans, loss-of-function mutations of KCNJ10, which encodes the inward-rectifying potassium channel KIR4.1, causes seizures and progressive neurological decline. We investigated Kir4.1 functions in oligodendrocytes (OLs) during development, adulthood and after WM injury. We observed that Kir4.1 channels localized to perinodal areas and the inner myelin tongue, suggesting roles in juxta-axonal K+ removal. Conditional knockout (cKO) of OL-Kcnj10 resulted in late onset mitochondrial damage and axonal degeneration. This was accompanied by neuronal loss and neuro-axonal dysfunction in adult OL-Kcnj10 cKO mice as shown by delayed visual evoked potentials, inner retinal thinning and progressive motor deficits. Axon pathologies in OL-Kcnj10 cKO were exacerbated after WM injury in the spinal cord. Our findings point towards a critical role of OL-Kir4.1 for long-term maintenance of axon function and integrity during adulthood and after WM injury. © 2018, Schirmer et al. DOI: 10.7554/eLife.36428 Conflict of interest statement: LS Lucas Schirmer, filed a patent for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis (WO2015166057A1). WM, CZ, AC, LB, CC, LS, KK, BS, GT, AP, JW, JS, MD, DM, SC, KS, AG, RF, DR The other authors declare that no competing interests exist. KN Klaus-Armin Nave, Reviewing editor, eLife.


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82. EMBO J. 2018 Sep 20. pii: e98899. doi: 10.15252/embj.201798899. [Epub ahead of print]

Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy.

Sugo M(1), Kimura H(1), Arasaki K(2), Amemiya T(1), Hirota N(1), Dohmae N(3), Imai Y(4)(5), Inoshita T(6), Shiba-Fukushima K(6), Hattori N(4)(5)(6), Cheng J(7), Fujimoto T(7), Wakana Y(1), Inoue H(1), Tagaya M(2). Author information: (1)School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan. (2)School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan [email protected] [email protected]. (3)Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Japan. (4)Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan. (5)Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan. (6)Department of Treatment and Research in Multiple Sclerosis and Neuro-intractable Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan. (7)Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan. PGAM5, a mitochondrial protein phosphatase that is genetically and biochemically linked to PINK1, facilitates mitochondrial division by dephosphorylating the mitochondrial fission factor Drp1. At the onset of mitophagy, PGAM5 is cleaved by PARL, a rhomboid protease that degrades PINK1 in healthy cells, and the cleaved form facilitates the engulfment of damaged mitochondria by autophagosomes by dephosphorylating the mitophagy receptor FUNDC1. Here, we show that the function and localization of PGAM5 are regulated by syntaxin 17 (Stx17), a mitochondria-associated membrane/mitochondria protein implicated in mitochondrial dynamics in fed cells and autophagy in starved cells. In healthy cells, loss of Stx17 causes PGAM5 aggregation within mitochondria and thereby failure of the dephosphorylation of Drp1, leading to mitochondrial elongation. In Parkin-mediated mitophagy, Stx17 is prerequisite for PGAM5 to interact with FUNDC1. Our results reveal that the Stx17-PGAM5 axis plays pivotal roles in mitochondrial division and PINK1/Parkin-mediated mitophagy. © 2018 The Authors. DOI: 10.15252/embj.201798899

83. EMBO Mol Med. 2018 Sep 28. pii: e8926. doi: 10.15252/emmm.201808926. [Epub ahead of print]

Early auto-immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis.

Dembla M(1), Kesharwani A(2), Natarajan S(2), Fecher-Trost C(3), Fairless R(4), Williams SK(4), Flockerzi V(3), Diem R(4), Schwarz K(1), Schmitz F(1). Author information: (1)Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Medical School, Saarland University, Homburg, Germany [email protected] [email protected] [email protected]. (2)Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Medical School, Saarland University, Homburg, Germany. (3)Institute of Experimental and Clinical Pharmacology and Toxicology, Medical School, Saarland University, Homburg, Germany. (4)Department of Neurology, University Clinic Heidelberg, Heidelberg, Germany. Optic neuritis is one of the first manifestations of multiple sclerosis. Its pathogenesis is incompletely understood, but considered to be initiated by an auto-immune response directed against myelin sheaths of the optic nerve. Here, we demonstrate in two frequently used and well-validated mouse models of optic neuritis that ribbon synapses in the myelin-free retina are targeted by an auto-reactive immune system even before alterations in the optic nerve have developed. The auto-immune response is directed against two adhesion proteins (CASPR1/CNTN1) that are present both in the paranodal region of myelinated nerves as well as at retinal ribbon synapses. This occurs in parallel with altered synaptic vesicle cycling in retinal ribbon synapses and altered visual behavior before the onset of optic nerve demyelination. These findings indicate that early synaptic dysfunctions in the retina contribute to the pathology of optic neuritis in multiple sclerosis. © 2018 The Authors. Published under the terms of the CC BY 4.0 license. DOI: 10.15252/emmm.201808926


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84. eNeuro. 2018 Sep 24;5(5). pii: ENEURO.0239-18.2018. doi: 10.1523/ENEURO.0239-18.2018. eCollection 2018 Sep-Oct.

A Functionally Defined In Vivo Astrocyte Population Identified by c-Fos Activation in a Mouse Model of Multiple Sclerosis Modulated by S1P Signaling: Immediate-Early Astrocytes (ieAstrocytes).

Groves A(1), Kihara Y(1), Jonnalagadda D(1), Rivera R(1), Kennedy G(1), Mayford M(2), Chun J(1). Author information: (1)Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. (2)Department of Psychiatry, University of California San Diego, La Jolla, CA 92037. Astrocytes have prominent roles in central nervous system (CNS) function and disease, with subpopulations defined primarily by morphologies and molecular markers often determined in cell culture. Here, we identify an in vivo astrocyte subpopulation termed immediate-early astrocytes (ieAstrocytes) that is defined by functional c-Fos activation during CNS disease development. An unbiased screen for CNS cells showing c-Fos activation during experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), was developed by using inducible, TetTag c-Fos reporter mice that label activated cells with a temporally stable, nuclear green fluorescent protein (GFP). Four-dimensional (3D over time) c-Fos activation maps in the spinal cord were produced by combining tissue clearing (iDISCO) and confocal microscopy that identified onset and expansion of GFP+ cell populations during EAE. More than 95% of the GFP+ cells showed glial fibrillary acidic protein (GFAP) immunoreactivity-in contrast to absent or rare labeling of neurons, microglia, and infiltrating immune cells-which constituted ieAstrocytes that linearly increased in number with progression of EAE. ieAstrocyte formation was reduced by either astrocyte-specific genetic removal of sphingosine 1-phosphate receptor 1 (S1P1) or pharmacological inhibition by fingolimod (FTY720), an FDA-approved MS medicine that can functionally antagonize S1P1. ieAstrocytes thus represent a functionally defined subset of disease-linked astrocytes that are the first and predominant CNS cell population activated during EAE, and that track with disease severity in vivo. Their reduction by a disease-modifying agent supports their therapeutic relevance to MS and potentially other neuroinflammatory and neurodegenerative diseases. DOI: 10.1523/ENEURO.0239-18.2018 PMCID: PMC6153337

85. eNeurologicalSci. 2018 Jul 4;12:42-46. doi: 10.1016/j.ensci.2018.07.002. eCollection 2018 Sep.

Brain and spinal cord MRI lesions in primary progressive vs. relapsing-remitting multiple sclerosis.

Dastagir A(1), Healy BC(1)(2), Chua AS(1), Chitnis T(1), Weiner HL(1), Bakshi R(1)(3), Tauhid S(1). Author information: (1)Departments of Neurology and Brigham and Women's Hospital, Laboratory for Neuroimaging Research, Partners MS Center, Harvard Medical School, USA. (2)Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA. (3)Radiology, Brigham and Women's Hospital, Laboratory for Neuroimaging Research, Partners MS Center, Harvard Medical School, USA. Background: Primary progressive (PP) multiple sclerosis (MS) is considered a clinically distinct entity from the spectrum of relapsing-remitting (RR) forms of the disease. Objective: To compare the presence of brain and spinal cord lesions between PP and RR subjects. Methods: We studied people with PPMS [n = 40, 17 (42.5%) men, age 50.7 ± 7.7 years, disease duration 10.1 ± 7.4 years, Expanded Disability Status Scale (EDSS) score 4.6 ± 2.1] and RRMS [n = 40, 12 (30%) men, age 47.9 ± 4.2, disease duration 13.7 ± 5.9, EDSS 1.7 ± 1.3]. MRI of the brain and full spinal cord at 1.5T was analyzed to define patients having: 1. brain only, 2. spinal cord only, or 3. brain and spinal cord MS lesions. Results: Lesions in the brain only were less common in PP (n = 1, 2.5% of people) than RR (n = 10, 25%) (Fisher's exact p = 0.007). Lesions in the spinal cord only (PP: n = 6, 15%, RR: n = 3, 7.5%, p = 0.481) or brain plus spinal cord (PP: n = 33, 83%, RR: n = 27, 68%, p = 0.196) were similar between groups. PP had higher EDSS and timed 25-ft walk (Wilcoxon tests, both p < 0.001), higher age (t-test p = 0.049), lower disease duration (t-test, p = 0.02), and a similar sex ratio (Fisher's exact p = 0.352) vs. RR. Conclusions: We report a topographic difference in MRI lesion involvement between PPMS and RRMS. Lesions restricted to the brain are more common in RRMS. These findings provide support to the notion that PP may have features distinctive from the RR spectrum of the disease. Longitudinal comparisons and quantitative MRI analysis would be necessary to confirm and extend these results. DOI: 10.1016/j.ensci.2018.07.002 PMCID: PMC6141305


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86. Environ Int. 2018 Aug 30;121(Pt 1):31-40. doi: 10.1016/j.envint.2018.08.044. [Epub ahead of print]

PON1 DNA methylation and neurobehavior in Mexican-American children with prenatal organophosphate exposure.

Huen K(1), Solomon O(2), Kogut K(3), Eskenazi B(3), Holland N(2). Author information: (1)Children's Environmental Health Laboratory, Global Berkeley Campus, 1301 S. 46th Street, Bldg 112, Richmond, CA 94804, USA. Electronic address: [email protected]. (2)Children's Environmental Health Laboratory, Global Berkeley Campus, 1301 S. 46th Street, Bldg 112, Richmond, CA 94804, USA. (3)Center for Children's Environmental Health, School of Public Health, University of California, Berkeley, 1995 University Avenue Suite 265, Berkeley, CA 94720, USA. PON1 is a multifunctional enzyme involved in oxidative stress and detoxification of some organophosphate (OP) pesticides. It has been associated with nervous system diseases like Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and autism. We previously found that PON1 susceptible genotypes were associated with lower IQ scores in children. Epigenetic marks, such as DNA methylation, can regulate gene expression. Yet, data on whether DNA methylation may influence the relationship between PON1 levels and neurobehavior are limited. In this study, we used Illumina 450K and EPIC BeadChip arrays to assess PON1 DNA methylation in blood specimens collected from children (n = 238) at birth (cord blood) and age 7 years and examined their relationship with cognitive outcomes. The Wechsler Intelligence Scale for Children was used to assess Full Scale IQ and four composite measures (Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed Indexes) in 7-year-old children. We observed a consistent yet nonsignificant inverse relationship of methylation at several CpG sites close to the PON1 transcription start site with Full Scale IQ and other composite measures of cognition. We also found an inverse relationship between cord blood methylation at cg15887283 with working memory and a positive association of 7-year-old methylation at cg22798737 with processing speed, independent of OP exposure. However, none of the associations remained significant after accounting for multiple comparisons. This study provides some evidence of the role DNA methylation may play in the known relationship between PON1 and neurobehavior in children, however it appears to be only suggestive and warrants additional research. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.envint.2018.08.044


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87. EPMA J. 2018 Jun 8;9(3):331-343. doi: 10.1007/s13167-018-0138-6. eCollection 2018 Sep.

Titanium implants and silent inflammation in jawbone-a critical interplay of dissolved titanium particles and cytokines TNF-α and RANTES/CCL5 on overall health?

Lechner J(1), Noumbissi S(2), von Baehr V(3). Author information: (1)Clinic for Integrative Dentistry, Grünwalder Str. 10A, Munich, Germany. (2)Miles of Smiles Implant Dentistry, 801 Wayne Ave no. G200, Silver Spring, USA. (3)Institute for Medical Diagnostics in MVZ GbR, Nicolaistr. 22, 12247 Berlin, Germany. Background and introduction: It is a well-known fact that titanium particles deriving from dental titanium implants (DTI) dissolve into the surrounding bone. Although titanium (TI) is regarded as a compatible implant material, increasing concern is coming up that the dissolved titanium particles induce inflammatory reactions around the implant. Specifically, the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) is expressed in the adjacent bone. The transition from TNF-α-induced local inflammation following insertion of DTI surgery to a chronic stage of "silent inflammation" could be a neglected cause of unexplained medical conditions. Material and methods: The signaling pathways involved in the induction of cytokine release were analyzed by multiplex analysis. We examined samples of jawbone (JB) for seven cytokines in two groups: specimens from 14 patients were analyzed in areas of DTI for particle-mediated release of cytokines. Each of the adjacent to DTI tissue samples showed clinically fatty degenerated and osteonecrotic medullary changes in the JB (FDOJ). Specimens from 19 patients were of healthy JB. In five cases, we measured the concentration of dissolved Ti particles by spectrometry. Results: All DTI-FDOJ samples showed RANTES/CCL5 (R/C) as the only extremely overexpressed cytokine. DTI-FDOJ cohort showed a 30-fold mean overexpression of R/C as compared with a control cohort of 19 healthy JB samples. Concentration of dissolved Ti particles in DTI-FDOJ was 30-fold higher than an estimated maximum of 1.000 μg/kg. Discussion: As R/C is discussed in the literature as a possible contributor to inflammatory diseases, the here-presented research examines the question of whether common DTI may provoke the development of chronic inflammation in the jawbone in an impaired state of healing. Such changes in areas of the JB may lead to hyperactivated signaling pathways of TNF-α induced R/C overexpression, and result in unrecognized sources of silent inflammation. This may contribute to disease patterns like rheumatic arthritis, multiple sclerosis, and other systemic-inflammatory diseases, which is widely discussed in scientific papers. Conclusion: From a systemic perspective, we recommend that more attention be paid to the cytokine cross-talk that is provoked by dissolved Ti particles from DTI in medicine and dentistry. This may contribute to further development of personalized strategies in preventive medicine. DOI: 10.1007/s13167-018-0138-6 PMCID: PMC6107454 Conflict of interest statement: The authors declare that they have no competing interests.Not applicable.All the patients were informed about the purposes of the study and consequently have signed their “consent of the patient.” All investigations conformed to the principles outlined in the Declaration of Helsinki and were performed with permission by the responsible Ethics Committee of IMD-Berlin forensic accredited Institute DIN EN 15189/DIN EN 17025. This article does not contain any studies with animals performed by any of the authors.


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88. EPMA J. 2018 Aug 10;9(3):249-256. doi: 10.1007/s13167-018-0143-9. eCollection 2018 Sep.

Neuromyelitis optica spectrum disorders and pregnancy: relapse-preventive measures and personalized treatment strategies.

Borisow N(1), Hellwig K(2), Paul F(1)(3). 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, Charitéplatz 1, 10117 Berlin, Germany. (2)2Clinic for Neurology, St. Josef Hospital, Ruhr Universität Bochum, Bochum, Germany. (3)3Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany. Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune inflammatory diseases of the central nervous system that predominately affect women. Some of these patients are of childbearing age at NMOSD onset. This study reviews, on the one hand, the role NMOSD play in fertility, pregnancy complications and pregnancy outcome, and on the other, the effect of pregnancy on NMOSD disease course and treatment options available during pregnancy. Animal studies show lower fertility rates in NMOSD; however, investigations into fertility in NMOSD patients are lacking. Pregnancies in NMOSD patients are associated with increased disease activity and more severe disability postpartum. Some studies found higher risks of pregnancy complications, e.g., miscarriages and preeclampsia. Acute relapses during pregnancy can be treated with methylprednisolone and/or plasma exchange/immunoadsorption. A decision to either stop or continue immunosuppressive therapy with azathioprine or rituximab during pregnancy should be evaluated carefully and factor in the patient's history of disease activity. To this end, involving neuroimmunological specialist centers in the treatment and care of pregnant NMOSD patients is recommended, particularly in specific situations like pregnancy. DOI: 10.1007/s13167-018-0143-9 PMCID: PMC6107451 [Available on 2019-09-01] Conflict of interest statement: For this type of study, formal consent is not required.N. Borisow declares no conflict of interest. F. Paul is a member of the scientific advisory board of Novartis; has received lecture fees and travel reimbursement from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is academic editor of PLoS One, Associate Editor of Neurology® Neuroimmunology & Neuroinflammation; consulted for Sanofi-Genzyme, Biogen Idec, MedImmune, Shire, and Alexion; and received research support from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Alexion, Merck Serono, the German Research Foundation, the Werth Foundation of the city of Cologne, the German Federal Ministry of Research and Education, the Arthur Arnstein Stiftung Berlin, the EU FP7 Framework Program, Jackson Charitable Foundation, and the National Multiple Sclerosis of the USA. K. Hellwig received consultant and lecture fees and research support from Bayer Healthcare, Biogen, Novartis Pharma, Teva Pharma, Roche, and Sanofi-Genzyme und Merck. The NEMOS cohort/NationNMO is supported by the German Ministry for Education and Research (BMBF) as part of the German Competence Network Multiple Sclerosis (KKNMS; for NEMOS NationNMO-LAB FKZ 01GI1602A to B.W., NationNMO-PAT FKZ 01GI1602B to O.A., and NationNMO-DAB FKZ 01GI1602C to J.S.).This paper included no studies of humans or animals.


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89. Eur J Clin Nutr. 2018 Sep 3. doi: 10.1038/s41430-018-0294-8. [Epub ahead of print]

Dietary Inflammatory Index and clinical course of multiple sclerosis.

da Costa Silva BY(1)(2), de Carvalho Sampaio HA(3)(4), Shivappa N(5)(6)(7), Hebert JR(5)(6)(7), da Silva Albuquerque L(8), Carioca AAF(4)(8)(9), D'Almeida JAC(10), Maia CSC(11), de Melo MLP(4)(10)(11). Author information: (1)Postgraduate Program in Public Health, Ceará State University, Av. Dr. Silas Munguba, 1700-Itaperi, Fortaleza, CE, 60741-000, Brazil. [email protected]. (2)Group of Research in Nutrition and Chronic Diseases, Ceará State University, Av. Dr. Silas Munguba, 1700-Itaperi, Fortaleza, CE, 60741-000, Brazil. [email protected]. (3)Postgraduate Program in Public Health, Ceará State University, Av. Dr. Silas Munguba, 1700-Itaperi, Fortaleza, CE, 60741-000, Brazil. (4)Group of Research in Nutrition and Chronic Diseases, Ceará State University, Av. Dr. Silas Munguba, 1700-Itaperi, Fortaleza, CE, 60741-000, Brazil. (5)South Carolina Statewide Cancer Prevention and Control Program, University of South Carolina, Columbia, SC, 29208, USA. (6)Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29208, USA. (7)Connecting Health Innovations-LLC, Columbia, SC, 29201, USA. (8)Graduate Course in Nutrition, University of Fortaleza, Av. Washington Soares, 1321-Edson Queiroz, Fortaleza, CE, 60811-905, Brazil. (9)Department of Nutrition, University of São Paulo, Av. Dr. Arnaldo, 925-Sumaré, São Paulo, SP, 01255-00, Brazil. (10)Neurology Service of the Fortaleza General Hospital-Rua Ávila Goulart, 900-Papicu, Fortaleza, CE, 60175-295, Brazil. (11)Masters in Nutrition and Health, Ceará State University, Av. Dr. Silas Munguba, 1700-Itaperi, Fortaleza, CE, 60741-000, Brazil. OBJECTIVES: This study aims at analyzing the association between the Dietary Inflammatory Index (DII) and the clinical condition of multiple sclerosis (MS) patients. METHODS: It is a quantitative, cross-sectional analytical study that included 137 MS patients assisted at a reference center for MS treatment in the Brazilian northeast. Data was collated through a structured questionnaire and medical records consultation, also involving demographic, clinical, and nutritional variables. Clinical variables included the MS type, diagnosis and follow-up start dates, investigation of recent urinary tract symptoms, use of immunomodulatory, vitamin D supplementation, number of recent pulse therapies, relapse rate in the last 2 years, muscular strength assessment (MRC), disability degree (EDSS), and a gadolinium-enhanced magnetic resonance imaging (MRI) scan in the central white matter (CWM). The DII was calculated according to the Shivappa et al. methodology. RESULTS: There was no difference in any of the variables according to the DII (p > 0.05). CONCLUSIONS: The Dietary Inflammatory Index did not affect the clinical condition of individuals with multiple sclerosis. DOI: 10.1038/s41430-018-0294-8

90. Eur J Immunol. 2018 Sep 14. doi: 10.1002/eji.201847580. [Epub ahead of print]

Prophylactic treatment against GM-CSF, but not IL-17, abolishes relapses in a chronic murine model of multiple sclerosis.

Uyttenhove C(1)(2), Gaignage M(1)(2), Donckers D(1)(2), Nasr Z(3), Cheou P(2), van Snick J(1)(2), D'Auria L(3), van Pesch V(3). Author information: (1)Ludwig Cancer Research, Brussels Branch, Brussels, Belgium. (2)de Duve Institute, Université Catholique de Louvain, Brussels, Belgium. (3)Neurochemistry Unit, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium. The pathogenic role of IL-17 and GM-CSF has been unravelled in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). However, in most models, EAE is characterised by a monophasic attack which is not representative of the relapsing nature nor the chronicity displayed in MS. Here, we used proteolipid protein peptide (PLP139-151 ) to trigger EAE-relapses (EAE-II) in SJL mice that had recovered from a primary-EAE episode (EAE-I). This procedure resulted in severe and irreversible disease that, unlike EAE-I, was not abolished by anti-IL-17-mAb. In contrast, prophylactic anti-GM-CSF-mAb treatment prevented EAE-I and -II. Strikingly, the expression of T-cell transcription factors and cytokines/chemokines in mice treated with anti-GM-CSF during both EAE episodes was silenced. Anti-GM-CSF-mAb treatment administered only during EAE-II did not completely prevent relapses but mice ultimately reached full recovery. Anti-GM-CSF treatment also strongly impaired and ultimately resolved monophasic MOG35-55 -induced EAE in C57Bl/6 mice. In such protected mice, anti-GM-CSF treatment also prevented a further relapse induced by MOG-revaccination. These results underscore the critical role of GM-CSF on pro-inflammatory mediator production. Furthermore, we observed a strong preventive and curative effect of anti-GM-CSF neutralisation in two EAE models, relapsing and chronic. Altogether these findings are relevant for further MS research. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. DOI: 10.1002/eji.201847580


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91. Eur J Neurol. 2018 Sep 17. doi: 10.1111/ene.13810. [Epub ahead of print]

Leveraging technology to identify subclinical deficits in radiologically isolated syndrome.

Okuda DT(1). Author information: (1)UT Southwestern Medical Center, Department of Neurology & Neurotherapeutics, Neuroinnovation Program, Multiple Sclerosis & Neuroimmunology Imaging Program, Clinical Center for Multiple Sclerosis, Dallas, Texas, U.S.A. The neurological examination serves as the foundation for neuroanatomical localization in the determination of focal deficits, the magnitude of nervous system involvement and impact on other body systems, and, most importantly, the identification of the origin of disease. Applied techniques are associated with a range in sensitivities for discovering central nervous system (CNS) involvement. When present, an identified deficiency, not apparent to the patient, may indicate a disturbance in neurological function. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/ene.13810

92. Eur J Neurol. 2018 Sep 1. doi: 10.1111/ene.13805. [Epub ahead of print]

Predicting responsiveness to fampridine in gait-impaired patients with multiple sclerosis.

Filli L(1), Werner J(1), Beyer G(1), Reuter K(1), Petersen JA(1), Weller M(1), Zörner B(2), Linnebank M(1)(3). Author information: (1)Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland. (2)Spinal Cord Injury Center, Balgrist University Hospital, Forchstrasse 344, 8008, Zurich, Switzerland. (3)Department of Neurology, Helios-Klinik Hagen-Ambrock, Hagen/ University Witten/ Herdecke, Ambrocker Weg 60, 58091, Germany. BACKGROUND: Fampridine leads to significant walking improvements in many persons with multiple sclerosis (PwMS). However, a relevant proportion of PwMS does not respond to fampridine and predictors of initial drug responsiveness are unknown. METHODS: Drug response to prolonged-release (PR)-fampridine was assessed in 55 PwMS using the timed 25-foot walk (T25FW), the 6-minute walk test (6MWT) and the 12-item multiple sclerosis walking scale (MSWS-12) as outcome parameters. Patients were treated with PR-fampridine and placebo each for 6 weeks in a randomised, double-blind, placebo-controlled trial with cross-over design (NCT01576354). Possible predictors of drug responsiveness were investigated by multiple correlation analysis and binary logistic regression models. An additional longitudinal analysis followed drug responses of 32 patients treated with PR-fampridine over 3 years to identify potential predictors of long-term drug responsiveness. RESULTS: Severity of walking disability was positively correlated with enhanced responses to PR-fampridine. The strongest single predictor of drug responsiveness was poor 6MWT performance at baseline, which was positively correlated with enhanced drug response in the 6MWT (R=-0.541; P<0.001). A multivariable logistic regression model including 6MWT and T25FW baseline performances predicted PR-fampridine responder status with an accuracy of 85.5% (specificity: 90.0%; sensitivity: 73.3%), with a threshold of 211m in the 6MWT best separating responders from non-responders. Enhanced drug responsiveness after 3 years correlated with decline in walking endurance during this period (R=-0.634; P=0.001). CONCLUSIONS: Initial walking impairment is a good predictor of therapeutic responsiveness to PR-fampridine. Valid predictors of patients' responsiveness to PR-fampridine are essential for patient stratification and optimisation of MS treatment. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/ene.13805


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93. Eur J Paediatr Neurol. 2018 Aug 28. pii: S1090-3798(17)31679-3. doi: 10.1016/j.ejpn.2018.08.003. [Epub ahead of print]

Clinical and magnetic resonance imaging features of children, adolescents, and adults with a clinically isolated syndrome.

Milos RI(1), Szimacsek M(2), Leutmezer F(3), Rostasy K(4), Blaschek A(5), Karenfort M(6), Schimmel M(7), Pritsch M(8), Storm Van's Gravesande K(9), Weber M(2), Schmoeger M(3), Seidl R(10), Prayer D(2), Kornek B(3). Author information: (1)Department of Biomedical Imaging and Image-guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Medical University of Vienna, Vienna, Austria. Electronic address: [email protected]. (2)Department of Biomedical Imaging and Image-guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Medical University of Vienna, Vienna, Austria. (3)Department of Neurology, Medical University of Vienna, Vienna, Austria. (4)Department of Pediatric Neurology, Vestische Kinder- und Jugendklinik Datteln, University Witten, Herdecke, Germany. (5)Department of Pediatric Neurology and Developmental Medicine, Dr von Hauner's Childrens Hospital, Ludwig Maximilians University, Munich, Germany. (6)Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Duesseldorf, Germany. (7)Children's Hospital Kinikum Augsburg, Augsburg, Germany. (8)DRK Childrens' Hospital Siegen, Siegen, Germany. (9)Department of Pediatrics, University Hospital Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany. (10)Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. BACKGROUND: The diagnosis of multiple sclerosis (MS) both in children and adults is based on clinical and magnetic resonance imaging (MRI) features according to the McDonald criteria. Little is known about differences in the presentation between pre-pubertal children, adolescents, and adult patients at disease onset. OBJECTIVE: To compare (1) the clinical, cerebrospinal fluid (CSF), and MRI characteristics, and (2) the diagnostic performance of the 2010 McDonald criteria between pre-pubertal, adolescent, and adult patients with a clinically isolated syndrome (CIS). METHODS: We performed a retrospective analysis of the initial brain and spinal cord MRI scans from 11 pre-pubertal children, 46 adolescents, and 56 adults with a CIS. Furthermore, clinical, CSF characteristics, and the performance of the 2010 McDonald criteria were compared. RESULTS: The first inter-attack interval tended to increase with age. With respect to MRI presentation, significantly fewer pre-pubertal children presented with juxtacortical and callosal lesions. We found no significant differences in the fulfillment of the 2010 McDonald criteria between the groups. CONCLUSION: In this retrospective series, subtle differences between children, adolescents, and adults with a CIS were noted. Larger samples are required in order to establish distinct features of the different age groups. Copyright © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ejpn.2018.08.003


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94. Eur Neurol. 2018 Aug 31;80(1-2):34-41. doi: 10.1159/000492126. [Epub ahead of print]

Sexual Dysfunction Seems to Trigger Depression in Female Multiple Sclerosis Patients.

Hösl KM(1), Deutsch M(2), Wang R(2), Roy S(2), Winder K(2), Niklewski G(1), Lee DH(2), Linker RA(2), Hilz MJ(2)(3). Author information: (1)Department of Psychiatry and Psychotherapy, Paracelsus Medical University, Nuremberg, Germany. (2)Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany. (3)Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. BACKGROUND: In women with multiple sclerosis (MS), depression and sexual dysfunction (SD) are common. Whether SD promotes depression or vice versa remains unclear despite therapeutic relevance. Therefore, we aimed to assess whether SD more likely triggers depression or vice versa. METHODS: In 83 female MS patients and 21 age-matched healthy women, we assessed depression, using the Beck Depression Inventory-V (BDI-V), and SD using the Female Sexual Function Index (FSFI). We diagnosed depression with BDI-V-scores >35 and SD with FSFI scores < 26.55. We divided patients into groups with and without SD, with and without depression. Between groups, we compared prevalence of SD and depression (Fisher's-exact-test), age, MS-duration, MS-severity, BDI-V-, and FSFI scores (Mann-Whitney U-test; significance: p < 0.05). RESULTS: A total of 37/83 MS patients and 1/21 controls had SD; 28/83 patients and 3/21 controls had depression; 51.4% patients with SD but only 19.6% without SD had depression (p = 0.003). SD was present in 67.9% depressed and 32.7% non-depressed patients. BDI-V-scores were higher in patients with SD than in patients without SD. FSFI scores were lower in depressed than non-depressed patients. CONCLUSION: In conclusion, SD was more common than depression. SD afflicted 67.9% depressed MS patients and was also more common in non-depressed MS patients than controls. SD may occur independently from depression while increased depressiveness seems linked to coexistent SD. © 2018 S. Karger AG, Basel. DOI: 10.1159/000492126


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95. Eur Radiol. 2018 Sep 21. doi: 10.1007/s00330-018-5710-x. [Epub ahead of print]

Repeatability and reproducibility of FreeSurfer, FSL-SIENAX and SPM brain volumetric measurements and the effect of lesion filling in multiple sclerosis.

Guo C(1)(2), Ferreira D(1), Fink K(3)(4), Westman E(1), Granberg T(5)(6). Author information: (1)Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. (2)Department of Radiology, The First Hospital of Jilin University, Changchun, China. (3)Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. (4)Department of Neurology, Karolinska University Hospital, Stockholm, Sweden. (5)Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. [email protected]. (6)Division of Neuroradiology, Department of Radiology, Karolinska University Hospital, 141 86, Stockholm, Sweden. [email protected]. OBJECTIVES: To compare the cross-sectional robustness of commonly used volumetric software and effects of lesion filling in multiple sclerosis (MS). METHODS: Nine MS patients (six females; age 38±13 years, disease duration 7.3±5.2 years) were scanned twice with repositioning on three MRI scanners (Siemens Aera 1.5T, Avanto 1.5T, Trio 3.0T) the same day. Volumetric T1-weighted images were processed with FreeSurfer, FSL-SIENAX, SPM and SPM-CAT before and after 3D FLAIR lesion filling with LST. The whole-brain, grey matter (GM) and white matter (WM) volumes were calculated with and without normalisation to the intracranial volume or FSL-SIENAX scaling factor. Robustness was assessed using the coefficient of variation (CoV). RESULTS: Variability in volumetrics was lower within than between scanners (CoV 0.17-0.96% vs. 0.65-5.0%, p<0.001). All software provided similarly robust segmentations of the brain volume on the same scanner (CoV 0.17-0.28%, p=0.076). Normalisation improved inter-scanner reproducibility in FreeSurfer and SPM-based methods, but the FSL-SIENAX scaling factor did not improve robustness. Generally, SPM-based methods produced the most consistent volumetrics, while FreeSurfer was more robust for WM volumes on different scanners. FreeSurfer had more robust normalised brain and GM volumes on different scanners than FSL-SIENAX (p=0.004). MS lesion filling changed the output of FSL-SIENAX, SPM and SPM-CAT but not FreeSurfer. CONCLUSIONS: Consistent use of the same scanner is essential and normalisation to the intracranial volume is recommended for multiple scanners. Based on robustness, SPM-based methods are particularly suitable for cross-sectional volumetry. FreeSurfer poses a suitable alternative with WM segmentations less sensitive to MS lesions. KEY POINTS: • The same scanner should be used for brain volumetry. If different scanners are used, the intracranial volume normalisation improves the FreeSurfer and SPM robustness (but not the FSL scaling factor). • FreeSurfer, FSL and SPM all provide robust measures of the whole brain volume on the same MRI scanner. SPM-based methods overall provide the most robust segmentations (except white matter segmentations on different scanners where FreeSurfer is more robust). • MS lesion filling with Lesion Segmentation Toolbox changes the output of FSL-SIENAX and SPM. FreeSurfer output is not affected by MS lesion filling since it already takes white matter hypointensities into account and is therefore particularly suitable for MS brain volumetry. DOI: 10.1007/s00330-018-5710-x


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96. Eur Rev Med Pharmacol Sci. 2018 Sep;22(17):5747-5754. doi: 10.26355/eurrev_201809_15843.

Childhood multiple sclerosis: clinical features and recent developments on treatment choices and outcomes.

An Q(1), Fan CH, Xu SM. Author information: (1)Department of Internal Medicine, Xuzhou Children's Hospital, Xuzhou, Jiangsu, P.R. China. [email protected]. Multiple sclerosis (MS) is an inflammatory idiopathic autoimmune disease causing demyelination of central nervous system (CNS). The incidence of pediatric MS is relatively rare, affecting 0.2 to 0.64/100,000 subjects; cases with MS onset before age 10-12 years, account for less than 1% of all MS cases, while 2.7 to 10.5% of all MS cases worldwide are seen in children <18 years of age, with a strong female preponderance. The disease course of MS varies from a benign type with relatively low level of disability after a long duration (15 years) of the disease, to a malignant type of MS with severe disability or even death within few months following onset. Diagnostic criteria for pediatric MS include ≥ 2 clinical events involving more areas of CNS inflammation in the absence of encephalopathy, separated by > 30 days, along with the involvement of brainstem. Pediatric MS generally presents relapsing-remittent form of MS, with majority of the patients recovering from the first attack. Major histocompatibility complex, more specifically, mutations in the human leukocyte antigen (HLA) DRB1*15 allele, are considered most important genetic factors that are contributory to the disease. Treatment choices for pediatric MS include many disease-modifying therapies (DMT) that are currently being used for adult MS and these are interferon-β 1a/1b (IFN-β1a/1b), glatiramer acetate, teriflunomide, dimethyl fumarate, alemtuzumab, etc. However, most of these have not gone through complete testing in randomized, placebo-controlled clinical trials for pediatric MS and are being prescribed off-label by clinicians. As these studies are progressing, it is important to address if these approaches of treating pediatric MS patients have any long-term impact on patients, in particular, physical, cognitive, developmental and social outcomes of the children.

97. Exp Biol Med (Maywood). 2018 Sep 25:1535370218801309. doi: 10.1177/1535370218801309. [Epub ahead of print]

Drug discovery and development: Biomarkers of neurotoxicity and neurodegeneration.

Walker AL(1), Imam SZ(2), Roberts RA(3)(4). Author information: (1)1 Brain Science Masters Programme, Department of Neuroscience and Psychology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. (2)2 Division of Neurotoxicology, US FDA NCTR, Jefferson, AR 72079, USA. (3)3 Apconix, Alderley Park, SK10 4TG, UK. (4)4 University of Birmingham, Edgbaston B15 2TT, UK. The discovery and development of new drugs are vital if we are to improve and expand treatment options available to improve outcomes for patients. Overall, therapeutic strategies fall into two broad categories: small molecules and biologics, although more recently there has been a growth in novel platforms such as miRNAs and oligonucleotides. On average, the development of a small molecule drug takes around 12 years and costs around $50m. Despite this huge investment of time and money, attrition remains a major challenge and very few molecules actually make it through to the market. Here, we look at reasons for attrition in the small molecule field with a focus on neurotoxicology and efforts being made to improve success via the development of imaging and fluidic biomarkers. We also look at learnings from other models of CNS damage and degeneration such as Parkinson's disease, traumatic brain injury, and multiple sclerosis since these may offer the opportunity to improve tools available to nonclinical toxicologists in the early detection of potential neurotoxicity. Reciprocally, learnings from studies of animal neurotoxicity may offer better ways to potentially monitor patients during clinical development of new drugs for neurodegeneration. Impact statement Attrition in drug discovery and development remains a major challenge. Safety/toxicity is the most prevalent reason for failure with cardiovascular and CNS toxicities predominating. Non-invasive biomarkers of neurotoxicity would provide significant advantage by allowing earlier prediction of likely neurotoxicity in preclinical studies as well as facilitating clinical trials of new therapies for neurodegenerative conditions such as Parkinson's disease (PD) and multiple sclerosis (MS). DOI: 10.1177/1535370218801309


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98. Expert Opin Pharmacother. 2018 Sep 12:1-8. doi: 10.1080/14656566.2018.1516207. [Epub ahead of print]

Pharmacological management of depression in patients with multiple sclerosis.

Carta MG(1), Paribello P(1), Anastasia A(2), De Berardis D(3), Nardi AE(4), Fornaro M(5). Author information: (1)a Department of Health Sciences and Public Health , University of Cagliari , Cagliari , Italy. (2)b Villa Camaldoli Alma Mater SpA , Naples , Italy. (3)c National Health Care System , Mazzini Hospital , Teramo , Italy. (4)d Medical School - Institute of Psychiatry , Federal University of Rio de Janeiro National Academy of Medicine , Rio de Janeiro , Brazil. (5)e Neuroscience, Reproductive Science and Odontostolmatology , Federico II University of Naples , Naples , Italy. INTRODUCTION: The pharmacotherapeutic management of depression in patients with multiple sclerosis (MS) is a matter of debate that cannot be decided from the evidence available in the current literature. Therefore, its management essentially relies on the clinical experience of the prescribing clinician rather than on evidence-based approaches. Areas covered: This review provides a clinically oriented critical perspective on the connection between MS and major depressive disorder (MDD) or depression associated with bipolar disorder (BD), focusing on its optimal pharmacotherapy. Both clinical and pharmacological considerations are accounted in order to promote rational pharmacotherapy, both in terms of efficacy and tolerability. Expert opinion: Despite its clinical burden and relatively frequent occurrence, the interplay of MS and depression still requires further controlled trials to better clarify the appropriate pharmacotherapy across varying 'diseases categories' of MS itself, as well as discriminating between depressive symptoms that do not necessarily reach the threshold of either MDD or BD. Additional insight into new mood-tolerated neurological pharmacotherapy for MS is likewise warranted toward a more effective, immune- and patient-tailored pharmacotherapy, while promoting innovation in drug design, with the ultimate goal of enhancing the overall quality life of the affected individual, his/her caregivers, and to reduce the associated economic and social burden. DOI: 10.1080/14656566.2018.1516207

99. Expert Rev Neurother. 2018 Sep 20:1-7. doi: 10.1080/14737175.2018.1510772. [Epub ahead of print]

A review of the effects of baclofen and of THC:CBD oromucosal spray on spasticity-related walking impairment in multiple sclerosis.

Arroyo González R(1). Author information: (1)a Neurology Department , Hospital Universitario Quironsalud Madrid , Pozuelo de Alarcón, Madrid , Spain. INTRODUCTION: Multiple sclerosis (MS) is a complex disease with a heterogeneous and unpredictable clinical course. Mobility impairment after progressive paralyses and muscle tone spasticity is common. Areas covered: The prevalence, assessment, and pharmacological management of gait impairment and spasticity in MS and their effects on health-related quality of life (HRQoL) are discussed. The roles of oral and intrathecal baclofen and of delta-9-tetrahydrocannabinol/cannabidiol (THC:CBD) oromucosal spray in treating MS spasticity-related gait impairment are reviewed. Expert commentary: Mobility impairment and spasticity are experienced by approximately 90% and 80% of MS patients, respectively, during the disease course. Prevalence and severity of gait impairment and spasticity increase as disease progresses. The symptoms are related and both impact negatively on HRQoL. Oral baclofen and tizanidine are generally used for first-line treatment of MS spasticity but are ineffective in approximately 40% of cases. Second-line therapy includes add-on THC:CBD spray for patients with resistant MS spasticity. Results of studies evaluating baclofen for treating MS spasticity gait impairment are equivocal. In studies of patients with resistant MS spasticity, THC:CBD spray consistently improved the timed 10-meter walk test and significantly improved multiple spatial-temporal and kinematic gait parameters. THC:CBD oromucosal spray warrants further investigation as a treatment for MS spasticity-related gait impairment. DOI: 10.1080/14737175.2018.1510772


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100. Folia Histochem Cytobiol. 2018;56(3):151-158. doi: 10.5603/FHC.a2018.0018. Epub 2018 Sep 6.

Immunohistochemical analysis of spinal cord components in mouse model of experimental autoimmune encephalomyelitis.

Pyka-Fosciak G(1), Stasiolek M, Litwin JA. Author information: (1)Department of Histology, Jagiellonian University Medical College, Krakow, Poland. [email protected]. INTRODUCTION: Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for studying immunopathology of multiple sclerosis (MS) because it repeats the hallmarks of the human disease, such as focal inflammation and demyelination of the central nervous system, subsequently leading to axonal and neuronal loss. The interrelationships, timing and sequence of different pathological processes that lead to histologically observed lesions in SM are still incompletely understood. MATERIAL AND METHODS: EAE was induced in female C57Bl/6 mice by active immunization with MOG35-55 antigen. Development of the neurological symptoms in the animals was monitored and on that basis spinal cords were collected in three successive phases of the disease (onset, peak, chronic). Total leukocytes, T cells, macrophages/microglia, oligodendrocytes, damaged axons and surviving neuronal cell bodies were visualized using appropriate immunohistochemical markers and their density was quantitatively assessed using image analysis software. RESULTS: The density of all studied cells except neurons was significantly higher in EAE mice than in the control mice. The density of total leukocytes, T cells, and damaged axons increased from the onset to the peak phase and decreased in the chronic phase to reach values lower than those in the peak phase. The density of macrophages/microglia increased in the peak phase and remained at the elevated level in the chronic phase. Oligodendrocytes showed the highest density in the onset phase and gradually decreased afterwards. The density of neuronal cell bodies decreased only in the chronic phase of the disease. CONCLUSIONS: In mouse model of EAE, inflammatory cells predominate in the early phases of the disease. This study shows for the first time that inflammation precedes oligodendrocyte death and neuronal loss and that macrophages/ microglia are the only cells persisting in large numbers in the chronic phase of the disease, probably because of the switch from proinflammatory to anti-inflammatory phenotype. DOI: 10.5603/FHC.a2018.0018

101. Front Aging Neurosci. 2018 Aug 21;10:254. doi: 10.3389/fnagi.2018.00254. eCollection 2018.

Expression Pattern of Myelin-Related Apolipoprotein D in Human Multiple Sclerosis Lesions.

Navarro A(1)(2)(3), Rioseras B(3), Del Valle E(1)(2)(3), Martínez-Pinilla E(1)(2)(3), Astudillo A(2)(4), Tolivia J(1)(2)(3). Author information: (1)Instituto de Neurociencias del Principado de Asturias (INEUROPA), Asturias, Spain. (2)Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain. (3)Departamento de Morfología y Biología Celular, Facultad de Biología y Medicina, Universidad de Oviedo, Oviedo, Spain. (4)Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain. Apolipoprotein D (Apo D) is a key molecule in the lipid transport during homeostasis and repair processes in normal and pathological conditions of the nervous system with a putative neuroprotective effect. In the last decades, huge experimental efforts have been made to know the exact mechanism of action of Apo D, even though, it remains an open question. In this regard, studies in mammals and flies have suggested that Apo D seems to act through a variety of cellular mechanisms related with its ability to selectively bind different lipid ligands. For instance, this apolipoprotein is required to myelin compaction, it participates in axon regeneration/remyelination, and it can control the magnitude and timing of the inflammatory response after injury, promoting myelin clearance, and regulating the number of immune cells recruited to the damaged area. These, among others, are some of the reasons to study Apo D in multiple sclerosis (MS) pathology, where it could be particularly important since the autoimmune reaction against oligodendrocytes (OLGs) and myelin is generally assumed as the most plausible cause of this pathology. The aim of this work was to investigate the Apo D expression pattern in MS lesions, including active and inactive demyelinating plaques, and also remyelinating ones. Human brain tissues with inflammatory demyelination consistent with MS were used to quantify Apo D immunosignal in different lesions. Our results show a clear decrease of Apo D expression in all sclerosis plaques, being lower in the inactive than in active areas but recovers in the remyelination ones. Apo D is mainly produced by the matured OLGs of white matter and is located in cell processes surrounding the myelin sheath. All these data seem to indicate an important role of Apo D in myelination/remyelination processes as a molecule with a neuroprotective potential, and may serve as a good starting point for its study in MS. DOI: 10.3389/fnagi.2018.00254 PMCID: PMC6110904


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102. Front Cell Infect Microbiol. 2018 Sep 4;8:311. doi: 10.3389/fcimb.2018.00311. eCollection 2018.

Intracranial Inoculation Is More Potent Than Intranasal Inoculation for Inducing Optic Neuritis in the Mouse Hepatitis Virus-Induced Model of Multiple Sclerosis.

Singh M(1), Khan RS(2), Dine K(2), Das Sarma J(1), Shindler KS(2). Author information: (1)Department of Biological Science, Indian Institute of Science Education and Research Kolkata, Mohanpur, India. (2)FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, United States. Neurotropic strains of mouse hepatitis virus (MHV) induce acute inflammation and chronic demyelination in the spinal cord and optic nerves mediated by axonal spread following intracranial inoculation in mice, with pathologic features similar to the human demyelinating disease multiple sclerosis. Spinal cord demyelination is also induced following intranasal inoculation with neurotropic MHV strains, however much higher viral doses are required as compared to intracranial inoculation. Recently, it was shown that intranasal administration of low concentrations of proteins leads to significant, rapid accumulation of protein in the optic nerve and in the eye, with only low levels reaching spinal cord and other brain regions. Thus, we examined whether intranasal inoculation with MHV at doses equivalent to those given intracranially could induce optic neuritis-inflammation, demyelination and loss of retinal ganglion cells (RGCs) in the optic nerve with or without inducing spinal cord demyelination. Four week old male C57BL/6J mice were inoculated intracranially with the recombinant demyelinating strain RSA59, or intranasally with RSA59 or the non-demyelinating strain RSMHV2 as control. One month post-inoculation, mice inoculated intracranially with RSA59 had significant myelin loss in both spinal cord and optic nerves, with significant loss of RGCs as well, consistent with prior studies. As expected, intranasal inoculation with RSA59 failed to induce demyelination in spinal cord; however, it also did not induce optic nerve demyelination. No acute inflammation was found, and no viral antigen was detected, in the optic nerve or retina 1 day after inoculation. Results confirm the neurotropic effects of RSA59 following intracranial inoculation, and suggest that direct infection with axonal transport of virus from brain to spinal cord and optic nerve is required to induce demyelinating disease. These studies suggest that MHV does not selectively concentrate in optic nerve and retina to sufficient levels to induce demyelination following intranasal inoculation. Intracranial inoculation should continue to be considered a preferred method for studies of MHV-induced optic neuritis and central nervous system (CNS) demyelinating disease. DOI: 10.3389/fcimb.2018.00311 PMCID: PMC6132074

103. Front Cell Neurosci. 2018 Sep 12;12:297. doi: 10.3389/fncel.2018.00297. eCollection 2018.

Galectin-3-Mediated Glial Crosstalk Drives Oligodendrocyte Differentiation and (Re)myelination.

Thomas L(1)(2), Pasquini LA(1)(2). Author information: (1)Department of Biological Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina. (2)Institute of Chemistry and Biological Physicochemistry (IQUIFIB), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina. Galectin-3 (Gal-3) is the only chimeric protein in the galectin family. Gal-3 structure comprises unusual tandem repeats of proline and glycine-rich short stretches bound to a carbohydrate-recognition domain (CRD). The present review summarizes Gal-3 functions in the extracellular and intracellular space, its regulation and its internalization and secretion, with a focus on the current knowledge of Gal-3 role in central nervous system (CNS) health and disease, particularly oligodendrocyte (OLG) differentiation, myelination and remyelination in experimental models of multiple sclerosis (MS). During myelination, microglia-expressed Gal-3 promotes OLG differentiation by binding glycoconjugates present only on the cell surface of OLG precursor cells (OPC). During remyelination, microglia-expressed Gal-3 favors an M2 microglial phenotype, hence fostering myelin debris phagocytosis through TREM-2b phagocytic receptor and OLG differentiation. Gal-3 is necessary for myelin integrity and function, as evidenced by myelin ultrastructural and behavioral studies from LGALS3- / - mice. Mechanistically, Gal-3 enhances actin assembly and reduces Erk 1/2 activation, leading to early OLG branching. Gal-3 later induces Akt activation and increases MBP expression, promoting gelsolin release and actin disassembly and thus regulating OLG final differentiation. Altogether, findings indicate that Gal-3 mediates the glial crosstalk driving OLG differentiation and (re)myelination and may be regarded as a target in the design of future therapies for a variety of demyelinating diseases. DOI: 10.3389/fncel.2018.00297 PMCID: PMC6143789


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104. Front Med (Lausanne). 2018 Sep 4;5:238. doi: 10.3389/fmed.2018.00238. eCollection 2018.

Comorbidities and Treatment Strategies in Bullous Pemphigoid: An Appraisal of the Existing Litterature.

Bech R(1), Kibsgaard L(1), Vestergaard C(1). Author information: (1)Aarhus University Hospital, Aarhus, Denmark. Bullous Pemphigoid is an autoimmune skin blistering disease. It is caused by deposition of auto antibodies along the dermal-epidermal border leading to inflammation. The antibodies are directed against anchoring filaments in the epidermis, but these antigens are also present in the neurological tissues and this has led to speculation of an association between multiple sclerosis and bullous pemphigoid. Additionally recent epidemiological studies have pointed at an increased risk of cardio-vascualr diseases and an increased moratality among the patients with bullous pemphigoid. In this mini review we present the recent findings in this area and as well as the treatment strategies when comorbidities are taken into consideration. DOI: 10.3389/fmed.2018.00238 PMCID: PMC6131533

105. Front Mol Neurosci. 2018 Sep 4;11:320. doi: 10.3389/fnmol.2018.00320. eCollection 2018.

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases.

Shao BZ(1), Cao Q(1), Liu C(1). Author information: (1)Department of Pharmacology, Second Military Medical University, Shanghai, China. Central nervous system (CNS) is one of the largest killers of people's health all over the world. The overactivation of the immune and inflammatory responses is considered as an important factor, contributing to the pathogenesis and progression of CNS disorders. Among all kinds of immune and inflammatory reaction, the inflammasome, a complex of proteins, has been drawn increasingly attention to by researchers. The initiation and activation of the inflammasome is involved in the onset of various kinds of diseases. The NLRP3 inflammasome, the most studied member of the inflammasome, is closely associated with many kinds of CNS disorders. Here in this review, the roles of the NLRP3 inflammasome in the pathogenesis and progression of several well-known CNS diseases would be discussed, including cerebrovascular diseases, neurodegenerative diseases, multiple sclerosis, depression as well as other CNS disorders. In addition, several therapeutic strategies targeting on the NLRP3 inflammasome for the treatment of CNS disorders would be described in this review. DOI: 10.3389/fnmol.2018.00320 PMCID: PMC6131647

106. Front Neurol. 2018 Sep 4;9:740. doi: 10.3389/fneur.2018.00740. eCollection 2018.

Identifying and Quantifying Neurological Disability via Smartphone.

Boukhvalova AK(1), Kowalczyk E(1)(2), Harris T(1), Kosa P(1), Wichman A(1), Sandford MA(1), Memon A(2), Bielekova B(1). Author information: (1)Laboratory of Clinical Immunology and Microbiology, Neuroimmunological Diseases Section, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States. (2)Department of Computer Science, University of Maryland, College Park, MD, United States. Embedded sensors of the smartphones offer opportunities for granular, patient-autonomous measurements of neurological dysfunctions for disease identification, management, and for drug development. We hypothesized that aggregating data from two simple smartphone tests of fine finger movements with differing contribution of specific neurological domains (i.e., strength & cerebellar functions, vision, and reaction time) will allow establishment of secondary outcomes that reflect domain-specific deficit. This hypothesis was tested by assessing correlations of smartphone-derived outcomes with relevant parts of neurological examination in multiple sclerosis (MS) patients. We developed MS test suite on Android platform, consisting of several simple functional tests. This paper compares cross-sectional and longitudinal performance of Finger tapping and Balloon popping tests by 76 MS patients and 19 healthy volunteers (HV). The primary outcomes of smartphone tests, the average number of taps (per two 10-s intervals) and the average number of pops (per two 26-s intervals) differentiated MS from HV with similar power to traditional, investigator-administered test of fine finger movements, 9-hole peg test (9HPT). Additionally, the secondary outcomes identified patients with predominant cerebellar dysfunction, motor fatigue and poor eye-hand coordination and/or reaction time, as evidenced by significant correlations between these derived outcomes and relevant parts of neurological examination. The intra-individual variance in longitudinal sampling was low. In the time necessary for performing 9HPT, smartphone tests provide much richer and reliable measurements of several distinct neurological functions. These data suggest that combing more creatively-construed smartphone apps may one day recreate the entire neurological examination. DOI: 10.3389/fneur.2018.00740 PMCID: PMC6131483


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107. Front Neurol. 2018 Aug 30;9:735. doi: 10.3389/fneur.2018.00735. eCollection 2018.

Restless Legs Syndrome in Chinese Patients With Sporadic Amyotrophic Lateral Sclerosis.

Liu S(1), Shen D(1), Tai H(1), Su N(1), Ding Q(1), Fu H(1), Zhang K(1), Wang Z(1), Liu M(1), Huang Y(1), Cui L(1)(2). Author information: (1)Department of Neurology, Peking Union Medical College Hospital, Beijing, China. (2)Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China. Objective: To evaluate the frequency and clinical features of restless legs syndrome (RLS) in a group of Chinese patients with amyotrophic lateral sclerosis (ALS). Methods: 109 Patients included in this study fulfilled the revised El Escorial diagnostic criteria for clinically definite, probable and lab-supported probable ALS, and a group of 109 control subjects was matched for age and sex to the ALS group. Disease severity was assessed by the revised ALS functional rating scale (ALSFRS-R). The diagnosis of RLS was made according to the criteria of the International RLS Study Group. Other characteristics including sleep quality, excessive daytime sleepiness (EDS), REM sleep behavior disorder (RBD), depression and anxiety were also evaluated in ALS patients. Results: RLS was significantly more frequent in ALS patients than in control subjects (14.6 vs. 0.9%; P < 0.05). Compared to those without RLS, ALS patients with RLS reported a higher frequency of anxiety and EDS. ALS patients with RLS showed more severe legs dysfunction. EDS and legs function scores of the ALSFRS-R were independent factors significantly associated with RLS in ALS patients. Conclusions: Our findings suggest that Chinese ALS patients exhibit a high frequency of RLS symptoms and that these patients may benefit from recognition of the condition and optimized management of its symptoms. Moreover, ALS patients might cause circadian rhythms disturbance and our study further supports that ALS is a heterogeneous disorder involving multiple systems; further studies are needed to confirm these preliminary findings. DOI: 10.3389/fneur.2018.00735 PMCID: PMC6125374


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MRI Markers and Functional Performance in Patients With CIS and MS: A Cross-Sectional Study.

Rasche L(1), Scheel M(1)(2), Otte K(1)(3), Althoff P(1), van Vuuren AB(1)(4), Gieß RM(1), Kuchling J(1)(5), Bellmann-Strobl J(1)(6), Ruprecht K(5), Paul F(1)(5)(6), Brandt AU(1)(7), Schmitz-Hübsch T(1). 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, NeuroCure Cluster of Excellence, Berlin, Germany. (2)Department of Neuroradiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. (3)Motognosis GmbH, Berlin, Germany. (4)VU University Medical Center, Amsterdam, Netherlands. (5)Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. (6)Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrück Center for Molecular Medicine, Berlin, Germany. (7)Department of Neurology, University of California, Irvine, Irvine, CA, United States. Introduction: Brain atrophy is a widely accepted marker of disease severity with association to clinical disability in multiple sclerosis (MS). It is unclear to which extent this association reflects common age effects on both atrophy and function. Objective: To explore how functional performance in gait, upper extremities and cognition is associated with brain atrophy in patients with Clinically Isolated Syndrome (CIS) and relapsing-remitting MS (RRMS), controlling for effects of age and sex. Methods: In 27 patients with CIS, 59 with RRMS (EDSS ≤3) and 63 healthy controls (HC), 3T MRI were analyzed for T2 lesion count (T2C), volume (T2V) and brain volumes [normalized brain volume (NBV), gray matter volume (NGMV), white matter volume (NWMV), thalamic volume (NThalV)]. Functional performance was measured with short maximum walking speed (SMSW speed), 9-hole peg test (9HPT) and symbol digit modalities test (SDMT). Linear regression models were created for functional variables with stepwise inclusion of age, sex and MR imaging markers. Results: CIS differed from HC only in T2C and T2V. RRMS differed from HC in NBV, NGMV and NThalV, T2C and T2V, but not in NWMV. A strong association with age was seen in HC, CIS and RRMS groups for NBV (r = -0.5 to -0.6) and NGMV (r = -0.6 to -0.8). Associations with age were seen in HC and RRMS but not CIS for NThalV (r = -0.3; r = -0.5), T2C (rs = 0.3; rs = 0.2) and T2V (rs = 0.3; rs = 0.3). No effect of age was seen on NWMV. Correlations of functional performance with age in RRMS were seen for SMSW speed, 9HPTand SDMT (r = -0.27 to -0.46). Regression analyses yielded significant models only in the RRMS group for 9HPT, SMSW speed and EDSS. These included NBV, NGMV, NThalV, NWMV, logT2V, age and sex as predictors. NThalV was the only MRI variable predicting a functional measure (9HPTr) with a higher standardized beta than age and sex (R2 = 0.36, p < 1e-04). Conclusion: Thalamic atrophy was a stronger predictor of hand function (9HPT) in RRMS, than age and sex. This underlines the clinical relevance of thalamic atrophy and the relevance of hand function as a clinical marker even in mildly disabled patients. DOI: 10.3389/fneur.2018.00718 PMCID: PMC6123531


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A Pilot Study Examining Speed of Processing Training (SPT) to Improve Processing Speed in Persons With Multiple Sclerosis.

Chiaravalloti ND(1)(2), Goverover Y(1)(3), Costa SL(1)(2), DeLuca J(1)(2)(4). Author information: (1)Neuropsychology and Neuroscience Laboratory, Kessler Foundation, West Orange, NJ, United States. (2)Department of Physical Medicine and Rehabilitation, Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States. (3)Department of Occupational Therapy, New York University, New York, NY, United States. (4)Department of Neurology, Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States. Background: Individuals with Multiple Sclerosis (MS) have significant impairments in processing speed (PS) and such impairments may underlie other cognitive deficits common in MS and limit performance of everyday life activities. Objective: To examine the efficacy of a computerized PS intervention, Speed of Processing Training (SPT), in persons with MS on PS, memory and everyday activities. Methods: Twenty-one individuals with clinically definite MS and an objectively assessed impairment in PS were included in a controlled randomized clinical trial, randomly assigned to a treatment group or a control group. Participants were assessed prior to and within 1 week of completing the treatment. Outcome measures included traditional neuropsychological tests measuring PS and memory, and an assessment of PS in daily life activities. Results: The treatment group showed a significant improvement on neuropsychological tests of PS and new learning and memory. A significant improvement was additionally noted in the treatment group on measures of PS in everyday life. These changes were not observed in the control group. Conclusions: Results provide preliminary data in support of SPT in treating PS deficits in persons with MS. Additional research is needed with larger samples and more comprehensive outcome measures. DOI: 10.3389/fneur.2018.00685 PMCID: PMC6119725


Occulomotor Neural Integrator Dysfunction in Multiple Sclerosis: Insights From Neuroimaging.

Bede P(1)(2)(3), Finegan E(1)(3), Chipika RH(1), Li Hi Shing S(1), Lambe J(3), Meaney J(4)(5), Redmond J(3). Author information: (1)Computational Neuroimaging Group, Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland. (2)Laboratoire d'Imagerie Biomédicale, Sorbonne University, CNRS, INSERM, Paris, France. (3)Department of Neurology, St James's Hospital, Dublin, Ireland. (4)Centre for Advanced Medical Imaging (CAMI), St James's Hospital, Dublin, Ireland. (5)School of Medicine, Trinity College Dublin, Dublin, Ireland. Background: Magnetic resonance imaging is a key diagnostic and monitoring tool in multiple Sclerosis (MS). While the substrates of motor and neuropsychological symptoms in MS have been extensively investigated, nystagmus-associated imaging signatures are relatively under studied. Accordingly, the objective of this study is the comprehensive characterisation of cortical, subcortical, and brainstem involvement in a cohort of MS patients with gaze-evoked nystagmus. Methods: Patients were recruited from a specialist MS clinic and underwent multimodal neuroimaging including high-resolution structural and diffusion tensor data acquisitions. Morphometric analyses were carried out to evaluate patterns of cortical, subcortical, brainstem, and cerebellar gray matter pathology. Volumetric analyses were also performed to further characterize subcortical gray matter degeneration. White matter integrity was evaluated using axial-, mean-, and radial diffusivity as well as fractional anisotropy. Results: Whole-brain morphometry highlighted considerable brainstem and cerebellar gray matter atrophy, and the tract-wise evaluation of white matter metrics revealed widespread pathology in frontotemporal and parietal regions. Nystagmus-associated gray matter degeneration was identified in medial cerebellar, posterior medullar, central pontine, and superior collicular regions. Volume reductions were identified in the putamen, thalamus and hippocampus. Conclusions: Multiple sclerosis is associated with widespread gray matter pathology which is not limited to cortical regions but involves striatal, thalamic, cerebellar, and hippocampal foci. The imaging signature of gaze-evoked nystagmus in MS confirms the degeneration of key structures of the neural integrator network. DOI: 10.3389/fneur.2018.00691 PMCID: PMC6116658


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Balance Changes in Patients With Relapsing-Remitting Multiple Sclerosis: A Pilot Study Comparing the Dynamics of the Relapse and Remitting Phases.

Findling O(1)(2), Rust H(1)(3), Yaldizli Ö(1), Timmermans DPH(4)(5), Scheltinga A(4)(5), Allum JHJ(1)(5). Author information: (1)Department of Neurology, University of Basel Hospital, Basel, Switzerland. (2)Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland. (3)Division of Brain Sciences, Imperial College London, Charing Cross Hospital, London, United Kingdom. (4)Radboud University Nijmegen, Nijmegen, Netherlands. (5)Division of Audiology and Neurootology, Department of ORL, University of Basel Hospital, Basel, Switzerland. Aims: To compare balance changes over time during the relapse phase of relapsing-remitting multiple sclerosis (RRMS) with balance control during the remitting phase. Methods: Balance control during stance and gait tasks of 24 remitting-phase patients (mean age 43.7 ± 10.5, 15 women, mean EDSS at baseline 2.45 ± 1.01) was examined every 3 months over 9 months and compared to that of nine relapsing patients (age 42.0 ± 12.7, all women, mean EDSS at relapse onset 3.11 ± 0.96) examined at relapse onset and 3 months later. Balance was also compared to that of 40 healthy controls (HCs) (age 39.7 ± 12.6, 25 women). Balance control was measured as lower-trunk sway angles with body-worn gyroscopes. Expanded Disability Status Scale scores (EDSS) were used to monitor, clinically, disease progression. Results: Remitting-phase patients showed more unstable stance balance control than HCs (p < 0.04) with no worsening over the observation period of 9 months. Gait balance control was normal (p > 0.06). Relapsing patients had stance balance control significantly worse at onset compared to remitting-phase patients and HCs (p < 0.04). Gait tasks showed a significant decrease of gait speed and trunk sway in relapsing patients (p = 0.018) compatible with having increased gait instability at normal speeds. Improvement to levels of remitting patients generally took longer than 3 months. Balance and EDSS scores were correlated for remitting but not for relapse patients. Conclusions: Balance in remitting RRMS patients does not change significantly over 9 months and correlated well with EDSS scores. Our results indicate that balance control is a useful measure to assess recovery after a relapse, particularly in patients with unchanged EDSS scores. Based on our results, balance could be considered as additional measurement to assess recovery after a relapse, particularly in patients with unchanged EDSS. DOI: 10.3389/fneur.2018.00686 PMCID: PMC6110896


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Functional Connectivity Alterations Reveal Complex Mechanisms Based on Clinical and Radiological Status in Mild Relapsing Remitting Multiple Sclerosis.

Castellazzi G(1)(2), Debernard L(3)(4), Melzer TR(3)(4)(5), Dalrymple-Alford JC(3)(5)(6), D'Angelo E(7)(8), Miller DH(1)(3)(4), Gandini Wheeler-Kingshott CAM(1)(7)(9), Mason DF(3)(4)(10). Author information: (1)NMR Research Unit, Department of Neuroinflammation, Queen Square MS Centre, UCL Institute of Neurology, London, United Kingdom. (2)Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy. (3)New Zealand Brain Research Institute, Christchurch, New Zealand. (4)Department of Medicine, University of Otago, Christchurch, New Zealand. (5)Brain Research New Zealand, Auckland, New Zealand. (6)Department of Psychology, University of Canterbury, Christchurch, New Zealand. (7)Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. (8)Brain Connectivity Center, IRCCS Mondino Foundation, Pavia, Italy. (9)Brain MRI 3T Center, IRCCS Mondino Foundation, Pavia, Italy. (10)Department of Neurology, Christchurch Hospital, Christchurch, New Zealand. Resting state functional MRI (rs-fMRI) has provided important insights into functional reorganization in subjects with Multiple Sclerosis (MS) at different stage of disease. In this cross-sectional study we first assessed, by means of rs-fMRI, the impact of overall T2 lesion load (T2LL) and MS severity score (MSSS) on resting state networks (RSNs) in 62 relapsing remitting MS (RRMS) patients with mild disability (MSSS < 3). Independent Component Analysis (ICA) followed by dual regression analysis confirmed functional connectivity (FC) alterations of many RSNs in RRMS subjects compared to healthy controls. The anterior default mode network (DMNa) and the superior precuneus network (PNsup) showed the largest areas of decreased FC, while the sensory motor networks area M1 (SMNm1) and the medial visual network (MVN) showed the largest areas of increased FC. In order to better understand the nature of these alterations as well as the mechanisms of functional alterations in MS we proposed a method, based on linear regression, that takes into account FC changes and their correlation with T2LL and MSSS. Depending on the sign of the correlation between FC and T2LL, and furthermore the sign of the correlation with MSSS, we suggested the following possible underlying mechanisms to interpret altered FC: (1) FC reduction driven by MS lesions, (2) "true" functional compensatory mechanism, (3a) functional compensation attempt, (3b) "false" functional compensation, (4a) neurodegeneration, (4b) pre-symptomatic condition (damage precedes MS clinical manifestation). Our data shows areas satisfying 4 of these 6 conditions (i.e., 1,2,3b,4b), supporting the suggestion that increased FC has a complex nature that may exceed the simplistic assumption of an underlying compensatory mechanism attempting to limit the brain damage caused by MS progression. Exploring differences between RRMS subjects with short disease duration (MSshort) and RRMS with similar disability but longer disease duration (MSlong), we found that MSshort and MSlong were characterized by clearly distinct pattern of FC, involving predominantly sensory and cognitive networks respectively. Overall, these results suggest that the analysis of FC alterations in multiple large-scale networks in relation to radiological (T2LL) and clinical (MSSS, disease duration) status may provide new insights into the pathophysiology of relapse onset MS evolution. DOI: 10.3389/fneur.2018.00690 PMCID: PMC6109785


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113. Front Neurosci. 2018 Aug 29;12:622. doi: 10.3389/fnins.2018.00622. eCollection 2018.

Dysregulation of Astrocytic HMGB1 Signaling in Amyotrophic Lateral Sclerosis.

Brambilla L(1), Martorana F(1), Guidotti G(1), Rossi D(1). Author information: (1)Laboratory for Research on Neurodegenerative Disorders, IRCCS Istituti Clinici Scientifici Maugeri (ICS Maugeri), Pavia, Italy. Astrocytes have emerged as critical elements for the maintenance and function of the central nervous system. The expression on their cell membrane of RAGE and TLR4 receptors makes astrocytes susceptible to High-mobility group box 1 (HMGB1), a nuclear protein typically released in the extracellular milieu by living cells experiencing physiological stress conditions or by damaged cells. Here, we show that the interaction of HMGB1 with normal spinal cord astrocytes induces the astrocytic production of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Multiple investigations suggest a role for HMGB1 in amyotrophic lateral sclerosis (ALS). Yet, no mechanistic information on the implication of HMGB1 signaling in this disorder is currently available. We demonstrate that non-transgenic and transgenic SOD1WT spinal motor neurons exhibit only a basal nucleus-to-cytoplasm shuttling of the HMGB1 protein. Conversely, in SOD1G93A ALS mouse spinal cords, HMGB1 significantly translocates from the nucleus to the cytoplasm of motor neurons, thereby suggesting that it may be eventually released in the extracellular environment during the progression of the disease. We postulate that extracellular HMGB1 can paracrinally interact with the neighboring astrocytes in an attempt to counteract the neurodegenerative process. Yet, at variance with normal cells, SOD1G93A-expressing astrocytes show impaired capacity to raise BDNF and GDNF levels upon HMGB1 stimulation. Our data suggest that HMGB1 have a potential to promote neuroprotective actions by healthy astrocytes. However, this neurotrophic response is disrupted in ALS astrocytes. This indicates that diseased astroglial cells may exacerbate motor neuron degeneration in ALS because of the loss of their neurosupportive functions. DOI: 10.3389/fnins.2018.00622 PMCID: PMC6123379

114. Front Physiol. 2018 Aug 24;9:1177. doi: 10.3389/fphys.2018.01177. eCollection 2018.

The Role of Oxidative Stress in the Development of Systemic Sclerosis Related Vasculopathy.

Abdulle AE(1), Diercks GFH(2), Feelisch M(3), Mulder DJ(1), van Goor H(2). Author information: (1)Department of Internal Medicine, Division of Vascular Medicine, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands. (2)Section Pathology, Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands. (3)Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. Systemic sclerosis (SSc) is a rare connective tissue disease characterized by autoimmunity, vasculopathy, and progressive fibrosis typically affecting multiple organs including the skin. SSc often is a lethal disorder, because effective disease-modifying treatment still remains unavailable. Vasculopathy with endothelial dysfunction, perivascular infiltration of mononuclear cells, vascular wall remodeling and rarefaction of capillaries is the hallmark of the disease. Most patients present with vasospastic attacks of the digital arteries referred to as 'Raynaud's phenomenon,' which is often an indication of an underlying widespread vasculopathy. Although autoimmune responses and inflammation are both found to play an important role in the pathogenesis of this vasculopathy, no definite initiating factors have been identified. Recently, several studies have underlined the potential role of oxidative stress in the pathogenesis of SSc vasculopathy thereby proposing a new aspect in the pathogenesis of this disease. For instance, circulating levels of reactive oxygen species (ROS) related markers have been found to correlate with SSc vasculopathy, the formation of fibrosis and the production of autoantibodies. Excess ROS formation is well-known to lead to endothelial cell (EC) injury and vascular complications. Collectively, these findings suggest a potential role of ROS in the initiation and progression of SSc vasculopathy. In this review, we present the background of oxidative stress related processes (e.g., EC injury, autoimmunity, inflammation, and vascular wall remodeling) that may contribute to SSc vasculopathy. Finally, we describe the use of oxidative stress related read-outs as clinical biomarkers of disease activity and evaluate potential anti-oxidative strategies in SSc. DOI: 10.3389/fphys.2018.01177 PMCID: PMC6117399


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115. Front Psychiatry. 2018 Sep 7;9:422. doi: 10.3389/fpsyt.2018.00422. eCollection 2018.

Human Endogenous Retroviral Envelope Protein Syncytin-1 and Inflammatory Abnormalities in Neuropsychological Diseases.

Wang X(1)(2), Huang J(3), Zhu F(1)(4). Author information: (1)Department of Medical Microbiology, School of Medicine Wuhan University, Wuhan, China. (2)Department of Medical Laboratory, The Central Hospital of Wuhan Huazhong University of Science and Technology, Wuhan, China. (3)Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan Huazhong University of Science and Technology, Wuhan, China. (4)Hubei Province Key Laboratory of Allergy and Immunology Wuhan University, Wuhan, China. Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome. Recent studies have considered HERVs as potential pathogenic factors. The majority of HERV genes are mutated and not capable of encoding functional proteins; regardless, some HERV genes, such as HERV-W envelope (env) glycoprotein, are known to have intact open reading frames. The HERV-W element on 7q21.2, which encodes a protein referred to as Syncytin-1, participates in human placental morphogenesis and can activate a pro-inflammatory and autoimmune cascade. Neuropsychological disorders are typically linked to inflammatory abnormalities. In this study, we review that Syncytin-1 has been increasingly involved in the development of neuropsychological disorders, such as schizophrenia and multiple sclerosis (MS). This study also presents inflammation imbalances in schizophrenia and MS. More importantly, we discuss the potential role and molecular mechanisms by which Syncytin-1 regulates inflammatory abnormalities in neuropsychological diseases. In summary, Syncytin-1 activity may represent a novel molecular pathogenic mechanism in neuropyschological diseases, such as schizophrenia and MS. DOI: 10.3389/fpsyt.2018.00422 PMCID: PMC6137383

116. Glia. 2018 Sep 8. doi: 10.1002/glia.23484. [Epub ahead of print]

How to reprogram microglia toward beneficial functions.

Fumagalli M(1), Lombardi M(2), Gressens P(3)(4), Verderio C(2)(5). Author information: (1)Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti, 9 -20133, Milan, Italy. (2)IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy. (3)PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, 1141 Paris, France. (4)Centre for the Developing Brain, Department of Perinatal Health and Imaging, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, United Kingdom. (5)CNR Institute of Neuroscience, via Vanvitelli 32, 20129 Milan, Italy. Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders. © 2018 The Authors. Glia published by Wiley Periodicals, Inc. DOI: 10.1002/glia.23484


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Nav1.5 in astrocytes plays a sex-specific role in clinical outcomes in a mouse model of multiple sclerosis.

Pappalardo LW(1)(2), Samad OA(1)(2), Liu S(1)(2), Zwinger PJ(1)(2), Black JA(1)(2), Waxman SG(1)(2). Author information: (1)Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, 06510. (2)Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, Connecticut, 06516. Astrogliosis is a hallmark of neuroinflammatory disorders such as multiple sclerosis (MS). A detailed understanding of the underlying molecular mechanisms governing astrogliosis might facilitate the development of therapeutic targets. We investigated whether Nav1.5 expression in astrocytes plays a role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine model of MS. We created a conditional knockout of Nav1.5 in astrocytes and determined whether this affects the clinical course of EAE, focal macrophage and T cell infiltration, and diffuse activation of astrocytes. We show that deletion of Nav1.5 from astrocytes leads to significantly worsened clinical outcomes in EAE, with increased inflammatory infiltrate in both early and late stages of disease, unexpectedly, in a sex-specific manner. Removal of Nav1.5 in astrocytes leads to increased inflammation in female mice with EAE, including increased astroglial response and infiltration of T cells and phagocytic monocytes. These cellular changes are consistent with more severe EAE clinical scores. Additionally, we found evidence suggesting possible dysregulation of the immune response-particularly with regard to infiltrating macrophages and activated microglia-in female Nav1.5 KO mice compared with WT littermate controls. Together, our results show that deletion of Nav1.5 from astrocytes leads to significantly worsened clinical outcomes in EAE, with increased inflammatory infiltrate in both early and late stages of disease, in a sex-specific manner. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/glia.23470


Distinct patterns of glia repair and remyelination in antibody-mediated demyelination models of multiple sclerosis and neuromyelitis optica.

Liu Y(1), Given KS(2), Owens GP(1), Macklin WB(2)(3), Bennett JL(1)(4)(3). Author information: (1)Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado. (2)Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado. (3)Program in Neuroscience, University of Colorado School of Medicine, Aurora, Colorado. (4)Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Colorado. Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory demyelinating disorders of the central nervous system with evidence of antibody-mediated pathology. Using ex vivo organotypic mouse cerebellar slice cultures, we have demonstrated that recombinant antibodies (rAbs) cloned from cerebrospinal fluid plasmablasts of MS and NMO patients target myelin- and astrocyte-specific antigens to induce disease-specific oligodendrocyte loss and myelin degradation. In this study, we examined glial cell responses and myelin integrity during recovery from disease-specific antibody-mediated injury. Following exposure to MS rAb and human complement (HC) in cerebellar explants, myelinating oligodendrocytes repopulated the demyelinated tissue and formed new myelin sheaths along axons. Remyelination was accompanied by pronounced microglial activation. In contrast, following treatment with NMO rAb and HC, there was rapid regeneration of astrocytes and pre-myelinating oligodendrocytes but little formation of myelin sheaths on preserved axons. Deficient remyelination was associated with progressive axonal loss and the return of microglia to a resting state. Our results indicate that antibody-mediated demyelination in MS and NMO show distinct capacities for recovery associated with differential injury to adjacent axons and variable activation of microglia. Remyelination was rapid in MS rAb plus HC-induced demyelination. By contrast, oligodendrocyte maturation and remyelination failed following NMO rAb-mediated injury despite the rapid restoration of astrocytes and preservation of axons in early lesions. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/glia.23512


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The TAM receptor TYRO3 is a critical regulator of myelin thickness in the central nervous system.

Blades F(1), Aprico A(1), Akkermann R(2), Ellis S(3), Binder MD(1)(2), Kilpatrick TJ(1)(2). Author information: (1)Multiple Sclerosis division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia. (2)Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia. (3)Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). Major deficits arise in MS patients due to an inability to repair damaged myelin sheaths following CNS insult, resulting in prolonged axonal exposure and neurodegeneration. The TAM receptors (Tyro3, Axl, and Mertk) have been implicated in MS susceptibility, demyelination and remyelination. Previously, we have shown that Tyro3 regulates developmental myelination and myelin thickness within the optic nerve and rostral region of the corpus callosum (CC) of adult mice. In this study we have verified and extended our previous findings via a comprehensive analysis of axonal ensheathment and myelin thickness in the CC of unchallenged mice, following demyelination and during myelin repair. We show that the loss of the Tyro3 receptor correlates with significantly thinner myelin sheaths in both unchallenged mice and during remyelination, particularly in larger caliber axons. The hypomyelinated phenotype observed in the absence of Tyro3 occurs independently of any influence upon oligodendrocyte precursor cell (OPC) maturation, or density of oligodendrocytes (OLs) or microglia. Rather, the primary effect of Tyro3 is upon the radial expansion of myelin. The loss of Tyro3 leads to a reduction in the number of myelin lamellae on axons, and is therefore most likely a key component of the regulatory mechanism by which oligodendrocytes match myelin production to axonal diameter. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/glia.23481

120. Health Policy. 2018 Sep 6. pii: S0168-8510(18)30440-8. doi: 10.1016/j.healthpol.2018.08.019. [Epub ahead of print]

Value assessment of disease-modifying therapies for Relapsing-Remitting Multiple Sclerosis: HTA evidence from seven OECD countries.

Visintin E(1), Tinelli M(2), Kanavos P(3). Author information: (1)Department of Health Policy, Medical Technology Research Group, LSE Health, London School of Economics, Houghton Street, London WC2A 2AE, England, United Kingdom. Electronic address: [email protected]. (2)Department of Health Policy, Medical Technology Research Group, LSE Health, London School of Economics, Houghton Street, London WC2A 2AE, England, United Kingdom. Electronic address: [email protected]. (3)Department of Health Policy, Medical Technology Research Group, LSE Health, London School of Economics, Houghton Street, London WC2A 2AE, England, United Kingdom. Electronic address: [email protected]. This study systematically compares HTA recommendations on a number of disease-modifying therapies for patients with Relapsing-Remitting Multiple Sclerosis. We analysed publicly available HTA reports for nine medicine-indication pairs across seven OECD countries using a methodological framework enabling systematic analysis of HTA recommendations. The analysis was conducted based on a number of value dimensions, including clinical and economic variables, as well as several other dimensions of value beyond cost-effectiveness. The material was qualitatively and quantitatively coded following the different stages of HTA decision-making process. Fifty-seven medicine-indication pairs were assessed across the study countries. Of those, eight medicine indication-pairs reported diverging HTA recommendations. Although HTA recommendations were based on the same evidence submitted in most cases, significant variations were identified in interpretation and acceptance of evidence resulting in different uncertainties raised and different ways of addressing them. Uncertainties arose both in terms of the clinical and the economic evidence, including the design of key trials or the data quality in economic models. Beyond costs and effects, additional dimensions of value had an impact in the direction of recommendations, however with different magnitude across countries. We show that there is heterogeneity across countries in HTA for evaluating DMTs for RRMS with a lack of standardised methods in evaluating clinical and economic evidence and the use of social value judgments to inform decision-making. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.healthpol.2018.08.019


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121. Histochem Cell Biol. 2018 Sep 15. doi: 10.1007/s00418-018-1722-5. [Epub ahead of print]

The peroxisome: an update on mysteries 2.0.

Islinger M(1), Voelkl A(2), Fahimi HD(2), Schrader M(3). Author information: (1)Institute of Neuroanatomy, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Manheim, University of Heidelberg, 68167, Mannheim, Germany. (2)Institute for Anatomy and Cell Biology, University of Heidelberg, 69120, Heidelberg, Germany. (3)Biosciences, University of Exeter, Exeter, EX4 4QD, UK. [email protected]. Peroxisomes are key metabolic organelles, which contribute to cellular lipid metabolism, e.g. the β-oxidation of fatty acids and the synthesis of myelin sheath lipids, as well as cellular redox balance. Peroxisomal dysfunction has been linked to severe metabolic disorders in man, but peroxisomes are now also recognized as protective organelles with a wider significance in human health and potential impact on a large number of globally important human diseases such as neurodegeneration, obesity, cancer, and age-related disorders. Therefore, the interest in peroxisomes and their physiological functions has significantly increased in recent years. In this review, we intend to highlight recent discoveries, advancements and trends in peroxisome research, and present an update as well as a continuation of two former review articles addressing the unsolved mysteries of this astonishing organelle. We summarize novel findings on the biological functions of peroxisomes, their biogenesis, formation, membrane dynamics and division, as well as on peroxisome-organelle contacts and cooperation. Furthermore, novel peroxisomal proteins and machineries at the peroxisomal membrane are discussed. Finally, we address recent findings on the role of peroxisomes in the brain, in neurological disorders, and in the development of cancer. DOI: 10.1007/s00418-018-1722-5

122. Hum Brain Mapp. 2018 Sep 21. doi: 10.1002/hbm.24343. [Epub ahead of print]

Education, and the balance between dynamic and stationary functional connectivity jointly support executive functions in relapsing-remitting multiple sclerosis.

Lin SJ(1)(2), Vavasour I(3), Kosaka B(4), Li DKB(3)(5), Traboulsee A(5), MacKay A(3)(6), McKeown MJ(1)(2)(5). Author information: (1)Graduate Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada. (2)Pacific Parkinson's Research Centre, University of British Columbia Hospital, Vancouver, British Columbia, Canada. (3)Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada. (4)Department of Psychiatry, University of British Columbia Hospital, Vancouver, British Columbia, Canada. (5)Faculty of Medicine, Neurology, University of British Columbia, Vancouver, British Columbia, Canada. (6)Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada. Graphical network characteristics and nonstationary functional connectivity features, both derived from resting-state functional magnetic resonance imaging (rsfMRI) data, have been associated with cognitive performance in healthy subjects. How these features jointly relate to cognition in diseased states has not been investigated. In this study, 46 relapsing-remitting multiple sclerosis subjects underwent rsfMRI scans and a focused cognitive battery. With a sliding window approach, we examined six dynamic network features that indicated how connectivity changed over time as well as six measures derived from graph theory to reflect static network characteristics. Multiset canonical correlation analysis (MCCA) was then carried out to investigate the relations between dynamic network features, stationary network characteristics, cognitive testing, demographic, disease severity, and mood. Multiple sclerosis (MS) subjects demonstrated weaker connectivity strength, decreased network density, reduced global changes, but increased changes in interhemispheric connectivity compared to controls. The MCCA model determined that executive functions and processing speed ability measured by Wechsler Adult Intelligence Scale IV (WAIS-IV) Working Memory Index, WAIS-IV Processing Speed Index, and the Verbal Fluency Test were positively correlated with education, dynamic connectivity, and static connectivity strength; while poor task switching was correlated with disease severity, psychiatric comorbidities such as depression, anxiety, and fatigue, and static network density. Taken together, our results suggest that better executive functioning in MS requires maintenance of a continued coordination between stationary and dynamic functional connectivity as well as the support of education, and dynamic functional connectivity may provide an additional cognitive biomarker of disease severity in the MS population. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/hbm.24343


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123. Hum Mol Genet. 2018 Sep 13. doi: 10.1093/hmg/ddy326. [Epub ahead of print]

Nuclear localization and phosphorylation modulate pathological effects of Alpha-Synuclein.

Pinho R(1)(2), Paiva I(1), Jercic KG(3), Fonseca-Ornelas L(4), Gerhardt E(1), Fahlbusch C(1), Garcia-Esparcia P(5), Kerimoglu C(6), Pavlou MA(1), Villar-Piqué A(1), Szego É(1), Fonseca TL(1), Odoardi F(7), Soeroes S(8)(9), Rego AC(10), Fischle W(8)(11), Schwamborn JC(12), Meyer T(13), Kügler S(14), Ferrer I(5), Attems J(15), Fischer A(6)(16), Becker S(4), Zweckstetter M(4)(14)(17), Borovecki F(3)(18), Outeiro TF(1)(15)(19)(20). Author information: (1)Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany. (2)Faculty of Medicine, University of Porto,4200 - 319, Porto, Portugal. (3)Department for Functional Genomics, Center for Translational and Clinical Research, University Hospital Center Zagreb, University of Zagreb School of Medicine, 10 000, Zagreb, Croatia. (4)Max Planck Institute for Biophysical Chemistry, 37077, Göttingen, Germany. (5)Institute of Neuropathology,Bellvitge University Hospital, University of Barcelona, Bellvitge Biomedical Research Institute, Hospitalet de Llobregat; Biomedical Research Center of Neurodegenerative Diseases, 08908, Barcelona, Spain. (6)Department for Psychiatry and Psychotherapy, University Medical Center, 37075, Göttingen, Germany. (7)Institute of Neuroimmunology and Institute for Multiple Sclerosis Research,University Medical Centre Göttingen, 37073, Göttingen, Germany. (8)Max Planck Institute for Biophysical Chemistry,Laboratory of Chromatin Biochemistry, 37077, Göttingen, Germany. (9)Oxford Nanopore Technologies LTD, OX4 4DQ, Oxford, United Kingdom. (10)Center for Neuroscience and Cell Biology and Faculty of Medicine, University of Coimbra, 3004-517, Coimbra, Portugal. (11)King Abdullah University of Science and Technology (KAUST),Environmental Epigenetics Program, 23955, Thuwal, Saudi Arabia. (12)Development and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 2721, Esch-sur-Alzette, Luxembourg. (13)Klinik für Psychosomatische Medizin und Psychotherapie, Universitätsmedizin Göttingen, 37073, Göttingen, Germany. (14)Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany. (15)Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, NE1 7RU, Newcastle upon Tyne, United Kingdom. (16)Department of Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany. (17)Structural Biology in Dementia, German Center for Neurodegenerative Diseases (DZNE), 37075, Göttingen, Germany. (18)Department of Neurology, University Hospital Center Zagreb, 10 000, Zagreb, Croatia. (19)Chronic Disease Research Center (CEDOC), NOVA Medical School, 1150-082, Lisboa, Portugal and. (20)Max Planck Institute for Experimental Medicine, 37075, Göttingen, Germany. Alpha-synuclein (aSyn) is a central player in Parkinson's disease (PD) but the precise molecular mechanisms underlying its pathogenicity remain unclear. It has recently been suggested that nuclear aSyn may modulate gene expression, possibly via interactions with DNA. However, the biological behavior of aSyn in the nucleus and the factors affecting its transcriptional role are not known. Here, we investigated the mechanisms underlying aSyn-mediated transcription deregulation by assessing its effects in the nucleus and the impact of phosphorylation in these dynamics. We found that aSyn induced severe transcriptional deregulation, including the downregulation of important cell cycle-related genes. Importantly, transcriptional deregulation was concomitant with reduced binding of aSyn to DNA. By forcing the nuclear presence of aSyn in the nucleus (aSyn-NLS), we found the accumulation of high molecular weight aSyn species altered gene expression and reduced toxicity when compared to the wild-type or exclusively cytosolic protein. Interestingly, nuclear localization of aSyn, and the effect on gene expression and cytotoxicity, was also modulated by phosphorylation on serine 129. Thus, we hypothesize that the role of aSyn on gene expression and, ultimately, toxicity, may be modulated by the phosphorylation status and nuclear presence of different aSyn species. Our findings shed new light onto the subcellular dynamics of aSyn and unveil an intricate interplay between subcellular location, phosphorylation, and toxicity, opening novel avenues for the design of future strategies for therapeutic intervention in PD and other synucleinopathies. DOI: 10.1093/hmg/ddy326


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124. Hum Vaccin Immunother. 2018 Sep 27. doi: 10.1080/21645515.2018.1528835. [Epub ahead of print]

HBV vaccine and risk of developing multiple sclerosis: a systematic review and meta-analysis.

Sestili C(1), Grazina I(2), La Torre G(1). Author information: (1)a Department of Public Health and Infectious Diseases , Sapienza University , Rome. (2)b University of Lisbon. Hepatitis B virus (HBV) infection is one the most common in the world. Aim of this study is to perform a systematic review on the relationship between HBV vaccination and multiple sclerosis. Research was conducted on Pubmed, ISI Web of Science, and Scopus. Terms "hepatitis b vaccination" and "multiple sclerosis" were used. Meta-analysis and metaregression were performed. 414 papers were found. Seven articles were selected. For the reported crude risk estimates for MS no statistically significant association was observed with pooled OR 1,19 (95%CI: 0,96-1,49). For the adjusted ORs, the pooled odds ratio (OR) was 0, 965 (95%CI: 0,886- 1,051). Meta regression show that year of publication is negatively (β: -0,019; P < 0.001) and NOS score and publishing in Europe are positively associated with O.R. value. Funnel plot showed the presence of publication bias. Results showed that Hepatitis B vaccination is not associated with an increased risk of developing MS. DOI: 10.1080/21645515.2018.1528835

125. Immunology. 2018 Sep 17. doi: 10.1111/imm.13004. [Epub ahead of print]

Impact of sex hormones on immune function and MS development.

Ysrraelit MC(1), Correale J(1). Author information: (1)Department of Neurology, Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires, Argentina. Multiple sclerosis (MS) is a chronic inflammatory disease of the Central Nervous System (CNS) affecting young people and leading to demyelination and neurodegeneration. The disease is clearly more common in women in whom incidence has been rising. Gender differences include: earlier disease onset and more frequent relapses in women; and faster progression and worse outcomes in men. Hormone-related physiological conditions in women such as puberty, pregnancy, puerperium and menopause also exert significant influence both on disease prevalence as well as on outcomes. Hormonal and/or genetic factors are therefore believed to be involved in regulating the course of disease. In this review, we discuss clinical evidence of sex hormone (estrogens, progesterone, prolactin and testosterone) impact on MS, and attempt to elucidate hormonal and immunological mechanisms potentially underlying these changes. We also review current knowledge on the relationship between sex hormones and resident CNS cells, and provide new insights in the context of MS. Understanding these molecular mechanisms may contribute to the development of new and safer treatments for both men and women. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. DOI: 10.1111/imm.13004


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126. Ind Health. 2018 Sep 21. doi: 10.2486/indhealth.2017-0214. [Epub ahead of print]

Improving the job-retention strategies in multiple sclerosis workers: the role of occupational physicians.

Persechino B(1), Fontana L(1), Buresti G(1), Fortuna G(1), Valenti A(1), Iavicoli S(1). Author information: (1)INAIL, Italian Workers' Compensation Authority, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Italy. Several studies evaluated whether a person with multiple sclerosis is employed or not and investigated the main symptoms that hinder the job performance. However, despite occupational physicians are fundamental in managing disabled subjects, there is a serious lack of data regarding their role in improving employability of these workers. In this regard, we assessed occupational physicians' professional activity and training/updating needs in order to identify and develop management tools, operative procedures and training programs helpful to support and implement adequate job-retention strategies. 403 Italian occupational physicians compiled a self-administered questionnaire to evaluate individual demographics, health surveillance system, fitness for work and training needs. Our findings confirmed the suitability to adopt environmental adjustments at workplace (particularly referring to the ergonomics of workstation, the typology of occupational risk factors and the working time) to accommodate individual's needs in order to improve working ability among multiple sclerosis workers. Moreover, training events discussing operational guidelines and standardized instruments and/or methodologies to adequately manage the disable workers should be fostered. Therefore, in this regard, occupational physicians could play a key role but they need more high-quality training especially concerning the different tools that are currently available to assess the work issues in multiple sclerosis patients. DOI: 10.2486/indhealth.2017-0214

127. Indian J Microbiol. 2018 Dec;58(4):496-506. doi: 10.1007/s12088-018-0754-9. Epub 2018 Jul 12.

Terminalia chebula Retz. Fruit Extracts Inhibit Bacterial Triggers of Some Autoimmune Diseases and Potentiate the Activity of Tetracycline.

Mandeville A(1), Cock IE(1)(2). Author information: (1)1School of Natural Sciences, Nathan Campus, Griffith University, 170 Kessels Rd, Nathan, QLD 4111 Australia. (2)2Environmental Futures Research Institute, Nathan Campus, Griffith University, 170 Kessels Rd, Nathan, QLD 4111 Australia. Terminalia chebula Retz. is a northern Indian plant species known for its anti-inflammatory and antimicrobial properties. T. chebula fruit powder was extracted with solvents of varying polarity and screened for bacterial growth inhibition by disc diffusion assay. The minimum inhibitory concentration (MIC) was quantified by both liquid dilution and disc diffusion techniques. To screen for combinatorial effects, the T. chebula fruit extracts were combined with a range of conventional antibiotics and tested against each bacteria using a liquid dilution assay. Where synergy was detected, the optimal ratios were determined using isobologram analysis. Toxicity was examined using Artemia nauplii and HDF bioassays. T. chebula fruit methanolic, aqueous and ethyl acetate extracts displayed strong antimicrobial activity against the bacterial triggers of all autoimmune inflammatory diseases except K. pneumoniae, for which only moderate inhibition was observed. Indeed, MIC values as low as 195 μg/mL were measured for the aqueous extract against a resistant strain of P. aeruginosa. Of further note, both the aqueous and ethyl acetate extracts interacted synergistically in combination with tetracycline against K. pneumoniae (Σ FIC 0.38 and 0.25 respectively). All extracts were nontoxic in the Artemia and HDF toxicity assays, further indicating their potential for medicinal use. DOI: 10.1007/s12088-018-0754-9 PMCID: PMC6141404 [Available on 2019-12-01]


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128. Inflamm Res. 2018 Sep 3. doi: 10.1007/s00011-018-1185-0. [Epub ahead of print]

A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future.

Gholamzad M(1), Ebtekar M(2), Ardestani MS(3), Azimi M(4), Mahmodi Z(5), Mousavi MJ(4)(6)(7), Aslani S(4)(7). Author information: (1)Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Khaghani St., Shariati Ave., P.O Box: 19395/1495, Tehran, Iran. [email protected]. (2)Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. (3)Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. (4)Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. (5)Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Khaghani St., Shariati Ave., P.O Box: 19395/1495, Tehran, Iran. (6)Department of Hematology, Faculty of Allied Medicine, Bushehr University of Medical Sciences, Bushehr, Iran. (7)Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran. BACKGROUND: Multiple sclerosis (MS) is a chronic and autoimmune disease of the central nervous system (CNS), mainly characterized by inflammatory demyelination, which manifests as relapses and diffuse damage and brain volume loss, both accounting for neurodegeneration, and therefore, physical disability. MS typically affects young adults and is commonly diagnosed in the early years by acute relapses, which then followed through partial or complete remission period. The clinical course of MS is characterized as four major classifications, including relapsing-remitting (RRMS), primary progressive (PPMS), progressive relapsing (PRMS), and secondary progressive (SPMS). PURPOSE: This review provides comprehensive overview of the current treatments and future innovative approaches in the treatment of MS. RESULTS: Currently, there is no definite cure for MS. The treatment of MS has mainly been based on the prescription of immunosuppressive and immune-modulating agents. However, a number of disease-modifying treatments (DMTs) have been designed that reduce the attack rate and delay progression and mainly target inflammation settings in these patients. Although remarkable advancements have occurred in the therapy of MS, the rate of progressive disability and early mortality is still worrisome. Recently, a monoclonal antibody (ocrelizumab) was demonstrated to be beneficial in a clinical trial of primary progressive MS. Furthermore, novel treatment strategies concentrating on the remyelination or neuroprotection are under evaluation. CONCLUSIONS: In spite of prosperous experiences in MS therapy, the future research, hopefully, will bring substantial improvements in the understanding and approaches of MS therapy. DOI: 10.1007/s00011-018-1185-0


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129. Inflammation. 2018 Sep 3. doi: 10.1007/s10753-018-0872-x. [Epub ahead of print]

Immunoregulatory Effects of Silymarin on Proliferation and Activation of Th1 Cells Isolated from Newly Diagnosed and IFN-ß1b-Treated MS Patients.

Navabi F(1), Shaygannejad V(2)(3), Abbasirad F(1), Vaez E(1), Hosseininasab F(1), Kazemi M(2), Mirmosayyeb O(2)(4), Alsahebfosoul F(1), Esmaeil N(5). Author information: (1)Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 81744-176, Iran. (2)Isfahan Neurosciences Research Center, Alzahra Hospital, Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran. (3)Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. (4)Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran. (5)Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 81744-176, Iran. [email protected]. Multiple sclerosis (MS) is a central nervous system autoimmune disease characterized by demyelination. Autoreactive T cells mainly interferon gamma (IFN-γ) producing T helper cells (Th1) have an important role in MS pathogenesis. Silymarin is a unique blend produced from milk thistle (Silybum marianum) plant which its imunomodulatory role has been indicated in studies. In the present study, the effects of silymarin on isolated Th1 cells were investigated in newly diagnosed MS patients and those who received betaferon. PBMCs were separated from newly diagnosed and IFN-β-treated MS patients. The Th1 cell isolation from PBMCs was performed using a human Th1 cell isolation kit. Th1 cells were cultured in the presence of silymarin (50, 100, and 150 μM for 48, 72, and 120 h). Th1 cell proliferation and CD69 expression were assessed by flow cytometry. Also, IFN-γ production and T-bet gene expression were measured by ELISA and real-time PCR respectively. In vitro cultured Th1 cells showed that silymarin suppresses Th1 cell proliferation dose and time dependently in newly diagnosed and IFN-β-treated MS patients in comparison to DMSO control. Also, CD69 expression as an early activation marker was changed after Th1 cell treatment with different doses of silymarin at different times. T-bet gene expression was significantly decreased in Th1 cells isolated from newly diagnosed and IFN-β-treated RRMS patients after treatment with silymarin compared to DMSO control. Additionally, IFN-γ production by Th1 cells was decreased after treatment silymarin in newly diagnosed patients; however, in IFN-β treated after 48-h treatment with silymarin, IFN-γ concentration was decreased at concentrations of 100 and 150 μM, and after 120 h, a significant increase was observed in the IFN-γ level at a concentration of 100 μM in comparison with DMSO. Our findings here clearly show that silymarin is an effective regulator for Th1 response in vitro condition. It not only suppresses Th1 proliferating activity but also inhibits T-bet gene expression and IFN-γ production by these cells. DOI: 10.1007/s10753-018-0872-x

130. Inflammopharmacology. 2018 Sep 12. doi: 10.1007/s10787-018-0528-3. [Epub ahead of print]

Early P2X7R-dependent activation of microglia during the asymptomatic phase of autoimmune encephalomyelitis.

Grygorowicz T(1), Strużyńska L(2). Author information: (1)Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego str., 02-106, Warsaw, Poland. (2)Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawińskiego str., 02-106, Warsaw, Poland. [email protected]. Microglia-mediated neuroinflammation accompanies many central nervous system (CNS) diseases, including multiple sclerosis (MS), and is strongly dependent on the purinergic P2X7 receptor. The nature of the inflammatory response in MS is studied for decades indicating, that proinflammatory microgliosis is involved in advanced stages of MS and is associated with active tissue damage and neurological dysfunctions. Evidence on the role of microgliosis in initial stages of the disease is scarce. Thus, in the present study, we investigated the time course of microglial activation in rat brain subjected to experimental autoimmune encephalomyelitis (EAE) which is the animal model of MS. We show that activation of microglia occurs in brains of immunized rats at a very early stage of EAE, well before the development of neurological symptoms of the disease. Enhanced immunoreactivity of microglia/macrophage-specific protein Iba-1, together with morphological features of microgliosis, was identified beginning at day 4 post immunization. Concomitantly, microglial expression of P2X7R was also examined. Moreover, our results reveal that administration of Brilliant Blue G, an antagonist of P2X7R, delays the onset of the disease and partially inhibits development of neurological symptoms in EAE rats. Blockage of P2X7R significantly reduces activation of microglia as confirmed by decreased Iba-1 immunoreactivity and suppresses neuroinflammation in EAE rat brains, as indicated by decreased protein levels of investigated proinflammatory cytokines: IL-1β, IL-6 and TNF-α. Our results indicate that microglia are involved in inducing neuroinflammation at a very early stage of MS/EAE via a P2X7R-dependent mechanism. DOI: 10.1007/s10787-018-0528-3


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131. Int Immunopharmacol. 2018 Sep 12;64:275-279. doi: 10.1016/j.intimp.2018.09.014. [Epub ahead of print]

Polymorphisms in the angiotensin I converting enzyme (ACE) gene are associated with multiple sclerosis risk and response to Interferon-β treatment.

Yaeghmaie R(1), Ghafouri-Fard S(2), Noroozi R(3), Tavakoli F(1), Taheri M(4), Ayatollahi SA(5). Author information: (1)Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. (2)Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (3)Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (4)Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: [email protected]. (5)Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Chemistry, Richardson College of the Environmental Science Complex, The University of Winnipeg, Winnipeg, Canada. Electronic address: [email protected]. BACKGROUND: Multiple sclerosis (MS) as a chronic autoimmune demyelinating disorder of the central nervous system has been associated with numerous genetic and environmental factors among them are functional variants within the angiotensin I converting enzyme (ACE) gene. METHODS: In the present study, we genotyped the rs4359 (C/T) and rs1799752 (Insertion (I)/Deletion (D)) of this gene in 391 MS patients and 380 age- and sex-matched controls. RESULTS: We found significant overrepresentation of the I allele of the rs1799752 in MS patients compared with healthy subjects (Adjusted P value = 0.03, OR (95% CI) = 1.28 (1.05-1.57). The same allele was associated with MS risk in co-dominant and dominant models (Adjusted P values of 0.007 and 0.002 respectively). The allele and genotype frequencies of the rs4359 were not significantly different between cases and controls. Moreover, the I allele of the rs1799752 was significantly overrepresented in MS patients who were irresponsive to IFN-β compared with healthy subjects (Adjusted P value = 0.04, OR (95% CI) = 1.57 (1.08-2.29)). The same allele was associated with irresponsiveness to IFN-β in dominant model (Adjusted P value = 0.02, OR (95% CI) = 2.32 (1.22-4.42)). CONCLUSION: The present study provides further evidences for the role of ACE in MS risk or response of patients to IFN-β treatment. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.intimp.2018.09.014

132. Int J Genomics. 2018 Sep 4;2018:5121540. doi: 10.1155/2018/5121540. eCollection 2018.

Common DNA Variants Accurately Rank an Individual of Extreme Height.

Sexton CE(1), Ebbert MTW(2), Miller RH(3), Ferrel M(1), Tschanz JAT(4)(5), Corcoran CD(5)(6); Alzheimer's Disease Neuroimaging Initiative, Ridge PG(1), Kauwe JSK(1). Author information: (1)Department of Biology, Brigham Young University, Provo, UT 84602, USA. (2)Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. (3)Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA. (4)Department of Psychology, Utah State University, Logan, UT, USA. (5)Center for Epidemiologic Studies, Utah State University, Logan, UT, USA. (6)Department of Mathematics and Statistics, Utah State University, Logan, UT, USA. Polygenic scores (or genetic risk scores) quantify the aggregate of small effects from many common genetic loci that have been associated with a trait through genome-wide association. Polygenic scores were first used successfully in schizophrenia and have since been applied to multiple phenotypes including multiple sclerosis, rheumatoid arthritis, and height. Because human height is an easily-measured and complex polygenic trait, polygenic height scores provide exciting insights into the predictability of aggregate common variant effect on the phenotype. Shawn Bradley is an extremely tall former professional basketball player from Brigham Young University and the National Basketball Association (NBA), measuring 2.29 meters (7'6″, 99.99999th percentile for height) tall, with no known medical conditions. Here, we present a case where a rare combination of common SNPs in one individual results in an extremely high polygenic height score that is correlated with an extreme phenotype. While polygenic scores are not clinically significant in the average case, our findings suggest that for extreme phenotypes, polygenic scores may be more successful for the prediction of individuals. DOI: 10.1155/2018/5121540 PMCID: PMC6142724


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133. Int J Health Geogr. 2018 Sep 14;17(1):34. doi: 10.1186/s12942-018-0154-8.

Spatial analyzes of HLA data in Rio Grande do Sul, south Brazil: genetic structure and possible correlation with autoimmune diseases.

Boquett JA(1)(2), Zagonel-Oliveira M(1)(3), Jobim LF(4), Jobim M(4), Gonzaga L Jr(1)(3), Veronez MR(1)(3), Fagundes NJR(1)(2), Schüler-Faccini L(5)(6). Author information: (1)Instituto Nacional de Genética Médica Populacional (INaGeMP), Porto Alegre, Brazil. (2)Post-Graduate Program in Genetics and Molecular Biology, Departamento de Genética, Universidade Federal do Rio Grande do Sul, Agencia Campus UFRGS, Caixa Postal 15053, Porto Alegre, RS, CEP 91501-970, Brazil. (3)Advanced Visualization and Geoinformatics Laboratory (VIZLab), Applied Computing Graduate Program, Universidade do Vale do Rio dos Sinos, São Leopoldo, RS, Brazil. (4)Department of Immunology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. (5)Instituto Nacional de Genética Médica Populacional (INaGeMP), Porto Alegre, Brazil. [email protected]. (6)Post-Graduate Program in Genetics and Molecular Biology, Departamento de Genética, Universidade Federal do Rio Grande do Sul, Agencia Campus UFRGS, Caixa Postal 15053, Porto Alegre, RS, CEP 91501-970, Brazil. [email protected]. BACKGROUND: HLA genes are the most polymorphic of the human genome and have distinct allelic frequencies in populations of different geographical regions of the world, serving as genetic markers in ancestry studies. In addition, specific HLA alleles may be associated with various autoimmune and infectious diseases. The bone marrow donor registry in Brazil is the third largest in the world, and it counts with genetic typing of HLA-A, -B, and -DRB1. Since 1991 Brazil has maintained the DATASUS database, a system fed with epidemiological and health data from compulsory registration throughout the country. METHODS: In this work, we perform spatial analysis and georeferencing of HLA genetic data from more than 86,000 bone marrow donors from Rio Grande do Sul (RS) and data of hospitalization for rheumatoid arthritis, multiple sclerosis and Crohn's disease in RS, comprising the period from 1995 to 2016 obtained through the DATASUS system. The allele frequencies were georeferenced using Empirical Bayesian Kriging; the diseases prevalence were georeferenced using Inverse Distance Weighted and cluster analysis for both allele and disease were performed using Getis-Ord Gi* method. Spearman's test was used to test the correlation between each allele and disease. RESULTS: The results indicate a HLA genetic structure compatible with the history of RS colonization, where it is possible to observe differentiation between regions that underwent different colonization processes. Spatial analyzes of autoimmune disease hospitalization data were performed revealing clusters for different regions of the state for each disease analyzed. The correlation test between allelic frequency and the occurrence of autoimmune diseases indicated a significant correlation between the HLA-B*08 allele and rheumatoid arthritis. CONCLUSIONS: Genetic mapping of populations and the spatial analyzes such as those performed in this work have great economic relevance and can be very useful in the formulation of public health campaigns and policies, contributing to the planning and adjustment of clinical actions, as well as informing and educating professionals and the population. DOI: 10.1186/s12942-018-0154-8 PMCID: PMC6137739


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134. Int J Immunogenet. 2018 Sep 28. doi: 10.1111/iji.12401. [Epub ahead of print]

Association of nod-like receptor protein-3 single nucleotide gene polymorphisms and expression with the susceptibility to relapsing-remitting multiple sclerosis.

Imani D(1), Azimi A(2)(3), Salehi Z(1), Rezaei N(1)(4), Emamnejad R(5), Sadr M(4), Izad M(1)(3). Author information: (1)Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. (2)Neurology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. (3)MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. (4)Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran. (5)Immunology Department, School of Medicine, Shahre-Kord University of Medical Sciences, Shahre-Kord, Iran. Nod-like receptor protein 3 (NLRP3) inflammasome is a multi-protein complex that controls the production of pro-inflammatory cytokines, IL-18 and IL-1β, through caspase-1 activation. These inflammatory cytokines play an important role in the development of multiple sclerosis (MS). The inflammasome NLRP3 gene variations and expression level have been suggested to affect the immune system activity. This case-control study was performed to determine the association of NLRP3 genetic variants and differential expression with MS. We analysed four common single nucleotide polymorphisms (SNPs) of NLRP3 (rs-10754558, rs-35829419, rs-3806265, rs-4612666) in a group of 150 Iranian patients with relapsing-remitting MS (RRMS) in comparison with 100 healthy controls. The genotyping was performed using the TaqMan method. For the analysis of NLRP3 gene expression level, we studied a group of 37 RRMS patients (18 patients at relapse phase and 19 at remission phase, treated with IFN-β) in comparison with 22 healthy controls using real-time PCR. In this study, we found that NLRP3 rs3806265 C allele and CC genotype were significantly more frequent in the RRMS patients (p value = 0.03 OR = 1.66, 95% CI = 1.14-2.43) and p value = 0.04, OR = 3.26, 95% CI = 1.19-8.93, respectively), while the frequency of T allele significantly decreased in controls (p value = 0.03, OR = 0.6, 95% CI = 0.41-0.87). The frequency of CG genotype at position rs10754558 was also significantly higher in the controls compared with patients (p value = 0.03, OR = 0.5, 95% CI = 0.30-0.80). Moreover, expression level of the NLRP3 in patients at remission phase was significantly reduced in comparison with patients at relapse phase and also healthy controls (p = 0.01 and p = 0.04, respectively). The association of NLRP3 polymorphisms with the susceptibility of MS and its reduced expression after IFN-β therapy, support the idea that NLRP3 inflammasome could have a critical role in inflammatory responses in MS. © 2018 John Wiley & Sons Ltd. DOI: 10.1111/iji.12401

135. Int J Integr Care. 2018 Jul 5;18(3):3. doi: 10.5334/ijic.3745.

Advancing a Systemic Perspective on Multidisciplinary Teams: A Comparative Case Study of Work Organisation in Four Multiple Sclerosis Hospitals.

Pless S(1), Van Hootegem G(2), Dessers E(1). Author information: (1)Centre for Sociological Research, KU Leuven, Parkstraat 45, Leuven 3000, BE. (2)Centre for Sociological Research, HIVA Research Institute for Work and Society, KU Leuven, Parkstraat 45, Leuven 3000, BE. Introduction: Many care organisations claim to employ multidisciplinary teams, but the term is used to describe quite different forms of collaboration. A systemic view of the work organisation of care delivery is presented and applied in this article that allows to identify and understand often overlooked yet important differences regarding team composition, working relationships and therapeutic relationships. Theory and Methods: We used modern socio-technical systems theory to study care delivery for a particular patient population as a system of interrelated activities. The concept of work organisation refers to the way in which the composite task of care delivery is divided into distinct tasks and how these are grouped in either monodisciplinary or multidisciplinary organisational units. The systemic perspective was applied in a comparative case study of four Multiple Sclerosis hospitals. Results: Among the hospitals, one was characterised by a functional work organisation, with similar tasks grouped in monodisciplinary teams. Cross-disciplinary working and therapeutic relationships were established on an ad hoc basis. The three other hospitals adopted a more process-oriented work organisation (which groups all tasks related to a specific care process within a single, multidisciplinary team). The more process-oriented the work organisation, the more working relationships and therapeutic relationships appeared to be fixed and continuous. Conclusion and discussion: The systemic view adopted in this study yields a better understanding of multidisciplinary teams through the concept of work organisation. The actual composition of multidisciplinary teams, and the related working and therapeutic relationships will vary depending on the type of underlying work organisation. Further validation of this conclusion will be needed in other settings. DOI: 10.5334/ijic.3745 PMCID: PMC6133025


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136. Int J Mol Sci. 2018 Sep 27;19(10). pii: E2937. doi: 10.3390/ijms19102937.

Ageing, Cellular Senescence and Neurodegenerative Disease.

Kritsilis M(1), V Rizou S(2), Koutsoudaki PN(3), Evangelou K(4), Gorgoulis VG(5), Papadopoulos D(6). Author information: (1)Laboratory of Histology & Embryology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 115-27 Athens, Greece. [email protected]. (2)Laboratory of Histology & Embryology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 115-27 Athens, Greece. [email protected]. (3)Laboratory of Histology & Embryology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 115-27 Athens, Greece. [email protected]. (4)Laboratory of Histology & Embryology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 115-27 Athens, Greece. [email protected]. (5)Laboratory of Histology & Embryology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 115-27 Athens, Greece. [email protected]. (6)Laboratory of Histology & Embryology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, 115-27 Athens, Greece. [email protected]. Ageing is a major risk factor for developing many neurodegenerative diseases. Cellular senescence is a homeostatic biological process that has a key role in driving ageing. There is evidence that senescent cells accumulate in the nervous system with ageing and neurodegenerative disease and may predispose a person to the appearance of a neurodegenerative condition or may aggravate its course. Research into senescence has long been hindered by its variable and cell-type specific features and the lack of a universal marker to unequivocally detect senescent cells. Recent advances in senescence markers and genetically modified animal models have boosted our knowledge on the role of cellular senescence in ageing and age-related disease. The aim now is to fully elucidate its role in neurodegeneration in order to efficiently and safely exploit cellular senescence as a therapeutic target. Here, we review evidence of cellular senescence in neurons and glial cells and we discuss its putative role in Alzheimer's disease, Parkinson's disease and multiple sclerosis and we provide, for the first time, evidence of senescence in neurons and glia in multiple sclerosis, using the novel GL13 lipofuscin stain as a marker of cellular senescence. DOI: 10.3390/ijms19102937

137. Int J Nanomedicine. 2018 Aug 29;13:4845. doi: 10.2147/IJN.S179354. eCollection 2018.

Erratum: Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant [Corrigendum].

[No authors listed] Erratum for Int J Nanomedicine. 2015 Nov 20;10:7165-74. [This corrects the article on p. 7165 in vol. 10, DOI: 10.2147/IJN.S179354 PMCID: PMC6122897


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138. Int J Neurosci. 2018 Sep 21:1-18. doi: 10.1080/00207454.2018.1527330. [Epub ahead of print]

Role of developmental venous anomalies in etiopathogenesis of demyelinating diseases.

Halicioglu S(1), Turkoglu SA(2). Author information: (1)a Department of Radiology , Abant Izzet Baysal University Medical Faculty , Bolu , Turkey. (2)b Department of Neurology , Abant Izzet Baysal University Medical Faculty , Bolu , Turkey. OBJECTIVE: Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. T2W-hyperintense demyelinating lesions are detected in cranial magnetic resonance imaging (MRI). Developmental venous anomalies (DVAs) have frequently been detected in enhanced cranial MRI images, and are generally accepted as normal variants of venous development. The aim of the present study was to investigate whether there was an association between demyelinating diseases and venous anomalies. METHODS: One hundred five patients who were diagnosed as having MS in accordance with the McDonald diagnostic criteria, and 105 patients who were diagnosed as having vascular headache who had no lesions similar to MS were included in the present retrospective study. RESULTS: DVAs were detected in 31 of the study group and in 14 patients in the control group. A statistically significant higher rate of developmental venous anomalies and abnormal signal increase in the neighboring tissue was detected in the study group (p = 0.004) (p = 0.006). The DVA was superficially localized in the RRMS, It was deeply located in RIS. CONCLUSION: Recent studies have emphasized the association of the central vein and the lesion severity of MS with the detection of the central collecting vein in MS lesions. In our study, DVAs, which are generally regarded as innocent developmental anomalies, and neighboring signal increase were found significantly higher in the MS group compared with the control group. The role of developmental venous anomalies in the etiology of demyelinating lesions must be clarified through comprehensive future studies that use more advanced techniques. DOI: 10.1080/00207454.2018.1527330

139. Int J Technol Assess Health Care. 2018 Sep 25:1-9. doi: 10.1017/S0266462318000557. [Epub ahead of print]

DIFFERENTIATION OF HEALTH-RELATED QUALITY OF LIFE OUTCOMES BETWEEN FIVE DISEASE AREAS: RESULTS FROM AN INTERNATIONAL SURVEY OF PATIENTS.

Efthymiadou O(1), Mossman J(2), Kanavos P(3). Author information: (1)Medical Technology Research Group,LSE Health,London School of [email protected]. (2)Medical Technology Research Group,LSE Health,London School of Economics. (3)Department of Social Policy,Medical Technology Research Group,LSE Health. OBJECTIVES: Health-related quality of life (HRQoL) data generated by generic, preference-based instruments (i.e., EQ-5D) are highly demanded in health policy decision making, because they allow for direct comparisons of HRQoL outcomes between disease areas. We aimed to quantify HRQoL outcomes in breast cancer (BC), rheumatoid arthritis (RA), multiple sclerosis (MS), rare cancers (RC), and rare disease (RD) patients and understand the patterns that differentiate HRQoL outcomes between these disease areas, and more specifically between rare and more common disease population groups. METHODS: An international, Web survey of patients measured HRQoL (EQ-5D-5L), self-perceived health (EQ-5D-5L Visual Analogue Scale), and additional QoL dimensions, such as patient disability level. RESULTS: We received 675 completed responses. Average utility loss was 53.5 percent, 32.5 percent, and 33.3 percent for RD, RA, and MS patients, respectively, in contrast to 18.6 percent for BC and RC patients. Statistically significant differences (p < .05) were observed between disease groups in all EQ-5D-5L domain outcomes, apart from that of "Anxiety/Depression." Severe and/or extreme problems were reported in performing usual activities for RD and RC (34 percent and 13 percent of overall problems reported respectively), mobility for MS (18 percent), pain/discomfort for RA (13 percent), and anxiety/depression for BC (7 percent) patients. CONCLUSIONS: We demonstrated significant differences in the dimensions that drive HRQoL outcomes between rare and more common diseases and showcased that the same EQ-5D utility may reflect very different severities depending on the patient population under investigation. Future research should examine whether outcomes in other, critical HRQoL domains not included in generic measures also highlight significant differences across disease areas. DOI: 10.1017/S0266462318000557


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140. Int J Technol Assess Health Care. 2018 Jan;34(4):425-433. doi: 10.1017/S0266462318000491.

PREFERENCES OF PATIENTS WITH MULTIPLE SCLEROSIS FOR ATTRIBUTES OF INJECTABLE MULTIPLE SCLEROSIS TREATMENTS IN THE UNITED KINGDOM AND FRANCE.

Poulos C(1), Kinter E(2), van Beek J(2), Christensen K(2), Posner J(3). Author information: (1)RTI Health [email protected]. (2)Biogen. (3)RTI Health Solutions. OBJECTIVES: Adherence to injectable disease-modifying treatments in patients with multiple sclerosis (MS) impacts outcomes and can be influenced by perceptions of treatment efficacy, side effects, injection frequency, and the duration of injection. This study aimed to quantify preferences for selected attributes of injectable treatments among individuals with MS in the United Kingdom and France. METHODS: Respondents with a self-reported diagnosis of MS completed an online discrete-choice-experiment survey, consisting of a series of treatment-choice questions. Each choice question presented two hypothetical treatments, each with six attributes (years until disability progression, relapses in the next 4 years, injection time, injection frequency, flu-like symptoms (FLS), and injection-site reactions), each with various levels. Mixed-logit regression analysis was used to estimate preference weights for attribute levels and to calculate the relative importance of changes in treatment attributes (vertical distance between preference weights). Minimum acceptable efficacy estimates indicate improvement in efficacy that respondents would require in exchange for worsening injection frequency and FLS. RESULTS: In both countries, 100 respondents completed the survey. In the United Kingdom and France, respectively, improving the time until disability progression from 2 to 4 years, reducing injection frequency from "daily" to "every 2 weeks", and reducing FLS from 3 days after every injection to none had a relative importance of 2.9 and 2.6, 3.0 and 3.5, and 2.5 and 3.1. Given the ranges included in the study, changes in these attributes were more important than most changes in other attributes assessed. CONCLUSIONS: Reductions in the injection frequency of MS treatments and FLS can be as important to patients as improvements in treatment efficacy. DOI: 10.1017/S0266462318000491

141. Iran J Immunol. 2018 Sep;15(3):165-174. doi: 10.22034/IJI.2018.39386.

Role of Interleukin-37 in Inflammatory and Autoimmune Diseases.

Wang X(1), Xu K, Chen S, Li Y, Li M. Author information: (1)Department of Immunology, Medical School of Ningbo University, Ningbo, China. Interleukin-1 family 7 (IL-1F7) is a novel member of IL-1F cytokines. IL-1F7 is more commonly known as IL-37. IL-37 can join the α-subunit of the IL-18 receptor, or IL-18 binding protein (IL-18BP), and binding of these proteins can enhance the IL-18 suppression. IL-37 also translocates to the cell nucleus and affects gene transcription. IL-37 inhibits the phosphorylation of p38 mitogen-activated protein kinases. Almost all reports showed that IL-37 has remarkable anti-inflammatory activity. IL-37 plays an important role in a variety of inflammatory and autoimmune diseases, as well. Recently, studies demonstrated that the expression of IL-37 is abnormal in many diseases such as inflammatory bowel diseases, inflammatory respiratory diseases, atherosclerosis, hepatitis, obesity, contact hypersensitivity, Graves' disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, and Behcet's disease. Here, we will review the biological characteristics of IL-37 and its key roles in various inflammatory and autoimmune diseases. DOI: 10.22034/IJI.2018.39386


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142. Iran J Neurol. 2018 Jan 5;17(1):24-30.

Transdifferentiation of human adipose-derived mesenchymal stem cells into oligodendrocyte progenitor cells.

Ghasemi N(1). Author information: (1)Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. Background: Stem cell-based therapy is a new method for the treatment of neurodegenerative diseases such as multiple sclerosis (MS). Human adipose-derived stem cells (hADSCs) are a kind of adult stem cells which have a higher frequency in the fat tissue and have the ability to differentiate into other cell types outside their lineage. Due to some serious adverse events of cell-based therapy such as tumorigenic potential, the aim of this study was to evaluate of hADSCs differentiation into oligodendrocytes as a valuable way for future cell transplantation. Methods: hADSC were isolated from lipoaspirate samples of human abdominal fat. After hADSC characterization via flow cytometry, the cells were induced to oligodendrocytes using a special differentiation medium. Finally, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), immunocytochemistry, and real-time polymerase chain reaction (RT-PCR) techniques were used for the evaluation of differentiated cells. Results: Flow cytometry indicated that hADSCs were CD105- and CD49-positive, but were negative for CD31 and CD45 markers. In addition, immunocytochemistry analysis revealed that a high percent of differentiated cells expressed oligodendrocyte progenitor cells markers [A2B5 and oligodendrocyte transcription factor (Olig2)] which were significantly higher than myelin basic protein (MBP) which is mature oligodendrocytes marker. Moreover, a very low percentage of differentiated cells expressed glial fibrillary acidic protein (GFAP) marker. Finally, real-time reverse transcription PCR analysis confirmed the results of immunocytochemistry. Conclusion: Since hADSCs have the potential to differentiate into multi-lineage cells and due to their additional characteristics such as immunomodulatory and neuroprotective properties, it seems that these cells may be an ideal cell source for oligodendrocytes differentiation. PMCID: PMC6121205

143. Iran J Neurol. 2018 Apr 4;17(2):91-94.

Interferon beta-1b-induced thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) in a patient treated for multiple sclerosis: A case report.

Etemadifar M(1), Sabeti F(1), Salari M(2). Author information: (1)Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. (2)Department of Neurology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. PMCID: PMC6131335

144. Iran J Neurol. 2018 Apr 4;17(2):89-90.

Thrombotic microangiopathy associated with interferon-beta treatment in patients with multiple sclerosis.

Baghbanian SM(1), Moghadasi AN(2). Author information: (1)Bualicina Hospital, Mazandaran University of Medical Sciences, Sari, Iran. (2)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. PMCID: PMC6131330


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145. Iran J Neurol. 2018 Apr 4;17(2):78-81.

Evaluating the relationship between emotional intelligence and cognitive disorders in patients with Multiple Sclerosis.

Owji M(1), Sahraian MA(1), Bidadian M(2), Ghadiri F(1), Etesam F(3), Azimi A(1), Moghadasi AN(1). 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)Department of Psychiatry, Baharloo Hospital, Tehran University of Medical Sciences, Tehran, Iran. Background: Emotional intelligence refers to a process through which an individual is not only capable of understanding his/her/others' emotions, but also is able to manage them. Emotional intelligence can get disturbed due to different neurological diseases. Since cognition and emotion are directly and closely related, the present study aims to evaluate the relationship between emotional intelligence and cognitive disorders in patients with Multiple Sclerosis (MS). Methods: The demographic data of 92 MS patients participating in this study were recorded. The emotional intelligence and cognitive disorders were studied using the Bradberry-Greaves, and MS Neuropsychological Questionnaire (MSNQ) tests, respectively. Results: 16 men and 76 women were considered in this study. The mean age of the participants was 33.4 years, the mean duration of the disease was 6.8 years, the mean of Expanded Disability Status Scale (EDSS) was 1.97, the mean MSNQ was 21.58, and the mean emotional quotient (EQ) of the patients was 74.18. The MSNQ had a significant relationship with the total EQ and its sub-categories (P < 0.05). Conclusion: This study showed that EQ and cognitive disorders are directly relevant to each other; as cognitive disorder increases, the EQ rate decreases. Therefore, cognitive rehabilitation might be effective in enhancing the EQ in these patients. PMCID: PMC6131332

146. Iran J Neurol. 2018 Apr 4;17(2):64-70.

Evaluation of the risk of cervical cancer in patients with Multiple Sclerosis treated with cytotoxic agents: A cohort study.

Doosti R(1), Togha M(1)(2), Moghadasi AN(1)(2), Aghsaie A(1), Azimi AR(1)(2), Khorramnia S(1), Moinfar Z(1), Ensani F(3), Harirchian MH(4), Minagar A(5), Sahraian MA(1)(4). Author information: (1)Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. (2)Department of Neurology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. (3)Department of Pathology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran. (4)Iranian Center for Neurological Research, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran. (5)Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA. Background: Since most patients with relapsing-remitting multiple sclerosis (RRMS) are women, the present study aimed to determine whether treatment of patients with MS by cytotoxic agents is associated with an increased risk of cervical dysplasia. Cancer screening is often neglected in the chronic diseases such as MS, so more attention in this field was needed. Decreasing morbidity and mortality due to cervical cancer is the most important goal of screening in female MS patients especially in child bearing age. Thus, it can be said that this is the first study which investigated this important issue. Methods: A total of 129 individuals participated in this cohort study. They were assigned into 3 groups including 43 patients with MS who were treated with cytotoxic drugs, 43 patients with MS on immunomodulators, and 43 normal healthy controls. Pap smears were performed following standard methods and the results obtained from the three groups were compared by statistical analysis. Demographic data, Expanded Disability Status Scale (EDSS), and Pap smear changes were analyzed by SPSS software. Results: The most commonly detected abnormality in all examined patients and healthy controls was inflammation. Five patients with MS who were treated with cytotoxic agents revealed benign cellular changes (BCC) in their Pap smear that were statistically significant in comparison with other groups (P = 0.03). Patients who took Mitoxantrone presented BCC more than other groups [Odds ratio (OR) = 9.44, 95% confidence interval (CI): 1.46-60.70]. There was no significant difference between mean duration of MS diagnosis (P = 0.12), mean duration of previous MS treatments (P = 0.25), and mean duration of current MS treatments (P = 0.21) in patients with BCC compared to normal healthy controls or inflammatory change. Conclusion: According to the results of present study, BCC is more frequently observed in patients with MS who were treated with cytotoxic agents with immunosuppressive effect. Since BCC is a 'premalignant condition', the authors suggest that mandatory annual Pap smear should be performed for patients with MS who are treated with cytotoxic agents irrespective of their age in order to detect early signs of malignancy. PMCID: PMC6131331


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147. J Autoimmun. 2018 Sep 20. pii: S0896-8411(18)30350-0. doi: 10.1016/j.jaut.2018.09.005. [Epub ahead of print]

GPR15+ T cells are Th17 like, increased in smokers and associated with multiple sclerosis.

Ammitzbøll C(1), von Essen MR(2), Börnsen L(3), Petersen ER(4), McWilliam O(5), Ratzer R(6), Jeppe RC(7), Oturai AB(8), Søndergaard HB(9), Sellebjerg F(10). Author information: (1)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Denmark. Electronic address: [email protected]. (2)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Denmark. Electronic address: [email protected]. (3)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Denmark. Electronic address: [email protected]. (4)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Denmark. Electronic address: [email protected]. (5)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Denmark. Electronic address: [email protected]. (6)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Denmark. Electronic address: [email protected]. (7)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Denmark. Electronic address: [email protected]. (8)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Denmark. Electronic address: [email protected]. (9)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Denmark. Electronic address: [email protected]. (10)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Denmark. Electronic address: [email protected]. Smoking is a risk factor for the development and progression of multiple sclerosis (MS); however, the pathogenic effects of smoking are poorly understood. We studied the smoking-associated chemokine receptor-like molecule GPR15 in relation to relapsing-remitting MS (RRMS). Using microarray analyses and qPCR we found elevated GPR15 in blood cells from smokers, and increased GPR15 expression in RRMS. By flow cytometry we detected increased frequencies of GPR15 expressing T and B cells in smokers, but no difference between patients with RRMS and healthy controls. However, after cell culture with the autoantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein, frequencies of MBP-reactive and non-proliferating GPR15+CD4+ T cells were increased in patients with RRMS compared with healthy controls. GPR15+CD4+ T cells produced IL-17 and were enriched in the cerebrospinal fluid (CSF). Furthermore, in the CSF of patients with RRMS, GPR15+ T cells were associated with CCR6+CXCR3+/CCR6-CXCR3+ phenotypes and correlated positively with concentrations of the newly identified GPR15-ligand (GPR15L), myelin degradation and disability. In conclusion, we have identified a proinflammatory cell type linking smoking with pathogenic immune cell functions in RRMS. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.jaut.2018.09.005


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148. J Cataract Refract Surg. 2018 Oct;44(10):1261-1266. doi: 10.1016/j.jcrs.2018.04.044. Epub 2018 Aug 29.

Prophylactic exposure of human corneal endothelial cells to Rho-associated kinase inhibitor reduced apoptosis rate after phacoemulsification: Ex vivo study.

Achiron A(1), Feldman A(2), Karmona L(2), Avizemer H(2), Barequet IS(2), Rosner M(2), Knyazer B(2), Bartov E(2), Burgansky Z(2), Vishnevskia-Dai V(2). Author information: (1)From the Department of Ophthalmology (Achiron, Karmona, Avizemer, Bartov, Burgansky), the Edith Wolfson Medical Center, Holon, the Sackler Faculty of Medicine (Achiron, Feldman, Karmona, Avizemer, Barequet, Rosner, Bartov, Burgansky, Vishnevskia-Dai),Tel Aviv University, Tel Aviv, the Multiple Sclerosis Center (Feldman), Sheba Medical Center, Tel-Hashomer and the Goldschleger Eye Institute (Barequet, Rosner, Vishnevskia-Dai), Sheba Medical Center, Tel-Hashomer, and the Department of Ophthalmology (Knyazer), Soroka University Medical Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address: [email protected]. (2)From the Department of Ophthalmology (Achiron, Karmona, Avizemer, Bartov, Burgansky), the Edith Wolfson Medical Center, Holon, the Sackler Faculty of Medicine (Achiron, Feldman, Karmona, Avizemer, Barequet, Rosner, Bartov, Burgansky, Vishnevskia-Dai),Tel Aviv University, Tel Aviv, the Multiple Sclerosis Center (Feldman), Sheba Medical Center, Tel-Hashomer and the Goldschleger Eye Institute (Barequet, Rosner, Vishnevskia-Dai), Sheba Medical Center, Tel-Hashomer, and the Department of Ophthalmology (Knyazer), Soroka University Medical Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel. PURPOSE: To evaluate whether prophylactic exposure of corneal endothelial cells (CECs) to a selective Rho-associated kinase (ROCK) inhibitor will inhibit CEC apoptosis after phacoemulsification. SETTING: Laboratory evaluations at the Edith Wolfson Medical Center, Holon, Israel and the Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel and the Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. DESIGN: Experimental study. METHOD: Human donor corneolimbal rings were divided into fragments that were stored in commercial storage media with or without the addition of 10 mM ROCK inhibitor for 1 week and were then exposed to phacoemulsification energy. Samples were dissociated into single cells by trypsin digestion and CECs were targeted using the antihuman CD166 antibody, a new biomarker. The CEC survival was evaluated for early and late apoptosis rate with flow cytometric analysis of annexin-V and propidium iodide (PI) double staining. RESULTS: Six corneoscleral rings from 4 donors were studied. After phacoemulsification, CEC exposed to ROCK inhibitor demonstrated a 37.06% reduction in early apoptosis rate (29.36% ± 4.33% [SD] versus 46.65% ± 1.51%, P = .006) and 45.27% reduction in late apoptosis rate (17.6% ± 16.81% versus 32.16% ± 26.30%, P = .007), compared with controls. Subsequently, ROCK levels in apoptotic CECs were significantly lower in cells incubated with ROCK inhibitor than the control medium. CONCLUSIONS: In this ex vivo study, ROCK inhibitor reduced endothelial loss and thus, could be used to limit or slow down CEC loss. Rho-associated kinase inhibitor might be used before cataract surgery, especially in high risk patients. This might be a promising new method for preventing pseudophakic bullous keratopathy. Copyright © 2018 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.jcrs.2018.04.044


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149. J Cell Mol Med. 2018 Sep 28. doi: 10.1111/jcmm.13850. [Epub ahead of print]

Changes in cell differentiation and proliferation lead to production of abzymes in EAE mice treated with DNA-Histone complexes.

Aulova KS(1), Toporkova LB(2), Lopatnikova JA(2), Alshevskaya AA(2), Sedykh SE(1), Buneva VN(1), Budde T(3), Meuth SG(4), Popova NA(5)(6), Orlovskaya IA(2), Nevinsky GA(1)(6). Author information: (1)Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia. (2)Institute of Fundamental and Clinical Immunology, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia. (3)Institut für Physiologie I, Westfälische Wilhelms-Universität, Münster, Germany. (4)Department of Neurology, Westfälische Wilhelms-Universität, Münster, Germany. (5)Institute Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia. (6)Novosibirsk State University, Novosibirsk, Russia. Experimental autoimmune encephalomyelitis (EAE)-prone C57BL/6 mice are used as a model of human multiple sclerosis. We immunize mice with myelin oligodendrocyte glycoprotein (MOG), DNA-histone and DNA-methylated bovine serum albumin (met-BSA) complexes to reveal different characteristics of EAE development including bone marrow lymphocyte proliferation and differentiation profiles of hematopoietic stem cells. Immunization of C57BL/6 mice with MOG35-55 results in the acceleration of EAE development. Anti-DNA antibodies are usually directed against DNA-histone complexes resulting from cell apoptosis. During the acute EAE phase (7-20 days after immunization), catalytic antibodies efficiently hydrolysing myelin basic protein (MBP), MOG and DNA are produced with parallel suppression of antibodies hydrolysing histones. We could show that in contrast to MOG, immunization with histone-DNA results in a reduction of proteinuria, a significant increase in anti-DNA, anti-MBP and anti-MOG antibody titres, as well as an increase in their catalytic activities for antigen hydrolysis, but slightly changes the concentration of cytokines. Contrary to MOG, DNA-histone and DNA-met-BSA only stimulated the formation of anti-DNA antibodies hydrolysing DNA with a long delay (15-20 days after immunization). Our data indicate that for C57BL/6 mice immunization with DNA-met-BSA and DNA-histone complexes may have opposing effects compared to MOG. DNA-histone stimulates the appearance of histone-hydrolysing abzymes in the acute EAE phase, while abzymes with DNase activity appear at significantly later time-points. We conclude that MOG, DNA-histone and DNA-met-BSA have different effects on numerous bone marrow, cellular, immunological and biochemical parameters of immunized mice, but all antigens finally significantly stimulate the development of the EAE. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. DOI: 10.1111/jcmm.13850


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150. J Cell Physiol. 2018 Sep 10. doi: 10.1002/jcp.27330. [Epub ahead of print]

A comparative system-level analysis of the neurodegenerative diseases.

Godini R(1), Fallahi H(1), Ebrahimie E(2)(3)(4)(5). Author information: (1)Department of Biology, School of Sciences, Razi University, Kermanshah, Iran. (2)Dame Roma Mitchell Cancer Research Laboratories (DRMCRL), Adelaide Medical School, The University of Adelaide, Adelaide, Australia. (3)Institute of Biotechnology, Shiraz University, Shiraz, Iran. (4)Division of Information Technology, Engineering and the Environment, School of Information Technology and Mathematical Sciences, The University of South Australia, Adelaide, Australia. (5)Molecular Biology and Biotechnology, School of Biological Sciences, Faculty of Science and Engineering, Flinders University, Adelaide, Australia. Neurodegenerative diseases are disorders in the central nervous system with consequent progressive neurological symptoms including behavioral and cognitive disabilities. Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, multiple sclerosis, and schizophrenia are the most important and abundant neurodegenerative diseases that affect different parts of the brain. Detailed studies unveiled the molecular mechanisms and pathways affected in each of these disorders. The role of many genes has been documented in the onset and progression of each disease. Although many system-level approaches have been used to understand the exact cause of these diseases, there is no comparative analysis in this regard. Despite all differences in the molecular basis of these diseases, overlapping symptoms might indicate the involvement of the similar pathways and processes. Here, we have applied a system biology approach to uncover many aspects of main neurodegenerative diseases using microarray data obtained from 118 cases of postmortem brain samples. Our analysis has identified key genes that might contribute to the status of diseases. We have also compared the involved biological process and pathway between different disease to find possible similar mechanisms that exist in all of them. We also predicted potentially important transcription factors in each disease and predicted the core gene regulatory networks. We have provided a list of possible new key regulators that could be further explored and also discussed the role of these hub genes. The results of this study would be useful to develop new diagnostic strategies and also to find new drug targets. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/jcp.27330

151. J Clin Anesth. 2018 Sep 20;52:119-120. doi: 10.1016/j.jclinane.2018.09.024. [Epub ahead of print]

Benefit of sugammadex in a morbidly obese patient with multiple sclerosis and severe respiratory dysfunction.

Carron M(1), Ieppariello G(2). Author information: (1)Department of Medicine - DIMED, Section of Anesthesiology and Intensive Care, University of Padova, Padova, Italy. Electronic address: [email protected]. (2)Department of Medicine - DIMED, Section of Anesthesiology and Intensive Care, University of Padova, Padova, Italy. DOI: 10.1016/j.jclinane.2018.09.024


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152. J Clin Apher. 2018 Sep 3. doi: 10.1002/jca.21645. [Epub ahead of print]

The impact of motivational interviewing on self-perceived burden in patients receiving therapeutic plasma exchange.

Dill R(1), Olson DM(1), Session-Augustine N(1), Mariani D(1), Stutzman SE(1). Author information: (1)Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas. BACKGROUND: Autoimmune disorders and neurodegenerative disorders take a physical and emotional toll on patients that undergo therapeutic plasma exchange (TPE) treatments. Previous literature has shown that these patients may feel a greater sense of self-burden. Motivational Interviewing (MI) is a technique used in various settings that has the potential to decrease feelings of self-burden. MI for patients who receive TPE has not been tested. The purpose of this study was to examine the impact of MI in patients with a neurodegenerative diagnosis (eg, transverse myelitis, myasthenia gravis, multiple sclerosis, and chronic inflammatory demyelinating polyneuropathy) that are undergoing TPE treatments. METHODS: This was a prospective, non-randomized, longitudinal study of the impact of MI with patients at high risk of sense of self-burden who underwent apheresis treatments. Consented patients underwent three to six MI sessions with a trained clinician. Patients completed a self-report baseline and post-test of self-perceived burden. RESULTS: Thirty participants consented to the study; 27 were included in the analysis. The Self-Perceived Burden Scale scores were significantly higher at baseline (m = 26.2) when compared to scores post MI sessions (m = 21.48, P < .05). The number of MI sessions (3, 4, 5, 6 sessions) did not significantly impact the outcome score (r2 = 0.001; P = .901). CONCLUSION: MI is a straightforward technique that is feasible and shown to be effective to be used by bedside clinicians while working with patients who receive TPE to decrease levels of self-perceived burden. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/jca.21645


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153. J Clin Densitom. 2018 Jul 29. pii: S1094-6950(18)30065-9. doi: 10.1016/j.jocd.2018.07.003. [Epub ahead of print]

Peripheral Quantitative Computed Tomography: Review of Evidence and Recommendations for Image Acquisition, Analysis, and Reporting, Among Individuals With Neurological Impairment.

Cervinka T(1), Giangregorio L(2), Sievanen H(3), Cheung AM(4), Craven BC(5). Author information: (1)Neural Engineering and Therapeutics Team, Toronto Rehabilitation Research Institute-University Health Network, Toronto, Ontario, Canada. Electronic address: [email protected]. (2)Neural Engineering and Therapeutics Team, Toronto Rehabilitation Research Institute-University Health Network, Toronto, Ontario, Canada; Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada. (3)Bone Research Group, UKK Institute, Tampere, Finland. (4)Centre of Excellence in Skeletal Health Assessment, University Health Network, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada. (5)Neural Engineering and Therapeutics Team, Toronto Rehabilitation Research Institute-University Health Network, Toronto, Ontario, Canada; Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada; Centre of Excellence in Skeletal Health Assessment, University Health Network, Toronto, Ontario, Canada; Brain and Spinal Cord Rehabilitation Program, Toronto Rehabilitation Institute-University Health Network, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada. In 2015, the International Society for Clinical Densitometry (ISCD) position statement regarding peripheral quantitative computed tomography (pQCT) did not recommend routine use of pQCT, in clinical settings until consistency in image acquisition and analysis protocols are reached, normative studies conducted, and treatment thresholds identified. To date, the lack of consensus-derived recommendations regarding pQCT implementation remains a barrier to implementation of pQCT technology. Thus, based on description of available evidence and literature synthesis, this review recommends the most appropriate pQCT acquisition and analysis protocols for clinical care and research purposes, and recommends specific measures for diagnosis of osteoporosis, assigning fracture risk, and monitoring osteoporosis treatment effectiveness, among patients with neurological impairment. A systematic literature search of MEDLINE, EMBASE©, CINAHL, and PubMed for available pQCT studies assessing bone health was carried out from inception to August 8th, 2017. The search was limited to individuals with neurological impairment (spinal cord injury, stroke, and multiple sclerosis) as these groups have rapid and severe regional declines in bone mass. Of 923 references, we identified 69 that met review inclusion criteria. The majority of studies (n = 60) used the Stratec XCT 2000/3000 pQCT scanners as reflected in our evaluation of acquisition and analysis protocols. Overall congruence with the ISCD Official Positions was poor. Only 11% (n = 6) studies met quality reporting criteria for image acquisition and 32% (n = 19) reported their data analysis in a format suitable for reproduction. Therefore, based on current literature synthesis, ISCD position statement standards and the authors' expertise, we propose acquisition and analysis protocols at the radius, tibia, and femur sites using Stratec XCT 2000/3000 pQCT scanners among patients with neurological impairment for clinical and research purposes in order to drive practice change, develop normative datasets and complete future meta-analysis to inform fracture risk and treatment efficacy evaluation. Copyright © 2018 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.jocd.2018.07.003


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154. J Clin Invest. 2018 Sep 18. pii: 123708. doi: 10.1172/JCI123708. [Epub ahead of print]

CNS resident classical DCs play a critical role in CNS autoimmune disease.

Giles DA, Duncker PC, Wilkinson NM, Washnock-Schmid JM, Segal BM. Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS), induced by the adoptive transfer of myelin-reactive CD4+ T cells into naïve syngeneic mice. It is widely used as a rodent model of multiple sclerosis (MS). EAE lesion development is initiated when transferred CD4+ T cells access the CNS and are reactivated by local antigen presenting cells (APC) bearing endogenous myelin peptide/ MHC Class II complexes. The identity of the CNS resident, lesion-initiating APC is widely debated. Here we demonstrate that classical dendritic cells (cDC) normally reside in the meninges, brain, and spinal cord in the steady state. These cells are unique among candidate CNS APC in their ability to stimulate naïve, as well as effector, myelin-specific T cells to proliferate and produce pro-inflammatory cytokines directly ex vivo. cDC expanded in the meninges and CNS parenchyma in association with disease progression. Selective depletion of cDC led to a decrease in the number of myelin-primed donor T cells in the CNS and reduced the incidence of clinical EAE by half. Based on our findings, we propose that cDC, and the factors that regulate them, be further investigated as potential therapeutic targets in MS. DOI: 10.1172/JCI123708

155. J Clin Med. 2018 Sep 14;7(9). pii: E281. doi: 10.3390/jcm7090281.

Can the Fact That Myelin Proteins Are Old and Break down Explain the Origin of Multiple Sclerosis in Some People?

Truscott RJW(1), Friedrich MG(2). Author information: (1)Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia. [email protected]. (2)Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia. [email protected]. Recent discoveries may change the way that multiple sclerosis (MS) is viewed, particularly with regard to the reasons for the untoward immune response. The fact that myelin proteins are long-lived, and that by the time we are adults, they are extensively degraded, alters our perspective on the reasons for the onset of autoimmunity and the origin of MS. For example, myelin basic protein (MBP) from every human brain past the age of 20 years, is so greatly modified, that it is effectively a different protein from the one that was laid down in childhood. Since only a subset of people with such degraded MBP develop MS, a focus on understanding the mechanism of immune responses to central nervous system (CNS) antigens and cerebral immune tolerance appear to be worthwhile avenues to explore. In accord with this, it will be productive to examine why all people, whose brains contain large quantities of a "foreign antigen", do not develop MS. Importantly for the potential causation of MS, MBP from MS patients breaks down differently from the MBP in aged controls. If the novel structures formed in these MS-specific regions are particularly antigenic, it could help explain the origin of MS. If verified, these findings could provide an avenue for the rational synthesis of drugs to prevent and treat MS. DOI: 10.3390/jcm7090281


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156. J Clin Med. 2018 Sep 11;7(9). pii: E272. doi: 10.3390/jcm7090272.

Aerobic Capacity Is Not Associated with Most Cognitive Domains in Patients with Multiple Sclerosis-A Cross-Sectional Investigation.

Langeskov-Christensen M(1), Eskildsen S(2), Stenager E(3), Boye Jensen H(4)(5), Hvilsted Nielsen H(6), Petersen T(7), Grøndahl Hvid L(8), Hämäläinen P(9), Marstrand L(10), Dalgas U(11). Author information: (1)Section for Sport Science, Department of Public Health, Aarhus University, 8000 Aarhus C, Denmark. [email protected]. (2)Section for Sport Science, Department of Public Health, Aarhus University, 8000 Aarhus C, Denmark. [email protected]. (3)Department of Regional Health Research, University of Southern Denmark, Odense, Denmark/MS-Clinic of Southern Jutland (Sønderborg, Kolding, Esbjerg), Department of Neurology, Hospital of Southern Denmark, 6400 Sønderborg, Denmark. [email protected]. (4)Department of Regional Health Research, University of Southern Denmark, Odense, Denmark/MS-Clinic of Southern Jutland (Sønderborg, Kolding, Esbjerg), Department of Neurology, Hospital of Southern Denmark, 6400 Sønderborg, Denmark. [email protected]. (5)Brain and Nerve Diseases, Department of Neurology, Hospital Lillebaelt, 6000 Kolding, Denmark. [email protected]. (6)The Multiple Sclerosis Clinic, Department of Neurology, Odense University Hospital, 5000 Odense C, Denmark. [email protected]. (7)The Multiple Sclerosis Clinic, Department of Neurology, Aarhus University Hospital, 8000 Aarhus C, Denmark. [email protected]. (8)Section for Sport Science, Department of Public Health, Aarhus University, 8000 Aarhus C, Denmark. [email protected]. (9)Masku Neurological Rehabilitation Centre, 21250 Masku, Finland. [email protected]. (10)The Danish Multiple Sclerosis Centre, Department of Neurology, Rigshospitalet, 2100 Copenhagen, Denmark. [email protected]. (11)Section for Sport Science, Department of Public Health, Aarhus University, 8000 Aarhus C, Denmark. [email protected]. (1) Background: Cognitive impairment is highly prevalent in multiple sclerosis (MS). Staying physically fit may be associated with preservation of cognitive performance in persons with MS (pwMS); (2) Objective: To investigate the association between aerobic capacity and the cognitive domains of information processing, learning and memory, and verbal fluency as well as single and composite z-scores of the Brief Repeatable Battery of Neuropsychological tests (BRBNT) in pwMS; (3) Methods: All subjects first performed the BRBNT

and then a maximal oxygen consumption (VO₂-max) test on a bicycle ergometer as a measure of aerobic capacity. Simple and multiple (adjusting for age, sex, and education level) regression analyses were performed to evaluate the relationship between aerobic capacity and cognitive performance in different domains. Published international norms were used to compute z-scores for each individual and composite BRBNT score. Furthermore, cognitive impairment was defined as one or more z-scores ≤-1.5 standard deviation (SD) of healthy controls; (4) Results: Eighty-four subjects were included (44.9 ± 9 years, 16.3 ± 2 education years, Expanded Disability Status Scale (EDSS): 2.6 ± 1.4, MS-type (relapsing-remitting, primary

progressive, or secondary progressive): 73/6/5, disease duration: 9.9 ± 7 years, VO₂-max: 28.4 ± 7.0 mL O₂/min/kg). No significant associations between aerobic capacity and cognitive performance in the individual BRBNT tests were found, except that a weak relationship was found between aerobic capacity and the composite processing speed z-score (R² = 0.06, p = 0.02). The average global BRBNT z-score (-0.2 ± 0.66) was not associated with aerobic capacity. Comparison of the cognitively impaired group (34.5%) with the nonimpaired group (65.5%) showed lower aerobic capacity in the impaired group (25.9 ± 1 vs. 29.7 ± 1

mLO₂/min/kg, p = 0.02); (5) Conclusions: Limited support was found for an association between performance in most cognitive domains and aerobic capacity in the present MS group with a third of patients showing signs of cognitive impairments. DOI: 10.3390/jcm7090272

157. J Clin Neurol. 2018 Sep 6. [Epub ahead of print]

Safe Childbirth after Taking Teriflunomide in a Woman with Multiple Sclerosis.

Cho BH(1), Lee SH(2). Author information: (1)Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. (2)Department of Neurology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea. [email protected]. Conflict of interest statement: The authors have no financial conflicts of interest.


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158. J Clin Neurol. 2018 Jul 30. [Epub ahead of print]

The Role of Information Processing Speed in Clinical and Social Support Variables of Patients with Multiple Sclerosis.

Eizaguirre MB(1), Vanotti S(2), Merino Á(2), Yastremiz C(2), Silva B(2), Alonso R(2), Garcea O(2). Author information: (1)Multiple Sclerosis Clinic and University of Buenos Aires Neurology Center, Ramos Mejía Hospital, Buenos Aires, Argentina. [email protected]. (2)Multiple Sclerosis Clinic and University of Buenos Aires Neurology Center, Ramos Mejía Hospital, Buenos Aires, Argentina. BACKGROUND AND PURPOSE: Information processing speed is one of the most impaired cognitive functions in multiple sclerosis (MS). There are two tests widely used for evaluating information processing speed: the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT). To analyze the relationship between processing speed and the clinical and social support variables of patients with MS. METHODS: A group of 47 patients with relapsing-remitting MS was studied, 31 were women and 16, men. Age: 39.04±13.17, years of schooling: 13.00±3.87, Expanded Disability Status Scale (EDSS): 2.78±1.81, and disease evolution: 8.07±6.26. Instruments of measure; processing speed: SDMT, PASAT, clinical variables: EDSS, Fatigue Severity Scale (FSS), Beck's Depression Inventory II (BDI-II), and social support: Medical Outcomes Study Social Support Survey (MOS). RESULTS: Significant correlations were found between information processing speed and psychiatric, motor disability and social support variables. The SDMT correlated significantly and negatively with BDI-II, FSS, EDSS, and MOS (p<0.05), whereas the PASAT correlated negatively with FSS and positively with MOS (p<0.05). Information processing speed appeared as the performance predictor of these variables. The SDMT produced significant changes in EDSS (R²=0.343, p=0.000); FSS (R²=0.109, p=0.031); BDI-II (R²=0.124, p=0.018), and MOS (R²=between 0.212 and 0.379, p<0.05). CONCLUSIONS: Information processing speed has influence on the clinical variables and the social support of patients with MS. These aspects are important to bear in mind for therapeutic approach. Copyright © 2018 Korean Neurological Association. Conflict of interest statement: The authors have no financial conflicts of interest.

159. J Clin Neurol. 2018 Jul 30. [Epub ahead of print]

Changes in the Multiple Sclerosis Treatment Paradigm. What Do We Do Now and What Were We Doing Before?

Alonso R(1), Eizaguirre MB(2), Zavala L(2), Pita C(2), Silva B(2), Garcea O(2). Author information: (1)Multiple Sclerosis Clinic, Ramos Mejia Hospital, Buenos Aires, Argentina. [email protected]. (2)Multiple Sclerosis Clinic, Ramos Mejia Hospital, Buenos Aires, Argentina. BACKGROUND AND PURPOSE: The number of disease-modifying drugs (DMDs) available for treating relapsing-remitting multiple sclerosis is increasing. Numerous drugs have been approved since 2010 in South America, which has increased the complexity of the treatment algorithm. The aim of this study was to determine the changes in multiple sclerosis treatments relative to the underlying causes and the availability of new DMDs in Argentina. METHODS: A descriptive retrospective study was carried out on a group of 59 patients diagnosed with RRMS who use more than one DMD. RESULTS: The first treatment switch occurred before 2010 in 27% of the patients and after 2010 in the other 73%. Efficacy was the main reason for switching during both periods. A second treatment switch was required in 25% of the patients, with this occurring after 2010 in 86.6% of them. Interferon was the most-used drug before 2010 and fingolimod was the most-used drug thereafter. CONCLUSIONS: We have identified that the tendency for treatment changes has increased following the arrival of new drugs. Efficacy has been the main cause of these changes. Copyright © 2018 Korean Neurological Association. Conflict of interest statement: Ricardo Alonso has received honorary-speaker payments from Biogen and Gemzyme. María Bárbara Eizaguirre has received an honoraryspeaker payment from Novartis. Lucía Zavala declares that he has no conflict of interest. Cecilia Pita declares that he has no conflict of interest. Berenice Silva has received honorary-speaker payments from Novartis, Biogen, and Gemzyme. Orlando Garcea has received honorary-speaker payments from Teva, Novartis Biogen, and Gemzyme, and has received research grants from Teva and Novartis.


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160. J Clin Neurosci. 2018 Sep 4. pii: S0967-5868(18)30660-X. doi: 10.1016/j.jocn.2018.08.037. [Epub ahead of print]

Remotely-supervised transcranial direct current stimulation paired with cognitive training in Parkinson's disease: An open-label study.

Agarwal S(1), Pawlak N(2), Cucca A(3), Sharma K(4), Dobbs B(5), Shaw M(6), Charvet L(7), Biagioni M(8). Author information: (1)Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, NYU School of Medicine, New York, NY 10016, USA. Electronic address: [email protected]. (2)NYU Langone Multiple Sclerosis Comprehensive Care Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address: [email protected]. (3)Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, NYU School of Medicine, New York, NY 10016, USA. Electronic address: [email protected]. (4)Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, NYU School of Medicine, New York, NY 10016, USA. Electronic address: [email protected]. (5)NYU Langone Multiple Sclerosis Comprehensive Care Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address: [email protected]. (6)NYU Langone Multiple Sclerosis Comprehensive Care Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address: [email protected]. (7)NYU Langone Multiple Sclerosis Comprehensive Care Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address: [email protected]. (8)Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, NYU School of Medicine, New York, NY 10016, USA. Electronic address: [email protected]. BACKGROUND: Transcranial direct current stimulation (tDCS) has been explored as a potential intervention in Parkinson's disease (PD) and recent studies have shown promising results in cognitive, gait and motor function. However, evidence of efficacy is limited due to small size studies, short treatment periods, lack of standardization of methodologies and other study design limitations. Remotely supervised-tDCS (RS-tDCS) allows "at-home" study participation, potentially easing recruitment, compliance and overall feasibility for clinical studies. OBJECTIVE: Here, we aim to explore preliminary effects of RS-tDCS paired with cognitive training in PD by delivering RS-tDCS neuromodulation at participant's home while still maintaining clinical trial standards. METHODS: This was a prospective, open-label study using RS-tDCS paired with cognitive training. Each PD participant completed 10 tDCS sessions (20-min, 1.5-2.0-mA, bi-hemispheric DLPFC montage, left anodal), over a span of two weeks. All tDCS sessions were supervised in real-time through videoconferencing. Outcomes included the Unified Parkinson's Disease Rating Scale (UPDRS) and Grooved Pegboard Test. RESULTS: All RS-tDCS sessions were well tolerated and completed successfully. Total UPDRS and motor UPDRS-III scores decreased significantly. Pegboard completion time improved significantly for the non-dominant hand. There was a strong positive correlation between the time of the sessions, and motor improvements in UPDRS part-III. CONCLUSION: RS-tDCS paradigm through a 'telemedicine protocol' holds therapeutic potential for motor symptoms in PD while maximizing compliance and ease of recruitment. Conducting afternoon sessions might be more effective than during the morning. Our paradigm may be influential in designing future studies and facilitating larger and longer duration clinical trials. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.jocn.2018.08.037


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161. J Hand Surg Am. 2018 Aug 31. pii: S0363-5023(18)30436-2. doi: 10.1016/j.jhsa.2018.07.007. [Epub ahead of print]

Lessons From Leprosy: Peripheral Neuropathies and Deformities in Chronic Demyelinating Diseases.

Chan JP(1), Uong J(1), Nassiri N(1), Gupta R(2). Author information: (1)Peripheral Nerve Research Lab, Gillespie Neuroscience Research Facility, Irvine, Orange, CA; Department of Orthopaedic Surgery, University of California, Irvine, Orange, CA. (2)Peripheral Nerve Research Lab, Gillespie Neuroscience Research Facility, Irvine, Orange, CA; Department of Orthopaedic Surgery, University of California, Irvine, Orange, CA. Electronic address: [email protected]. In light of the World Health Organization's push to accelerate progress toward a leprosy-free world by 2020, it is fitting to look back on the evolution of progress in treating lepromatous neuropathy and limb deformities. To date, no surgeon has had as great an impact on the understanding and treatment of this disease as Dr Paul Brand. Before Dr Brand's accomplishments, few surgeons participated in the management of the deformed leprous patient. By challenging conventional beliefs, Dr Brand revealed that many of the deformities associated with leprosy were in fact caused by nerve damage and subsequent limb anesthesia. His pioneering work centered on tendon transfers to provide hand and foot mobility to leprous patients, revolutionizing the surgical management of this patient population and restoring functionality to the lives of otherwise stigmatized and functionally handicapped individuals. In the process, he provided us with the surgical principles and techniques that we still apply today. Because of its predilection for the peripheral nervous system, leprosy also provides an excellent opportunity to investigate mechanisms of demyelination and chronic nerve degeneration in nonacute peripheral neuropathies. Processes underlying demyelination of infectious, traumatic, and genetic etiologies overlap and precede the onset of acute neuronal derangement. Glial pathology has been shown to be a common pathological element in leprosy, Charcot-Marie-Tooth type I, multiple sclerosis, and chronic nerve compression injury. The aim of this article is to provide an overview of lepromatous neuropathy with its subsequent deformities as it relates to the pathophysiology, surgical management, and potential therapeutic targets of other modern peripheral neuropathies. Copyright © 2018 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.jhsa.2018.07.007

162. J Immunoassay Immunochem. 2018 Sep 25:1-7. doi: 10.1080/15321819.2018.1520128. [Epub ahead of print]

Serum level of interleukin 36 in patients with multiple sclerosis.

Alsahebfosoul F(1), Jahanbani-Ardakani H(2), Ghavimi R(3), Sedaghat N(1), Etemadifar M(4). Author information: (1)a Department of Immunology, School of medicine , Isfahan University of Medical Sciences , Isfahan , Iran. (2)b Isfahan Medical Students Research Center (IMSRC), Isfahan University of Medical Sciences , Isfahan , Iran . (3)c Department of Pharmaceutical Biotechnology , School of Pharmacy, Isfahan University of Medical Sciences , Isfahan , Iran. (4)d Department of Neurology, School of Medicine , Isfahan University of Medical Sciences , Isfahan , Iran. INTRODUCTION: Multiple sclerosis is a chronic autoimmune demyelinating disorder of central nervous system with unknown origin. In MS disease, T cells are pointed to myelin antigens and it leads to myelin loss and axonal degeneration. Cytokines are important regulators of immune system and has critical roles in MS pathogenesis. Interleukin 36, a member of interleukin 1 family, has been shown having important roles in some autoimmune disorders due to its proinflammatory actions and its role in host immunity. METHODS AND MATERIALS: In the current study, 49 relapsing remitting multiple sclerosis patients and 41 healthy individuals were recruited. IL36 measurement was performed using enzyme-linked immunosorbent assay technique. RESULTS: Mean age of RRMS patient and control group were 31.84 ± 6.89 and 34.27 ± 8.83 years, respectively. Serum level of IL36 were 61.91 ± 16.29 in MS patients and 42.26 ± 17.54 in healthy group (P < 0.001). CONCLUSION: in this study for the first time, significantly higher serum level of IL36 was determined in RRMS patients comparing healthy individuals. This data may suggest important roles of this cytokine in MS pathogenesis. DOI: 10.1080/15321819.2018.1520128


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163. J Korean Acad Nurs. 2018 Aug;48(4):454-464. doi: 10.4040/jkan.2018.48.4.454.

[Factors Influencing Psychosocial Well-Being in Family Caregivers of People with Amyotrophic Lateral Sclerosis].

[Article in Korean] Chu HS(1)(2), Tak YR(3), Kim SH(2)(4). Author information: (1)College of Nursing, Hanyang University, Seoul, Korea. (2)Cell Therapy Center for Neurological Disorders, Hanyang University Hospital, Seoul, Korea. (3)College of Nursing, Hanyang University, Seoul, Korea. [email protected]. (4)Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea. PURPOSE: The purpose of this study was to identify factors influencing psychosocial well-being in family caregivers of patients with amyotrophic lateral sclerosis (ALS). METHODS: A descriptive correlational design was used. The transactional model of stress and coping was used to investigate the psychosocial well-being of 137 family caregivers of patients with ALS. Data were collected through self-reported questionnaires from January to November 2016. Data were analyzed using an independent t-test, one-way ANOVA, Pearson's correlation, and hierarchical multiple regression analysis with the SPSS WIN 21.0 program. RESULTS: The regression model had an adjusted R² of .49, which indicated that meaning-focused coping, social support, ALS patient-family caregiver relationship (especially a spousal relationship), and tracheostomy were significant predictors of caregivers' psychosocial well-being. CONCLUSION: Meaning-focused coping and social support significantly influenced caregivers' psychosocial well-being. Therefore, interventions to improve caregivers' psychosocial well-being must focus on increasing meaning-focused coping and social support resources. © 2018 Korean Society of Nursing Science. DOI: 10.4040/jkan.2018.48.4.454 Conflict of interest statement: The authors declared no conflict of interest.

164. J Magn Reson Imaging. 2018 Sep 21. doi: 10.1002/jmri.26278. [Epub ahead of print]

Evaluation of Normal-Appearing White Matter in Multiple Sclerosis Using Direct Visualization of Short Transverse Relaxation Time Component (ViSTa) Myelin Water Imaging and Gradient Echo and Spin Echo (GRASE) Myelin Water Imaging.

Choi JY(1), Jeong IH(2), Oh SH(3), Oh CH(4), Park NY(2), Kim HJ(2), Lee J(1). Author information: (1)Laboratory for Imaging Science and Technology, Department of Electrical and Computer Engineering, Seoul National University, Seoul, Republic of Korea. (2)Department of Neurology, Research Institute and Hospital of National Cancer Center, Gyeonggi-do, Republic of Korea. (3)Department of Biomedical Engineering, Hankuk University of Foreign Studies, Gyeonggi-do, Republic of Korea. (4)Department of Electronics and Information Engineering, Korea University, Sejong, Republic of Korea. BACKGROUND: In multiple sclerosis (MS), not only lesions but also normal MRI-appearing white matter (NAWM) may undergo demyelination. PURPOSE: To demonstrate the detection of NAWM demyelination using direct visualization of short transverse relaxation time component myelin water imaging (ViSTa-MWI) and to compare the results with those of conventional gradient echo and spin echo (GRASE)-MWI. STUDY TYPE: Control/cohort. POPULATION: Twenty-five MS patients and 18 healthy controls (HC). FIELD STRENGTH/SEQUENCE: 3T/ViSTa and GRASE-MWI. ASSESSMENT: Using ViSTa and GRASE-MWI, myelin water fraction (MWF) of NAWM or normal WM was compared between MS (all patients or early-stage MS patients) and HC. The comparison was performed for a global WM mask and five regional WM masks. STATISTICAL TESTS: A general linear model was applied for the comparison. A statistical power and a minimum sample size for the significant difference were obtained. Spearman's correlation coefficient was calculated between MWF and clinical measures and between ViSTa-MWF and GRASE-MWF for the global WM mask. RESULTS: MWFs of ViSTa were significantly lower in the MS patients than those in the HC in all masks (P < 0.001). GRASE-MWI results revealed reduced MWFs only in global WM, genu, and optic radiation. ViSTa-MWI had higher statistical powers than that of GRASE-MWI (power: ViSTa = 99.2 ± 1.6% and GRASE = 75.5 ± 31.0%; sample size: ViSTa = 18 ± 9 and GRASE = 78 ± 75). In early-stage MS, MWFs of ViSTa were significantly lower than those of the HC in all masks except for centrum semiovale; however, MWFs of GRASE MWI were significantly lower only in optic radiation. Disease duration was correlated with both MWIs (ViSTa; r = -0.437 and GRASE; r = -0.445). ViSTa and GRASE MWFs were significantly correlated in the HC (r = 0.664) and MS (r = 0.768). DATA CONCLUSION: ViSTa-MWI may detect a reduction of MWF in NAWM of MS. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine. DOI: 10.1002/jmri.26278


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165. J Magn Reson Imaging. 2018 Sep 19. doi: 10.1002/jmri.26328. [Epub ahead of print]

Characterizing Structural Changes With Devolving Remyelination Following Experimental Demyelination Using High Angular Resolution Diffusion MRI and Texture Analysis.

Luo T(1), Oladosu O(2), Rawji KS(2), Zhai P(3)(4)(5), Pridham G(3)(4)(5), Hossain S(6), Zhang Y(3)(4)(5). Author information: (1)Bachelor of Health Sciences Program, University of Calgary, AB, Canada. (2)Department of Neuroscience, University of Calgary, AB, Canada. (3)Department of Radiology, University of Calgary, AB, Canada. (4)Department of Clinical Neurosciences, University of Calgary, AB, Canada. (5)Hotchkiss Brain Institute, University of Calgary, AB, Canada. (6)Department of Medical Sciences, University of Calgary, AB, Canada. BACKGROUND: Changes in myelin integrity are associated with the pathophysiology of many neurological diseases, including multiple sclerosis. However, noninvasive measurement of myelin injury and repair remains challenging. Advanced MRI techniques including diffusion tensor imaging (DTI), neurite orientation dispersion and density index (NODDI), and texture analysis have shown promise in quantifying subtle abnormalities in white matter structure. PURPOSE: To determine whether and how these advanced imaging methods help understand remyelination changes after demyelination using a mouse model. STUDY TYPE: Prospective, longitudinal. ANIMAL MODEL: Demyelination was induced in the thoracic spinal cord of 21 mice using the chemical toxin lysolecithin. FIELD STRENGTH/SEQUENCES: 9.4T ASSESSMENT: Imaging was done at day 7 (demyelination) and days 14 to 35 (ongoing remyelination) postsurgery, followed by histology. Image analysis focused on both lesions and peri-lesional areas where remyelination began. In histology, we quantified the complexity of tissue alignment using angular entropy, in addition to staining area. STATISTICAL ANALYSIS: Two-way analysis of variance was performed for assessing differences between tissue types and across timepoints, followed by post-hoc analysis to correct for multiple comparisons (P < 0.05). RESULTS: All diffusion and texture parameters were worse in lesions than the control tissue (P < 0.05) except orientation dispersion index (ODI) and neurite density index (NDI) over late remyelination. Longitudinally, ODI decreased and NDI increased persistently in both lesions and peri-lesion regions (P < 0.05). Fractional anisotropy showed a mild decrease at day 35 after increase, when lesion texture heterogeneity showed a trend to decrease (P > 0.05). Both lesion size and angular entropy decreased over time, and no change in any measure in the control tissue. DATA CONCLUSION: Diffusion and MRI texture metrics may provide compensatory information on myelin repair and ODI and NDI could be sensitive measures of evolving remyelination, deserving further validation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine. DOI: 10.1002/jmri.26328


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166. J Mol Med (Berl). 2018 Sep 18. doi: 10.1007/s00109-018-1686-x. [Epub ahead of print]

Targeting senescence to delay progression of multiple sclerosis.

Oost W(1), Talma N(2)(3), Meilof JF(4)(5), Laman JD(6)(7). Author information: (1)University of Groningen, Groningen, The Netherlands. (2)European Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. (3)Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. (4)Department of Neurology, Martini Hospital, Groningen, The Netherlands. (5)MS Center Noord Nederland (MSCNN), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. (6)Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. [email protected]. (7)MS Center Noord Nederland (MSCNN), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. [email protected]. Multiple sclerosis (MS) is a chronic and often progressive, demyelinating disease of the central nervous system (CNS) white and gray matter and the single most common cause of disability in young adults. Age is one of the factors most strongly influencing the course of progression in MS. One of the hallmarks of aging is cellular senescence. The elimination of senescent cells with senolytics has very recently been shown to delay age-related dysfunction in animal models for other neurological diseases. In this review, the possible link between cellular senescence and the progression of MS is discussed, and the potential use of senolytics as a treatment for progressive MS is explored. Currently, there is no cure for MS and there are limited treatment options to slow the progression of MS. Current treatment is based on immunomodulatory approaches. Various cell types present in the CNS can become senescent and thus potentially contribute to MS disease progression. We propose that, after cellular senescence has indeed been shown to be directly implicated in disease progression, administration of senolytics should be tested as a potential therapeutic approach for the treatment of progressive MS. DOI: 10.1007/s00109-018-1686-x

167. J Neuroimaging. 2018 Sep 19. doi: 10.1111/jon.12561. [Epub ahead of print]

Teriflunomide's Effect on Glia in Experimental Demyelinating Disease: A Neuroimaging and Histologic Study.

Pol S(1), Sveinsson M(1), Sudyn M(1), Babek N(1), Siebert D(1), Bertolino N(1), Modica CM(1), Preda M(1)(2), Schweser F(1)(2), Zivadinov R(1)(2). Author information: (1)Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY. (2)Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, NY. BACKGROUND AND PURPOSE: Teriflunomide reduces disability progression and brain atrophy in multiple sclerosis patients. The exact mechanism of action by which teriflunomide exerts these effects is currently unknown. We assessed the effect of teriflunomide on brain glial cells in the Theiler's murine encephalomyelitis virus (TMEV) by using a histological approach in combination with neuroimaging. METHODS: Forty-eight SJL female mice received an intracerebral injection of TMEV at 6-8 weeks of age and were then treated with teriflunomide (n = 24) or placebo (n = 24) for 9 months. They were examined with MRI and behavioral testing at 2, 6, and 9 months postinduction (mPI). Of those, 18 teriflunomide-treated and 17 controls mice were analyzed histologically at 9 mPI to sample from different brain regions for myelination status, microglial density, and oligodendroglial lineage. The histological and MRI outcomes were correlated. RESULTS: Corpus callosum microglial density was numerically lower in the teriflunomide-treated mice compared to the control group (141.1 ± 21.7 SEM vs. 214.74 ± 34.79 SEM, Iba1+ cells/mm2 , P = .087). Basal ganglia (BG) microglial density in the teriflunomide group exhibited a negative correlation with fractional anisotropy (P = .021) and a positive correlation with mean diffusivity (P = .034), indicating less inflammation and axonal damage. Oligodendroglial lineage cell and myelin density were not significantly different between treatment groups. However, a significant positive correlation between BG oligodendrocytes and BG volume (P = .027), and with N-acetyl aspartate concentration (P = .008), was found in the teriflunomide group, indicating less axonal loss. CONCLUSION: Teriflunomide altered microglia density and oligodendrocytes differentiation, which was associated with less evident microstructural damage on MRI. © 2018 by the American Society of Neuroimaging. DOI: 10.1111/jon.12561


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168. J Neuroimaging. 2018 Sep 19. doi: 10.1111/jon.12559. [Epub ahead of print]

Multicenter Measurements of T1 Relaxation and Diffusion Tensor Imaging: Intra and Intersite Reproducibility.

Vavasour IM(1), Meyers SM(2), Mädler B(3), Harris T(1), Fu E(4), Li DKB(1)(5), Traboulsee A(5), MacKay AL(1)(2), Laule C(1)(2)(6)(7). Author information: (1)Department of Radiology, University of British Columbia, UBC MRI Research Centre, Vancouver, British Columbia, Canada. (2)Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada. (3)Philips Healthcare, Hamburg, Germany. (4)Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada. (5)Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. (6)Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. (7)International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, British Columbia, Canada. BACKGROUND AND PURPOSE: Quantitative T1 and diffusion tensor imaging (DTI) may provide information about pathological changes underlying disability and progression in diseases like multiple sclerosis (MS). Imaging the corpus callosum (CC), a primary site of damage in MS with a critical role in interhemispheric connectivity, may be useful for assessing overall brain health, prognosis, and therapy efficacy. We assessed the feasibility of multisite clinical trials using advanced MRI by examining the intra and intersite reproducibility of T1 and DTI measurements in the CC and segmented white matter (WM). METHODS: Five healthy volunteers were scanned twice within 24 hours at six 3T sites. Coefficients of variation (COVs) and intraclass correlation coefficients (ICCs) for CC and WM T1 , fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Dax ), and radial diffusivity (Drad ) assessed intrasite and intersite reliability. RESULTS: CC and WM T1 showed excellent intrasite reproducibility with low COVs (mean = .90% and .89%, respectively) and good ICCs (CC = .78, WM = .90). T1 also demonstrated intersite reliability (low COVs: CC = 2.4%, WM = 1.8%; moderate ICCs: CC = .43, WM = .69). DTI had low intrasite COVs (CC: FA = 1.3%, MD = 1.5%, Dax = 1.4%, Drad = 2.2%; WM: FA = .9%, MD = .9%, Dax = .7%, Drad = 1.2%) and high intrasite ICCs (CC: FA = .95, MD = .97, Dax = .94, Drad = .97; CC: FA = .9, MD = .66, Dax = .88, Drad = .63), indicating excellent intrasite reproducibility. DTI also showed excellent intersite reliability with low COVs (CC: FA = 2.1%, MD = 4.1%, Dax = 3.4%, Drad = 5.3%, WM: FA = 1.3%, MD = 1.9%, Dax = 1.8%, Drad = 2.1%,) and good ICCs (CC: FA = .90, MD = .84, Dax = .72, Drad = .90; WM: FA = .83, MD = .34, Dax = .62, Drad = .41). CONCLUSIONS: T1 and DTI measures are reproducible using equivalent MRI scanners and sequence protocols. Using a similar MR system, it is feasible to carry out multicenter studies using T1 and DTI to evaluate changes within the CC and WM. © 2018 by the American Society of Neuroimaging. DOI: 10.1111/jon.12559


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169. J Neuroimmunol. 2018 Sep 7. pii: S0165-5728(18)30276-5. doi: 10.1016/j.jneuroim.2018.09.001. [Epub ahead of print]

B cells from patients with multiple sclerosis have a pathogenic phenotype and increased LTα and TGFβ1 response.

McWilliam O(1), Sellebjerg F(2), Marquart HV(3), von Essen MR(2). Author information: (1)The Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen, Denmark. Electronic address: [email protected]. (2)The Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen, Denmark. (3)Department for Clinical Immunology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen, Denmark. The contribution of B cells to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS) is currently of great interest due to the positive outcomes of treatment with B cell-depleting monoclonal antibodies. In this exploratory study we examined the phenotype and cytokine response of B cells from untreated patients with RRMS and healthy controls. The CNS migration potential of the individual blood B cell subpopulations was evaluated according to the expression of CD49d, ALCAM, CXCR3, and CCR7, and cerebrospinal fluid (CSF) samples were analyzed to establish the phenotype of migrated B cells. The frequency of the individual blood B cell subsets expressing CD5, CD43, CD69, CD80, CD83, DC-SIGN and CD138 was similar in patients with RRMS and healthy controls. However, a higher percentage of CD27-IgD-IgM+ memory B cells were found in the blood of patients with RRMS, a population also identified in the CSF samples. We also observed an increased percentage of B cells producing LTα and a higher level of TGFβ1 in patients with RRMS. Altogether, we found that patients with RRMS have an increased frequency of blood CD27-IgD-IgM+ memory B cells that are recruited to the CSF together with other memory B cell populations. Furthermore, we report an increased B cell production of LTα and TGFβ1 in patients with RRMS. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.jneuroim.2018.09.001

170. J Neuroimmunol. 2018 Sep 22;324:115-118. doi: 10.1016/j.jneuroim.2018.09.010. [Epub ahead of print]

Recurrent optic neuritis - Different patterns in multiple sclerosis, neuromyelitis optica spectrum disorders and MOG-antibody disease.

Lotan I(1), Hellmann MA(2), Benninger F(2), Stiebel-Kalish H(3), Steiner I(2). Author information: (1)Department of Neurology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: [email protected]. (2)Department of Neurology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. (3)Neuro-Ophtalmology Unit, Department of Ophthalmology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. BACKGROUND: Optic neuritis is a frequent finding in multiple sclerosis (MS) and in neuromyelitis optica spectrum disorder (NMOSD), as well as in Myelin-Oligodendrocyte Glycoprotein (MOG) -positive disease. While both NMOSD and MOG-antibody disease are known to be associated with a humoral, antibody-mediated attack against a specific antigen, much less is known about the etiology and pathogenesis of MS. The aim of this study was to determine if the localization of recurrent episodes of ON follows the same pattern in MS as in NMOSD and in MOG-positive recurrent ON. METHODS: We retrospectively reviewed our database to identify patients with recurrent ON. The eye affected in each episode of ON was recorded, and the findings were analyzed. RESULTS: Forty-seven patients met the inclusion criteria. In the MS group, all episodes of ON recurred on the same side in 15 of the 29 patients (51.7%), accounting for 32 of the total 78 episodes (41%).In the NMSOD group, all episodes of ON recurred on the same side in 2 of the 12 patients (16.6%), accounting for 6 of the total 49 episodes (12.5%).In the MOG-positive group, all episodes of ON recurred on the same side in 1 out of 6 patients (16.6%), accounting for 2 of 21 episodes (9.5%).The between-group difference in the rate of recurrences affecting the ipsilateral side was statistically significant (p = .0007 and p = .0085 for the MS-NMOSD and MS-MOG groups, respectively). CONCLUSIONS: The pattern of recurrent ON differs significantly between MS and NMOSD and MOG-positive recurrent ON. This finding suggests that in MS recurrences may be provoked by previous tissue damage, disruption of the blood-brain barrier, and other local factors while in NMOSD and MOG-antibody disease attacks are indeed due to localization of the auto antigen. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.09.010


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1,25-Dihydroxyvitamin D3 increases the methionine cycle, CD4+ T cell DNA methylation and Helios+Foxp3+ T regulatory cells to reverse autoimmune neurodegenerative disease.

Moore JR(1), Hubler SL(2), Nelson CD(3), Nashold FE(1), Spanier JA(4), Hayes CE(5). Author information: (1)Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States. (2)Rhapsody Data, LLC, Madison, WI 53705, United States. (3)Department of Animal Sciences, University of Florida, Gainesville, FL 32611, United States. (4)Rheumatic and Autoimmune Diseases, Center for Immunology, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: [email protected]. (5)Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States. Electronic address: [email protected]. We investigated how one calcitriol dose plus vitamin D3 reverses experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. This protocol rapidly increased CD4+ T cell Ikzf2 transcripts, Helios protein, and CD4+Helios+FoxP3+ T regulatory cells. It also rapidly increased CD4+ T cell Bhmt1 transcripts, betaine:homocysteine methyltransferase-1 (BHMT1) enzyme activity, and global DNA methylation. BHMT1 transmethylates homocysteine to replenish methionine. Targeting the Vdr gene in T cells decreased Ikzf2 and Bhmt1 gene expression, reduced DNA methylation, and elevated systemic homocysteine in mice with EAE. We hypothesize that calcitriol drives a transition from encephalitogenic CD4+ T cell to Treg cell dominance by upregulating Ikzf2 and Bhmt1, recycling homocysteine to methionine, reducing homocysteine toxicity, maintaining DNA methylation, and stabilizing CD4+Helios+FoxP3+Tregulatory cells. Conserved vitamin D-responsive element (VDRE)-type sequences in the Bhmt1 and Ikzf2 promoters, the universal need for methionine in epigenetic regulation, and betaine's protective effects in MTHFR-deficiency suggest similar regulatory mechanisms exist in humans. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.jneuroim.2018.09.008


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Prevalence of anti-aquaporin 4 antibody in a diagnostic cohort of patients being investigated for possible neuromyelitis optica spectrum disorder in Western Australia.

Fabis-Pedrini MJ(1), Bundell C(2), Wee CK(1), Lucas M(3), McLean-Tooke A(4), Mastaglia FL(1), Carroll WM(5), Kermode AG(6). Author information: (1)Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perron Institute for Neurological & Translational Science, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia. (2)PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia. (3)PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia; School of Medicine and Pharmacology, School of Pathology and Laboratory Medicine, UWA, Perth, Western Australia, Australia; Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia; Department of Immunology, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia. (4)PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia; Department of Immunology, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia. (5)Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perron Institute for Neurological & Translational Science, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia; Department of Neurology & Clinical Neurophysiology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. (6)Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perron Institute for Neurological & Translational Science, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia; Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia; Department of Neurology & Clinical Neurophysiology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. Electronic address: [email protected]. OBJECTIVE: To evaluate the prevalence of anti-AQP4 antibody in serum and CSF samples from patients being investigated for possible neuromyelitis optica spectrum disorder (NMOSD) referred to the PathWest State reference laboratory using a sensitive cell-based assay (CBA). BACKGROUND: NMOSD is an inflammatory CNS disease distinct from MS, which is relatively rare in Western countries. A proportion of patients with NMOSD have detectable serum IgG antibodies that target the water channel aquaporin-4 (AQP4-IgG), but the frequency varies in different populations studied and according to the assay method employed. METHODS: Sera or CSF from a diagnostic cohort of 196 consecutive patients with possible NMOSD which had previously been screened by indirect immunofluorescence (IIF) on primate cerebellum were re-tested for AQP4-IgG reactivity to the M1 and M23 isoforms of AQP4 using a commercial CBA. A control group of 205 patients with definite MS was also included in the study. RESULTS: Of the 196 patients, only 5 sera were AQP4-IgG positive, representing 2.6% of patients in the diagnostic cohort. All 5 AQP4-IgG positive patients fulfilled the 2015 revised diagnostic criteria for NMOSD and were females of varied ethnic origins, 4 of whom had longitudinally extensive transverse myelitis. The CBA confirmed AQP4-IgG positivity in the four patients previously reported as positive by IIF, and an additional patient with NMOSD who had previously been diagnosed as MS was also identified. None of the 205 MS sera were AQP4-IgG positive. CONCLUSIONS: Our study confirms the utility and greater reliability of the M1/M23 CBA for detecting AQP4-IgG in patients with possible NMOSD, and indicates a prevalence of seropositive NMOSD in the Western Australian population similar to that in other Western populations. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.09.006


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Therapeutic potentials of ginger for treatment of Multiple sclerosis: A review with emphasis on its immunomodulatory, anti-inflammatory and anti-oxidative properties.

Jafarzadeh A(1), Nemati M(2). Author information: (1)Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. Electronic address: [email protected]. (2)Department of Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran. Multiple sclerosis (MS) is characterized by chronic inflammatory response-induced demyelination of the neurons and degeneration of the axons within the central nervous system (CNS). A complex network of immunopathological-, inflammatory- and oxidative parameters involve in the development and advancement of MS. The anti-inflammatory, immunomodulatory and anti-oxidative characteristics of the ginger and several of its components have been indicated in some of experimental and clinical investigations. The possible therapeutic potentials of ginger and its ingredients in the treatment of MS may exert mainly through the regulation of the Th1-, Th2-, Th9-, Th17-, Th22- and Treg cell-related immune responses, down-regulation of the B cell-related immune responses, modulation of the macrophages-related responses, modulation of the production of pro- and anti-inflammatory cytokines, down-regulation of the arachidonic acid-derived mediators, interfering with the toll like receptor-related signaling pathways, suppression of the inflammasomes, down-regulation of the oxidative stress, reduction of the adhesion molecules expression, and down-regulation of the expression of the chemokines and chemokine receptors. This review aimed to provide a comprehensive knowledge regarding the immunomodulatory-, anti-inflammatory and anti-oxidative properties of ginger and its components, and highlight novel insights into the possible therapeutic potentials of this plant for treatment of MS. The review encourages more investigations to consider the therapeutic potentials of ginger and its effective components for managing of MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.09.003


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174. J Neuroimmunol. 2018 Oct 15;323:94-104. doi: 10.1016/j.jneuroim.2018.07.005. Epub 2018 Jul 25.

Calcitonin gene-related peptide decreases IL-1beta, IL-6 as well as Ym1, Arg1, CD163 expression in a brain tissue context-dependent manner while ameliorating experimental autoimmune encephalomyelitis.

Rossetti I(1), Zambusi L(2), Finardi A(3), Bodini A(4), Provini L(5), Furlan R(6), Morara S(7). Author information: (1)Neuroscience Institute, National Research Council (CNR), Milano Unit, Via Vanvitelli 32, Milano 20129, Italy. Electronic address: [email protected]. (2)Neuroscience Institute, National Research Council (CNR), Milano Unit, Via Vanvitelli 32, Milano 20129, Italy; Department of Biotechnology and Translational Medicine, Milano University, Via Vanvitelli 32, Milano 2129, Italy. Electronic address: [email protected]. (3)Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 60, Milano 20132, Italy. Electronic address: [email protected]. (4)Institute of Applied Mathematics and Information Technology "E. Magenes", National Research Council (CNR), Milano Unit, Via Bassini 15, 20133 Milano, (Italy). Electronic address: [email protected]. (5)Neuroscience Institute, National Research Council (CNR), Milano Unit, Via Vanvitelli 32, Milano 20129, Italy. Electronic address: [email protected]. (6)Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 60, Milano 20132, Italy. Electronic address: [email protected]. (7)Neuroscience Institute, National Research Council (CNR), Milano Unit, Via Vanvitelli 32, Milano 20129, Italy; Department of Biotechnology and Translational Medicine, Milano University, Via Vanvitelli 32, Milano 2129, Italy. Electronic address: [email protected]. Activation states of immune cells (among them, the so-called pro- or anti-inflammatory states) influence the pathogenesis of multiple sclerosis (MS). The neuropeptide calcitonin gene-related peptide (CGRP) can exert a pro- or anti-inflammatory role in a context-dependent manner. In mice CGRP was found to attenuate the development of experimental autoimmune encephalomyelitis (EAE, a common MS animal model). We analyzed CGRP effects on the expression of cytokines and markers of activation states, as well as its intracellular cascade, following intrathecal administration during EAE immunization. Real Time quantitative-PCR (RT-PCR) showed that IL-1beta and IL-6 (associated to a pro-inflammatory state in EAE), but also Ym1 (also known as Chil3), Arg1 and CD163 (associated to an anti-inflammatory state in EAE) were decreased in the encephalon (devoid of cerebellum). In the cerebellum itself, IL-1beta and Ym1 were decreased. TNF-alpha (associated to a pro-inflammatory state in EAE), but also IL-10 (associated to another type of anti-inflammatory state) and BDNF were unchanged in these two regions. No changes were detected in the spinal cord. Additional tendencies toward a change (as revealed by RT-PCR) were again decreases: IL-10 in the encephalon and Arg1 in the spinal cord. CGRP decreased percentage of Ym1+/CD68+ immunoreactive cells and cell density of infiltrates in the cervical spinal cord pia mater. Instead, Ym1 in the underlying parenchyma and at thoracic and lumbar levels, as well as Arg1, were unchanged. In cultured microglia the neuropeptide decreased Ym1, but not Arg1, immunoreactivity. Inducible NOS (iNOS) was unchanged in spinal cord microglia and astrocytes. The neuropeptide increased the activation of ERK1/2 in the astrocytes of the spinal cord and in culture, but did not influence the activation of ERK1/2 or p38 in the spinal cord microglia. Finally, in areas adjacent to infiltration sites CGRP-treated microglia showed a larger ramification radius. In conclusion, CGRP-induced EAE amelioration was associated to a concomitant, context-dependent decrease in the expression of markers belonging to both pro- or anti-inflammatory activation states of immune cells. It can be hypothesized that CGRP-induced EAE attenuation is obtained through a novel mechanism that promotes down-regulation of immune cell activation that facilitates the establishment of a beneficial environment in EAE provided possibly also by other factors. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.07.005


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Serum levels of leptin and adiponectin are not associated with disease activity or treatment response in multiple sclerosis.

Kvistad SS(1), Myhr KM(2), Holmøy T(3), Benth JŠ(4), Wergeland S(2), Beiske AG(5), Bjerve KS(6), Hovdal H(7), Midgard R(8), Sagen JV(9), Torkildsen Ø(10). Author information: (1)Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway. Electronic address: [email protected]. (2)Department of Clinical Medicine, University of Bergen, Bergen, Norway; Norwegian Multiple Sclerosis Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway. (3)Department of Neurology, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (4)Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Health Services Research Unit, Akershus University Hospital, Lørenskog, Norway. (5)Neurology Group, Oslo, Norway. (6)Department of Medical Biochemistry, St. Olav's Hospital, Trondheim University Hospital, Norway; Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway. (7)Department of Neurology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. (8)Department of Neurology, Molde Hospital, Norway; Unit for Applied Clinical Research, Norwegian University of Science and Technology, Trondheim, Norway. (9)Department of Clinical Medicine, University of Bergen, Bergen, Norway; Hormone Laboratory, Department of Laboratory Medicine and Pathology, Haukeland University Hospital, Bergen, Norway. (10)Department of Clinical Medicine, University of Bergen, Bergen, Norway; Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway. Adipokines secreted by fatty tissue have inflammatory properties and are suggested biomarkers of MS disease activity. To assess this, 88 MS patients were followed with nine repeated measurements of leptin and adiponectin and 12 magnetic resonance imaging (MRI) scans for two years; six months without any immunomodulatory treatment followed by 18 months during interferon-beta (IFNB) treatment. Serum levels of leptin dropped and adiponectin increased upon initiation of IFNB-therapy, but were not associated with clinical or MRI disease activity or with treatment response. Our findings indicate that leptin and adiponectin are not useful as biomarkers of MS disease activity. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.07.011


High levels of antibodies against PtpA and PknG secreted by Mycobacterium avium ssp. paratuberculosis are present in neuromyelitis optica spectrum disorder and multiple sclerosis patients.

Slavin YN(1), Bo M(2), Caggiu E(2), Sechi G(3), Arru G(3), Bach H(4), Sechi LA(5). Author information: (1)Division of Infectious Diseases, Faculty of Medicine, The University of British Columbia, Vancouver, BC V6H 3Z6, Canada. (2)Dipartimento di Scienze Biomediche, Università di Sassari, Viale San Pietro 43 b, 07100 Sassari, Italy. (3)Dipartimento di Scienze Cliniche, Chirurgiche e Sperimentali, Viale San Pietro 8, Università di Sassari, Sassari 07100, Italy. (4)Division of Infectious Diseases, Faculty of Medicine, The University of British Columbia, Vancouver, BC V6H 3Z6, Canada. Electronic address: [email protected]. (5)Dipartimento di Scienze Biomediche, Università di Sassari, Viale San Pietro 43 b, 07100 Sassari, Italy. Electronic address: [email protected]. Mycobacterium avium ssp. paratuberculosis (Map) is the etiological agent of Paratuberculosis in ruminants. Protein tyrosine phosphatase A (PtpA) and protein kinase G (PknG) are secreted proteins necessary for the survival of the pathogen within macrophages. In this study we analyzed if Map was able to grow within astrocytes and investigated on the presence of antibodies against PtpA and PknG proteins in MS and NMOSD patients by ELISA. Map was unable to proliferate in astrocytes after of 72 h post-infection, but we observed a high level of antibodies against both virulence factors, suggesting that these patients have been exposed/infected with Map. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.07.007


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Effect of fingolimod action on the release of monocyte-derived microvesicles in multiple sclerosis patients.

Amoruso A(1), Blonda M(2), D'Arrigo G(3), Grasso R(2), Di Francescantonio V(2), Verderio C(4), Avolio C(2). Author information: (1)Department of Medical and Surgical Sciences, University Of Foggia, Foggia, Italy. Electronic address: [email protected]. (2)Department of Medical and Surgical Sciences, University Of Foggia, Foggia, Italy. (3)Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy. (4)CNR Institute of Neuroscience, Milan, Italy. Recently, microvesicles (MVs) were considered as important mediators of intercellular communication, especially in pathological conditions as Multiple Sclerosis (MS). In myeloid cells, MV shedding is induced by the receptor P2X7 with the involvement of acid sphingomyelinase (A-SMase) and release of the IL-1β. In this study we evaluate how Fingolimod affects MVs production by the monocytes, as well as P2X7R, IL-1β expression and A-SMase activity. Treatment decreased MVs production and IL-1β expression. This effect was associated with the inhibition of A-SMase activity in BzATP-stimulated monocytes from MS patients. These evidences suggest monocyte MVs as a possible disease and drug-efficacy biomarkers. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.07.008


Age-adjusted CSF β2-microglobulin and lactate are increased and ACE is decreased in patients with multiple sclerosis, but only lactate correlates with clinical disease duration and severity.

Haarmann A(1), Hähnel L(2), Schuhmann MK(3), Buttmann M(4). Author information: (1)Department of Neurology, University of Würzburg, Würzburg, Germany. Electronic address: [email protected]. (2)Department of Neurology, University of Würzburg, Würzburg, Germany. Electronic address: [email protected]. (3)Department of Neurology, University of Würzburg, Würzburg, Germany. Electronic address: [email protected]. (4)Department of Neurology, University of Würzburg, Würzburg, Germany; Department of Neurology, Caritas Hospital, Bad Mergentheim, Germany. Electronic address: [email protected]. We compared cerebrospinal fluid levels of lactate, β2-microglobulin and angiotensin-converting enzyme (ACE) between 438 untreated patients with multiple sclerosis and 276 patients with non-inflammatory neurological disorders. Age-adjusted β2-microglobulin and lactate were significantly higher and ACE was significantly lower in MS patients than in controls. β2-microglobulin and ACE positively correlated with high significance both in MS patients and controls. While disease duration negatively correlated and progression index, defined as EDSS score divided by disease duration in years, positively correlated with age-adjusted lactate levels, both did neither correlate with β2-microglobulin nor with ACE. Both CSF β2-microglobulin and ACE deserve further investigation as biomarkers of multiple sclerosis pathophysiology. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.07.001


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179. J Neuroimmunol. 2018 Oct 15;323:109-114. doi: 10.1016/j.jneuroim.2018.07.016. Epub 2018 Aug 2.

Genome-wide association study in Guillain-Barré syndrome.

Blum S(1), Ji Y(2), Pennisi D(3), Li Z(3), Leo P(3), McCombe P(1), Brown MA(4). Author information: (1)The University of Queensland, UQ Centre for Clinical Research, Royal Brisbane & Women's Hospital, Brisbane, Australia. (2)Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT) at Translational Research Institute, Brisbane, Australia; Department of Neurology, Peking University Third Hospital, Beijing, PR China. (3)Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT) at Translational Research Institute, Brisbane, Australia. (4)Translational Genomics Group, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT) at Translational Research Institute, Brisbane, Australia. Electronic address: [email protected]. Guillain-Barré syndrome (GBS) is considered to have an immune-mediated basis, but the genetic contribution to GBS is unclear. We conducted a GWAS involving 215 GBS patients and 1,105 healthy controls. No significant associations of individual SNPs or imputed HLA types were observed. We performed a genome-wide complex trait analysis for evaluation of the heritability of GBS, and found that common SNPs contribute up to 25% of susceptibility to the disease. Genetic risk score analysis showed no evidence of overlap in genetic susceptibility factors of GBS and multiple sclerosis. Given the unexplained heritability of the trait further larger GWAS are indicated. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.07.016

180. J Neuroimmunol. 2018 Oct 15;323:105-108. doi: 10.1016/j.jneuroim.2018.08.004. Epub 2018 Aug 8.

CTLA-4, PD-1 and TIM-3 expression predominantly downregulated in MS patients.

Mohammadzadeh A(1), Rad IA(2), Ahmadi-Salmasi B(3). Author information: (1)Department of Immunology and genetic, Urmia University of Medical Sciences, Urmia, Iran. Electronic address: [email protected]. (2)Department of Genetics, Urmia University of Medical Sciences, Urmia, Iran. (3)Department of Neurology, Imam Khomeini Hospital, Urmia University of Medical Sciences, Urmia, Iran. Multiple sclerosis (MS), is an autoimmune disorder of central nervous system (CNS) characterized by inflammation and demyelination. Self-tolerance impairment is considered to be induced by a combination of inherited susceptibility and environmental agents. In this work, we demonstrate that a reduction in the comparative expression of well-known inhibitory receptors (i.e., CTLA-4, PD-1, and TIM-3) is importantly linked with MS patients compared to healthy controls. The relative expression of interested genes was performed on peripheral blood mononuclear cells (PBMCs), by using quantitative real time-PCR (qRT-PCR). Our data highlighted the role of inhibitory receptors in the maintenance of immune homeostasis in autoimmune disease. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.08.004


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Granulocyte-macrophage colony-stimulating factor as a mediator of autoimmunity in multiple sclerosis.

Kostic M(1), Zivkovic N(2), Cvetanovic A(3), Stojanovic I(4). Author information: (1)University of Nis, Medical Faculty of Nis, Department of Immunology, Blvd. dr Zorana Djindjica 81, 18000 Nis, Serbia. Electronic address: [email protected]. (2)University of Nis, Medical Faculty of Nis, Department of Pathology, Blvd. dr Zorana Djindjica 81, 18000 Nis, Serbia. Electronic address: [email protected]. (3)University of Nis, Medical Faculty of Nis, Department of Oncology, Blvd. dr Zorana Djindjica 81, 18000 Nis, Serbia. Electronic address: [email protected]. (4)University of Nis, Medical Faculty of Nis, Department of Biochemistry, Blvd. dr Zorana Djindjica 81, 18000 Nis, Serbia. Electronic address: [email protected]. Autoreactive, myelin-specific, CD4+ T cells have a central role in multiple sclerosis (MS) pathogenesis; however the exact phenotype characteristics of these cells remain elusive. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF) expression has emerged as the main pathological signature of the encephalogenicity in both T and B cell compartment. In this review we have summarized the current data supporting GM-CSF relevance in MS pathophysiology, in the context of both immunomodulatory and neuroinflammatory processes; as well as the potential cellular sources of this stimulating factor, including different T and B cell subsets. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.07.002

182. J Neuroimmunol. 2018 Aug 29;324:22-25. doi: 10.1016/j.jneuroim.2018.08.014. [Epub ahead of print]

Clinical and radiological characteristics of neuromyelitis optica spectrum disorder in the North Egyptian Nile Delta.

Salama S(1), Marouf H(2), Ihab Reda M(3), Mansour AR(4), ELKholy O(2), Levy M(5). Author information: (1)Department of Neurology and Psychiatry, University of Alexandria, Alexandria, Egypt; Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. Electronic address: [email protected]. (2)Department of Neurology and Psychiatry, University of Alexandria, Alexandria, Egypt. (3)Department of Radiology, University of Alexandria, Alexandria, Egypt. (4)Department of Clinical Pathology, University of Alexandria, Alexandria, Egypt. (5)Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disorder of the central nervous system that was previously thought to be a subtype of multiple sclerosis (MS). Epidemiology studies of NMOSD are rare in both Middle East and North African countries. To our knowledge, there are no such studies in Egypt. Herein, we describe a case series of NMOSD patients from North Egyptian Nile Delta region and compare them to NMOSD in other parts in the Middle East and the world. METHODS: This is a case series study of NMOSD patients who were seen at the neuroimmunology clinic, Elhadara Hospital, University of Alexandria, Egypt, from January 2017 to January 2018. We describe their clinical, serological and radiological features. RESULTS: Our study identified twenty Egyptian patients, all of who fulfilled the 2015 international NMOSD diagnostic criteria. Ten tested positive for AQP4 antibodies in the serum while the other ten were seronegative. The mean age at onset was 27.8 years with an average disease duration of 6.8 years. There was a strong female predominance with a ratio of 5.6:1. We identified clinical features of the cohort that differ from those reported in other worldwide studies. INTERPRETATION: This is the first NMOSD case series in Egypt. Despite some limitation in testing and access to care, there are features of our NMOSD cases that appear to be different from other worldwide cohorts reported in the literature. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.08.014


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183. J Neuroimmunol. 2018 Aug 29. pii: S0165-5728(17)30480-0. doi: 10.1016/j.jneuroim.2018.07.010. [Epub ahead of print]

Effects of inflammatory cytokines IFN-γ, TNF-α and IL-6 on the viability and functionality of human pluripotent stem cell-derived neural cells.

Hagman S(1), Mäkinen A(1), Ylä-Outinen L(2), Huhtala H(3), Elovaara I(4), Narkilahti S(5). Author information: (1)Neuroimmunology Unit, Medical School, The Faculty of Medicine and Life Sciences, Tampere University Hospital, University of Tampere, Tampere, Finland; Neuro Group, BioMeditech, The Faculty of Medicine and Life Sciences, University of Tampere, Finland. (2)Neuro Group, BioMeditech, The Faculty of Medicine and Life Sciences, University of Tampere, Finland. (3)Faculty of Social Sciences, University of Tampere, Tampere, Finland. (4)Neuroimmunology Unit, Medical School, The Faculty of Medicine and Life Sciences, Tampere University Hospital, University of Tampere, Tampere, Finland. (5)Neuro Group, BioMeditech, The Faculty of Medicine and Life Sciences, University of Tampere, Finland. Electronic address: [email protected]. Multiple Sclerosis (MS) is an inflammatory neurodegenerative disease, where neural progenitor cell (NPC) transplantation has been suggested as a potential neuroprotective therapeutic strategy. Since the effect of inflammation on NPCs is poorly known, their effect on the survival and functionality of human NPCs were studied. Treatment with interleukin (IL)-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ did not induced cytotoxicity, but IFN-γ treatment showed decreased proliferation and neuronal migration. By contrast, increased proliferation and inhibition of electrical activity were detected after TNF-α treatment. Treatments induced secretion of inflammatory factors. Inflammatory cytokines appear to modulate proliferation as well as the cellular and functional properties of human NPCs. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.07.010


Dysfunctional RNA binding proteins and stress granules in multiple sclerosis.

Salapa HE(1), Johnson C(2), Hutchinson C(3), Popescu BF(1), Levin MC(4). Author information: (1)Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, SK, Canada; Cameco Multiple Sclerosis Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada. (2)Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, SK, Canada. (3)Department of Medicine, Neurology Division, University of Saskatchewan, Saskatoon, SK, Canada; Cameco Multiple Sclerosis Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada. (4)Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK, Canada; Department of Medicine, Neurology Division, University of Saskatchewan, Saskatoon, SK, Canada; Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, SK, Canada; Cameco Multiple Sclerosis Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada. Electronic address: [email protected]. Dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonuclear protein A1 (hnRNP A1) has been shown to contribute to the pathogenesis of neurodegenerative diseases, but its involvement in multiple sclerosis (MS) is largely unknown. In a neuronal cell line, interferon-γ caused hnRNP A1 nucleocytoplasmic mislocalization; colocalization of hnRNP A1 in stress granules (SGs); and inhibition of translation. Neurons in the brain of a MS patient showed pathogenic RBP dysfunction, including nuclear depletion of hnRNP A1, its mislocalization to the cytoplasm, and its colocalization in SGs. These data indicate a role for dysfunctional hnRNP A1 in the pathogenesis of MS. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.jneuroim.2018.08.015


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185. J Neuroimmunol. 2018 Aug 27;324:26-34. doi: 10.1016/j.jneuroim.2018.08.012. [Epub ahead of print]

Rapamycin and fingolimod modulate Treg/Th17 cells in experimental autoimmune encephalomyelitis by regulating the Akt-mTOR and MAPK/ERK pathways.

Hou H(1), Cao R(1), Quan M(1), Sun Y(1), Sun H(1), Zhang J(1), Li B(1), Guo L(1), Song X(2). Author information: (1)Department of Neurology, Key Laboratory of Hebei Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. (2)Department of Neurology, Key Laboratory of Hebei Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China. Electronic address: [email protected]. Rapamycin prevents experimental autoimmune encephalomyelitis (EAE) and activates the MAPK/ERK pathway in EAE. Thus, we hypothesized combining rapamycin and fingolimod treatments would have synergistic effects in EAE. We show that combination therapy ameliorated EAE and regulated spinal cord IL-17 and TGF-β levels in EAE mice. Combination therapy also modulated IL-17 and TGF-β concentration, RoRγt and Foxp3 mRNA levels, and Th17 cell and Treg frequencies in the spleen. Moreover, rapamycin decreased ps6k and increased pAkt and pERK, while combination therapy downregulated pAkt, ps6 k and pERK in EAE mice. Our findings provide insight into using this drug combination to treat EAE. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.08.012


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LncRNAs expression profile in peripheral blood mononuclear cells from multiple sclerosis patients.

Fenoglio C(1), Oldoni E(2), Serpente M(3), De Riz MA(4), Arcaro M(5), D'Anca M(6), Pietroboni AM(7), Calvi A(8), Lecchi E(9), Goris A(10), Mallants K(11), Dubois B(12), Comi C(13), Cantello R(14), Scarpini E(15), Galimberti D(16). Author information: (1)University of Milan, Dino Ferrari Center, Milan, Italy. Electronic address: [email protected]. (2)University of Milan, Dino Ferrari Center, Milan, Italy; Laboratory for Neuroimmunology, Department of Neurosciences, KU Leuven, Herestraat 49 bus 1022, 3000 Leuven, Belgium. Electronic address: [email protected]. (3)University of Milan, Dino Ferrari Center, Milan, Italy. Electronic address: [email protected]. (4)Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy. Electronic address: [email protected]. (5)Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy. Electronic address: [email protected]. (6)University of Milan, Dino Ferrari Center, Milan, Italy. Electronic address: [email protected]. (7)Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy. Electronic address: [email protected]. (8)University of Milan, Dino Ferrari Center, Milan, Italy. Electronic address: [email protected]. (9)Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy. (10)Laboratory for Neuroimmunology, Department of Neurosciences, KU Leuven, Herestraat 49 bus 1022, 3000 Leuven, Belgium. Electronic address: [email protected]. (11)Laboratory for Neuroimmunology, Department of Neurosciences, KU Leuven, Herestraat 49 bus 1022, 3000 Leuven, Belgium. Electronic address: [email protected]. (12)Laboratory for Neuroimmunology, Department of Neurosciences, KU Leuven, Herestraat 49 bus 1022, 3000 Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: [email protected]. (13)Department of Translational Medicine, Section of Neurology, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy. Electronic address: [email protected]. (14)Department of Translational Medicine, Section of Neurology, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy. Electronic address: [email protected]. (15)University of Milan, Dino Ferrari Center, Milan, Italy; Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy. Electronic address: [email protected]. (16)University of Milan, Dino Ferrari Center, Milan, Italy; Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy. Electronic address: [email protected]. LncRNA PCR arrays containing 90 common LncRNAs were used to screen lncRNA expression levels in PBMC from a discovery population of patients with MS. Data from discovery and replications cohorts showed a generalized dysregulation of lncRNA levels in MS patients compared with controls. MALAT1, MEG9, NRON, ANRIL, TUG1, XIST, SOX2OT, GOMAFU, HULC, BACE-1AS were significantly downregulated in MS patients in comparison with controls. Therefore, we performed a validation analysis in an independent cohort of Belgian origin. In this study, NRON and TUG1 downregulations in MS patients compared with controls were confirmed (p ≤ .05 and p ≤ .0001 respectively), whereas considering the other lncRNAs, the statistical threshold was not reached. LncRNAs profiling could thus represent a new challenge in the research of easy detectable biomarkers of disease susceptibility and progression. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.08.008


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Inflammatory markers of CHMP2B-mediated frontotemporal dementia.

Roos P(1), von Essen MR(2), Nielsen TT(3), Johannsen P(3), Stokholm J(3), Bie AS(3), Waldemar G(3), Simonsen AH(3), Heslegrave A(4), Zetterberg H(5); FReJA consortium, Sellebjerg F(2), Nielsen JE(3). Author information: (1)Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark. Electronic address: [email protected]. (2)Danish Multiple Sclerosis Center, University of Copenhagen, Department of Neurology, Rigshospitalet, Denmark. (3)Danish Dementia Research Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark. (4)Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom. (5)Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. Histopathological studies and animal models have suggested an inflammatory component in the pathomechanism of the CHMP2B associated frontotemporal dementia (FTD-3). In this cross-sectional study, serum and cerebrospinal fluid were analyzed for inflammatory markers in CHMP2B mutation carriers. Serum levels of CCL4 were increased throughout life. Serum levels of IL-15, CXCL10, CCL22 and TNF-α were significantly associated with cognitive decline, suggesting a peripheral inflammatory response to neurodegeneration. CSF levels of sTREM2 appeared to increase more rapidly with age in CHMP2B mutation carriers. The identification of a peripheral inflammatory response to disease progression supports the involvement of an inflammatory component in FTD-3. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneuroim.2018.08.009


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188. J Neuroinflammation. 2018 Sep 5;15(1):255. doi: 10.1186/s12974-018-1295-1.

A comparison of brain magnetic resonance imaging lesions in multiple sclerosis by race with reference to disability progression.

Nakamura Y(1), Gaetano L(2)(3), Matsushita T(1), Anna A(2)(4), Sprenger T(5), Radue EW(6), Wuerfel J(2)(4), Bauer L(2)(7), Amann M(2)(3)(8), Shinoda K(1), Isobe N(9), Yamasaki R(1), Saida T(10)(11), Kappos L(3), Kira JI(12). Author information: (1)Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. (2)Medical Image Analysis Center (MIAC AG), Marktgasse 8, 4051, Basel, Switzerland. (3)Neurology and Department of Biomedicine, University Hospital Basel, Spitalstrasse 21, 4031, Basel, Switzerland. (4)Department of Biomedical Engineering, University of Basel, Marktgasse 8, 4051, Basel, Switzerland. (5)DKD Helios Klinik Wiesbaden, Aukammallee 33, 65191, Wiesbaden, Germany. (6)Biomedical Research and Education GmbH, Mittlere Strasse 91, 4031, Basel, Switzerland. (7)Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany. (8)Division of Diagnostic and Interventional Neuroradiology, Department of Radiology, University Hospital Basel, Spitalstrasse 21, 4031, Basel, Switzerland. (9)Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. (10)Institute of Neurotherapeutics, 16-1 Nishinokyoukasugachou, Nakagyo-ku, Kyoto, 604-8453, Japan. (11)Department of Neurology, Kyoto Min-Iren-Central Hospital, 16-1 Nishinokyoukasugachou, Nakagyo-ku, Kyoto, 604-8453, Japan. (12)Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. [email protected]. BACKGROUND: We compared the magnetic resonance imaging (MRI) features between Japanese and Caucasian patients with multiple sclerosis (MS), and identified the relationships between MRI features and disability. METHODS: From the baseline data of phase II fingolimod trials, 95 Japanese and 246 Caucasian relapsing-remitting MS patients were enrolled. The number, volume, and distribution of brain MRI lesions were evaluated using T2-weighted (T2W) images. Cross-sectional total normalized brain volume (NBV), normalized cortical gray matter volume, normalized deep gray matter volume (NDGMV), normalized white matter volume (NWMV), and normalized thalamic volume were measured. RESULTS: Japanese patients had significantly lower Expanded Disability Status Scale (EDSS) scores than Caucasian patients (mean 2.0 vs. 2.3, p = 0.008), despite a similar disease duration. Japanese patients showed a trend towards fewer T2W-lesions (median 50 vs. 65, p = 0.08) and significantly lower frequencies of cerebellar and parietal lobe lesions (p = 0.02 for both) than Caucasian patients. There were no differences in T2W-lesion volume between races, whereas Japanese patients had a significantly larger T2W-lesion volume per lesion compared with Caucasian patients (median 140 mm3 vs. 85 mm3, p < 0.0001). T2W-lesion volumes were positively correlated with EDSS scores in Japanese patients (p < 0.0001). In both races, NBV, normalized cortical gray matter volume, NDGMV, and thalamic volume were negatively correlated with disease duration and EDSS scores (p < 0.01 for all). NWMV was negatively correlated with disease duration and EDSS scores only in Caucasian patients (p = 0.03 and p = 0.004, respectively). NBV, NDGMV, NWMV, and thalamic volume were consistently smaller in Japanese compared with Caucasian patients throughout the entire examined disease duration (p = 0.046, p = 0.01, p = 0.005, and p = 0.04, respectively). Japanese patients had a significantly faster reduction in NDGMV (p = 0.001), particularly for thalamic volume (p = 0.001), with disease duration compared with Caucasian patients. CONCLUSIONS: Gray matter atrophy is a common denominator for disability in Japanese and Caucasian patients. Additional contributory factors for disability include T2W-lesion volume in Japanese patients and white matter atrophy in Caucasian patients. Less frequent parietal and cerebellar involvement with fewer T2W-lesions may underlie milder disability in Japanese patients. DOI: 10.1186/s12974-018-1295-1 PMCID: PMC6125988


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Expression of the neuroprotective protein aryl hydrocarbon receptor nuclear translocator 2 correlates with neuronal stress and disability in models of multiple sclerosis.

Rahim T(1), Becquart P(1), Baeva ME(1), Quandt J(2). Author information: (1)Department of Pathology and Laboratory Medicine, University of British Columbia, G227-2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada. (2)Department of Pathology and Laboratory Medicine, University of British Columbia, G227-2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada. [email protected]. BACKGROUND: Axonal degeneration and neuronal loss have been described as the major causes of irreversible clinical disability in multiple sclerosis (MS). The aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) protein has been associated with neuroprotection in models of ischemia and neuronal responses to stressors. METHODS: To characterize its potential to influence inflammatory neurodegeneration, we examined ARNT2 expression in the experimental autoimmune encephalomyelitis (EAE) model of MS and characterized mediators that influence ARNT2 expression as well as plausible partners and targets. RESULTS: Arnt2 message and protein levels dropped significantly in EAE spinal cords as disease developed and were lowest at peak disability. ARNT2 expression is prominent in neuronal cell bodies within the gray matter with some staining in glial fibrillary acidic protein (GFAP)+ astrocytes in healthy animals. At peak disease, ARNT2 expression is reduced by 20-50% in gray matter neurons compared to healthy controls. ARNT2 intensity in neurons throughout the EAE spinal cord correlated inversely with the degree of immune cell infiltration (r = - 0.5085, p < 0.01) and axonal damage identified with SMI32 staining (r = - 0.376, p = 0.032). To understand the relationship between ARNT2 expression and neuronal health, we exposed enriched cortical cultures of neurons to hydrogen peroxide (H2O2) to mimic oxidative stress. H2O2 at lower doses rapidly increased ARNT2 protein levels which returned to baseline within 3-4 h. Exposure to higher doses of H2O2) dropped ARNT2 levels below baseline, preceding cytotoxicity measured by morphological changes and lactate dehydrogenase release from cells. Decreases in ARNT2 secondary to staurosporine and H2O2 preceded increases in cleaved caspase 3 and associated apoptosis. We also examined expression of neuronal pas 4 (Npas4), whose heterodimerization with ARNT2 drives expression of the neurotrophic factor brain-derived neurotrophic factor (Bdnf). Like ARNT2, Npas4 levels also decline at the onset of EAE and are linked to decreases in Bdnf. In vitro, H2O2 exposure drives Npas4 expression that is tied to increases in Bdnf. CONCLUSION: Our data support ARNT2 as a neuronal transcription factor whose sustained expression is linked to neuronal and axonal health, protection that may primarily be driven through its partnering with Npas4 to influence BDNF expression. DOI: 10.1186/s12974-018-1290-6 PMCID: PMC6145183


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Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course.

Gil-Varea E(1), Urcelay E(2), Vilariño-Güell C(3), Costa C(1), Midaglia L(1), Matesanz F(4), Rodríguez-Antigüedad A(5), Oksenberg J(6), Espino-Paisan L(2), Dessa Sadovnick A(3), Saiz A(7), Villar LM(8), García-Merino JA(9), Ramió-Torrentà L(10), Triviño JC(11), Quintana E(10), Robles R(10), Sánchez-López A(9), Arroyo R(12), Alvarez-Cermeño JC(8), Vidal-Jordana A(1), Malhotra S(1), Fissolo N(1), Montalban X(1), Comabella M(13). Author information: (1)Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. (2)Immunology Department, Hospital Clinico San Carlos, Instituto de Investigacion Sanitaria San Carlos (IdISSC), Madrid, Spain. (3)Department of Medical Genetics, University of British Columbia, Vancouver, Canada. (4)Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain. (5)Servicio de Neurología, Hospital Universitario Basurto-Osakidetza, Bilbao, Spain. (6)Department of Neurology, University of California, San Francisco, CA, USA. (7)Neurology Service, Hospital Clinic and Institut d'Investigació Biomèdica Pi i Sunyer (IDIBAPS), Barcelona, Spain. (8)Departments of Immunology and Neurology, Multiple Sclerosis Unit, Hospital Ramon y Cajal, (IRYCIS), Madrid, Spain. (9)Neuroimmunology Unit, Puerta de Hierro University Hospital and Research Institute, Universidad Autónoma de Madrid, Madrid, Spain. (10)Neuroimmunology and Multiple Sclerosis Unit, Department of Neurology, Hospital Dr Josep Trueta, IDIBGI, University of Girona, Girona, Spain. (11)Genomic Systems, Valencia, Spain. (12)Servicio de Neurología, Hospital Universitario Quirón Salud, Madrid, Spain. (13)Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. [email protected]. BACKGROUND: It remains unclear whether disease course in multiple sclerosis (MS) is influenced by genetic polymorphisms. Here, we aimed to identify genetic variants associated with benign and aggressive disease courses in MS patients. METHODS: MS patients were classified into benign and aggressive phenotypes according to clinical criteria. We performed exome sequencing in a discovery cohort, which included 20 MS patients, 10 with benign and 10 with aggressive disease course, and genotyping in 2 independent validation cohorts. The first validation cohort encompassed 194 MS patients, 107 with benign and 87 with aggressive phenotypes. The second validation cohort comprised 257 patients, of whom 224 patients had benign phenotypes and 33 aggressive disease courses. Brain immunohistochemistries were performed using disease course associated genes antibodies. RESULTS: By means of single-nucleotide polymorphism (SNP) detection and comparison of allele frequencies between patients with benign and aggressive phenotypes, a total of 16 SNPs were selected for validation from the exome sequencing data in the discovery cohort. Meta-analysis of genotyping results in two validation cohorts revealed two polymorphisms, rs28469012 and rs10894768, significantly associated with disease course. SNP rs28469012 is located in CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with aggressive disease course (uncorrected p value < 0.05). SNP rs10894768, which is positioned in IGSF9B (immunoglobulin superfamily member 9B) was associated with benign phenotype (uncorrected p value < 0.05). In addition, a trend for association with benign phenotype was observed for a third SNP, rs10423927, in NLRP9 (NLR family pyrin domain containing 9). Brain immunohistochemistries in chronic active lesions from MS patients revealed expression of IGSF9B in astrocytes and macrophages/microglial cells, and expression of CPXM2 and NLRP9 restricted to brain macrophages/microglia. CONCLUSIONS: Genetic variants located in CPXM2, IGSF9B, and NLRP9 have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. Altogether, the reported results from this study support the influence of genetic factors in MS disease course and may help to better understand the complex molecular mechanisms underlying disease pathogenesis. DOI: 10.1186/s12974-018-1307-1 PMCID: PMC6138928


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191. J Neurol. 2018 Sep 8. doi: 10.1007/s00415-018-9048-8. [Epub ahead of print]

2017 revisions of McDonald criteria shorten the time to diagnosis of multiple sclerosis in clinically isolated syndromes.

Gaetani L(1), Prosperini L(2)(3), Mancini A(1), Eusebi P(1), Cerri MC(1), Pozzilli C(2), Calabresi P(1)(4), Sarchielli P(1), Di Filippo M(5). Author information: (1)Clinica Neurologica, Dipartimento di Medicina, Ospedale S. Maria della Misericordia, Università degli Studi di Perugia, 06156, Perugia, Italy. (2)Department of Neurology and Psychiatry, Sapienza University, Rome, Italy. (3)Department of Neurosciences, S. Camillo-Forlanini Hospital, Rome, Italy. (4)IRCCS Fondazione Santa Lucia, Rome, Italy. (5)Clinica Neurologica, Dipartimento di Medicina, Ospedale S. Maria della Misericordia, Università degli Studi di Perugia, 06156, Perugia, Italy. [email protected]. OBJECTIVES: To investigate the impact of the 2017 revisions of McDonald criteria on the diagnosis of multiple sclerosis (MS) in a cohort of patients with clinically isolated syndrome (CIS) and dissemination in space (DIS) of demyelinating lesions. METHODS: We retrospectively analyzed 137 patients with CIS + DIS from two Italian MS centers. RESULTS: Application of the 2017 revisions of McDonald criteria in our cohort led to a diagnosis of MS in 82.5% of the patients who could have not been diagnosed with MS according to the previous criteria at the time of the first demyelinating event. After a follow-up of 3.8 ± 2.9 years, 85.8% of these patients eventually satisfied also the previous (2010) criteria. CONCLUSIONS: Application of the 2017 revisions of McDonald criteria results in an earlier diagnosis of MS in a large percentage of CIS patients destined to convert to MS. DOI: 10.1007/s00415-018-9048-8


Targeting phosphocreatine metabolism in relapsing-remitting multiple sclerosis: evaluation with brain MRI, 1H and 31P MRS, and clinical and cognitive testing.

Cambron M(1)(2), Reynders T(3)(4), Debruyne J(5), Reyngoudt H(6), Ribbens A(7), Achten E(6), Laureys G(5). Author information: (1)Department of Neurology, Universitair Ziekenhuis Brussel, Jette, Belgium. [email protected]. (2)Department of Neurology, AZ Sint-Jan Hospital, Ruddershove 10, 8000, Brugge, Belgium. [email protected]. (3)Department of Neurology, Universitair Ziekenhuis Brussel, Jette, Belgium. (4)Department of Neurology, University Hospital Antwerp, Antwerp, Belgium. (5)Department of Neurology, University Hospital Ghent, Ghent, Belgium. (6)Department of Radiology and Nuclear Medicine, Ghent University, Ghent, Belgium. (7)Icometrix, Leuven, Belgium. BACKGROUND/OBJECTIVES: Fluoxetine and prucalopride might change phosphocreatine (PCr) levels via the cAMP-PKA pathway, an interesting target in the neurodegenerative mechanisms of MS. METHODS: We conducted a two-center double-blind, placebo-controlled, randomized trial including 48 relapsing-remitting MS patients. Patients were randomized to receive placebo (n = 13), fluoxetine (n = 15), or prucalopride (n = 14) for 6 weeks. Proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) as well as volumetric and perfusion MR imaging were performed at weeks 0, 2, and 6. Clinical and cognitive testing were evaluated at weeks 0 and 6. RESULTS: No significant changes were observed for both 31P and 1H MRS indices. We found a significant effect on white matter volume and a trend towards an increase in grey matter and whole brain volume in the fluoxetine group at week 2; however, these effects were not sustained at week 6 for white matter and whole brain volume. Fluoxetine and prucalopride showed a positive effect on 9-HPT, depression, and fatigue scores. CONCLUSION: Both fluoxetine and prucalopride had a symptomatic effect on upper limb function, fatigue, and depression, but this should be interpreted with caution. No effect of treatment was found on 31P and 1H MRS parameters, suggesting that these molecules do not influence the PCr metabolism. DOI: 10.1007/s00415-018-9039-9


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193. J Neurol. 2018 Sep 26. doi: 10.1007/s00415-018-9070-x. [Epub ahead of print]

No evidence of disease activity (NEDA-3) and disability improvement after alemtuzumab treatment for multiple sclerosis: a 36-month real-world study.

Prosperini L(1), Annovazzi P(2), Boffa L(3), Buscarinu MC(4), Gallo A(5), Matta M(6), Moiola L(7), Musu L(8), Perini P(9), Avolio C(10), Barcella V(11), Bianco A(12), Farina D(13), Ferraro E(14), Pontecorvo S(15), Granella F(16), Grimaldi LME(17), Laroni A(18)(19), Lus G(5), Patti F(20), Pucci E(21), Pasca M(22), Sarchielli P(23); Italian Alemtuzumab Study Group. Collaborators: Ghezzi A, Zaffaroni M, Baroncini D, Buttari F, Centonze D, Fornasiero A, Salvetti M, Docimo R, Signoriello E, Tedeschi G, Bertolotto A, Capobianco M, Comi G, Cocco E, Gallo P, Puthenparampil M, Grasso R, Di Francescantonio V, Rottoli MR, Mirabella M, Lugaresi A, De Luca G, Di Ioia M, Di Tommaso V, Mancinelli L, Di Battista G, Francia A, Ruggieri S, Pozzilli C, Curti E, Tsantes E, Palmeri B, Lapicci C, Mancardi GL, Uccelli A, Chisari C, D'Amico E, Cartechini E, Repice AM, Magnani E, Massaccesi L, Calabresi P, Di Filippo M, Di Gregorio M. Author information: (1)Department of Neurosciences, S. Camillo-Forlanini Hospital, C.ne Gianicolense 87, 00152, Rome, Italy. [email protected]. (2)MS Centre, S. Antonio Abate Hospital, Gallarate, VA, Italy. (3)Department of Neurosciences, MS Center, Tor Vergata University, Rome, Italy. (4)Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University, S. Andrea Hospital, Rome, Italy. (5)Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. (6)Regional MS Centre, S. Luigi Gonzaga Hospital, Orbassano, TO, Italy. (7)Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, S. Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. (8)MS Center, Binaghi Hospital, ASSL Cagliari, ATS regione Sardegna, Cagliari, Italy. (9)Department of Neurosciences, MS Centre, University Hospital, Padua, Italy. (10)Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. (11)MS Center, ASST Papa Giovanni XXIII, Bergamo, MI, Italy. (12)Fondazione Policlinico A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy. (13)Department of Neuroscience and Imaging, University "G. d'Annunzio", Chieti, Italy. (14)Neurology Unit, S. Filippo Neri Hospital, Rome, Italy. (15)Department of Neurology and Psychiatry, Sapienza University, Rome, Italy. (16)Department of Medicine and Surgery, University of Parma, Parma, Italy. (17)U.O.C. Neurologia, Fondazione Istituto "G.Giglio, Cefalù, PA, Italy. (18)Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI) and Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy. (19)Departement of Neurosciences, IRCCS Osp. Policlinico S. Martino, Genoa, Italy. (20)Department of Medical and Surgical Sciences and Advanced Technologies, Neuroscience Section, University of Catania, Catania, Italy. (21)UOC Neurologia Ospedale "A. Murri", ASUR Marche - AV4, Fermo, Italy. (22)Department of Neurofarba, University of Florence, Florence, Italy. (23)Neurology Unit, Osp.e Santa Maria della Misericordia, University of Perugia, Perugia, Italy. In this retrospective, multicenter, real-world study we collected clinical and magnetic resonance imaging (MRI) data of all patients (n = 40) with relapsing-remitting multiple sclerosis (RRMS) treated with alemtuzumab according to a "free-of-charge" protocol available before the drug marketing approval in Italy. Almost all (39/40) started alemtuzumab after discontinuing multiple disease-modifying treatments (DMTs) because of either lack of response or safety concerns. We considered the proportion of alemtuzumab-treated patients who had no evidence of disease activity (NEDA-3) and disability improvement over a 36-month follow-up period. NEDA-3 was defined as absence of relapses, disability worsening, and MRI activity. Disability improvement was defined as a sustained reduction of ≥ 1-point in Expanded Disability Status Scale (EDSS) score. At follow-up, 18 (45%) patients achieved NEDA-3, 30 (75%) were relapse-free, 33 (82.5%) were EDSS worsening-free, and 25 (62.5%) were MRI activity-free. Eleven (27.5%) patients had a sustained disability improvement. We found no predictor for the NEDA-3 status, while the interaction of higher EDSS score by higher number of pre-alemtuzumab relapses was associated with a greater chance of disability improvement (odds ratio 1.10, p = 0.049). Our study provides real-world evidence that alemtuzumab can promote clinical and MRI disease remission, as well as disability improvement, in a significant proportion of patients with RRMS despite prior multiple DMT failures. The drug safety profile was consistent with data available from clinical trials. DOI: 10.1007/s00415-018-9070-x


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Identifying barriers to help-seeking for sexual dysfunction in multiple sclerosis.

Tudor KI(1)(2), Eames S(3), Haslam C(3), Chataway J(4), Liechti MD(3)(5), Panicker JN(3). Author information: (1)Department of Neurology, University Hospital Centre Zagreb, Kispaticeva 12, 10000, Zagreb, Croatia. [email protected]. (2)Department of Uro-Neurology, The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London, UK. [email protected]. (3)Department of Uro-Neurology, The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London, UK. (4)Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, UK. (5)Neuro-Urology, Spinal Cord Injury Center and Research Lab Hospital, University of Zürich, Balgrist University, Zürich, Switzerland. BACKGROUND: Sexual dysfunction (SD) is common in multiple sclerosis (MS), however, under-reported. OBJECTIVE: The aim of this study was to identify barriers faced by patients with MS and healthcare professionals (HCPs) in discussing SD. METHODS: This was a two-part prospective study carried out at a tertiary care centre. Patients with MS were surveyed using a 29-item questionnaire and SD was assessed using the MSISQ and ASEX questionnaires; depression screened with PHQ-2. HCPs were surveyed using a 23-item questionnaire. RESULTS: Seventy four patients (mean age 42.4 ± 10.7, 54 females) and 98 HCPs (mean age 45.8 ± 8.9, 90 females) participated. SD was significant, with primary (36.4%), secondary (27%) and tertiary (29.8%) contributory factors. Commonest barriers reported by patients were dominance of neurological symptoms (N = 30, 40.5%), presence of family or friends (N = 28, 37.8%), and not being asked (N = 25, 33.8%), while HCPs reported presence of family or friends (N = 34, 34.7%), lack of knowledge about SD (N = 30, 30.6%), and inadequate time during the consultation (N = 27, 27.6%). CONCLUSIONS: Barriers to discussing SD are similar between patients and HCPs. The most common barriers are addressable through modifications in the clinic environment, raising awareness and providing training opportunities. DOI: 10.1007/s00415-018-9064-8


Efficacy and safety of mycophenolate mofetil in progressive multiple sclerosis patients.

Fakih R(1), Matiello M(2), Chitnis T(1), Stankiewicz JM(3). Author information: (1)Harvard Medical School, Brigham and Women's Hospital, Partners Multiple Sclerosis Center, 60 Fenwood Road, Boston, MA, 02115, USA. (2)Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. (3)Harvard Medical School, Brigham and Women's Hospital, Partners Multiple Sclerosis Center, 60 Fenwood Road, Boston, MA, 02115, USA. [email protected]. OBJECTIVES: There are increasingly effective therapies for relapsing forms of multiple sclerosis (MS); however, the options for the progressive patient population are limited. The effect of mycophenolate mofetil (MMF), a disease-modifying agent for several autoimmune diseases, in progressive MS has not been explored effectively. We performed a prospective study to assess the safety and efficacy of MMF in progressive MS patients. METHODS: We identified 64 patients enrolled in the comprehensive longitudinal database at the Partners MS Center, who fulfilled our inclusion criteria. They were exposed to MMF for at least 1 year with recorded clinical outcomes. Efficacy was assessed by comparing the absolute relapse rate (ARR), and the mean Expanded Disability Status Scale (EDSS) and timed 25 foot walk (T25FW) test scores before and after MMF treatment. RESULTS: At the start of MMF, 78% of patients (n = 50) were in the 4-7.5 EDSS range. There was a slight increase in mean EDSS from 5.49 ± 1.65 (n = 48) 1 year before MMF start to 5.85 ± 1.56 (n = 48) 1 year after (p = 0.020). The mean T25FW score increased 1 year before MMF from 12.3 ± 9.6 s (n = 38) to 15.6 ± 12.3 s (n = 38) 1 year after (p = 0.009). The ARR in the 2 years pre-MMF period was 0.30 ± 0.63, which decreased to a 0.09 ± 0.29 (p = 0.022) 2 years post MMF. CONCLUSION: MMF did not affect disease progression but did influence relapse rate. We believe that other medication options should be considered before MMF in advanced progressive patients. DOI: 10.1007/s00415-018-9050-1


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196. J Neurol. 2018 Aug 31. doi: 10.1007/s00415-018-9034-1. [Epub ahead of print]

The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS): results from the German validation study.

Filser M(1), Schreiber H(2), Pöttgen J(3), Ullrich S(4), Lang M(2), Penner IK(5)(6). Author information: (1)Cogito Center for Applied Neurocognition and Neuropsychological Research, Düsseldorf, Germany. (2)Neurological Practice and Neuropoint Academy, Ulm, Germany. (3)Institut für Neuroimmunologie und Multiple Sklerose, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. (4).05 Statistikberatung, Düsseldorf, Germany. (5)Cogito Center for Applied Neurocognition and Neuropsychological Research, Düsseldorf, Germany. [email protected]. (6)Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. [email protected]. BACKGROUND: Recent research has convincingly shown that the ability to work mainly depends on the cognitive status in multiple sclerosis (MS). An international committee of experts recommended a brief neuropsychological battery to evaluate cognitive performance in MS. BICAMS comprises three tests, the Symbol Digit Modalities Test (SDMT), the learning trials of the California Verbal Learning Test II (CVLT-II), and the Brief Visuospatial Memory Test-Revised (BVMT-R). OBJECTIVE: To validate BICAMS on a sample of German MS patients and healthy controls (HCs). METHODS: According to the international guidelines for validation, examiner's instructions were standardized and translated into German. Due to the availability of better normative data for future applications in routine clinical care and classification of individual performance degree, the Rey Auditory Verbal Learning Test (RAVLT) (German version: Verbaler Lern- und Merkfähigkeits-Test, VLMT) was chosen instead of CVLT-II. 172 MS patients and 100 HCs entered the study. BICAMS was administered at baseline and retest (after 3-4 weeks). RESULTS: The groups did not differ in age, gender or education. Mean age of MS patients was 43.33 years (SD 11.64); 68% were female and 86.9% had relapsing-remitting MS. Patients performed significantly worse than HCs on the SDMT (p < 0.01) and on BVMT-R (p < 0.05) but not on VLMT. In addition, BICAMS was shown to be reliable over time: r = 0.71 for BVMT-R, r = 0.72 for VLMT and r = 0.85 for SDMT. SDMT z-score proved to be a good predictor for the ability to work in a full-time (p < 0.001) as well as in a part-time job (p < 0.001). VLMT z-score turned out to be a significant predictor only for the ability to work in a part-time job, while BVMT-R z-score showed no significant predictive value. CONCLUSION: In this German validation study with the VLMT, the modified BICAMS (BICAMS-M) turned out to reliably detect cognitive problems in MS patients and to monitor cognitive performance over time. SDMT revealed the best predictive value for working ability. Moreover, only the SDMT was able to predict the ability to work in a part-time or full-time job. Following these results, application of the SDMT is recommended for medical statements on working ability of MS patients. DOI: 10.1007/s00415-018-9034-1


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197. J Neurol. 2018 Aug 28. doi: 10.1007/s00415-018-8994-5. [Epub ahead of print]

Delayed treatment of MS is associated with high CSF levels of IL-6 and IL-8 and worse future disease course.

Stampanoni Bassi M(1)(2), Iezzi E(1), Landi D(2), Monteleone F(2), Gilio L(1)(2), Simonelli I(3), Musella A(4), Mandolesi G(4), De Vito F(4), Furlan R(5), Finardi A(5), Marfia GA(1)(2), Centonze D(6)(7), Buttari F(1). Author information: (1)Unit of Neurology and Neurorehabilitation, IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy. (2)Multiple Sclerosis Research Unit, Department of Systems Medicine, Tor Vergata University, Via Montpellier 1, 00133, Rome, Italy. (3)Service of Medical Statistics and Information Technology, Fatebenefratelli Foundation for Health Research and Education, Rome, Italy. (4)Laboratory of Neuroimmunology and Synaptic Plasticity, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00163, Rome, Italy. (5)Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSpe), San Raffaele Scientific Institute, Milan, Italy. (6)Unit of Neurology and Neurorehabilitation, IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy. [email protected]. (7)Multiple Sclerosis Research Unit, Department of Systems Medicine, Tor Vergata University, Via Montpellier 1, 00133, Rome, Italy. [email protected]. BACKGROUND: Clinical deterioration of relapsing-remitting MS (RR-MS) patients reflects not only the number and severity of overt inflammatory and demyelinating episodes, but also subtle central damage caused by persistent exposure to inflammatory molecules. OBJECTIVE: To explore the correlation between levels of CSF inflammatory molecules at the time of diagnosis and both demographic and clinical characteristics of a large sample of RR-MS patients, as well as the predictive value of cytokine levels on their prospective disease course. METHODS: In 205 patients diagnosed with RR-MS, we measured at the time of diagnosis the CSF levels of inflammatory molecules. Clinical and MRI evaluation was collected at the time of CSF withdrawal and during a median follow-up of 3 years. RESULTS: The time interval between the first anamnestic episode of focal neurological dysfunction and RR-MS diagnosis was the main factor associated with high CSF levels of IL-6 and IL-8. Furthermore, elevated CSF levels of these cytokines correlated with enhanced risk of clinical and radiological disease reactivation, switch to second-line treatments, and with disability progression in the follow-up. CONCLUSIONS: Delayed diagnosis and treatment initiation are associated with higher CSF levels of IL-6 and IL-8 in RR-MS, leading to worsening disease course and poor response to treatments. DOI: 10.1007/s00415-018-8994-5


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198. J Neurol Neurosurg Psychiatry. 2018 Sep 8. pii: jnnp-2018-319014. doi: 10.1136/jnnp-2018-319014. [Epub ahead of print]

X linked Charcot-Marie-Tooth disease and multiple sclerosis: emerging evidence for an association.

Koutsis G(1), Breza M(2), Velonakis G(3), Tzartos J(4), Kasselimis D(5)(6), Kartanou C(2), Karavasilis E(3), Tzanetakos D(4), Anagnostouli M(4), Andreadou E(4), Evangelopoulos ME(4), Kilidireas C(4), Potagas C(5), Panas M(2), Karadima G(2). Author information: (1)Neurogenetics Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece [email protected]. (2)Neurogenetics Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece. (3)2nd Department of Radiology, Medical School, Attikon Hospital, National and Kapodistrian University of Athens, Athens, Greece. (4)Demyelinating Diseases Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece. (5)Neuropsychology and Speech Pathology Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece. (6)Division of Psychiatry and Behavioral Sciences, School of Medicine, University of Crete, Crete, Greece. OBJECTIVE: X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary neuropathy caused by mutations in GJB1 coding for connexin-32, a gap junction protein expressed in Schwann cells, but also found in oligodendrocytes. Four patients with CMTX developing central nervous system (CNS) demyelination compatible with multiple sclerosis (MS) have been individually published. We presently sought to systematically investigate the relationship between CMTX and MS. METHODS: Over 20 years, 70 consecutive patients (36 men) with GJB1 mutations were identified at our Neurogenetics Unit, Athens, Greece, and assessed for clinical features suggestive of MS. Additionally, 18 patients with CMTX without CNS symptoms and 18 matched controls underwent brain MRI to investigate incidental findings. Serum from patients with CMTX and MS was tested for CNS immunoreactivity. RESULTS: We identified three patients with CMTX who developed clinical features suggestive of inflammatory CNS demyelination fulfilling MS diagnostic criteria. The resulting 20-year MS incidence (4.3%) differed significantly from the highest background 20-year MS incidence ever reported from Greece (p=0.00039). The search for incidental brain MRI findings identified two CMTX cases (11%) with lesions suggestive of focal demyelination compared with 0 control. Moreover, 10 cases in the CMTX cohort had hyperintensity in the splenium of the corpus callosum compared with 0 control (p=0.0002). No specific CNS-reactive humoral factors were identified in patients with CMTX and MS. CONCLUSIONS: We have demonstrated a higher than expected frequency of MS in patients with CMTX and identified incidental focal demyelinating lesions on brain MRI in patients with CMTX without CNS symptoms. This provides circumstantial evidence for GJB1 mutations acting as a possible MS risk factor. © Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/jnnp-2018-319014 Conflict of interest statement: Competing interests: GK reports grants from Teva Pharmaceuticals and Genesis Pharma; personal fees from Novartis, Genesis Pharma, Sanofi-Genzyme and Teva Pharmaceuticals; non-financial support from Merck, Sanofi-Genzyme and Genesis Pharma; MB reports no disclosures; GV reports no disclosures; JT reports shares in a diagnostic laboratory (Tzartos Neurodiagnostics) in Athens; DK reports no disclosures; CK reports no disclosures; EK reports no disclosures; DT reports no disclosures; MA reports research grants from Biogen, Merck-Serono, Novartis, Teva, Bayer and Genzyme, as well as lecture-fees from Novartis, Teva, Biogen and Genzyme; EA reports research grants from Biogen, Merck-Serono, Novartis, and Sanofi-Aventis, as well as lecture-fees from Teva; M-EE reports consultation services and honoraria from Novartis, Biogen and Teva; CK reports research grants from Biogen, Novartis, Teva, and Merck-Serono; CP reports no disclosures; MP reports no disclosures; GK reports no disclosures.


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How common is truly benign MS in a UK population?

Tallantyre EC(1)(2), Major PC(2), Atherton MJ(2), Davies WA(2), Joseph F(3), Tomassini V(4)(2), Pickersgill TP(2), Harding KE(4)(2), Willis MD(4)(2), Winter M(5), Robertson NP(4)(2). Author information: (1)Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK [email protected]. (2)Helen Durham Centre for Neuroinflammation, University Hospital of Wales, Cardiff, UK. (3)Department of Neurology, Royal Gwent Hospital, Newport, UK. (4)Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK. (5)Department of Clinical Neuropsychology, University Hospital of Wales, Cardiff, UK. OBJECTIVES: The prevalence and definition of benign multiple sclerosis (BMS) remain controversial. Most definitions are based on the Expanded Disability Status Scale (EDSS), not encompassing the wider impact of disease. The explanation for favourable outcomes remains unclear. We aim to provide a detailed characterisation of patients with low EDSS scores at long disease durations. METHODS: We screened a population-based registry containing 3062 people with MS to identify individuals with unlimited walking ability at disease durations >15 years. A representative cohort underwent detailed clinical assessment and classified as having BMS according to EDSS score <3, no significant fatigue, mood disturbance, cognitive impairment or disrupted employment, and had not received a disease-modifying therapy. We determined patient-reported perceptions of MS status and made comparisons with EDSS-based definitions. RESULTS: Of 1049 patients with disease duration of >15 years, 200 (19.1%) had most recent EDSS score <4.0. Detailed contemporary clinical assessment of a representative sample of 60 of these patients revealed 48 (80%) had an EDSS score of <4.0, 35 (58%) <3.0 and 16 (27%) <2.0. Only nine (15%) fulfilled our criteria for BMS; impaired cognition (57%) and effects on employment (52%) the most common causes for exclusion. Meanwhile, 33/60 (69%) patients considered their disease benign. Population frequency for BMS was estimated at 2.9% (95% CI 2.0 to 4.1). CONCLUSIONS: Comprehensive assessment reveals a small minority of people with MS who appear genuinely benign after 15 years. Study of such individuals may uncover insights about disease pathogenesis. However, discrepancy between patient perception and clinician perception of BMS undermines use of the term 'benign' in clinical settings. © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/jnnp-2018-318802 Conflict of interest statement: Competing interests: None declared.


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Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme.

Palace J(1), Duddy M(2), Lawton M(3), Bregenzer T(4), Zhu F(5), Boggild M(6), Piske B(4), Robertson NP(7), Oger J(5), Tremlett H(5), Tilling K(3), Ben-Shlomo Y(#)(3), Lilford R(#)(8), Dobson C(9). Author information: (1)Clinical Neurology, The Oxford University Hospitals Trust, Oxford, UK [email protected]. (2)Department of Neurology, The Newcastle upon Tyne Hospitals Trust, Newcastle upon Tyne, UK. (3)Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. (4)Biostatistics, PAREXEL International, Berlin, Germany. (5)Department of Medicine (Neurology), University of British Columbia, Vancouver, British Columbia, Canada. (6)The Townsville Hospital, Townsville, Queensland, Australia. (7)Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales, Cardiff, UK. (8)Warwick Medical School, University of Warwick, Warwick, UK. (9)Department of Health, Leeds, UK. (#)Contributed equally BACKGROUND: Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (EDSS) and utility) was set up, in conjunction with a risk-sharing agreement between payers and producers, to investigate this issue. METHODS: The outcomes of the UK treated patients were compared with a modelled untreated control based on the British Columbia MS data set to assess the long-term effectiveness of these treatments. Two complementary analysis models were used: a multilevel model (MLM) and a continuous Markov model. RESULTS: 4862 patients with MS were eligible for the primary analysis (mean and median follow-up times 8.7 and 10 years). EDSS worsening was reduced by 28% (MLM), 7% (Markov) and 24% time-adjusted Markov in the total cohort, and by 31% (MLM) and 14% (Markov) for relapsing remitting patients. The utility worsening was reduced by 23%-24% in the total cohort and by 24%-31% in the RR patients depending on the model used. All sensitivity analyses showed a treatment effect. There was a 4-year (CI 2.7 to 5.3) delay to EDSS 6.0. An apparent waning of treatment effect with time was seen. Subgroup analyses suggested better treatment effects in those treated earlier and with lower EDSS scores. CONCLUSIONS: This study supports a beneficial effect on long-term disability with first-line MS disease-modifying treatments, which is clinically meaningful. However the waning effect noted requires further study. © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/jnnp-2018-318360 Conflict of interest statement: Competing interests: None declared.


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201. J Neurol Sci. 2018 Sep 17;394:127-131. doi: 10.1016/j.jns.2018.09.020. [Epub ahead of print]

Long-term follow-up for multiple sclerosis patients initially treated with interferon-beta and glatiramer acetate.

Healy BC(1), Glanz BI(2), Zurawski JD(2), Mazzola M(2), Chitnis T(2), Weiner HL(2). Author information: (1)Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA. Electronic address: [email protected]. (2)Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA. OBJECTIVE: Our goal was to compare subjects treated with glatiramer acetate (GA) and interferon-beta (IFN-β) in terms of long-term clinical outcomes. METHODS: Subjects enrolled in the CLIMB who initiated either GA or IFN-β within five years of disease onset and prior to 2008 were identified (n = 150 for GA and n = 144 for IFN-β). The two treatment groups were compared in terms of long-term clinical outcomes: time to EDSS 4, time to EDSS 6 and EDSS score seven years after treatment initiation. Baseline confounders included in our analysis were age, gender, disease duration, attacks in the previous year, EDSS prior to treatment initiation, and year of treatment initiation. The groups were compared using three approaches to handle confounders: multiple regression adjusting for confounders, adjustment for the propensity score, and inverse probability of treatment weighting. In addition, we assessed potential predictors of differential treatment response using multiple regression models including appropriate interaction terms. RESULTS: Subjects initially treated with GA had a slightly higher hazard of reaching EDSS 4 and EDSS 6, but the difference between the groups was not statistically significant (adjusted HR for EDSS 4 = 1.48; 95% CI: 0.77,2.84; p = .24; adjusted HR for EDSS 6 = 1.46; 95% CI: 0.70,3.05; p = .316). For the EDSS score at year 7, there was also only a small difference between the groups. Subjects treated with GA had a longer time until treatment cessation (adjusted HR = 0.70; 95% CI: 0.53,0.93; p = .012). The interaction models did not show strong evidence for the baseline predictors being associated with treatment response. CONCLUSIONS: Subjects treated with glatiramer acetate and interferon-beta had similar long-term clinical course. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jns.2018.09.020


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202. J Neurol Sci. 2018 Aug 23;394:1-5. doi: 10.1016/j.jns.2018.08.019. [Epub ahead of print]

Mobile Universal Lexicon Evaluation System (MULES) in MS: Evaluation of a new visual test of rapid picture naming.

Seay M(1), Akhand O(2), Galetta MS(3), Cobbs L(4), Hasanaj L(5), Amorapanth P(6), Rizzo JR(7), Nolan R(8), Serrano L(9), Rucker JC(10), Galetta SL(11), Balcer LJ(12). Author information: (1)Departments of Neurolog, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (2)Departments of Neurolog, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (3)Departments of Neurolog, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (4)Departments of Neurolog, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (5)Departments of Neurolog, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (6)Physical Medicine and Rehabilitation, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (7)Departments of Neurolog, New York University School of Medicine, New York, NY, USA; Physical Medicine and Rehabilitation, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (8)Departments of Neurolog, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (9)Departments of Neurolog, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (10)Departments of Neurolog, New York University School of Medicine, New York, NY, USA; Ophthalmology, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (11)Departments of Neurolog, New York University School of Medicine, New York, NY, USA; Ophthalmology, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. (12)Departments of Neurolog, New York University School of Medicine, New York, NY, USA; Population Health, New York University School of Medicine, New York, NY, USA; Ophthalmology, New York University School of Medicine, New York, NY, USA. Electronic address: [email protected]. OBJECTIVE: The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming that is under investigation for concussion. MULES captures an extensive visual network, including pathways for eye movements, color perception, memory and object recognition. The purpose of this study was to introduce the MULES to visual assessment of patients with MS, and to examine associations with other tests of afferent and efferent visual function. METHODS: We administered the MULES in addition to binocular measures of low-contrast letter acuity (LCLA), high-contrast visual acuity (VA) and the King-Devick (K-D) test of rapid number naming in an MS cohort and in a group of disease-free controls. RESULTS: Among 24 patients with MS (median age 36 years, range 20-72, 64% female) and 22 disease-free controls (median age 34 years, range 19-59, 57% female), MULES test times were greater (worse) among the patients (60.0 vs. 40.0 s). Accounting for age, MS vs. control status was a predictor of MULES test times (P = .01, logistic regression). Faster testing times were noted among patients with MS who had greater (better) performance on binocular LCLA at 2.5% contrast (P < .001, linear regression, accounting for age), binocular high-contrast VA (P < .001), and K-D testing (P < .001). Both groups demonstrated approximately 10-s improvements in MULES test times between trials 1 and 2 (P < .0001, paired t-tests). CONCLUSION: The MULES test, a complex task of rapid picture naming involves an extensive visual network that captures eye movements, color perception and the characterization of objects. Color recognition, a key component of this novel assessment, is early in object processing and requires area V4 and the inferior temporal projections. MULES scores reflect performance of LCLA, a widely-used measure of visual function in MS clinical trials. These results provide evidence that the MULES test can add efficient visual screening to the assessment of patients with MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jns.2018.08.019


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203. J Neuroophthalmol. 2018 Sep 20. doi: 10.1097/WNO.0000000000000719. [Epub ahead of print]

Identifying Incidence of and Risk Factors for Fluoroscopy-Guided Lumbar Puncture and Subsequent Persistent Low-Pressure Syndrome in Patients With Idiopathic Intracranial Hypertension.

Lu P(1), Goyal M, Huecker JB, Gordon MO, Van Stavern GP. Author information: (1)Department of Ophthalmology and Visual Sciences (PL, JBH, MOG, GPVS), Washington University School of Medicine, St. Louis, Missouri; Mallinckrodt Institute of Radiology (MG), Washington University School of Medicine, St. Louis, Missouri; and Department of Neurology (MG, GPVS), Washington University School of Medicine, St. Louis, Missouri. BACKGROUND: To explore the incidence of and potential risk factors for developing persistent low-pressure syndrome after lumbar puncture (LP) in patients with idiopathic intracranial hypertension (IIH), as measured by use of blood patches. METHODS: A retrospective chart review was conducted of patients with definitively diagnosed IIH by clinical examination and LP, comparing them to patients with multiple sclerosis (MS) as controls who also received diagnostic LPs. Demographic, clinical, and radiological data were collected for each patient. The main outcome measure was the rate of post-LP blood patches in IIH patients compared with MS patients. Secondary outcome measures were the likelihood of undergoing an epidural blood patch related to age, body mass index, volume removed, opening pressure, the difference between opening and closing pressure, and the level of puncture within the IIH cohort. RESULTS: One hundred four IIH patients and 149 MS patients were included in the study. Among IIH patients, 12/104 (11.5%) underwent an epidural blood patch after LP as compared to 8/149 (5.4%) of the MS control patients (P = 0.086). Within the IIH population, none of the clinical or LP parameters were significantly correlated with increased risk of needing a blood patch. CONCLUSIONS: The incidence of low-pressure syndrome, as measured by blood patches, is similar in IIH patients and MS controls. This suggests that having elevated intracranial pressure before an LP is not protective against developing postpuncture low-pressure syndrome, contrary to common assumptions. DOI: 10.1097/WNO.0000000000000719

204. J Neuropathol Exp Neurol. 2018 Aug 24. doi: 10.1093/jnen/nly081. [Epub ahead of print]

Galectin-4, a Negative Regulator of Oligodendrocyte Differentiation, Is Persistently Present in Axons and Microglia/Macrophages in Multiple Sclerosis Lesions.

de Jong CGHM(1), Stancic M(1), Pinxterhuis TH(1), van Horssen J(2), van Dam AM(3), Gabius HJ(4), Baron W(1). Author information: (1)Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. (2)Department of Molecular Cell Biology and Immunology. (3)Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam, The Netherlands. (4)Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University Munich, Munich, Germany. Neuron-derived molecules are potent regulators of oligodendrocyte differentiation and myelination during brain development and upon demyelination. Their analysis will thus contribute to understanding remyelination failure in demyelinating diseases, such as multiple sclerosis (MS). Previously, we have identified neuronal galectin-4 as a novel negative soluble regulator in the timing of developmental myelination. Here, we investigated whether galectin-4 is re-expressed in axons upon demyelination to regulate the timing of remyelination. Our findings revealed that galectin-4 is transiently localized to axons in demyelinated areas upon cuprizone-induced demyelination. In contrast, in chronic demyelinated MS lesions, where remyelination fails, galectin-4 is permanently present on axons. Remarkably, microglia/macrophages in cuprizone-demyelinated areas also harbor galectin-4, as also observed in activated microglia/macrophages that are present in active MS lesions and in inflammatory infiltrates in chronic-relapsing experimental autoimmune encephalomyelitis. In vitro analysis showed that galectin-4 is effectively endocytosed by macrophages, and may scavenge galectin-4 from oligodendrocytes, and that endogenous galectin-4 levels are increased in alternatively interleukin-4-activated macrophages and microglia. Hence, similar to developmental myelination, the (re)expressed galectin-4 upon demyelination may act as factor in the timing of oligodendrocyte differentiation, while the persistent presence of galectin-4 on demyelinated axons may disrupt this fine-tuning of remyelination. DOI: 10.1093/jnen/nly081


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205. J Neurophysiol. 2018 Sep 12. doi: 10.1152/jn.00291.2018. [Epub ahead of print]

Motor imagery in multiple sclerosis: exploring applications in therapeutic treatment.

Hanson M(1), Concialdi M(1). Author information: (1)Health and Exercise Science, Colorado State University, United States. Motor imagery (MI) is a promising rehabilitation technique that has received significant interest for use in persons with multiple sclerosis (MS). Through alterations in neural networks, MI has the potential to improve measures of walking speed, walking distance, and fatigue in people with MS. Further research is required to assess the validity of MI in conjunction with other therapeutic MS treatments and provide objective outcome measures of motor improvements. DOI: 10.1152/jn.00291.2018

206. J Neuropsychiatry Clin Neurosci. 2018 Sep 6:appineuropsych18010011. doi: 10.1176/appi.neuropsych.18010011. [Epub ahead of print]

Depressive Symptoms Are Associated With More Negative Functional Outcomes Than Anxiety Symptoms in Persons With Multiple Sclerosis.

Gill S(1), Santo J(1), Blair M(1), Morrow SA(1). Author information: (1)From the Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada (SAM); the Department of Cognitive Neurology, Parkwood Institute, London, Ontario, Canada (SG, MB, SAM); and the Department of Psychology, University of Nebraska at Omaha (JS). Depression and anxiety are common among persons with multiple sclerosis (MS), and both negatively affect functional status. However, studies rarely account for overlap in depressive and anxiety symptoms on functional outcomes among people with MS. The authors aimed to examine the differential impact of depression and anxiety, measured by the Anxiety and Depression subscales of the Hospital Anxiety and Depression Scale (HADS-A and HADS-D), on functional outcomes among people with MS. Using a retrospective chart review of 128 people with MS, the authors used exploratory structural equation modeling to examine the relation of HADS-A and HADS-D to functional outcomes, namely employment status, fatigue (with the Fatigue Severity Scale), disability (with the Expanded Disability Status Scale [EDSS]), and cognition (with the Symbol Digit Modalities Test [SDMT]). After the authors controlled for the effects of covariates, HADS-A was negatively associated with EDSS (β=-0.22, p<0.05) and positively associated with vocation (β=0.23, p<0.05). In contrast, HADS-D was positively correlated with fatigue (β=0.37, p<0.05) and EDSS (β=0.26, p<0.05) and negatively correlated with vocation (β=-0.32, p<0.05) and SDMT (β=-0.28, p<0.05). HADS-A and HADS-D explained 5% of the variability in employment, 14.5% in fatigue, 1.6% in EDSS, and 4.3% in SDMT, beyond the effects of the covariates. Depressive symptoms have a significant negative impact on functional outcomes among people with MS, relative to anxiety symptoms. These findings support the importance of identifying and treating depressive symptoms among people with MS. DOI: 10.1176/appi.neuropsych.18010011


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207. J Neurosci. 2018 Sep 5. pii: 0398-18. doi: 10.1523/JNEUROSCI.0398-18.2018. [Epub ahead of print]

Reduced microglial activity and enhanced glutamate transmission in the basolateral amygdala in early CNS autoimmunity.

Acharjee S(1), Verbeek M(2), Daniel Gomez C(1), Bisht K(3), Lee B(1), Benoit L(1), Sharkey KA(1), Benediktsson A(2), Tremblay ME(3), Pittman QJ(4). Author information: (1)Hotchkiss Brain Institute, University of Calgary. (2)Department of Biology, Mount Royal University, Calgary, AB Canada. (3)Department of Molecular Medicine, Université Laval, Quebec City, QC Canada. (4)Hotchkiss Brain Institute, University of Calgary [email protected]. Emotional dysfunction is common in multiple sclerosis (MS) patients and in mouse models of MS, including experimental autoimmune encephalomyelitis (EAE); however, the etiology of these behaviours is poorly understood. To identify CNS changes associated with these behaviours, we focused on the the basolateral amygdala (BLA) because of its central role in the regulation of emotional behaviour. Whole-cell recordings were carried out in the principal neurons of the BLA in early EAE, prior to demyelination, T cell invasion and motor dysfunction. EAE female mice displayed increased frequency of miniature excitatory postsynaptic currents (EPSC), with no alteration in amplitude or evoked EPSC paired-pulse ratio compared to controls. We found an increase in the AMPA-NMDA ratio and dendritic spine density, indicating increased numbers of glutamatergic synapses. We saw similar electrophysiological changes in BLA principal neurons after microglia were either inactivated (minocycline) or depleted (Mac1-Saporin) in the BLA. Microglia regulate synapses through pruning, directed by complement protein 3 (C3) expression. C3 was downregulated in the BLA in EAE. Ultrastructural analysis of microglia revealed more complex ramifications and a reduced extracellular digestion of cellular elements. We also observed reduced IBA-1 and CD68 staining and lack of proinflammatory cytokine expression in the amygdala. Thus, early EAE is a state of microglial "de-activation" associated with reduced synaptic pruning. This contrasts with the prototypic microglial activation commonly associated with inflammatory CNS disease. Additionally, these data support a role for the acquired immune system to influence both neuronal and microglial function in early CNS autoimmunity.Significance Statement: Microglia help regulate synaptic homeostasis, but there has been little evidence for how this might be important in neuroinflammatory diseases. The data from this study reveal increased synaptic activity and spine density in early stages of EAE (an animal model of multiple sclerosis) in the basolateral amygdala, a nucleus important in the types of behavioural changes we have previously described. These electrophysiological and morphological effects occurred without any significant elevation of local inflammatory cytokines or local demyelination. Unexpectedly, in the context of inflammatory state, we found that microglia were "de-activated". This study provides strong evidence for a link between microglial activity and synaptic function; the conclusions contrast with the generally accepted view that microglia are activated in inflammatory disease. Copyright © 2018 the authors. DOI: 10.1523/JNEUROSCI.0398-18.2018


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208. J Neurosci. 2018 Sep 26;38(39):8484-8495. doi: 10.1523/JNEUROSCI.2203-17.2018. Epub 2018 Sep 10.

TRPM2 Exacerbates Central Nervous System Inflammation in Experimental Autoimmune Encephalomyelitis by Increasing Production of CXCL2 Chemokines.

Tsutsui M(1), Hirase R(1), Miyamura S(1), Nagayasu K(1), Nakagawa T(2), Mori Y(3), Shirakawa H(4), Kaneko S(1). Author information: (1)Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. (2)Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan, and. (3)Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Nishikyo-ku, Kyoto 615-8510, Japan. (4)Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan, [email protected]. Multiple sclerosis (MS) is a chronic inflammatory disorder of the CNS characterized by demyelination and axonal injury. Current therapies that mainly target lymphocytes do not fully meet clinical need due to the risk of severe side effects and lack of efficacy against progressive MS. Evidence suggests that MS is associated with CNS inflammation, although the underlying molecular mechanism is poorly understood. Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable nonselective cation channel, is expressed at high levels in the brain and by immune cells, including monocyte lineage cells. Here, we show that TRPM2 plays a pathological role in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Knockout (KO) or pharmacological inhibition of TRPM2 inhibited progression of EAE and TRPM2-KO mice showed lower activation of Iba1-immunopositive monocyte lineage cells and neutrophil infiltration of the CNS than WT mice. Moreover, CXCL2 production in TRPM2-KO mice was significantly reduced at day 14, although the severity of EAE was the same as that in WT mice at that time point. In addition, we used BM chimeric mice to show that TRPM2 expressed by CNS-infiltrating macrophages contributes to progression of EAE. Because CXCL2 induces migration of neutrophils, these results indicate that reduced expression of CXCL2 in the CNS suppresses neutrophil infiltration and slows progression of EAE in TRPM2-KO mice. Together, the results suggest that TRPM2 plays an important role in progression of EAE pathology and shed light on its putative role as a therapeutic target for MS.SIGNIFICANCE STATEMENT Current therapies for multiple sclerosis (MS), which mainly target lymphocytes, carry the risk of severe side effects and lack efficacy against the progressive form of the disease. Here, we found that the transient receptor potential melastatin 2 (TRPM2) channel, which is abundantly expressed in CNS-infiltrating macrophages, plays a crucial role in development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE progression was suppressed by Knockout (KO) or pharmacological inhibition of TRPM2; this was attributed to a reduction in CXCL2 chemokine production by CNS-infiltrating macrophages in TRPM2-KO mice, resulting in suppression of neutrophil infiltration into the CNS. These results reveal an important role of TRPM2 in the pathogenesis of EAE and shed light on its potential as a therapeutic target. Copyright © 2018 the authors 0270-6474/18/388484-12$15.00/0. DOI: 10.1523/JNEUROSCI.2203-17.2018


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209. J Neurosci. 2018 Sep 18. pii: 0585-18. doi: 10.1523/JNEUROSCI.0585-18.2018. [Epub ahead of print]

A sub-population of Foxj1 expressing, non-myelinating Schwann cells of the peripheral nervous system contribute to Schwann cell remyelination in the central nervous system.

Ma D(1), Wang B(1)(2), Zadwadzka M(1), Gonzalez G(1), Wu Z(1), Yu B(2), Rawlins EL(3), Franklin RJM(1), Zhao C(4). Author information: (1)Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Clifford Allbutt Building, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0AH, UK. (2)Department of Orthopaedic Surgery, Southern Medical University, Baiyun, Guangzhou 510515, P.R. China. (3)The Wellcome Trust/Cancer Research UK Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK. (4)Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Clifford Allbutt Building, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0AH, UK [email protected] [email protected]. New myelin sheaths can be restored to demyelinated axons in a spontaneous regenerative process called remyelination. In general, new myelin sheaths are made by oligodendrocytes newly generated from a widespread population of adult CNS progenitors called oligodendrocyte progenitor cells (OPCs). New myelin in CNS remyelination in both experimental models and clinical disease can also be generated by Schwann cells, the myelin forming cells of the peripheral nervous system. Fate mapping studies have shown that Schwann cells contributing to remyelination in the CNS are often derived from OPCs, and appear not to be derived from myelinating Schwann cells from the PNS. In this study we address whether CNS remyelinating Schwann cells can also be generated from PNS derived cells other than myelinating Schwann cells. Using a genetic fate mapping approach, we have found that a sub-population of non-myelinating Schwann cells identified by the expression of the transcription factor foxj1 also contribute to CNS Schwann cell remyelination, as well as to remyelination in the peripheral nervous system. We also find the ependymal cells lining the central canal of the spinal cord, which also express foxj1, do not generate cells that contribute to CNS remyelination. These findings therefore identify a previously unrecognised population of PNS glia that can participate in the regeneration of new myelin sheaths following CNS demyelination.SIGNIFICANCE STATEMENTRemyelination Failure in chronic demyelinating diseases such as multiple sclerosis drives the current quest for developing means by which remyelination in central nervous system can be enhanced therapeutically. Critical to this endeavour is the need to understand the mechanisms of remyelination including the nature and identity of the cells capable of generating new myelin sheath-forming cells. Here we report a previously unrecognised sub-population of non-myelinating Schwann cells in the peripheral nervous system, identified by the expression of the transcription factor foxj1, which can give rise to Schwann cells that are capable of remyelinating both PNS and CNS axons. These cells therefore represent a new cellular target for myelin regenerative strategies for the treatment of CNS disorders characterised by persistent demyelination. Copyright © 2018 Ma et al. DOI: 10.1523/JNEUROSCI.0585-18.2018


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210. J Neurosci Methods. 2018 Sep 19. pii: S0165-0270(18)30289-9. doi: 10.1016/j.jneumeth.2018.09.022. [Epub ahead of print]

Validation of a precision tremor measurement system for multiple sclerosis.

Perera T(1), Lee WL(2), Yohanandan SAC(3), Nguyen AL(4), Cruse B(4), Boonstra FMC(5), Noffs G(6), Vogel AP(7), Kolbe SC(8), Butzkueven H(9), Evans A(10), van der Walt A(11). Author information: (1)The Bionics Institute, East Melbourne, Australia; Department of Medical Bionics, University of Melbourne, Australia. Electronic address: [email protected]. (2)The Bionics Institute, East Melbourne, Australia. (3)The Bionics Institute, East Melbourne, Australia; Department of Computer Science and Information Technology, Royal Melbourne Institute of Technology, Victoria, Australia. (4)Department of Neurology, Royal Melbourne Hospital, Australia. (5)Department of Medicine and Radiology, University of Melbourne, Australia. (6)Department of Neurology, Royal Melbourne Hospital, Australia; Centre for Neuroscience of Speech, University of Melbourne, Victoria, Australia. (7)The Bionics Institute, East Melbourne, Australia; Centre for Neuroscience of Speech, University of Melbourne, Victoria, Australia; Redenlab, Victoria, Australia; Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany. (8)Department of Medicine and Radiology, University of Melbourne, Australia; Florey Institute of Neuroscience and Mental Health, Victoria, Australia. (9)Department of Neuroscience, Central Clinical School, Monash University, Victoria, Australia. (10)The Bionics Institute, East Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Australia. (11)The Bionics Institute, East Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Australia; Department of Neuroscience, Central Clinical School, Monash University, Victoria, Australia. BACKGROUND: Tremor is a debilitating symptom of Multiple Sclerosis (MS). Little is known about its pathophysiology and treatments are limited. Clinical trials investigating new interventions often rely on subjective clinical rating scales to provide supporting evidence of efficacy. NEW METHOD: We present a novel instrument (TREMBAL) which uses electromagnetic motion capture technology to quantify MS tremor. We aim to validate TREMBAL by comparison to clinical ratings using regression modelling with 310 samples of tremor captured from 13 MS participants who performed five different hand exercises during several follow-up visits. Minimum detectable change (MDC) and test-retest reliability were calculated and comparisons were made between MS tremor and data from 12 healthy volunteers. RESULTS: Velocity of the index finger was most congruent with clinical observation. Regression modelling combining different features, sensor configurations, and labelling exercises did not improve results. TREMBAL MDC was 84% of its initial measurement compared to 91% for the clinical rating. Intra-class correlations for test-retest reliability were 0.781 for TREMBAL and 0.703 for clinical ratings. Tremor was lower (p = 0.002) in healthy subjects. COMPARISON WITH EXISTING METHODS: Subjective scales have low sensitivity, suffer from ceiling effects, and mitigation against inter-rater variability is challenging. Inertial sensors are ubiquitous, however, their output is nonlinearly related to tremor frequency, compensation is required for gravitational artefacts, and their raw data cannot be intuitively comprehended. CONCLUSIONS: TREMBAL, compared with clinical ratings, gave measures in agreement with clinical observation, had marginally lower MDC, and similar test-retest reliability. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jneumeth.2018.09.022


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211. J Neurosci Methods. 2018 Sep 18. pii: S0165-0270(18)30287-5. doi: 10.1016/j.jneumeth.2018.09.020. [Epub ahead of print]

Correlating new directional measures of myelin and axonal integrity in T2-weighted MRI with quantitative histology in multiple sclerosis.

Sharma S(1), Laule C(2), Wayne Moore GR(3), Li DKB(4), Zhang Y(5). Author information: (1)Department of Radiology, University of Calgary, Alberta, Canada; Department of Clinical Neurosciences, University of Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Alberta, Canada. (2)Department of Radiology, University of British Columbia, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia, Canada; International Collaboration on Repair Discoveries (ICORD), University of British Columbia, British Columbia, Canada; Department of Physics & Astronomy, University of British Columbia, British Columbia, Canada. (3)Department of Pathology and Laboratory Medicine, University of British Columbia, British Columbia, Canada; International Collaboration on Repair Discoveries (ICORD), University of British Columbia, British Columbia, Canada. (4)Department of Radiology, University of British Columbia, British Columbia, Canada. (5)Department of Radiology, University of Calgary, Alberta, Canada; Department of Clinical Neurosciences, University of Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Alberta, Canada. Electronic address: [email protected]. BACKGROUND: Imaging measurement of structure alignment has shown increasing importance in determining tissue properties. It is not known if a similar ability for characterizing neuropathology exists. NEW METHODS: This study aimed to validate a new alignment-assessing method for measuring myelin and axonal properties using quantitative histological metrics. The new method involved analysis of the Fourier transform (FT) power spectrum in standard magnetic resonance imaging (MRI). T2-weighted MRI were collected from 10 post-mortem multiple sclerosis (MS) brain samples. Three tissue types were examined: lesions, diffusely abnormal white matter, and normal appearing white matter. MRI analysis included computing the FT power spectrum; extracting alignment histograms; and calculating dominant orientation and alignment complexity (angular entropy). Post MRI, the brain samples were processed for myelin and axonal staining, and the stained images were used to derive quantitative orientation measures using structure tensor analysis for MRI comparison. RESULTS: There were significant differences in orientation metrics between tissue types in both MRI and histology, and MRI measurements correlated strongly with histological indices. Moreover, the joint effect of myelin and axonal entropy explained over 95% of the variance of MRI angular entropy. COMPARISON WITH EXISTING METHOD: There is no established method for characterizing myelin and axonal pathology using standard MRI. Advanced MRI methods have the potential to do this but are still in research development and are not yet routinely acquired in clinical practice. CONCLUSIONS: Alignment measurement using clinical MRI scans may become a valuable new method for characterizing myelin and axonal properties in MS patients. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.jneumeth.2018.09.020


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212. J Neurosci Nurs. 2018 Oct;50(5):303-307. doi: 10.1097/JNN.0000000000000389.

Effect of Multiple Sclerosis on Dyadic Adjustment.

Hacivelioğlu D(1), Tavşanli NG, Kosova F, Mavioğlu H. Author information: (1)Questions or comments about this article may be directed to Nurgül Güngör Tavşanli, PhD, at [email protected]. She is an Assistant Professor, Internal Medicine Nursing, Health Science Faculty, Midwifery Department, Manisa Celal Bayar University, Manisa, Turkey. Dilek Hacivelioğlu, MSc, Health Science Institute, Manisa Celal Bayar University, Manisa, Turkey. Funda Kosova, is Associate Professor, Health Science Faculty, Midwifery Department, Medical Biochemistry, Manisa Celal Bayar University, Manisa, Turkey. Hatice Mavioğlu, is Professor, Medicine Faculty, Neurology Department, Manisa Celal Bayar University, Manisa, Turkey. PURPOSE: This study examines the dyadic adjustment of married men and women with multiple sclerosis (MS). METHOD: This cross-sectional study consists of 40 patients with MS who were married and being followed in the neurology clinic of a university hospital. Data collection was performed by face-to-face interviews with only the participant and the researcher present. The participants filled in the Expanded Disability Status Scale, a sociodemographic form, and a dyadic adjustment scale. RESULTS: The study group was 75% male, with age ranging from 27 to 65 years (mean, 44.40 ± 9.31 years). Expanded Disability Status Scale scores ranged from 0 to 7 (mean, 3.25 ± 1.94); 95% of the subjects were having relapses and remissions. Scores for patients with MS who were not considering divorce were statistically significantly higher than patients with MS who were considering divorce for dyadic adjustment (z = 3.845, P = .000), common view (z = 2.336, P = .020), endearment (z = 2.701, P = .007), and total scores (z = 3.399, P = .001). CONCLUSION: Most of the patients with MS who participated in this study were diagnosed with relapsing-remitting MS with a mean Expanded Disability Status Scale score of 3, indicating that patients had the physical ability to perform routine activities. The total dyadic adjustment scale score (107.7) is above average, indicating that dyadic adjustment was at a good level. DOI: 10.1097/JNN.0000000000000389

213. J Neurosci Nurs. 2018 Oct;50(5):302. doi: 10.1097/JNN.0000000000000405.

Factors Affecting the Adherence to Disease-Modifying Therapy in Patients With Multiple Sclerosis.

von Gaudecker JR(1). Author information: (1)Questions or comments about this article may be directed to Jane R. von Gaudecker, PhD RN, at [email protected]. She is an Assistant Professor, Indiana University School of Nursing, Indianapolis, IN. DOI: 10.1097/JNN.0000000000000405

214. J Neurosci Res. 2018 Sep 11. doi: 10.1002/jnr.24322. [Epub ahead of print]

Signaling pathways and therapeutic perspectives related to environmental factors associated with multiple sclerosis.

Tiwari S(1), Lapierre J(1), Ojha CR(1), Martins K(2), Parira T(1), Dutta RK(1), Caobi A(1), Garbinski L(3), Ceyhan Y(2), Esteban-Lopez M(2), El-Hage N(1). Author information: (1)Departments of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida. (2)Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida. (3)Cell Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida. Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of unknown etiology. Both genetic-susceptibility and environment exposures, including vitamin D deficiency, Epstein-Barr viral and Herpesvirus (HHV-6) infections are strongly implicated in the activation of T cells and MS-pathogenesis. Despite precise knowledge of how these factors could be operating alone or in combination to facilitate and aggravate the disease progression, it is clear that prolonged induction of inflammatory molecules and recruitment of other immune cells by the activated T cells results in demyelination and axonal damage. It is imperative to understand the risk factors associated with MS progression and how these factors contribute to disease pathology. Understanding of the underlying mechanisms of what factors triggers activation of T cells to attack myelin antigen are important to strategize therapeutics and therapies against MS. Current review provides a detailed literature to understand the role of both pathogenic and non-pathogenic factors on the impact of MS. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/jnr.24322


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215. J Neurosurg. 2018 Sep 28:1-8. doi: 10.3171/2018.4.JNS172995. [Epub ahead of print]

Reduced long-term cost and increased patient satisfaction with rechargeable implantable pulse generators for deep brain stimulation.

Hitti FL(1), Vaughan KA(1), Ramayya AG(1), McShane BJ(1), Baltuch GH(1). Author information: (1)Department of Neurosurgery, Pennsylvania Hospital, University of Pennsylvania, Philadelphia, Pennsylvania. OBJECTIVE: Deep brain stimulation (DBS) has revolutionized the treatment of neurological disease, but its therapeutic efficacy is limited by the lifetime of the implantable pulse generator (IPG) batteries. At the end of the battery life, IPG replacement surgery is required. New IPGs with rechargeable batteries (RC-IPGs) have recently been introduced and allow for decreased reoperation rates for IPG replacements. The authors aimed to examine the merits and limitations of these devices. METHODS: The authors reviewed the medical records of patients who underwent DBS implantation at their institution. RC-IPGs were placed either during initial DBS implantation or during an IPG change. A cost analysis was performed that compared RC-IPGs with standard IPGs, and telephone patient surveys were conducted to assess patient satisfaction. RESULTS: The authors identified 206 consecutive patients from 2011 to 2016 who underwent RC-IPG placement (mean age 61 years; 67 women, 33%). Parkinson's disease was the most common indication for DBS (n = 144, 70%), followed by essential tremor (n = 41, 20%), dystonia (n = 13, 6%), depression (n = 5, 2%), multiple sclerosis tremor (n = 2, 1%), and epilepsy (n = 1, 0.5%). DBS leads were typically placed bilaterally (n = 192, 93%) and targeted the subthalamic nucleus (n = 136, 66%), ventral intermediate nucleus of the thalamus (n = 43, 21%), internal globus pallidus (n = 21, 10%), ventral striatum (n = 5, 2%), or anterior nucleus of the thalamus (n = 1, 0.5%). RC-IPGs were inserted at initial DBS implantation in 123 patients (60%), while 83 patients (40%) were converted to RC-IPGs during an IPG replacement surgery. The authors found that RC-IPG implantation resulted in $60,900 of cost savings over the course of 9 years. Furthermore, patient satisfaction was high with RC-IPG implantation. Overall, 87.3% of patients who responded to the survey were satisfied with their device, and only 6.7% found the rechargeable component difficult to use. In patients who were switched from a standard IPG to RC-IPG, the majority who responded (70.3%) preferred the rechargeable IPG. CONCLUSIONS: RC-IPGs can provide DBS patients with long-term therapeutic benefit while minimizing the need for battery replacement surgery. The authors have implanted rechargeable stimulators in 206 patients undergoing DBS surgery, and here they demonstrate the cost-effectiveness and high patient satisfaction associated with this procedure. DOI: 10.3171/2018.4.JNS172995


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216. J Pediatr. 2018 Sep 5. pii: S0022-3476(18)30960-0. doi: 10.1016/j.jpeds.2018.07.055. [Epub ahead of print]

Comorbidities of Rare Epilepsies: Results from the Rare Epilepsy Network.

Ho NT(1), Kroner B(2), Grinspan Z(3), Fureman B(4), Farrell K(4), Zhang J(1), Buelow J(5), Hesdorffer DC(6); Rare Epilepsy Network Steering Committee. Collaborators: McDonald B(7), Weldon M(8), Bradish J(9), Vogel-Farley V(10), Nues P(11), Dixon-Salazar T(12), Bliss G(13), DeWoody Y(14), Nakagawa JA(15), Kroner B(16), Harris M(17), Arm G(18), Jackson H(19), Miller I(20), Vozenilek G(21), Wong N(22), Davidow A(23), Wagner K(24), Hecker J(25), Egan L(26), Grabenstatter H(27), Meskis MA(28), Bartenhagen M(29), Sims S(30), Walters J(31), Schoyer L(32), Nye K(33). Author information: (1)Gertrude H. Sergievsky Center, Department of Epidemiology, Columbia University, New York, NY. (2)Department of Epidemiology, Research Triangle Institute, Research Triangle Park, NC. (3)Weill Cornell Medical Center, New York, NY. (4)Research and New Therapies, Epilepsy Foundation, Landover, MD. (5)Indiana University School of Nursing, Indianapolis, IN. (6)Gertrude H. Sergievsky Center, Department of Epidemiology, Columbia University, New York, NY. Electronic address: [email protected]. (7)Aaron's Ohtahara Foundation, Omaha, NE. (8)Bridge the Gap SYNGAP, Cypress, TX. (9)The Cute Syndrome Foundation, Lawton, MI. (10)Dup15q Alliance, Highland Park, IL. (11)International Rett Syndrome Foundation, Cincinnati, OH. (12)Lennox-Gastaut Syndrome Foundation, Bohemia, NY. (13)Phelan - McDermid Syndrome Foundation, Houston, TX. (14)Ring 14 USA Outreach, Colorado Springs, CO. (15)Tuberous Sclerosis Alliance, Silver Spring, MD. (16)Aicardi Syndrome Foundation, Rockville, MD. (17)Carson Harris Foundation, Colorado Springs, CO. (18)Carson Harris Foundation Baltimore, MD. (19)Doose Syndrome Epilepsy Alliance, Colorado Springs, CO. (20)Hope for Hypothalamic Hamartomas, Bethesda, MD. (21)The Jack Pribaz Foundation, Peoria, IL. (22)The NORSE Institute, Summit, NJ. (23)Pitt Hopkins Research Foundation, Plymouth, MA. (24)Ring Chromosome 20 Alliance, York, PA. (25)Wishes for Elliott, Washington, DC. (26)Alternating Hemiplegia of Childhood Foundation, San Francisco, CA. (27)International Foundation for CDKL5 Research, Wadsworth, OH. (28)Dravet Syndrome Foundation, Cherry Hill, NJ. (29)Infantile Spasms Community, Gretna, NE. (30)KCNQ2 Cure Alliance, Denver, CO. (31)PCDH19 Alliance, Novato, CA. (32)RASopathies Network, Altadena, CA. (33)TESS Foundation, Menlo Park, CA. OBJECTIVE: To describe the prevalence and characteristics of comorbidities in persons with rare epilepsies. STUDY DESIGN: Persons with rare epilepsies and caregivers of those affected were recruited through the Epilepsy Foundation and more than 30 rare epilepsy advocacy organizations affiliated with the Rare Epilepsy Network (REN). A web-based survey was conducted using a questionnaire consisting of core sections to collect data from affected persons on various aspects, including comorbidities. Comorbidity information was grouped into 15 classes, 12 of which had a stem question followed by detailed branch questions and 3 that were created from a combination of related questions. RESULTS: Of 795 persons with more than 30 different rare epilepsy diagnosis groups, one-half had ≥5 comorbidity classes and 97% were classified as complex chronic disease (C-CD). The highest number of comorbidity classes reported per person were persons with Aicardi syndrome, Phelan-McDermid syndrome (median, 7.0; IQR, 5.0-9.0), and tuberous sclerosis complex (median, 6.0; IQR, 4.0-8.0). The most common comorbidity classes were learning/developmental disability (71%), mental health issues (71%), sleep disorders (60%), brain abnormalities (52%), oral issues (49%), bone-joint issues (42%), hyper/hypotonia (42%), and eye-vision disorders (38%). The prevalence of brain abnormalities, hyper/hypotonia, eye, and cardiac disorders was significantly higher in persons first diagnosed with epilepsy at a younger age (<9 months) than in those first diagnosed at an older age (P < .05 for trend). CONCLUSIONS: Nearly all persons with rare epilepsies are medically complex, with a high prevalence of multiple comorbidities, especially those who were diagnosed with epilepsy in the first year of life. Comorbidities should be carefully considered in the diagnosis and management of persons with rare epilepsies. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.jpeds.2018.07.055


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217. J Rehabil Med. 2018 Sep 28;50(9):821-827. doi: 10.2340/16501977-2375.

Physical behaviour is weakly associated with physical fatigue in persons with multiple sclerosis-related fatigue.

Blikman LJM(1), van Meeteren J, Rizopoulos D, de Groot V, Beckerman H, Stam HJ, Bussmann JBJ. Author information: (1)Rehabilitation Medicine, Erasmus MC, , 3000 CA Rotterdam, The Netherlands. [email protected]. BACKGROUND: Fatigue affects 80% of persons with multiple sclerosis and is associated with daily physical functioning. Both fatigue and physical behaviour are multidimensional concepts. OBJECTIVE: To study the association between the dimensions of physical behaviour and multiple sclerosis-related fatigue. METHODS: Cross-sectional analysis of 212 persons with multiple sclerosis. Participants were severely fatigued, with a Fatigue Severity Scale median (interquartile range): 5.4 (4.8-5.9) and were minimally to moderately neurologically impaired, based on the Expanded Disability Status Scale: 2.5 (2.0-3.5), 73% had relapsing-remitting multiple sclerosis. Fatigue was measured by questionnaires (i.e. Checklist Individual Strength, Modified Fatigue Impact Scale), and the dimensions subjective, physical, cognitive and psychological fatigue were distinguished. Physical behaviour was measured using an Actigraph GT3X+, and outcomes were categorized into the dimensions of activity amount, activity intensity, day pattern, and distribution of activities. RESULTS: The physical behaviour dimensions were significantly associated with only the physical fatigue dimension (omnibus F-test: 3.96; df1 = 4, df2 = 207; p = 0.004). Additional analysis showed that the amount of activity (unstandardized beta coefficient (β) = -0.16; 95% confidence interval (CI) -0.27 to -0.04; p = 0.007), activity intensity (β = -0.18; 95% CI -0.31 to -0.06; p = 0.004) and day pattern of activity (β = -0.17; 95% CI, -0.28 to -0.06; p = 0.002) were the physical behaviour dimensions that were significantly associated with physical fatigue. CONCLUSION: Physical behaviour is weakly associated with physical fatigue and is not associated with other dimensions of fatigue. DOI: 10.2340/16501977-2375

218. J Strength Cond Res. 2017 Dec 4. doi: 10.1519/JSC.0000000000002381. [Epub ahead of print]

A Meta-Analytic and Scoping Study on Strength Training in People with Multiple Sclerosis. Manca A(1), Dvir Z(2), Deriu F(1).

Author information: (1)Department of Biomedical Sciences, University of Sassari, Sassari, Italy. (2)Department of Physical Therapy, Sackler Faculty of Medicine, University of Tel Aviv, Israel. Aim of the study was to determine a pooled estimate of effect on muscle strength and functional capacity induced by strength training in people with multiple sclerosis (PwMS).Five databases and 2 public registries were searched from inception to May 2017. Indexing terms employed were: "multiple sclerosis", "resistance training" and "strength training".Following title/abstract screening, two independent reviewers evaluated the studies' eligibility, which were retained if PwMS were randomly assigned to strength training or to a no-intervention group. Of the 1467 items retrieved, 30 randomized controlled trials (RCTs) formed the initial database with 11 trials (426 subjects) entering the final meta-analysis.The quality of the included studies was assessed by the PEDro scale and the risk of bias using the Cochrane Risk-of-Bias tool. All meta-analyses were conducted using a random-effects model.Following interventions PwMS increased strength by 23.1% (CI 11.8-34.4; +12.1 N; CI 4.5-19.8; p=0.002; n= 366 subjects) at a small to moderate effect size (0.37; CI 0.2-0.6). Walking speed increased by 16.3±10.7% (p=0.0002; effect size 0.54; n=275 subjects), distance covered in the 2-Minute Walking Test by 6.7±6.4% (p=0.04; effect size 0.50; n=111 subjects.PwMS respond to resistance training with consistent strength gains. Methodological inconsistencies among studies and inadequate reporting of the findings limited a comprehensive determination of the impact of strength improvements on patient functioning, except for walking performance which appeared significantly improved. Methodological steps and scoping lines are provided to establish a common platform for future trials. DOI: 10.1519/JSC.0000000000002381

219. JAMA Neurol. 2018 Sep 17. doi: 10.1001/jamaneurol.2018.2689. [Epub ahead of print]

Deciding on the Best Multiple Sclerosis Therapy: Tough Choices.

Berger JR(1), Markowitz C(1). Author information: (1)Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. DOI: 10.1001/jamaneurol.2018.2689


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220. Lancet Child Adolesc Health. 2018 Mar;2(3):191-204. doi: 10.1016/S2352-4642(18)30026-9. Epub 2018 Feb 1.

MRI and laboratory features and the performance of international criteria in the diagnosis of multiple sclerosis in children and adolescents: a prospective cohort study.

Fadda G(1), Brown RA(1), Longoni G(2), Castro DA(3), O'Mahony J(4), Verhey LH(5), Branson HM(3), Waters P(6), Bar-Or A(7), Marrie RA(8), Yeh EA(2), Narayanan S(1), Arnold DL(1), Banwell B(9); Canadian Pediatric Demyelinating Disease Network. Collaborators: Wambera K, Connolly MB, Yager J, Mah JK, Sebire G, Callen D, Meaney B, Dilenge ME, Lortie A, Pohl D, Doja A, Venkateswaran S, Levin S, MacDonald EA, Meek D, Wood E, Buckley D, Awuku M, Baird JB, Bhan V, Arnaoutelis R, Nandamalavan D. Author information: (1)Montreal Neurological Institute, McGill University, Montreal, QC, Canada. (2)Department of Pediatrics, University of Toronto, Toronto, ON, USA; Division of Neurology, Department of Pediatrics, University of Toronto, ON, Canada; Department of Diagnostic Imaging, Neurosciences and Mental Health, SickKids Research Institute, University of Toronto, ON, Canada. (3)Division of Neuroradiology, University of Toronto, ON, Canada. (4)Department of Diagnostic Imaging, Neurosciences and Mental Health, SickKids Research Institute, University of Toronto, ON, Canada; The Hospital for Sick Children, and the Institute of Health Policy, Management and Evaluation, University of Toronto, ON, Canada. (5)College of Medicine, Central Michigan University, Mount Pleasant, MI, USA. (6)Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK. (7)Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (8)Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. (9)Division of Child Neurology, Department of Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected]. BACKGROUND: MRI and laboratory features have been incorporated into international diagnostic criteria for multiple sclerosis. We assessed the pattern of MRI lesions and contributions of cerebrospinal fluid (CSF) and serum antibody findings that best identifies children with multiple sclerosis, and the applicability of international diagnostic criteria in the paediatric context. METHODS: In this prospective cohort study, detailed clinical assessments, serum and CSF studies, and MRI scans were done in youth (aged 0·46-17·87 years) with incidental acquired demyelinating syndrome. Participants were examined prospectively to identify relapsing disease. All MRI scans were assessed using a validated scoring method. A random forest classifier identified imaging and laboratory features that best predicted a multiple sclerosis or monophasic outcome. Performance of the 2001, 2010, and 2017 international McDonald criteria for the diagnosis of multiple sclerosis, the 2016 MRI in multiple sclerosis (MAGNIMS) criteria, and our 2011 proposed (Verhey) criteria were determined; performance was adjudicated with generalised linear models. FINDINGS: Between Sept 1, 2004, and June 30, 2017, we included 324 participants with median follow-up of 72 months (range 6-150), 71 (22%) participants with multiple sclerosis, 237 (73%) with monophasic acquired demyelinating syndrome, 14 (4%) with relapsing non-multiple sclerosis, and two (1%) with alternative diagnoses. We scored 2391 brain, 444 spinal, and 67 dedicated orbital MRI scans. One or more T1 hypointense lesions plus one or more periventricular lesions (Verhey criteria) best predicted multiple sclerosis outcome. Performance of the 2017 McDonald criteria was comparable to the 2010 McDonald criteria and was easier to adjudicate. The ability of CSF oligoclonal bands to substitute for the requirement for both enhancing and non-enhancing lesions in the 2017 McDonald criteria improved its performance compared with the 2010 criteria. Myelin oligodendrocyte testing at baseline did not improve performance of the 2017 McDonald criteria. INTERPRETATION: The 2017 McDonald criteria for the diagnosis of multiple sclerosis, as applied at the time of incident attack, perform well in identifying children and youth with multiple sclerosis, indicating that the same diagnostic criteria for multiple sclerosis apply across the age span. The presence of so-called black holes on MRI and periventricular lesions at baseline (Verhey criteria) also effectively distinguish children with multiple sclerosis from children with monophasic demyelination. The presence of CSF oligoclonal bands improve diagnostic accuracy. Myelin oligodendrocyte glycoprotein antibodies identify children with acute disseminated encephalomyelitis, and those with relapsing non-multiple sclerosis, most of whom do not meet 2017 McDonald criteria at onset. FUNDING: The Multiple Sclerosis Scientific Research Foundation and The Children's Hospital of Philadelphia. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/S2352-4642(18)30026-9


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221. Lancet Child Adolesc Health. 2018 Mar;2(3):161-162. doi: 10.1016/S2352-4642(18)30028-2. Epub 2018 Feb 1.

Paediatric multiple sclerosis: early diagnosis as a first step.

Hintzen RQ(1). Author information: (1)MS Centre ErasMS, Dept of Neurology, Erasmus MC, 3000 CA Rotterdam, Netherlands. Electronic address: [email protected]. DOI: 10.1016/S2352-4642(18)30028-2

222. Lancet Child Adolesc Health. 2018 Feb;2(2):103-111. doi: 10.1016/S2352-4642(17)30174-8. Epub 2017 Dec 6.

Long-term prognosis after childhood convulsive status epilepticus: a prospective cohort study.

Pujar SS(1), Martinos MM(2), Cortina-Borja M(3), Chong WKK(4), De Haan M(2), Gillberg C(5), Neville BG(6), Scott RC(7), Chin RF(8); North London Epilepsy Research Network. Author information: (1)Clinical Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK; Clinical Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; Young Epilepsy, Lingfield, UK. Electronic address: [email protected]. (2)Cognitive Neuroscience and Neuropsychiatry Program, UCL Great Ormond Street Institute of Child Health, London, UK. (3)Population, Policy and Practice Program, UCL Great Ormond Street Institute of Child Health, London, UK. (4)Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. (5)Clinical Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK; Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden. (6)Clinical Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK; Young Epilepsy, Lingfield, UK. (7)Clinical Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK; Clinical Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; Young Epilepsy, Lingfield, UK; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA. (8)Clinical Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK; Muir Maxwell Epilepsy Centre, Department of Child Life and Health, The University of Edinburgh, Edinburgh, UK. BACKGROUND: The prognosis of convulsive status epilepticus (CSE), a common childhood medical neurological emergency, is not well characterised. We aimed to investigate the long-term outcomes in a cohort of participants who previously had CSE. METHODS: In this prospective study, we followed up a population-based childhood CSE cohort from north London, UK (the north London convulsive status epilepticus surveillance study cohort; NLSTEPSS). We collected data from structured clinical neurological assessment, neurocognitive assessment (Wechsler Abbreviated Scale of Intelligence), brain MRI, medical records, and structured interviews with participants and their parents to determine neurological outcomes, with adverse outcome defined as presence of one or more of epilepsy (active or in remission), motor disability, intellectual disability, or statement of special educational needs. We applied multiple imputation to address missing data and performed binary logistic regression analyses on complete-case and imputed datasets to investigate sociodemographic and CSE factors associated with adverse outcomes. FINDINGS: Of 203 survivors (90% of inception cohort), 134 (66%) were assessed at a median follow-up of 8·9 years (IQR 8·2-9·5). The cumulative incidence of epilepsy was 24·7% (95% CI 16·2-35·6), with most (89%) emerging within 18 months after CSE. The cumulative incidence of epilepsy was lower in patients with prolonged febrile seizures (14·3%, 6·3-29·4) and survivors of acute symptomatic CSE (13·3%, 3·7-37·9) than in those of remote symptomatic CSE (45·5%, 21·3-72·0) and unclassified CSE (50·0%, 25·4-74·6). One participant (2·9%, 0·5-14·5) in the prolonged febrile seizures group developed temporal lobe epilepsy with mesial temporal sclerosis. The absence of fever at CSE was the only predictor of incident epilepsy (odds ratio [OR] 7·5, 95% CI 2·25-25·1). Motor and intellectual disability was seen predominantly in participants who had idiopathic and cryptogenic CSE (seven [36·8%, 95% CI 19·1-59·0] and 16 [84·2%, 62·4-94·5] of 19, respectively) and remote symptomatic CSE (33 [62·3%, 48·8-74·1] and 40 [75·5%, 62·4-85·1] of 53), and most of these participants had pre-existing disabilities. Pre-existing epilepsy was the only predictor of intellectual disability (OR 8·0, 95% CI 1·1-59·6). 51·5% (95% CI 43·1-59·8) of those followed up had a statement of special educational needs. INTERPRETATION: Childhood CSE is associated with substantial long-term neurological morbidity, but primarily in those who have epilepsy, neurological abnormalities, or both before the episode of CSE. Survivors without neurological abnormalities before CSE have favourable outcomes. FUNDING: BUPA Foundation, The Academy of Medical Sciences, Wellcome Trust, National Institute for Health Research, and Young Epilepsy. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved. DOI: 10.1016/S2352-4642(17)30174-8


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223. Lancet Neurol. 2018 Oct;17(10):918-926. doi: 10.1016/S1474-4422(18)30309-0. Epub 2018 Sep 18.

The hippocampus in multiple sclerosis.

Rocca MA(1), Barkhof F(2), De Luca J(3), Frisén J(4), Geurts JJG(5), Hulst HE(5), Sastre-Garriga J(6), Filippi M(7); MAGNIMS Study Group. Collaborators: Barkhof F, Ciccarelli O, De Stefano N, Enzinger C, Filippi M, Frederiksen JL, Gasperini C, Kappos L, Palace J, Rocca MA, Rovira A, Sastre-Garriga J, Vrenken H, Yousry TA. Author information: (1)Neuroimaging Research Unit and Department of Neurology, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. (2)Department of Radiology and Nuclear Medicine, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC-location VUmc, Amsterdam, Netherlands; Institute of Neurology and Institute of Healthcare Engineering, UCL Institute of Neurology, London, UK. (3)Kessler Foundation, West Orange, NJ, USA; Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ, USA. (4)Department of Cell and Molecular Biology, Karolinska Institute, Sweden. (5)Department of Anatomy and Neurosciences, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC-location VUmc, Amsterdam, Netherlands. (6)Department of Neurology/Neuroimmunology, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. (7)Neuroimaging Research Unit and Department of Neurology, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. Electronic address: [email protected]. Some of the clinical manifestations of multiple sclerosis, such as memory impairment and depression, are, at least partly, related to involvement of the hippocampus. Pathological studies have shown extensive demyelination, neuronal damage, and synaptic abnormalities in the hippocampus of patients with multiple sclerosis, and improvements in MRI technology have provided novel ways to assess hippocampal involvement in vivo. It is now accepted that clinical manifestations related to the hippocampus are due not only to focal hippocampal damage, but also to disconnection of the hippocampus from several brain networks. Evidence suggests anatomical and functional subspecialisation of the different hippocampal subfields, resulting in variability between regions in the extent to which damage and repair occur. The hippocampus also has important roles in plasticity and neurogenesis, both of which potentially contribute to functional preservation and restoration. These findings underline the importance of evaluation of the hippocampus not only to improve understanding of the clinical manifestations of multiple sclerosis, but also as a potential future target for treatment. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/S1474-4422(18)30309-0


The hippocampus and behaviour in multiple sclerosis.

Feinstein A(1). Author information: (1)Department of Psychiatry, University of Toronto and Sunnybrook Health Sciences Centre, Toronto, ON M5R 3B6, Canada. Electronic address: [email protected]. DOI: 10.1016/S1474-4422(18)30324-7


Myelocortical multiple sclerosis: a new disease subtype?

Stys PK(1). Author information: (1)Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address: [email protected]. DOI: 10.1016/S1474-4422(18)30333-8


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226. Magn Reson Med. 2018 Sep 5. doi: 10.1002/mrm.27463. [Epub ahead of print]

Relevance of time-dependence for clinically viable diffusion imaging of the spinal cord.

Grussu F(1)(2), Ianuş A(2)(3), Tur C(1), Prados F(1)(4), Schneider T(5), Kaden E(2), Ourselin S(4), Drobnjak I(2), Zhang H(2), Alexander DC(2)(6), Gandini Wheeler-Kingshott CAM(1)(7)(8). Author information: (1)Queen Square MS Centre, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom. (2)Centre for Medical Image Computing, Department of Computer Science, University College London, London, United Kingdom. (3)Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal. (4)Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom. (5)Philips United Kingdom, Guildford, Surrey, United Kingdom. (6)Clinical Imaging Research Centre, National University of Singapore, Singapore, Singapore. (7)Brain MRI 3T Research Centre, C. Mondino National Neurological Institute, Pavia, Italy. (8)Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy. PURPOSE: Time-dependence is a key feature of the diffusion-weighted (DW) signal, knowledge of which informs biophysical modelling. Here, we study time-dependence in the human spinal cord, as its axonal structure is specific and different from the brain. THEORY AND METHODS: We run Monte Carlo simulations using a synthetic model of spinal cord white matter (WM) (large axons), and of brain WM (smaller axons). Furthermore, we study clinically feasible multi-shell DW scans of the cervical spinal cord (b = 0; b = 711 s mm-2 ; b = 2855 s mm-2 ), obtained using three diffusion times (Δ of 29, 52 and 76 ms) from three volunteers. RESULTS: Both intra-/extra-axonal perpendicular diffusivities and kurtosis excess show time-dependence in our synthetic spinal cord model. This time-dependence is reflected mostly in the intra-axonal perpendicular DW signal, which also exhibits strong decay, unlike our brain model. Time-dependence of the total DW signal appears detectable in the presence of noise in our synthetic spinal cord model, but not in the brain. In WM in vivo, we observe time-dependent macroscopic and microscopic diffusivities and diffusion kurtosis, NODDI and two-compartment SMT metrics. Accounting for large axon calibers improves fitting of multi-compartment models to a minor extent. CONCLUSIONS: Time-dependence of clinically viable DW MRI metrics can be detected in vivo in spinal cord WM, thus providing new opportunities for the non-invasive estimation of microstructural properties. The time-dependence of the perpendicular DW signal may feature strong intra-axonal contributions due to large spinal axon caliber. Hence, a popular model known as "stick" (zero-radius cylinder) may be sub-optimal to describe signals from the largest spinal axons. © 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. DOI: 10.1002/mrm.27463


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227. Med Sci (Basel). 2018 Sep 21;6(4). pii: E82. doi: 10.3390/medsci6040082.

Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization.

Toljan K(1), Vrooman B(2)(3). Author information: (1)Department of Pathophysiology, University of Zagreb School of Medicine, Kispaticeva 12, 10 000 Zagreb, Croatia. [email protected]. (2)Section of Pain Medicine, Department of Anesthesiology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756, USA. [email protected]. (3)Department of Anesthesiology, Geisel School of Medicine at Dartmouth, Hanover, NH 03756, USA. [email protected]. Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn's disease, multiple sclerosis, complex-regional pain syndrome, Hailey-Hailey disease, and cancer. In a dosing range at less than 1 μg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in μ-opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. A dosing range between 1 μg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed. DOI: 10.3390/medsci6040082

228. Medicina (B Aires). 2018;78 Suppl 2:75-81.

[Demyelinating disorders].

[Article in Spanish] Savransky A(1). Author information: (1)Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina. E-mail: [email protected]. Demyelinating diseases are a group of conditions of autoimmune etiology directed against the myelin of the central nervous system. In many cases, the onset of the illness is preceded by a nonspecific viral infection. Multiple sclerosis is a disease that evolves with relapses and remissions with polyfocal neurological deficits, being the most frequent optic neuritis, transverse myelitis and encephalic trunk involvement. Typically, magnetic resonance image (MRI) shows peri-ventricular, peri-callosal, cerebellum, brain stem and spinal cord hyperintensive lesions in T2 and FLAIR weighted images. Optic neuromyelitis is characterized by the presence of optic neuritis and transverse myelitis associated with the postrema and diencephalic area syndrome. MRI lesions are distributed in sectors rich with aquaporine-4 channels (AQP-4): hypothalamus, third and fourth ventricle, optic nerves and spinal cord. Finding anti AQP4 antibodies is useful for the diagnosis although they are not essential for it. Acute disseminated encephalomyelitis is typically a monophasic condition characterized by acute encephalopathy associated with hyperintense MRI large, bilateral and irregular asymmetric lesion in T2 and FLAIR weighted images. In all three cases, cerebral spine fluid (CSF) can show pleocytosis and hyperproteinorrachia. The presence of oligoclonal bands in CSF is characteristic of multiple sclerosis. In all cases, acute treatment includes high dose intravenous corticosteroids and plasmapheresis in non-responsive cases. Both multiple sclerosis and optic neuromyelitis require long-term treatment to prevent relapse and recurrent diseases.


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229. Microbiome. 2018 Sep 5;6(1):154. doi: 10.1186/s40168-018-0533-1.

Alteration of the cutaneous microbiome in psoriasis and potential role in Th17 polarization.

Chang HW(1), Yan D(1)(2), Singh R(1)(3), Liu J(1), Lu X(1)(4), Ucmak D(1)(5), Lee K(1), Afifi L(1)(6), Fadrosh D(7), Leech J(1), Vasquez KS(1), Lowe MM(1), Rosenblum MD(1), Scharschmidt TC(1), Lynch SV(7), Liao W(8). Author information: (1)Department of Dermatology, University of California, San Francisco, CA, 94115, USA. (2)Cleveland Clinic Lerner College of Medicine, Cleveland, OH, 44106, USA. (3)Department of Internal Medicine, Yale University, New Haven, CT, 06520, USA. (4)Dermatology Department, Peking University Third Hospital, Beijing, China. (5)Department of Dermatology, Dicle University School of Medicine, 21280, Diyarbakır, Turkey. (6)University of Miami Miller School of Medicine, Miami, FL, 33136, USA. (7)Division of Gastroenterology, University of California, San Francisco, San Francisco, CA, 94143, USA. (8)Department of Dermatology, University of California, San Francisco, CA, 94115, USA. [email protected]. BACKGROUND: Psoriasis impacts 1-3% of the world's population and is characterized by hyper-proliferation of keratinocytes and increased inflammation. At the molecular level, psoriasis is commonly driven by a Th17 response, which serves as a major therapeutic target. Microbiome perturbations have been associated with several immune-mediated diseases such as atopic dermatitis, asthma, and multiple sclerosis. Although a few studies have investigated the association between the skin microbiome and psoriasis, conflicting results have been reported plausibly due to the lack of standardized sampling and profiling protocols, or to inherent microbial variability across human subjects and underpowered studies. To better understand the link between the cutaneous microbiota and psoriasis, we conducted an analysis of skin bacterial communities of 28 psoriasis patients and 26 healthy subjects, sampled at six body sites using a standardized protocol and higher sequencing depth compared to previous studies. Mouse studies were employed to examine dermal microbial-immune interactions of bacterial species identified from our study. RESULTS: Skin microbiome profiling based on sequencing the 16S rRNA V1-V3 variable region revealed significant differences between the psoriasis-associated and healthy skin microbiota. Comparing the overall community structures, psoriasis-associated microbiota displayed higher diversity and more heterogeneity compared to healthy skin bacterial communities. Specific microbial signatures were associated with psoriatic lesional, psoriatic non-lesional, and healthy skin. Specifically, relative enrichment of Staphylococcus aureus was strongly associated with both lesional and non-lesional psoriatic skin. In contrast, Staphylococcus epidermidis and Propionibacterium acnes were underrepresented in psoriatic lesions compared to healthy skin, especially on the arm, gluteal fold, and trunk. Employing a mouse model to further study the impact of cutaneous Staphylcoccus species on the skin T cell differentiation, we found that newborn mice colonized with Staphylococcus aureus demonstrated strong Th17 polarization, whereas mice colonized with Staphylococcus epidermidis or un-colonized controls showed no such response. CONCLUSION: Our results suggest that microbial communities on psoriatic skin is substantially different from those on healthy skin. The psoriatic skin microbiome has increased diversity and reduced stability compared to the healthy skin microbiome. The loss of community stability and decrease in immunoregulatory bacteria such as Staphylococcus epidermidis and Propionibacterium acnes may lead to higher colonization with pathogens such as Staphylococcus aureus, which could exacerbate cutaneous inflammation along the Th17 axis. DOI: 10.1186/s40168-018-0533-1 PMCID: PMC6125946


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230. Mod Rheumatol. 2018 Sep 14:1-14. doi: 10.1080/14397595.2018.1523701. [Epub ahead of print]

Involvement of Midkine in Autoimmune and Autoinflammatory Diseases.

Aynacıoğlu AŞ(1), Bilir A(2), Tuna MY(3). Author information: (1)a Department of Medical Pharmacology , Istanbul Aydin University Medical Faculty , Istanbul , Turkey. (2)b Department of Histology and Embryology , Istanbul Aydin University Medical Faculty , Istanbul , Turkey. (3)c Department of Anatomy , Istanbul Aydin University Medical Faculty , Istanbul , Turkey. Midkine (MK) is a heparin-binding growth factor that markedly expressed during embryogenesis but downregulated to inconsiderable levels in healthy adults. However, MK is upregulated during tissue repair and in many pathologic conditions, mostly malignancies and inflammatory diseases. MK promotes a number of functions in target cells such as migration, proliferation, survival, growth, reproduction and repair, angiogenesis and gene expression. It acts as a pro-inflammatory cytokine and contributes to chronic inflammation via promoting chemotaxis and tissue infiltration of neutrophils and macrophages. Furthermore, MK upregulated the production of various inflammatory mediators (i.e. interleukin (IL) 6 and IL8). Recent studies have demonstrated strong evidence that MK is involved in the onset and progression of autoimmune rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) and other autoimmune conditions such as multiple sclerosis (MS). Additionally, it has been shown that MK is overexpressed in two major clinically defined forms of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), which are classified as autoinflammatory diseases. Taken together, MK is involved in the pathogenesis of autoimmune and autoinflammatory diseases and may serve as an indicator and biomarker in these conditions. Furthermore, MK inhibitors are expected to contribute in the management of these diseases. DOI: 10.1080/14397595.2018.1523701


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231. Mol Immunol. 2018 Sep;101:550-563. doi: 10.1016/j.molimm.2018.08.026. Epub 2018 Aug 30.

Interleukin-33 deficiency exacerbated experimental autoimmune encephalomyelitis with an influence on immune cells and glia cells.

Xiao Y(1), Lai L(2), Chen H(3), Shi J(1), Zeng F(1), Li J(1), Feng H(1), Mao J(1), Zhang F(1), Wu N(1), Xu Y(1), Tan Z(4), Gong F(4), Zheng F(5). Author information: (1)Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China. (2)Department of Clinical laboratory, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, PR China. (3)Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, PR China. (4)Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China. (5)Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, PR China. Electronic address: [email protected]. Interleukin (IL)-33, a member of the IL-1 cytokine family, is highly expressed in central nervous system (CNS), suggesting its potential role in CNS. Although some studies have focused on the role of IL-33 in multiple sclerosis (MS) / experimental autoimmune encephalomyelitis (EAE), an autoimmune disease characterized by demyelination and axonal damage in CNS, the exact role of IL-33 in MS/EAE remains unclear and controversial. Here, we used IL-33 knockout mice to clarify the role of endogenous IL-33 in EAE by simultaneously eliminating its role as a nuclear transcription factor and an extracellular cytokine. We found that the clinical score in IL-33 knockout EAE mice was higher accompanied by more severe demyelination compared with the wild-type (WT) EAE mice. As for the main immune cells participating in EAE in IL-33 knockout mice, pathogenic effector T cells increased both in peripheral immune organs and CNS, while CD4+FOXP3+ regulatory T cells decreased in spleen and lymph nodes, Th2 cells and natural killer (NK) cells decreased in CNS. Additionally, the populations of microglia/macrophages and CD11C+CD11B+ dendritic cells (DCs) increased in CNS of IL-33 knockout mice with EAE, among which iNOS-producing microglia/macrophages increased. Moreover, resident astrocytes/microglia were more activated in IL-33 knockout mice with EAE. In vitro, after blocking the IL-33, the proliferation of primary astrocytes, the production of MCP-1/CCL2 and TNF-α by astrocytes, and the production of TNF-α by primary microglia stimulated by the homogenate of the peak stage of EAE were increased. Our results indicate that IL-33 plays a protective role in EAE and exerts extensive influences on multiple immune cells and neural cells involved in EAE. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.molimm.2018.08.026


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232. Mol Med. 2018 Sep 27;24(1):51. doi: 10.1186/s10020-018-0052-3.

Leukemia inhibitory factor inhibits erythropoietin-induced myelin gene expression in oligodendrocytes.

Gyetvai G(1), Roe C(1), Heikal L(1), Ghezzi P(2), Mengozzi M(1). Author information: (1)Department of Clinical and Experimental Medicine, Brighton & Sussex Medical School, Brighton, BN1 9PS, UK. (2)Department of Clinical and Experimental Medicine, Brighton & Sussex Medical School, Brighton, BN1 9PS, UK. [email protected]. BACKGROUND: The pro-myelinating effects of leukemia inhibitory factor (LIF) and other cytokines of the gp130 family, including oncostatin M (OSM) and ciliary neurotrophic factor (CNTF), have long been known, but controversial results have also been reported. We recently overexpressed erythropoietin receptor (EPOR) in rat central glia-4 (CG4) oligodendrocyte progenitor cells (OPCs) to study the mechanisms mediating the pro-myelinating effects of erythropoietin (EPO). In this study, we investigated the effect of co-treatment with EPO and LIF. METHODS: Gene expression in undifferentiated and differentiating CG4 cells in response to EPO and LIF was analysed by DNA microarrays and by RT-qPCR. Experiments were performed in biological replicates of N ≥ 4. Functional annotation and biological term enrichment was performed using DAVID (Database for Annotation, Visualization and Integrated Discovery). The gene-gene interaction network was visualised using STRING (Search Tool for the Retrieval of Interacting Genes). RESULTS: In CG4 cells treated with 10 ng/ml of EPO and 10 ng/ml of LIF, EPO-induced myelin oligodendrocyte glycoprotein (MOG) expression, measured at day 3 of differentiation, was inhibited ≥4-fold (N = 5, P < 0.001). Inhibition of EPO-induced MOG was also observed with OSM and CNTF. Analysis of the gene expression profile of CG4 differentiating cells treated for 20 h with EPO and LIF revealed LIF inhibition of EPO-induced genes involved in lipid transport and metabolism, previously identified as positive regulators of myelination in this system. In addition, among the genes induced by LIF, and not by differentiation or by EPO, the role of suppressor of cytokine signaling 3 (SOCS3) and toll like receptor 2 (TLR2) as negative regulators of myelination was further explored. LIF-induced SOCS3 was associated with MOG inhibition; Pam3, an agonist of TLR2, inhibited EPO-induced MOG expression, suggesting that TLR2 is functional and its activation decreases myelination. CONCLUSIONS: Cytokines of the gp130 family may have negative effects on myelination, depending on the cytokine environment. DOI: 10.1186/s10020-018-0052-3

233. Mol Neurobiol. 2018 Sep 6. doi: 10.1007/s12035-018-1341-0. [Epub ahead of print]

Olfactory Dysfunction in CNS Neuroimmunological Disorders: a Review.

Shin T(1), Kim J(2), Ahn M(2), Moon C(3). Author information: (1)Department of Veterinary Anatomy, College of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University, 102 Jejudaehakno, Jeju, 63243, Republic of Korea. [email protected]. (2)Department of Veterinary Anatomy, College of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University, 102 Jejudaehakno, Jeju, 63243, Republic of Korea. (3)Department of Veterinary Anatomy, College of Veterinary Medicine and BK21 Plus Project Team, Chonnam National University, Gwangju, 61186, Republic of Korea. Olfactory dysfunction is deeply associated with quality of human life in the aging population. Olfactory dysfunction is an occasional presymptomatic sign of neuroimmunological multiple sclerosis, neuromyelitis optica, and systemic lupus erythematosus. Olfaction is initially processed by olfactory receptor cells that capture odor molecules, and the signals are transmitted to the glomeruli in the olfactory bulbs via olfactory nerves and processed in the primary olfactory cortex in the brain. Damage to either the olfactory receptor cells or the olfactory bulb and primary olfactory cortex may influence olfactory functioning. A close link between neuroimmunological disorders and olfactory dysfunction has been reported in patients and animal models. This review summarizes the literature data concerning olfactory dysfunction in autoimmune diseases including multiple sclerosis, neuromyelitis optica, and systemic lupus erythematosus; animal models thereof; and inflammation in the olfactory bulb. DOI: 10.1007/s12035-018-1341-0


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234. Mol Neurobiol. 2018 Sep 21. doi: 10.1007/s12035-018-1353-9. [Epub ahead of print]

Visualization of the Breakdown of the Axonal Transport Machinery: a Comparative Ultrastructural and Immunohistochemical Approach.

Rühling S(1), Kramer F(1), Schmutz S(1), Amor S(2)(3), Jiangshan Z(1), Schmitz C(1), Kipp M(1), Hochstrasser T(4). Author information: (1)Department of Neuroanatomy, Ludwig-Maximilians-University of Munich, Pettenkoferstr. 11, 80336, Munich, Germany. (2)Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. (3)Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. (4)Department of Neuroanatomy, Ludwig-Maximilians-University of Munich, Pettenkoferstr. 11, 80336, Munich, Germany. [email protected]. Axonal damage is a major factor contributing to disease progression in multiple sclerosis (MS) patients. On the histological level, acute axonal injury is most frequently analyzed by anti-amyloid precursor protein immunohistochemistry. To what extent this method truly detects axonal injury, and whether other proteins and organelles are as well subjected to axonal transport deficits in demyelinated tissues is not known. The aim of this study was to correlate ultrastructural morphology with the immunohistochemical appearance of acute axonal injury in a model of toxin-induced oligodendrocyte degeneration. C57BL/6J mice were intoxicated with 0.25% cuprizone to induce demyelination. The corpus callosum was investigated by serial block-face scanning electron microscopy (i.e., 3D EM), immunohistochemistry, and immunofluorescence microscopy. Brain tissues of progressive MS patients were included to test the relevance of our findings in mice for MS. Volumes of axonal swellings, determined by 3D EM, were comparable to volumes of axonal spheroids, determined by anti-APP immunofluorescence stains. Axonal swellings were present at myelinated and non-myelinated axonal internodes. Densities of amyloid precursor protein (APP)+ spheroids were highest during active demyelination. Besides APP, vesicular glutamate transporter 1 and mitochondrial proteins accumulated at sites of axonal spheroids. Such accumulations were found as well in lesions of progressive MS patients. In this correlative ultrastructural-immunohistochemical study, we provide strong evidence that breakdown of the axonal transport machinery results in focal accumulations of mitochondria and different synaptic proteins. We provide new marker proteins to visualize acute axonal injury, which helps to further understand the complex nature of axonal damage in progressive MS. DOI: 10.1007/s12035-018-1353-9


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235. Mol Ther Nucleic Acids. 2018 Sep 7;12:393-404. doi: 10.1016/j.omtn.2018.05.022. Epub 2018 Jul 11.

Integrative Analysis of lncRNAs in Th17 Cell Lineage to Discover New Potential Biomarkers and Therapeutic Targets in Autoimmune Diseases.

Teimuri S(1), Hosseini A(2), Rezaenasab A(1), Ghaedi K(3), Ghoveud E(2), Etemadifar M(4), Nasr-Esfahani MH(5), Megraw TL(6). Author information: (1)Division of Cellular and Molecular Biology, Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran. (2)Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran. (3)Division of Cellular and Molecular Biology, Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran; Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran. Electronic address: [email protected]. (4)Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. (5)Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran. Electronic address: [email protected]. (6)Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA. Electronic address: [email protected]. Th17 cells play a critical role in the pathogenesis of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, and inflammatory bowel disease. Despite the extensive investigation into this T cell lineage, little is understood regarding the role of Th17 lineage-specific lncRNAs (long non-coding RNAs) > 200 nt. lncRNAs may influence disease through a variety of mechanisms; their expression could be regulated by SNPs. lncRNAs can also affect the expression of neighboring genes or complementary miRNAs, and their expression may have lineage-specific patterns. In the system biology study presented here, the effective lncRNAs from different criteria were predicted for each autoimmune disease, and we then evaluated their expression levels in 50 MS patients compared to 25 controls using qRT-PCR. We identified changes in the expression levels of AL450992.2, AC009948.5, and RP11-98D18.3 as potential peripheral blood mononuclear cell (PBMC) biomarkers for MS among our studied lncRNAs in which co-expression analysis of AL450992.2 had the most AUCs, and the relationship to RORC was also assessed. We propose that the recurrently deregulated lncRNAs identified in this report could provide a valuable resource for studies aimed at delineating the relationship between functional lncRNAs and autoimmune disorders. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.omtn.2018.05.022 PMCID: PMC6128809

236. Molecules. 2018 Sep 27;23(10). pii: E2478. doi: 10.3390/molecules23102478.

Cannabinoid Delivery Systems for Pain and Inflammation Treatment.

Bruni N(1), Della Pepa C(2), Oliaro-Bosso S(3), Pessione E(4), Gastaldi D(5), Dosio F(6). Author information: (1)Istituto Farmaceutico Candioli, 10092 Beinasco, Italy. [email protected]. (2)Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy. [email protected]. (3)Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy. [email protected]. (4)Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy. [email protected]. (5)Department of Molecular Biotechnology and Health Sciences, University of Turin, 10125 Turin, Italy. [email protected]. (6)Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy. [email protected]. There is a growing body of evidence to suggest that cannabinoids are beneficial for a range of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, the symptoms of multiple sclerosis, anorexia, schizophrenia and other conditions. The transformation of cannabinoids from herbal preparations into highly regulated prescription drugs is therefore progressing rapidly. The development of such drugs requires well-controlled clinical trials to be carried out in order to objectively establish therapeutic efficacy, dose ranges and safety. The low oral bioavailability of cannabinoids has led to feasible methods of administration, such as the transdermal route, intranasal administration and transmucosal adsorption, being proposed. The highly lipophilic nature of cannabinoids means that they are seen as suitable candidates for advanced nanosized drug delivery systems, which can be applied via a range of routes. Nanotechnology-based drug delivery strategies have flourished in several therapeutic fields in recent years and numerous drugs have reached the market. This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment. Likely future directions are also considered and reported. DOI: 10.3390/molecules23102478


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237. Mult Scler. 2018 Sep 25:1352458518801727. doi: 10.1177/1352458518801727. [Epub ahead of print]

Smoking and its interaction with genetics in MS etiology.

Hedström AK(1). Author information: (1)Department of Clinical Neuroscience and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. The etiology of multiple sclerosis (MS) involves multifaceted interactions between genetic loci and environmental factors. Smoking is an important risk factor for MS that overall increases the risk of the disease with approximately 50%. However, the precise effects of smoking on MS development vary considerably in different contexts and in different populations. This review focuses on the influence of smoking on MS risk and its interaction with genetics in MS etiology. The possible biological mechanisms are presented in this paper. Further research is needed to establish the mechanisms of causality and to explore preventive strategies. DOI: 10.1177/1352458518801727


Autologous hematopoietic stem cell transplantation improves fatigue in multiple sclerosis.

Bose G(1), Atkins HL(2), Bowman M(3), Freedman MS(2). Author information: (1)Department of Neurology, The Ottawa Hospital Civic Campus, Ottawa, ON, Canada/Department of Medicine, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada. (2)Department of Medicine, University of Ottawa and The Ottawa Hospital Research Institute, Ottawa, ON, Canada. (3)Ambulatory Care, The Ottawa Hospital, Ottawa, ON, Canada. BACKGROUND: Fatigue is a common problem in multiple sclerosis (MS) affecting as many as 90% of patients. The Fatigue Impact Scale (FIS) is a validated measure of fatigue in MS patients. The cause of fatigue in MS is likely multifactorial, with some evidence that ongoing central nervous system (CNS) inflammation is a contributing factor. Immunoablation and autologous hematopoietic stem cell transplantation (aHSCT) have been shown to halt ongoing CNS inflammation. OBJECTIVE: To investigate whether halting all ongoing inflammation with aHSCT impacts FIS scores in patients with severe MS. METHODS: In the Canadian aHSCT study ( ClinicalTrials.gov , NCT01099930), 23 patients underwent aHSCT and had FIS prospectively collected every 6 months for 36 months of follow-up. Change in FIS was analysed by repeated-measures analysis of variance (RMANOVA) with multiple linear regression to determine independent predictors. RESULTS: The median FIS score decreased 36%, from 36 to 23 ( p = 0.001), and four patients had 100% reduction. Improvement in FIS correlated with lower age and Expanded Disability Status Scale at baseline, as well as increased independence as evidenced by a return to gainful employment and even driving. CONCLUSION: Patients had significantly less fatigue on average after aHSCT. This may serve to better understand the contribution of ongoing CNS inflammation to fatigue peculiar to MS. DOI: 10.1177/1352458518802544 239. Mult Scler. 2018 Sep 20:1352458518801479. doi: 10.1177/1352458518801479. [Epub ahead of print]

Treatment decisions in MS: Shifting the goal posts or changing how we see them?

Mahajan KR(1), Nakamura K(2), Ontaneda D(1).

Author information: (1)Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. (2)Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. DOI: 10.1177/1352458518801479


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Silent lesions on MRI imaging - Shifting goal posts for treatment decisions in multiple sclerosis.

Min M(1), Spelman T(2), Lugaresi A(3), Boz C(4), Spitaleri D(5), Pucci E(6), Grand'Maison F(7), Granella F(8), Izquierdo G(9), Butzkueven H(10), Sanchez-Menoyo JL(11), Barnett M(12), Girard M(13), Trojano M(14), Grammond P(15), Duquette P(16), Sola P(17), Alroughani R(18), Hupperts R(19), Vucic S(20), Kalincik T(21), Van Pesch V(22), Lechner-Scott J(23). Author information: (1)Department of Neurology, John Hunter Hospital, Newcastle, NSW, Australia. (2)Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden/ Burnet Institute for Medical Research and Public Health, Melbourne, VIC, Australia. (3)Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy/ IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. (4)KTU Medical Faculty Farabi Hospital, Trabzon, Turkey. (5)Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy. (6)UOC Neurologia, Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy. (7)Neuro Rive-Sud, Greenfield Park, QC, Canada. (8)Department of Medicine and Surgery, Unit of Neuroscience, University of Parma, Parma, Italy. (9)Hospital Universitario Virgen Macarena, Seville, Spain. (10)MS and Neuroimmunology Research, Central Clinical School, Monash University, MS and Neuroimmunology Service, Alfred Health, Australia. (11)Hospital de Galdakao-Usansolo, Galdakao, Spain. (12)Department of Neurology, Royal Prince Alfred Hospital, Sydney, NSW, Australia/ Brain and Mind Research Institute, Sydney, NSW, Australia. (13)Hotel-Dieu de Montreal, Montreal, QC, Canada. (14)Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy. (15)CISSS Chaudiere-Appalache, Levis, Canada. (16)CHUM Hopital Notre Dame, Montreal, Canada. (17)Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy. (18)Division of Neurology, Department of Medicine, Amiri Hospital, Sharq, Kuwait. (19)Zuyderland Ziekenhuis, Sittard, The Netherlands. (20)Westmead Hospital, Sydney, NSW, Australia. (21)CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia/ Department of Neurology, Royal Melbourne Hospital, Parkville, VIC, Australia. (22)Cliniques Universitaires Saint-Luc, Woluwe-Saint-Lambert, Belgium. (23)Department of Neurology, John Hunter Hospital, Newcastle, NSW, Australia/ School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia. BACKGROUND: The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients. OBJECTIVE: To evaluate the current practice of clinicians changing MS treatment based on subclinical new MRI lesions alone. METHODS: Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions. RESULTS: A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00-2.96 vs OR: 1.26 (95% CI: 1.22-1.29). DMT change with new MRI lesions occurred most frequently with 'injectable' DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28-1.59 vs before, OR: 0.98, 95% CI: 0.520-1.88). CONCLUSION: MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available. DOI: 10.1177/1352458518798147


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241. Mult Scler. 2018 Sep 19:1352458518799629. doi: 10.1177/1352458518799629. [Epub ahead of print] e-Health and multiple sclerosis: An update.

Lavorgna L(1), Brigo F(2), Moccia M(3), Leocani L(4), Lanzillo R(5), Clerico M(6), Abbadessa G(1), Schmierer K(7), Solaro C(8), Prosperini L(9), Tedeschi G(1), Giovannoni G(7), Bonavita S(1).

Author information: (1)Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, I Clinic of Neurology, University of Campania "Luigi Vanvitelli," Naples, Italy. (2)Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy/ Hospital Franz Tappeiner, Department of Neurology, Merano, Italy. (3)Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy/ Queen Square Multiple Sclerosis Centre, University College of London Institute of Neurology, London, UK. (4)Department of Neurology and Institute of Experimental Neurology-INSPE, University Hospital San Raffaele, Milan, Italy. (5)Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy. (6)Department of Clinical and Biological Sciences, University of Turin, AOU San Luigi Gonzaga, Orbassano, Italy. (7)The Blizard Institute (Neuroscience), Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK/ Clinical Board: Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, UK. (8)Department of Rehabilitation Mons L Novarese Hospital, Moncrivello, Italy. (9)Department of Neurosciences, S. Camillo-Forlanini Hospital, Roma, Italy. e-Health (or digital healthcare) is becoming increasingly relevant in multiple sclerosis (MS) clinical management. We aim to review and discuss current status and future perspective of e-health in people with multiple sclerosis (pwMS). The first part of this review describes how information on MS can be conveyed through the Web and digital media. The second part illustrates recent advances in digital technology that can improve clinical management and in motor and cognitive rehabilitation of pwMS. Finally, this review advocates future development of the "digital case manager" as a new figure to coordinate clinical management and care of pwMS. The digital revolution is changing the medical approach to MS in terms of information conveying and sharing, rehabilitation, and healthcare management. DOI: 10.1177/1352458518799629


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Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System.

Antonazzo IC(1), Poluzzi E(1), Forcesi E(1), Riise T(2), Bjornevik K(3), Baldin E(4), Muratori L(5), De Ponti F(1), Raschi E(1). Author information: (1)Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy. (2)Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway/The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway. (3)Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway/The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway/Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (4)Epidemiology and Biostatistics Service, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy. (5)Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy/ Center for the Study and Treatment of the Autoimmune Diseases of the Liver and Biliary System, Policlinico di Sant'Orsola, Bologna, Italy. BACKGROUND: Drug-induced liver injury (DILI) has been observed in patients with multiple sclerosis (MS), raising concerns on the liver safety of MS drugs. OBJECTIVE: To describe DILI events with MS drugs by analyzing the FDA Adverse Event Reporting System. METHODS: DILI reports were extracted and classified in overall liver injury (OLI), including asymptomatic elevation of liver enzymes, and severe liver injury (SLI). We performed disproportionality analysis by calculating adjusted reporting odds ratios (RORs) with 95% confidence interval (CI) and case-by-case evaluation for concomitant drugs with hepatotoxic potential. RESULTS: Fampridine showed statistically significant ROR for both OLI and SLI, whereas teriflunomide and fingolimod generated solid disproportionality (ROR > 2) only for OLI (ROR, 2.31; 95% CI, 2.12-2.52; and 2.53; 2.40-2.66, respectively). Among monoclonal antibodies, only alemtuzumab generated higher-than-expected ROR for OLI (1.34; 1.09-1.65). We also detected the expected hepatotoxic potential of beta interferon and mitoxantrone. Concomitant reporting of hepatotoxic drugs ranged from 26% (dimethyl fumarate) to 90% (mitoxantrone). CONCLUSION: These real-world pharmacovigilance findings suggest that DILI might be a common feature of MS drugs and call for (1) formal population-based study to verify the risk of fampridine and (2) awareness by clinicians, who should assess the possible responsibility of MS drugs when they diagnose DILI. DOI: 10.1177/1352458518799598


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Symptomatology and symptomatic treatment in multiple sclerosis: Results from a nationwide MS registry.

Rommer PS(1), Eichstädt K(2), Ellenberger D(3), Flachenecker P(4), Friede T(3), Haas J(5), Kleinschnitz C(6), Pöhlau D(7), Rienhoff O(8), Stahmann A(2), Zettl UK(9). Author information: (1)Department of Neurology, Neuroimmunological Section, University of Rostock, Rostock, Germany/Department of Neurology, Medical University of Vienna, Vienna, Austria. (2)MS Forschungs- und Projektentwicklungs-gGmbH, Hannover, Germany. (3)Department of Medical Statistics, University Medical Centre Göttingen, Göttingen, Germany. (4)Neurological Rehabilitation Center Quellenhof, Bad Wildbad, Germany. (5)MS-Center, Jewish Hospital Berlin, Berlin, Germany. (6)Department of Neurology, University Hospital Essen, Essen, Germany. (7)Department of Neurology, German Red Cross-Kamillus-Clinic, Asbach, Germany. (8)Department of Medical Informatics, University Medical Center Göttingen, Göttingen, Germany. (9)Department of Neurology, Neuroimmunological Section, University of Rostock, Rostock, Germany. BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease. Over time, symptoms accumulate leading to increased disability of patients. OBJECTIVE: The objective of this article is to analyze the prevalence of symptoms and symptomatic treatment patterns in a nationwide MS registry. METHODS: Data sets from 35,755 patients were analyzed. RESULTS: More than two-thirds of patients were women with a mean age of 46.1 (±12.8) years. Median Expanded Disability Status Score (EDSS) was 3.0. The most frequently reported symptoms were fatigue, spasticity, and voiding disorders. In patients with short disease duration, fatigue was reported most frequently. Symptomatic treatment was most common for spasticity and depression, whereas fatigue was treated only in a third of affected patients. Almost a fifth of

patients with EDSS ⩽ 3.5 and neuropsychological symptoms had retired from work. CONCLUSION: Whereas treatment for spasticity and depression is common in our cohort, sexual dysfunction, dysphagia, cognitive dysfunction, and fatigue are treated to a far lesser extent. The need for psychological support, physical, and occupational therapy has to be recognized as neuropsychological symptoms have a great impact on retirement at an early stage. Overall symptomatic treatment rates for the most common symptoms have increased over the last years ( p < 0.001). DOI: 10.1177/1352458518799580


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Glutamate-sensitive imaging and evaluation of cognitive impairment in multiple sclerosis.

O'Grady KP(1), Dula AN(2), Lyttle BD(1), Thompson LM(1), Conrad BN(3), Box BA(1), McKeithan LJ(1), Pawate S(4), Bagnato F(5), Landman BA(6), Newhouse P(7), Smith SA(8). Author information: (1)Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA. (2)Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA. (3)Neuroscience Graduate Program, Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, USA. (4)Vanderbilt Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA. (5)Neuroimaging Unit, Neuroimmunology Division, Vanderbilt Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA. (6)Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA/Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN, USA/Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA/Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. (7)Department of Psychiatry and Behavioral Sciences, Center for Cognitive Medicine, Vanderbilt University Medical Center, Nashville, TN, USA/Veterans Affairs Tennessee Valley Healthcare System Geriatric Research, Education, and Clinical Center (VA TVHS GRECC), Nashville, TN, USA. (8)Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA/Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA/Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. BACKGROUND: Cognitive impairment (CI) profoundly impacts quality of life for patients with multiple sclerosis (MS). Dysfunctional regulation of glutamate in gray matter (GM) has been implicated in the pathogenesis of MS by post-mortem pathological studies and in CI by in vivo magnetic resonance spectroscopy, yet GM pathology is subtle and difficult to detect using conventional T1- and T2-weighted magnetic resonance imaging (MRI). There is a need for high-resolution, clinically accessible imaging techniques that probe molecular changes in GM. OBJECTIVE: To study cortical GM pathology related to CI in MS using glutamate-sensitive chemical exchange saturation transfer (GluCEST) MRI at 7.0 Tesla (7T). METHODS: A total of 20 patients with relapsing-remitting MS and 20 healthy controls underwent cognitive testing, anatomical imaging, and GluCEST imaging. Glutamate-sensitive image contrast was quantified for cortical GM, compared between cohorts, and correlated with clinical measures of CI. RESULTS AND CONCLUSION: Glutamate-sensitive contrast was significantly increased in the prefrontal cortex of MS patients with accumulated disability ( p < 0.05). In addition, glutamate-sensitive contrast in the prefrontal cortex was significantly correlated with symbol digit modality test ( rS = -0.814) and choice reaction time ( rS = 0.772) scores in patients ( p < 0.05), suggesting that GluCEST MRI may have utility as a marker for GM pathology and CI. DOI: 10.1177/1352458518799583


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245. Mult Scler. 2018 Jun 1:1352458518781992. doi: 10.1177/1352458518781992. [Epub ahead of print]

Zika virus found in brain tissue of a multiple sclerosis patient undergoing an acute disseminated encephalomyelitis-like episode.

Alves-Leon SV(1), Lima MDR(2), Nunes PCG(2), Chimelli LMC(3), Rabelo K(4), Nogueira RMR(5), de Bruycker-Nogueira F(2), de Azeredo EL(2), Bahia PR(6), Rueda Lopes FC(6), Marcondes de Souza JPB(7), Fontes-Dantas FL(7), Paes MV(8), Lemos ER(9), Santos FB(2). Author information: (1)Centro de Referência e Pesquisa em Esclerose Múltipla e outras Doenças Desmielinizantes Inflamatórias Idiopáticas do SNC, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil/Programa de Pós Graduação em Neurologia da Universidade Federal do Estado do Rio de Janeiro (UNIRIO), Rio de Janeiro, Brazil. (2)Laboratório de Imunologia Viral, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil. (3)Laboratório de Neuropatologia, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil. (4)Laboratório de Ultraestrutura e Biologia Tecidual, Universidade do Estado do Rio de Janeiro (UNIRIO), Rio de Janeiro, Brazil. (5)Laboratório de Flavivírus, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil. (6)Centro de Referência e Pesquisa em Esclerose Múltipla e outras Doenças Desmielinizantes Inflamatórias Idiopáticas do SNC, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. (7)Programa de Pós Graduação em Neurologia da Universidade Federal do Estado do Rio de Janeiro (UNIRIO), Rio de Janeiro, Brazil. (8)Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil. (9)Laboratório de Hantaviroses e Rickettsioses, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil. BACKGROUND: A range of different neurological manifestations has been reported in fetuses and adults after Zika virus (ZIKV) infection. OBJECTIVE: We describe a detection of the ZIKV in the brain tissue from a multiple sclerosis (MS) patient with acute disseminated encephalomyelitis (ADEM)-like event in Rio de Janeiro, Brazil. METHODS: Biological samples collected during the hospitalization were tested by serology and molecular diagnostic for various infectious agents. Histopathological analysis was performed using the anti-flavivirus group 4G2 monoclonal antibody, anti-ZIKV non-structural 1 (NS1) monoclonal antibody, and anti-CD4, CD8, and CD11b antibodies. RESULTS: Anti-ZIKV IgM and IgG antibodies were positive in the serum and urine. A brain biopsy showed ZIKV protein in brain cells and T CD8 infiltration in brain tissue. CONCLUSION: Our data describe the coexistence of a recent central nervous system (CNS) ZIKV infection accompanied by a severe ADEM-like syndrome outcome in a patient with clinical history of MS. A de novo immune response concomitant with ZIKV infection might be involved in the mechanism of the ADEM-like syndrome and response to immunotherapy. The present report reinforces the importance of providing the differential diagnosis of acute episodes of MS exacerbation in an environment prone to ZIKV expression. DOI: 10.1177/1352458518781992

246. Mult Scler. 2018 Aug 31:1352458518798048. doi: 10.1177/1352458518798048. [Epub ahead of print]

gMS-Classifier1 does not predict disability progression in multiple sclerosis.

van Rossum JA(1), Killestein J(1), Villar LM(2), Riskind PN(3), Freedman MS(4), Teunissen C(5). Author information: (1)1 Department of Neurology, Amsterdam Neuroscience, MS Center Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands. (2)2 Department of Neurology, Hospital Universitario Ramón y Cajal, Madrid, Spain. (3)3 Memorial Multiple Sclerosis Center, Department of Neurology, UMass Memorial Medical Center, Worcester, MA, USA. (4)4 Division of Neurology, Department of Medicine, University of Ottawa, The Ottawa Hospital Research Institute, Ottawa, ON, Canada. (5)5 Department of Clinical Chemistry, Amsterdam University Medical Centers, The Netherlands. DOI: 10.1177/1352458518798048


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247. Mult Scler. 2018 Aug 31:1352458518796690. doi: 10.1177/1352458518796690. [Epub ahead of print]

Tasks of activities of daily living (ADL) are more valuable than the classical neurological examination to assess upper extremity function and mobility in multiple sclerosis.

van Munster CE(1), D'Souza M(2), Steinheimer S(3), Kamm CP(4), Burggraaff J(1), Diederich M(2), Kravalis K(2), Dorn J(5), Walsh L(5), Dahlke F(5), Kappos L(2), Uitdehaag BM(1). Author information: (1)Department of Neurology, Amsterdameuroscience and MS Center Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands. (2)Department of Neurology, Universitätsspital Basel, Basel, Switzerland. (3)Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. (4)Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland/Department of Neurology and Neurorehabilitation, Luzerner Kantonsspital, Lucerne, Switzerland. (5)Novartis Pharma AG, Basel, Switzerland. BACKGROUND: Accurate clinical assessment in multiple sclerosis (MS) is challenging. The Assess MS system is being developed to automatically quantify motor dysfunction in MS, including upper extremity function (UEF) and mobility. OBJECTIVE: To determine to what extent combinations of standardized movements included in the Assess MS system explain accepted measures of UEF and mobility. METHODS: MS patients were recruited at four European MS centres. Eight movements were selected, including tasks of activities of daily living (ADL) and classical neurological tests. Movements were recorded on video and rated by experienced neurologists ( n = 5). Subsequently, multivariate linear regression models were performed to explain the variance of the Nine-Hole Peg Test (9HPT), Arm Function in Multiple Sclerosis Questionnaire (AMSQ) and Timed-25 Foot Walk test (T25WT). RESULTS: In total, 257 patients were included. The movements explained 62.9% to 80.1% of the variance of the 9HPT models, 43.3% and 44.3% of the AMSQ models and 70.8% of the T25WT. In all models, tasks of ADL contributed most to the variance. CONCLUSION: Combinations of movements are valuable to assess UEF and mobility. Incorporating ADL tasks into daily clinical practice and clinical trials may be more valuable than the classical neurological examination of UEF and mobility. DOI: 10.1177/1352458518796690

248. Mult Scler J Exp Transl Clin. 2018 Sep 20;4(3):2055217318800810. doi: 10.1177/2055217318800810. eCollection 2018 Jul-Sep.

The effect of disease modifying therapies on CD62L expression in multiple sclerosis.

Voortman MM(1), Greiner P(1), Moser D(1), Stradner MH(2), Graninger W(2), Moser A(3), Haditsch B(4), Enzinger C(1)(5), Fuchs S(1), Fazekas F(1), Fessler J(2), Khalil M(1). Author information: (1)Department of Neurology, Medical University of Graz, Austria. (2)Division of Rheumatology and Immunology, Medical University of Graz, Austria. (3)Division of Gastroenterology and Hepatology, Medical University of Graz, Austria. (4)Steiermärkische Gebietskrankenkasse, Austria. (5)Division of Neuroradiology, Vascular and Interventional Radiology, Medical University of Graz, Austria. Background: The increasing armamentarium of disease-modifying therapies in multiple sclerosis is accompanied by potentially severe adverse effects. The cell-adhesion molecule CD62L, which facilitates leukocyte extravasation, has been proposed as a predictive marker for treatment tolerability. However, pre-analytical procedures might impact test results, thereby limiting its clinical usability. Whether the immediate analysis of CD62L expression of peripheral blood mononuclear cells can aid treatment decision making is yet unclear. Objective: To investigate the effect of various disease-modifying therapies in multiple sclerosis on CD62L expression of CD3+CD4+ peripheral blood mononuclear cells in freshly collected blood samples. Methods: We collected peripheral blood samples from patients with clinically isolated syndrome and multiple sclerosis (baseline/follow up n = 234/n = 98) and healthy controls (n = 51). CD62L+CD3+CD4+ expression was analysed within 1 hour by fluorescence-activated cell sorting. Results: CD62L+CD3+CD4+ expression was significantly decreased in patients treated with natalizumab (n = 26) and fingolimod (n = 20) and increased with dimethyl-fumarate (n = 15) compared to patients receiving interferon/glatiramer acetate (n = 90/30) or no disease-modifying therapies (n = 53) and controls (n = 51) (p<0.001). CD62L expression showed temporal stability during unchanged disease-modifying therapy usage, but increased after natalizumab withdrawal and decreased upon fingolimod introduction. Conclusion: CD62L+CD3+CD4+ expression is altered in patients treated with different disease-modifying therapies when measured in freshly collected samples. The clinical meaning of CD62L changes under disease-modifying therapies warrants further investigation. DOI: 10.1177/2055217318800810 PMCID: PMC6149021


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249. Mult Scler Relat Disord. 2018 Sep 8;26:103-111. doi: 10.1016/j.msard.2018.08.020. [Epub ahead of print]

Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability.

Edwards T(1), Motl RW(2), Sebastião E(3), Pilutti LA(4). Author information: (1)School of Human Kinetics, University of Ottawa, 200 Lees Avenue, Ottawa, ON K1N 6N5, Canada. (2)Department of Physical Therapy, University of Alabama at Birmingham, 1705 University Blvd., Birmingham, AL 35233-1212, USA. (3)Department of Kinesiology and Physical Education, Northern Illinois University, 1425 Lincoln Hwy, DeKalb, IL 60115 USA. (4)Interdisciplinary School of Health Sciences, Brain and Mind Research Institute, University of Ottawa, 200 Lees Avenue E250G, Ottawa, ON K1N 6N5, Canada. Electronic address: [email protected]. BACKGROUND: Exercise training has been shown to be beneficial for persons with multiple sclerosis (MS). Adapted exercise modalities are needed to accommodate those with severe mobility impairment (Expanded Disability Status Scale [EDSS] scores 5.5-6.5). Functional electrical stimulation (FES) cycling is one such exercise modality; however, few studies have examined the feasibility and potential benefits of FES cycling for people with MS with severe mobility impairment. OBJECTIVE: Determine the feasibility of FES cycling exercise for people with MS with severe mobility impairment, and the efficacy of FES cycling exercise for improving mobility and physiological fitness. METHODS: 11 participants with MS with mobility impairment (EDSS = 5.5-6.5) were randomly allocated to FES cycling exercise (n = 6) or passive leg cycling (PLC; n = 5). Feasibility metrics included participant recruitment, retention, adherence, safety, and satisfaction. The primary mobility outcome was walking speed assessed by the Timed 25-Foot Walk (T25FW) test. The primary physiological fitness outcome was peak oxygen consumption (VO2peak), assessed using a cardiopulmonary exercise test. RESULTS: Eight participants completed the intervention (FES n = 4; PLC n = 4) with an adherence rate ≥80%. Three participants (FES n = 2, PLC n = 1) withdrew due to a lack of time. Six Grade 1 (i.e., mild) adverse events were experienced by participants in the FES group. Participants in the FES cycling condition demonstrated small-to-moderate improvements on T25FW performance (Cohen's d = 0.40; 22.9%) and VO2peak (Cohen's d = 0.34; 13.8%) compared to participants in the PLC condition. CONCLUSIONS: We provide evidence that FES cycling exercise is feasible for individuals with MS with severe mobility impairment, and might have positive effects on mobility and physiological decondition. These results will inform the design of future efficacy trials of FES cycling exercise for persons with MS with mobility disability. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.08.020


Photophobia in multiple sclerosis.

Cortese A(1), Conte A(2), Ferrazzano G(3), Sgarlata E(4), Millefiorini E(4), Frontoni M(4), Berardelli A(2). Author information: (1)Department of Human Neurosciences, Sapienza University of Rome, v.le dell'Università 30, 00185 Rome, Italy. Electronic address: [email protected]. (2)Department of Human Neurosciences, Sapienza University of Rome, v.le dell'Università 30, 00185 Rome, Italy; IRCCS Neuromed, via Atinense 18, 86077 Pozzilli, IS, Italy. (3)IRCCS Neuromed, via Atinense 18, 86077 Pozzilli, IS, Italy. (4)Department of Human Neurosciences, Sapienza University of Rome, v.le dell'Università 30, 00185 Rome, Italy. BACKGROUND: Photophobia has never been investigated in MS. METHODS: In this pilot study we used photosensitivity questionnaire assessment (PAQ) to evaluate tolerability to light in 73 MS patients and 62 healthy controls. RESULTS: We identified a lower PAQ score and a higher number of photophobic subjects in MS than in controls. Moreover, clinical disability or previous optic neuritis did not predict the photosensitivity profile. CONCLUSION: Further studies to investigate the pathophysiological mechanisms underlying photophobia in MS are needed. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.09.005


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Static postural control disturbances among the different multiple sclerosis phenotypes: A Neurocom Balance Manager® evaluation study.

Cimino V(1), Chisari CG(2), Raciti G(1), Pappalardo A(3), Zappia M(2), Patti F(4). Author information: (1)Centro Neurolesi "Bonino Pulejo", IRCSS, Messina, Italy. (2)Department G.F. Ingrassia, section of Neuroscience, University of Catania, Via S. Sofia n°78, Catania 95123, Italy. (3)Department of Rehabilitation, S.Marta & S.Venera Hospital, Acireale, Catania, Italy. (4)Department G.F. Ingrassia, section of Neuroscience, University of Catania, Via S. Sofia n°78, Catania 95123, Italy. Electronic address: [email protected]. BACKGROUND: The computerized stabilometric platform can be used and privileged over clinical scales, as self-administered questionnaires to asses postural control and balance evaluation in Multiple sclerosis (MS). Aim of our study was to evaluate static postural control assessed by Neurocom Balance Manager® through the modified Clinical Test of Sensory Interaction on Balance (mCTSIB) in relapsing-remitting MS (RRMS), progressive MS (PMS) and CIS, compared to healthy controls (HC). METHODS: We screened MS patients consecutively referring to our MS Center at University of Catania, during July 2013-June 2014 diagnosed as CIS, RRMS and PMS. All MS patients underwent clinical and neurological evaluations and a complete postural exam by Neurocom Balance Manager® in order to evaluate Center of Pressure (COP), through mCTSIB. We evaluated the following parameters: Total Path Length-open eyes (TPL-OE), Total Path Length-closed eyes (TPL-CE), Sway Area-open eyes (SA-OE), Sway Area-closed eyes (SA-CE), Mean sway velocity-open eyes (MSV-OE), Mean sway velocity-closed eyes (MSV-CE). Additionally, patients were tested by Berg balance scale (BBS) for balance and Barthel Index (BI) for disability outcomes. RESULTS: Out of 170 MS patients assessed for eligibility, 163 met the inclusion/exclusion criteria and were finally enrolled. All balance parameters were found more impaired in MS group compared to controls and CIS. Moreover, no differences in terms of balance assessment were found between HC and CIS. The correlation analysis showed that BBS was strongly associated to SA-OE, SA-CE, TPL-OE and MSV-OE. We also found a correlation between BI and SA-CE. CONCLUSION: Our study revealed significant differences among HCs, CIS and MS. MS, especially PMS, exhibit the worst balance performances especially in EC trials. The higher correlation between balance parameters, especially sway area, and BBS score confirmed the reliability and sensibility of mCTSIB assessment in evaluating static postural control in MS patients. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.08.024


B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate.

Høglund RA(1), Polak J(2), Vartdal F(3), Holmøy T(4), Lossius A(5). Author information: (1)Department of Neurology, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: [email protected]. (2)Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Immunology and Transfusion Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. (3)Department of Immunology and Transfusion Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. (4)Department of Neurology, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. (5)Department of Neurology, Akershus University Hospital, Lørenskog, Norway; Department of Immunology and Transfusion Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: [email protected]. BACKGROUND: B cells may contribute to the immunopathogenesis of multiple sclerosis (MS). Dimethyl fumarate (DMF) has recently been shown to reduce the frequency of memory B cells in blood, but it is not known whether the drug influences the cellular composition in the cerebrospinal fluid (CSF). METHODS: A cross-sectional study examining the cellular composition in blood and cerebrospinal fluid (CSF) from 10 patients treated with DMF and 18 patients receiving other disease modifying drugs or no treatment. RESULTS: Patients treated with DMF had reduced proportions of memory B cells in blood compared to other MS patients (p = 0.0007), and the reduction correlated with treatment duration (rs = -0.75, p = 0.021). In the CSF, the absolute number of mononuclear cells were significantly lower in DMF-treated patients compared to the other patients (p = 0.023), and there was a disproportionate decrease of plasmablasts (p = 0.031). CONCLUSION: The results of this exploratory study support a B-cell mediated mechanism of action for DMF in both blood and CSF. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.08.032


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Recurrent schilder's disease.

Dunn-Pirio AM(1), Eckstein C(2). Author information: (1)Department of Neurology, Duke University School of Medicine, 112 Baker House, Durham, NC 27710, United States. Electronic address: [email protected]. (2)Department of Neurology, Duke University School of Medicine, 112 Baker House, Durham, NC 27710, United States. Schilder's disease is a rare and aggressive central nervous system demyelinating disorder that is typically monophasic and steroid responsive. Here, we present an unusual case of a teenager with Schilder's disease who was treated with corticosteroids and had a clinical and radiographic recurrence nearly one year after the initial presentation. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.09.001


Autoimmune encephalitis with elevated N-type calcium channel antibodies as a multiple sclerosis mimic.

Frey J(1), Murray A(2). Author information: (1)Department of Neurology, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26505, USA. Electronic address: [email protected]. (2)Department of Neurology, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26505, USA. BACKGROUND: Voltage gated calcium channels (VGCC) are well-known targets for antibody-associated disease. Of the 5 VGCC subtypes, the most well-known is the P/Q subtype associated with Lambert-Eaton Myasthenic Syndrome (LEMS). However, this case focuses on the much less understood N-type calcium channel antibody. The objective of this case is to review the literature regarding the clinical significance of the N-type calcium channel antibody and its relationship to MS. METHODS: A 37-year old male presented with vertigo, paranoia, and tremor and had MRI changes suggestive of demyelinating disease. Evaluation revealed positive N-type calcium channel antibodies. Steroids dramatically improved symptoms and normalized antibodies. Years later recurrent symptoms were again associated with elevated antibodies. RESULTS AND CONCLUSION: This patient likely has autoimmune encephalitis associated with elevated N-type calcium channel antibodies. This case highlights the clinical significance of N-type calcium channel antibodies and the importance of correctly diagnosing patients with antibody mediated disease that may very well mimic more common neurologic diseases such as multiple sclerosis (MS). Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.09.028


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Safety liver profile of teriflunomide versus interferon β in multiple sclerosis: Systematic review and indirect comparison meta-analysis.

Salas PAO(1), Parra CO(2), Florez CEP(3), Goez LM(2), Velez-van-Meerbeke A(4), Rodriguez JH(5). Author information: (1)Fundación Cardioinfantil, Instituto de Cardiologia, Bogotá, Colombia; Grupo de investigación en neurociencias NeURos, School of medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia. Electronic address: [email protected]. (2)Fundación Cardioinfantil, Instituto de Cardiologia, Bogotá, Colombia. (3)Epidemiology Department, Universidad de la Sabana, Colombia. (4)Grupo de investigación en neurociencias NeURos, School of medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia. (5)Fundación Cardioinfantil, Instituto de Cardiologia, Bogotá, Colombia; Grupo de investigación en neurociencias NeURos, School of medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia; Hospital Universitario Mederi, Bogotá, Colombia. OBJECTIVES: To compare the liver safety profile of interferon β (IFN β) and teriflunomide in patients with multiple sclerosis. METHODS: A network meta-analysis was carried out following the Cochrane Collaboration methodology. All trials comparing all types of IFN β with teriflunomide, or disease-modifying drugs, or placebo in RRMS were included. An indirect comparison network meta-analysis within a Bayesian framework with STATA (version 13.0) was done for this study. RESULTS: The database searches yielded 284 titles, with 15 records as duplicates. One study was identified by manually searching. Thirteen articles were included in the systematic review. Twelve studies compared IFN β (4203 patients) vs another DMT. Four studies evaluated the effectiveness and safety of teriflunomide (906 patients) vs another DMT. Six studies reported drug-induced liver injury as per the Hy's Law. However, only one study had a direct comparison and reported no cases of liver toxicity in either group, so it was not possible to estimate the OR. The indirect comparisons metanalysis shows that there was no statistically-significant difference between teriflunomide and IFN β (OR 1.09, 95% CI 0.02-2.16). CONCLUSIONS: There were no significant difference when comparing IFN β and teriflunomide in terms of liver failure or elevation of transaminases. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.09.014


Leptomeningeal inflammation in multiple sclerosis: Insights from animal and human studies.

Wicken C(1), Nguyen J(1), Karna R(1), Bhargava P(2). Author information: (1)Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St, Pathology 627, Baltimore, MD 21287, United States. (2)Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St, Pathology 627, Baltimore, MD 21287, United States. Electronic address: [email protected]. The presence of leptomeningeal inflammation (LMI) in MS was first identified in 2004 and multiple subsequent studies have confirmed the presence of immune cell collections in the meninges of a subset of MS patients. Pathologically, LMI can range from disorganized immune cell collections in the meninges of patients with relapsing remitting (RRMS) or primary progressive MS (PPMS) to well-organized ectopic lymphoid follicles in secondary progressive MS (SPMS). The presence of LMI has been linked to worse pathological (increased cortical demyelination and neuroaxonal damage) and clinical (earlier age at onset, more rapid progression, shorter time to death) outcomes. Recent studies have also demonstrated the ability of specific MRI sequences to detect areas of leptomeningeal contrast enhancement (LME) which may correspond pathologically to areas of LMI. We summarize findings from both pathological and radiological studies of LMI in MS. We also provide a brief overview of LMI in animal models of MS (experimental autoimmune encephalomyelitis) and ongoing clinical trials attempting to target LMI. Future research will help clarify the role of LMI in MS disease progression, identify the mechanisms through which LMI may contribute to MS pathology and test new approaches to target LMI. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.09.025


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Stress-full life events and multiple sclerosis: A population-based incident case-control study.

Abdollahpour I(1), Nedjat S(2), Mansournia MA(3), Eckert S(4), Weinstock-Guttman B(5). Author information: (1)Department of Epidemiology, School of Public Health, Arak University of Medical Sciences, Arak, Iran. Electronic address: [email protected]. (2)Department of Epidemiology and Biostatistics, School of Public Health, Knowledge Utilization Research Center, Tehran University of Medical Sciences, Tehran, Iran. (3)Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. (4)University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA. (5)Jacobs School of Medicine and Biomedical Science, University of Buffalo, NY, USA. AIM: While sizeable evidence regarding the association between stressful-life events and multiple sclerosis (MS) disease activity (clinical and/or radiological) was previously documented, their relation to MS risk is controversial. We aimed to investigate the possible association of stressful-life events and multiple sclerosis risk after adjustment for relevant confounders in an Iranian population. METHOD: This was a population-based incident case-control study that recruited 547 MS cases and 1057 healthy controls between August 2013 and February 2015, Tehran. The patients were identified using the Iranian MS Society based on 2010 McDonald criteria. We used standard random digit dialing protocol for control selection. Logistic regression model was applied to estimate the odds ratios (95% CI) adjusted for physical activity, age, gender, tobacco smoking, waterpipe smoking and passive smoking. RESULTS: While total life events number was not associated with risk of MS, homeless periods OR 3.85 (1.65-8.90), p = 0.002 as well as divorce OR 2.11 (1.24-3.58), p = 0.005 increased the risk of MS. However, marriage OR 0.59 (0.41-0.86), p = 0.006, death of ones' dear OR 0.60 (0.44-0.82), p = 0.002 and joblessness OR 0.61 (0.41-0.91) reduced the risk of MS. CONCLUSION: We could not detect a statistically significant role for the total stressful life event during the last 3 years and MS diagnosis. However, there is some evidence confirming the possible role of some individual life events, i.e. divorce and periods of homelessness as potential risk factors for MS and conversely, having married as a protective factor in MS onset. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.09.026


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Multiple sclerosis and fabry Disease, two sides of the coin? The case of an Italian family.

Russo C(1), Riccio E(2), Pontillo G(3), Cocozza S(4), Tedeschi E(5), Centonze D(6), Pisani A(7). Author information: (1)Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy. Electronic address: [email protected]. (2)Department of Public Health, Nephrology Unit, University "Federico II", Naples, Italy. Electronic address: [email protected]. (3)Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy. (4)Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy. Electronic address: [email protected]. (5)Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy. Electronic address: [email protected]. (6)Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, Tor Vergata University, Rome, Italy; IRCCS Istituto Neurologico Mediterraneo(INM) Neuromed, Pozzilli (Is), Italy. Electronic address: [email protected]. (7)Department of Public Health, Nephrology Unit, University "Federico II", Naples, Italy. BACKGROUND: Multiple Sclerosis (MS) is considered among possible differential diagnosis of Fabry Disease (FD), especially in early stages when findings are suggestive but not diagnostic for MS. We report the case of a family in which FD and MS coexist, offering an overview on clues for differential diagnosis and speculating on shared etiopathogenic mechanisms for these conditions. METHODS: Taking as starting point the diagnosis of FD in a dialysis patient during a screening programme, we retrospectively rebuilt his family history and revised clinical and imaging examinations of his five siblings, two of which with previous diagnosis of MS. RESULTS: After genetic testing, two subjects were found positive to a new α-galactosidase A mutation, probably causative for FD classical variant. The two subjects meeting diagnostic criteria for MS were found negative to any GLA gene mutation, therefore initial diagnosis was confirmed. The remaining two siblings resulted unaffected, with neither clinical nor instrumental evidence of FD and MS. CONCLUSIONS: Differential diagnosis between FD and MS may be challenging, especially in early clinical stages when only extensive clinical evaluation and correct MRI interpretation may reduce the risk of misdiagnosis. Moreover this report allows speculating on potential etiological and pathogenic mechanisms, common both to FD and MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.09.019


How does cognition relate to employment in multiple Sclerosis? A systematic Review.

Clemens L(1), Langdon D(2). Author information: (1)Royal Holloway, University of London. Egham Hill, Egham, TW20 0EX, UK. (2)Royal Holloway, University of London. Egham Hill, Egham, TW20 0EX, UK. Electronic address: [email protected]. BACKGROUND: Almost half of people with multiple sclerosis (MS), with low levels of physical disability, are unemployed. It is likely that the impact of "invisible" symptoms of MS, such as cognition, are involved. Evidence also suggests that cognition is a mediating factor between physical disabilities and unemployment. METHODS: A systematic review was conducted to investigate the link between objective cognitive performance and unemployment in MS. The search was carried out in September 2017 using identical search terms across three search engines: PubMed, PSYCH Info and Web of Science. Inclusion criteria included peer review, participant age range of 18 to 65, objective neuropsychological testing and self-reported employment information. RESULTS: The search returned a total of 910 articles of which 13 were considered eligible for inclusion. The eligible studies consistently found that people with MS who were unemployed, or who had more negative work-related events, performed less well on neuropsychological tests than both employed people with MS and healthy control groups. People with MS who were employed or had no changes in their work situation also performed less well than healthy controls on neuropsychological tests. Significant between group differences were seen in the following cognitive domains: information processing speed, immediate recall, delayed recall and executive function. CONCLUSION: Difficulties with employment and/or reduced work hours were associated with cognitive impairment in MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.09.018


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Pilot investigation of the relationship between hippocampal volume and pattern separation deficits in multiple sclerosis.

Zuppichini MD(1), Sandry J(2). Author information: (1)School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX, USA. (2)Psychology Department, Montclair State University, 1 Normal Ave, Montclair, NJ 07043, USA. Electronic address: [email protected]. Memory impairment and hippocampal atrophy are common in multiple sclerosis (MS). In the present pilot study, we investigate whether the mnemonic process of pattern separation is impaired and a predictor of hippocampal volume in relapsing remitting MS. MS participants and healthy controls completed the Mnemonic Similarities Task (MST) along with traditional neurocognitive assessments of memory. 3T structural magnetic resonance imaging was used to estimate whole hippocampal volumes (main aim) and hippocampal subfield volumes (exploratory aim). Results revealed that pattern separation performance was worse for MS participants compared to healthy controls (Cohen's d = 0.96). For MS participants, hippocampal volume was more strongly related to pattern separation performance (r = 0.83) than a traditional neurocognitive measure of visual memory (r = 0.65); hippocampal volume was not related to a traditional neurocognitive measure of verbal memory in this sample. No brain-behavior correlations were significant in the healthy control group. Results of the exploratory analysis revealed relationships between pattern separation performance and subiculum, molecular layer, and CA1 hippocampal subfield volumes for MS participants only. Pattern separation assessed using the MST may be a sensitive cognitive-biomarker of memory dysfunction and changes in hippocampal volume in relapsing-remitting MS. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.09.016


The Bayesian risk estimate at onset (BREMSO) correlates with cognitive and physical disability in patients with early multiple sclerosis.

Said M(1), El Ayoubi NK(1), Hannoun S(2), Haddad R(1), Saba L(3), Jalkh Y(1), Yamout BI(1), Khoury SJ(4). Author information: (1)Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, PO Box: 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon. (2)Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, PO Box: 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon; Abu-Haidar Neuroscience Institute, American University of Beirut Medical Center, PO Box: 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon. (3)UCD School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland. (4)Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, PO Box: 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon; Abu-Haidar Neuroscience Institute, American University of Beirut Medical Center, PO Box: 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon. Electronic address: [email protected]. BACKGROUND: Prevention of long-term disability is the goal of therapeutic intervention in Relapsing Remitting MS (RRMS). The Bayesian Risk Estimate for MS at Onset (BREMSO) gives an individual risk score predicting disease evolution into Secondary Progressive MS (SPMS). We investigated whether BREMSO correlates with physical disability, cognitive dysfunction, and regional brain atrophy early in MS. METHODS: One hundred RRMS patients with at least two years of follow-up were enrolled. BREMSO score as well as Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Severity Score (MSSS), Timed 25-Foot Walk Test (T25-FW) and 9-Hole Peg Test (9-HPT), were assessed. Intracranial volume (ICV), subcortical gray matter structures and corpus callosum (CC) were automatically segmented on MRI images and their volumes measured. RESULTS: BREMSO score correlated negatively with SDMT at visit1 (β = -0.33, p = 0.019), visit2 (β = -0.34, p = 0.017) and visit3 (β = -0.34, p = 0.014), and positively with MSSS at visit1 (r = 0.38, p = 0.006), visit2 (r = 0.47, p < 0.0001) and visit3 (r = 0.42, p = 0.002), but not with T25-FW and 9-HPT. BREMSO negatively correlated with CC volume at baseline (p < 0.03). No correlations were found with ICV and subcortical gray matter. CONCLUSIONS: BREMSO score at onset correlated with physical disability (MSSS), cognitive function (SDMT) and CC volume measurements in patients with early MS. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.09.003


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Severe disease exacerbation in a patient with neuromyelitis optica spectrum disorder during treatment with dimethyl fumarate.

Popiel M(1), Psujek M(2), Bartosik-Psujek H(3). Author information: (1)Neurology Clinic with Brain Stroke Sub-Unit, Clinical Hospital No. 2 in Rzeszow, Lwowska 60, Rzeszów 35-301, Poland. Electronic address: [email protected]. (2)Medical Faculty, University of Rzeszow, Poland. (3)Neurology Clinic with Brain Stroke Sub-Unit, Clinical Hospital No. 2 in Rzeszow, Lwowska 60, Rzeszów 35-301, Poland; Medical Faculty, University of Rzeszow, Poland. BACKGROUND: Certain disease-modifying drugs for multiple sclerosis are known to be ineffective in treating neuromyelitis optica spectrum disorder (NMOSD), and can even induce subsequent relapses. CASE PRESENTATION: Here, we report on a patient with NMOSD who was misdiagnosed with multiple sclerosis and experienced severe exacerbations 3 months following initiation of treatment with dimethyl fumarate. The patient developed severe relapse in the form of myelitis extending from the medulla down to the T1 vertebral level. Cord swelling seen as contrast enhancement on magnetic resonance imaging was observed. This swelling resulted in spastic hemiplegia with severe painful dysesthesia. After a diagnosis of NMOSD was confirmed, dimethyl fumarate was discontinued and treatment with azathioprine was initiated. Subsequently, although her neurological status stabilized, residual deficits persisted. CONCLUSION: The case described here suggests that dimethyl fumarate is unsuitable for NMOSD treatment as it may cause disease exacerbations. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.09.011


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Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review.

Gasim M(1), Bernstein CN(2), Graff LA(3), Patten SB(4), El-Gabalawy R(5), Sareen J(6), Bolton JM(6), Marriott JJ(2), Fisk JD(7), Marrie RA(8); CIHR team “Defining the burden and managing the effects of psychiatric comorbidity in chronic inflammatory disease”. Author information: (1)Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. (2)Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. (3)Department of Clinical Health Psychology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. (4)Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. (5)Department of Clinical Health Psychology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Department of Psychiatry, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CAN; Department of Anesthesia and Perioperative Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. (6)Department of Psychiatry, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CAN. (7)Departments of Psychiatry, Psychology& Neuroscience, and Medicine, Dalhousie University, Halifax, NS, Canada. (8)Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. Electronic address: [email protected]. BACKGROUND: Psychiatric comorbidity is prevalent in persons with multiple sclerosis (MS). Few studies have assessed whether second-generation disease-modifying therapies (DMT) are associated with adverse psychiatric effects. OBJECTIVE: We aimed to systematically review the literature regarding the APEs associated with natalizumab, fingolimod, dimethyl fumarate, teriflunomide and alemtuzumab in MS. As a secondary objective, we evaluated changes in anxiety or depression scores following treatment with the aforementioned DMTs. METHODS: We searched MEDLINE, EMBASE, International Pharmaceutical Abstracts, PsychINFO, Central Register of Controlled Trials & Cochrane database of systematic reviews for published studies, and clinicaltrials.gov and regulatory documents from the US and Canada for unpublished studies. Data sources were searched from inception to September 2017. Studies reporting adverse psychiatric effects involving any DMT of interest were included. We report the incidence proportions of the adverse psychiatric effects and, where applicable, risk differences between DMT-exposed and unexposed individuals along with the corresponding 95% confidence intervals. We calculated the standardized mean differences (SMD) of changes in anxiety and depression scores if reported as study outcomes, and pooled the data using random effects meta-analysis. RESULTS: Of 4389 abstracts screened, 78 met the inclusion criteria, including 48 clinical trials, 28 observational studies and 2 case reports. Depression was the most commonly reported adverse psychiatric effect. Incidence proportions for all adverse psychiatric effects ranged from 0 to 24.7%. None of the DMT studied were associated with a statistically significant increased risk of any adverse psychiatric effect (range of risk difference: -7.69% [95%CI: -16.06%, 5.56%] to 6.67 [-8.56, 15.59]). Eighteen studies examined changes in depression or anxiety following fingolimod, natalizumab or dimethyl fumarate treatment; depression symptoms improved in fingolimod-treated groups (SMD [95%CI]: 1.18 [0.17, 2.19]). We did not identify studies examining changes in these outcomes following treatment with any of the other DMTs. CONCLUSION: The DMTs reviewed were not associated with an increased risk of adverse psychiatric effect in MS, and some may reduce the incidence of depressive symptoms. This may reflect either a positive direct effect (e.g. immune modulation) or an indirect effect arising due to a positive impact on disease activity or course. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.09.008


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Primary progressive multiple sclerosis in Iran: A consensus recommendation for diagnosis and management.

Sahraian MA(1), Baghbanian SM(2), Langroodi HG(3), Abolfazli R(4), Alaie S(5), Asgari N(6), Ashtari F(7), Ayromlouh H(8), Moghadam NB(9), Foroughipour M(10), Majdinasab N(11), Mohammadianinejad SE(11), Nickseresht A(12), Nourian A(13), Shahmohammadi S(5), Shayegannejad V(14), Torabi HR(15). Author information: (1)MS Research Centre, Department of Neurology, Neuroscience Institute Tehran University of Medical Sciences, Sina Hospital, Hasan Abad Square, Tehran, 11367-46911, Iran. Electronic address: [email protected]. (2)Neurology Department, Booalisina Hospital, Mazandaran University of Medical Sciences, Pasdaran Boulevard, Sari, Iran. Electronic address: [email protected]. (3)Department of Internal medicine and Neurology, Ghaem Int. Hospital, Rasht, Iran. (4)Department of Neurology, Amiralam Hospital, Tehran University of Medical Sciences, Iran. Electronic address: [email protected]. (5)Scientific Committee, Iranian MS Society, Iran. (6)Owens-gruppen Næstved/Slagelse/Ringsted Sygehuse, Region Sjælland J.B. Winsløws Vej 9, indgang B, 1. Sal 5000, Odense, Denmark. Electronic address: [email protected]. (7)Department of Neurology, Kashani Hospital, Isfahan University of Medical Sciences, Iran; Isfahan Neurosciences Research Center, Alzahra Hospital, Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: [email protected]. (8)Department of Neurology, Faculty of Medicine, Tabriz University of Medical Sciences, Iran. (9)Department of Neurology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Iran. (10)Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran. Electronic address: [email protected]. (11)Department of Neurology, Golestan Hospital, Ahwaz University of Medical Sciences, Iran. (12)Department of Neurology, Namazi Hospital, Shiraz University of Medical Sciences, Iran. (13)Islamic Azad University, Faculty of Medicine, Khorasan Razavi Branch, Iran. (14)Isfahan Neurosciences Research Center, Alzahra Hospital, Department of Neurology, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: [email protected]. (15)Scientific Committee, Iranian MS Society, Iran. Electronic address: [email protected]. DOI: 10.1016/j.msard.2018.09.013


Considerations for using Natalizumab treatment in patients with a history of choroidal melanoma.

Kaye AE(1), Hawkes ED(1), Gout II(1), El-Amir AN(1), Neffendorf JE(2). Author information: (1)Prince Charles Eye Unit, King Edward VII Hospital, St. Leonard's Road, Windsor SL4 3DR, UK. (2)Prince Charles Eye Unit, King Edward VII Hospital, St. Leonard's Road, Windsor SL4 3DR, UK. Electronic address: [email protected]. Natalizumab is a monoclonal antibody licensed for the treatment of relapsing-remitting multiple sclerosis (RRMS). It is known to increase the potential risk of developing progressive multifocal leukoencephalopathy (PML). There is current debate in the literature regarding its association with malignant melanoma. Herein, we report a case of a 55-year old lady with RRMS for whom natalizumab therapy was being considered by her neurologist. Her medical history included a choroidal melanoma which had undergone successful treatment. Additionally, in this case study we discuss the issues regarding malignant melanoma risk and recurrence with natalizumab treatment. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.09.012


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Recurrent disseminated encephalomyelitis: A case report and literature review.

Shah S(1), Shah D(2), Skeen MB(2). Author information: (1)Duke University, Durham, NC, United States. Electronic address: [email protected]. (2)Duke University, Durham, NC, United States. BACKGROUND: Acute disseminated encephalomyelitis has been understood as a monophasic, often post-infectious illness that predominantly affects the pediatric population. Though that describes the majority of cases, exceptions do exist. In this case report, we present an adult case of recurrent disseminated encephalomyelitis (DEM) and review the available literature on this clinical entity. METHODS: PubMed search performed using the terms "MDEM" and "Recurrent ADEM" in April 2018. A total of 23 items resulted for the first search and another 142 for the second. We selected articles that described cases of recurrent ADEM with a preference for those publications describing adult cases and those written in English language. CONCLUSION: Recurrent disseminated encephalomyelitis is a distinct clinical entity that has features which overlap with multiple sclerosis, making it imperative to distinguish the two. Our case presentation and accompanying literature review highlights the limited scope of data available on recurrent DEM and the need for further study. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.09.007


Herpes simplex virus encephalitis temporally associated with dimethyl fumarate-induced lymphopenia in a multiple sclerosis patient.

Perini P(1), Rinaldi F(1), Puthenparampil M(2), Marcon M(3), Perini F(3), Gallo P(4). Author information: (1)Multiple Sclerosis Centre of the Veneto Region, Department of Neurosciences, DNS, University Hospital of Padua, Padua Italy. (2)Multiple Sclerosis Centre of the Veneto Region, Department of Neurosciences, DNS, University Hospital of Padua, Padua Italy. Electronic address: [email protected]. (3)Neurology Unit, Hospital of Vicenza, Italy. (4)Multiple Sclerosis Centre of the Veneto Region, Department of Neurosciences, DNS, University Hospital of Padua, Padua Italy. Electronic address: [email protected]. BACKGROUND: Dimethyl fumarate (DMF) is approved as first line therapy for relapsing-remitting multiple sclerosis (RRMS). In some (3%) patients, DMF induces a marked lymphopenia. Herpes simplex encephalitis (HSE) may occur in lymphopenic subjects under treatment with immune-suppressive drugs. CASE PRESENTATION: We report a case of a 39-year-old female patient with RRMS that developed HSE temporally associated with a marked and sudden drop in lymphocyte count, from 1200/µl to 600/µl, in the peripheral blood. HSE DNA was demonstrated in the cerebrospinal fluid. HSE had the features that characterize HSE occurring in immunosuppressed subjects, i.e. less prominent CSF pleocytosis, bilateral and mainly cortical involvement and less extensive tissue necrosis. Antiviral therapy determined a progressive, although incomplete, improvement. Three months later the patient presented only a mild short-term memory deficit and sporadic episodes of inappropriate emotionality. Lymphocyte count returned to normal values (1120/µl) after DMF discontinuation. CONCLUSION: Our case of HSE in a lymphopenic DMF-treated RRMS patient, points out the necessity of further studies on DMF-related lymphopenia, especially whether it implies an impaired immunity against viruses. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.09.009


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Clinical utility of anti-MOG antibody testing in a Danish cohort.

Papp V(1), Langkilde AR(2), Blinkenberg M(3), Schreiber K(3), Jensen PEH(3), Sellebjerg F(3). Author information: (1)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen 2100, Denmark; Department of Neurology, Aarhus University Hospital, Nørrebrogade 44, Aarhus 8000, Denmark. Electronic address: [email protected]. (2)Department of Radiology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen 2100, Denmark. (3)Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen 2100, Denmark. BACKGROUND: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) can be found in different immune-mediated inflammatory CNS disorders. The full range of clinical manifestations may not have been fully discovered yet. METHODS: In a cross-sectional study 184 adults (age ≥ 16) were tested for anti-MOG antibody (Ab) with a cell-based assay. To define the relevant target population for anti-MOG antibody testing in a neurology clinic, we divided the entire study population based on the presenting symptoms and classified cases followed for multiple sclerosis (MS) according to the clinical features and response to disease-modifying therapy. RESULTS: We identified eight (4.4%) MOG-Ab positive cases in the whole cohort. All eight cases had first manifestations suggestive of neuromyelitis optica spectrum disorder (NMOSD), but had highly variable disease courses and responses to therapy. This included a patient with chronic relapsing inflammatory optic neuropathy (CRION) responding only to therapy with infliximab. Four (3%) out of 134 cases followed for MS who tested positive for anti-MOG Ab showed atypical features and had poor response to therapy. CONCLUSION: A broad range of clinical and radiological features of anti-MOG associated disorder was observed in a single centre. MOG-Ab testing should be considered in patients with an NMOSD phenotype and in MS patients presenting atypical features. The potential use of infliximab therapy for MOG-Ab disease should be further investigated. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.09.010


Serum sickness (Like Reaction) in a patient treated with alemtuzumab for multiple sclerosis: A case report.

Lapucci C(1), Gualandi F(2), Mikulska M(3), Palmeri S(4), Mancardi G(5), Uccelli A(5), Laroni A(5). Author information: (1)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy. Electronic address: [email protected]. (2)Department of Hematology, Ospedale Policlinico San Martino IRCCS, Genoa, Italy. (3)Division of Infectious Diseases, University of Genova (DISSAL) and Ospedale Policlinico San Martino, Genoa, Italy. (4)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy. (5)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy; Ospedale Policlinico San Martino IRCCS, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy. BACKGROUND: Alemtuzumab is a monoclonal antibody approved for relapsing-remitting multiple sclerosis (RRMS). The only report of Serum Sickness (SS) in a MS patient occurred during treatment with natalizumab. Non-protein drugs, such as some antibiotics, may induce "SS-like" reactions (SSLR), whose clinical and laboratory features may partially overlap with the traditional SS. OBJECTIVE: To report a case of SS/SSLR in a RRMS patient treated with alemtuzumab. CASE REPORT: A 42-year-old-woman with RRMS developed SS/SSLR in the first week after the first alemtuzumab treatment. Concomitant medications included trimethoprim-sulfamethoxazole at low dose. Intravenous methylprednisolone therapy led to clinical resolution and normalization of serum inflammatory markers. CONCLUSION: SS/SSLR should be considered in patients treated with alemtuzumab developing delayed fever, rash and arthralgia and differentiated with Infusion Associated Reactions (IARs) and infections. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.09.006


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270. Mult Scler Relat Disord. 2018 Aug 6;25:276-281. doi: 10.1016/j.msard.2018.08.004. [Epub ahead of print]

Outcomes and treatment management of a French cohort suffering from multiple sclerosis: A retrospective epidemiological study.

Defer G(1), de Seze J(2), Bouee S(3), Courouve L(4), Longin J(5), Payet M(6), Deleglise ASJ(7); study group. Author information: (1)CHU of Caen, Avenue de la Côte de Nacre, Caen 14033, France. Electronic address: [email protected]. (2)Strasbourg University, 4 Rue Kirschleger, Strasbourg 67000, France. Electronic address: [email protected]. (3)CEMKA, 43 boulevard du Maréchal Joffre, Bourg La Reine 92340, France. Electronic address: [email protected]. (4)CEMKA, 43 boulevard du Maréchal Joffre, Bourg La Reine 92340, France. Electronic address: [email protected]. (5)Merck Santé S.A.S., 37 Rue Saint-Romain, Lyon 69008, France. Electronic address: [email protected]. (6)Merck Santé S.A.S., 37 Rue Saint-Romain, Lyon 69008, France. Electronic address: [email protected]. (7)Merck Santé S.A.S., 37 Rue Saint-Romain, Lyon 69008, France. Electronic address: [email protected]. BACKGROUND: Despite a recent interest in Real World Data, such studies are scarce in multiple sclerosis (MS) disease. The objective was to describe the patients, disease progression and use of DMDs in France and compare clinical effectiveness of first-line injectable DMDs. METHODS: We conducted a retrospective multicenter study in France, using data collected by 11 expert centers with the EDMUS software. RESULTS: Overall, 15,039 French MS patients were followed for a mean of 11.5 years. Mean age at start of disease was 32 years and 74% were women. After the disease onset, median time to reach EDSS 3 was 11 years and 51.8% of patients were relapse-free 2 years after the disease's onset. The mean delay between onset of disease and initiation of treatment was 5.7 ± 6.9 years. Over time, it decreased from 8.8 ± 7.8 to 0.7 ± 0.7 years for initiation of treatment before 2000 vs. after 2010, respectively. Two years after the initiation of treatment, the persistence rate of injectable disease modifying drugs (DMDs) was 60.7%. The effectiveness of these drugs were quite similar. CONCLUSION: This study brings new insight on the natural history of MS and the use and effectiveness of injectable DMDs in this condition. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.08.004


Modified Functional Walking Categories and participation in people with multiple sclerosis.

Bertoni R(1), Jonsdottir J(2), Feys P(3), Lamers I(3), Cattaneo D(2). Author information: (1)IRCCS Fondazione Don Carlo Gnocchi, Italy. Electronic address: [email protected]. (2)IRCCS Fondazione Don Carlo Gnocchi, Italy. (3)REVAL Rehabilitation Research Center, Hasselt University, Diepenbeek, Belgium. BACKGROUND: Gait velocity influences the ability of a person to move in different outdoor or indoor contexts and has accordingly been classified through the Modified Functional Walking Categories (MFWC). Community ambulation in persons with multiple sclerosis (PwMS) may give information on their social and productive participation, as well as independence in household activities. OBJECTIVES: To investigate factors associated with walking and mobility restrictions as classified by the Modified Functional Walking Categories (MFWC) and analyze the influence of disease characteristics, demographical and walking factors on participation in PwMS. METHODS: 155 PwMS attending two rehabilitation center were evaluated. Community ambulation was classified with the MFWC; participation was measured with the Community Integration Questionnaire (CIQ). MFWC and statistically significant variables associated with CIQ score were entered in a multivariate logistic model to assess the multiple relationships. RESULTS: PwMS with a secondary progressive type of disease, longer disease duration and using walking aids were classified in the worse MFWC. Participation restrictions were more frequent in Limited Household (72.3%) and in Physiological Walkers (93.7%). The final multivariate model (p < 0.0001) showed that the use of a walking aid (OR = 2.59), being male (OR = 2.94) and older (OR = 1.06) increased the likelihood of having participation restrictions. The same variables predicted home participation; MFWC and age predicted productive participation while only age influenced social participation. CONCLUSIONS: Modified Functional Walking Categories were associated with type of disease, disease duration, disability level and type of walking aid. The best clinical predictor of participation restriction was walking aid while walking categories only predicted productive participation. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.08.031


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Alemtuzumab-containing reduced intensity conditioning allogenic hematopoietic stem cell transplantation in a case of primary progressive multiple sclerosis.

AlKhaja M(1), Abanmy A(2), AlKhdairi A(3), AlRasheedi S(3), AlZahrani H(4), AlKhawajah M(2). Author information: (1)Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Electronic address: [email protected]. (2)Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. (3)Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. (4)Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Increasing evidence has emerged lately regarding the use of autologous hematopoietic stem cell transplantation (HSCT) in the treatment of aggressive multiple sclerosis (MS). However, data is scarce regarding the use of allogenic HSCT in treating MS. We present a 42 years old male with aplastic anemia who underwent allogenic HSCT for severe aplastic anemia. This patient was diagnosed with primary progressive multiple sclerosis (PPMS) one-year post transplant and had to undergo a second HSCT due to his hematological disorder. His second HSCT was conditioned with an alemtuzumab containing regimen, after which his MRI and expanded disability status scale (EDSS) remained to be stable for 18 months. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.08.028


Low vitamin D-25(OH) level in Indonesian multiple sclerosis and neuromyelitis optic patients.

Kusumadewi W(1), Imran D(1), Witjaksono F(2), Pakasi TA(3), Rusmana AI(1), Pangeran D(4), Marwadhani SS(4), Maharani K(1), Estiasari R(5). Author information: (1)Department of Neurology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia. (2)Department of Clinical Nutrition, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia. (3)Department of Community Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia. (4)Department of Neurology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia. (5)Department of Neurology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Electronic address: [email protected]. BACKGROUND: Vitamin D deficiency is commonly found in multiple sclerosis (MS) and Neuromyelitis Optic (NMO) patients and can impair the immunological status. As a tropical country, Indonesia has a lot of sunshine throughout the year as a source of vitamin D. The aim of this study was to evaluate and compare the serum vitamin D-25(OH) level in Indonesian MS and NMO patients to healthy individuals. METHODS: A cross-sectional study was conducted in Dr. Cipto Mangunkusumo General Hospital Jakarta from November 2016 to May 2017. Forty-eight patients (29 MS and 19 NMO) and 33 healthy controls were enrolled. We assessed the dietary recall, vitamin D supplementation, sunshine exposure, medication, annual relapse rate, and Expanded Disability Status Scale (EDSS). Vitamin D level was measured using direct competitive chemiluminescence immunoassay. RESULTS: Vitamin D deficiency was found in 48.4% of MS and 56.2% of NMO patients. The serum vitamin D level in MS and NMO groups was not significantly different from the healthy controls. Vitamin D level was not associated with EDSS and the annual relapse rate. Positive significant correlation was observed between sunshine exposure and vitamin D level in healthy control, but not evident in MS and NMO groups. MS and NMO subjects who still treated with corticosteroid had lower vitamin D level. CONCLUSION: Vitamin D deficiency is commonly found in Indonesian MS and NMO patients, but not associated with EDSS and annual relapse rate. Despite living in a country with adequate sunshine exposure, the physician should anticipate low serum vitamin D level, especially in MS or NMO patients who received corticosteroid. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.08.030


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Multiple Sclerosis: kFLC index values related to gender.

Pieri M(1), Zenobi R(1), Morello M(1), Storto M(2), Buttari F(3), Centonze D(3), Bernardini S(1), Dessi M(4). Author information: (1)Department of Experimental Medicine and Surgery, "Tor Vergata" University Hospital, Rome, Italy. (2)Clinical Pathology Unit, IRCCS Neuromed, Pozzilli (Is), Italy. (3)Unit of Neurology and Neurorehabilitation, IRCCS Neuromed, Pozzilli (IS), Italy. (4)Department of Experimental Medicine and Surgery, "Tor Vergata" University Hospital, Rome, Italy. Electronic address: [email protected]. BACKGROUND: Multiple sclerosis (MS) is a chronic multifactorial inflammatory and neurodegenerative disease of the central nervous system (CNS). The identification of biomarkers with good diagnostic and prognostic power is of great importance for monitoring and treating MS patients. METHODS: We analyzed serum and cerebrospinal fluid of 228 patients, with different neurological disorders and with MS to confirm our previous results and determine a possible gender difference of kFLC Index cut-off. RESULTS: We have obtained a kFLC Index cut-off of 12.5 (100% specificity and 90.4% sensitivity) and 11 (100% specificity and 97.5% sensitivity) for women and men with MS respectively. CONCLUSIONS: This study reinforces the importance that kFLC Index could have as a diagnostic aid to detect MS. Our data highlight a difference in the cut-off of the kFLC Index calculated by gender; male patients with a kFLC Index value greater than 11 are at higher risk to develop MS respect females having the same result. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.08.018


Efficacy and safety of monoclonal antibody therapies for relapsing remitting multiple sclerosis: A network meta-analysis.

Xu X(1), Chi S(2), Wang Q(1), Li C(3), Xu B(4), Zhang J(4), Chen X(5). Author information: (1)Department of Neurosurgery, Chinese PLA General Hospital, 28th Fuxing Road, Beijing 100853, China; National Clinical Research Center for Aging and Medicine, Chinese PLA General Hospital, Beijing, China. (2)Department of Physiology, Fourth Military Medical University, Air Force Medical University, Xi'an, China. (3)Department of Dermatology, Chinese PLA General Hospital, Beijing, China. (4)Department of Neurosurgery, Chinese PLA General Hospital, 28th Fuxing Road, Beijing 100853, China. (5)Department of Neurosurgery, Chinese PLA General Hospital, 28th Fuxing Road, Beijing 100853, China; National Clinical Research Center for Aging and Medicine, Chinese PLA General Hospital, Beijing, China. Electronic address: [email protected]. BACKGROUND: Several monoclonal antibodies have been licensed for relapsing remitting multiple sclerosis (RRMS). It is still unclear which treatment regimen should be recommended due to the lack of head-to-head randomized controlled trials (RCTs). This study aims to investigate the relative efficacy and safety of existing monoclonal antibody therapies in treating RRMS. METHODS: We searched PubMed, Embase, and the Cochrane Library for RCTs of monoclonal antibodies for treatment of RRMS. We performed a network meta-analysis to identify evidence comparing monoclonal antibodies with one another, interferon beta-1a (INFβ-1a), or placebo in adult patients with RRMS. The primary efficacy outcome was annualized relapse rate and the primary safety outcome was incidence rate of serious adverse events. RESULTS: A total of 14 eligible studies containing 9412 patients treated with 7 regimens were analyzed. INFβ-1a was the most common comparison treatment and showed an annualized relapse rate of 45.3%. All monoclonal antibody regimens, including natalizumab, natalizumab plus INFβ-1a, alemtuzumab, daclizumab, and ocrelizumab, were associated with significant reduction in annualized relapse rate and similar risks of serious adverse events. Cluster analysis showed that natalizumab plus INFβ-1a and alemtuzumab performed best in terms of high efficacy and safety. Natalizumab and daclizumab were characterized by high efficacy but relatively high risk of serious adverse events. Ocrelizumab was differentiated by high safety but relatively poor efficacy. CONCLUSION: This network meta-analysis provided a comprehensive summary of efficacy and safety of monoclonal antibodies for RRMS, which might provide a reference for treatment. More direct comparison studies are warranted. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.08.026


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Metabolomic profile of insulin resistance in patients with multiple sclerosis is associated to the severity of the disease.

Ruiz-Argüelles A(1), Méndez-Huerta MA(2), Lozano CD(3), Ruiz-Argüelles GJ(4). Author information: (1)Laboratorios Clínicos de Puebla, Diaz Ordaz 808, Puebla, PUE, México; Universidad Popular Autónoma del Estado de Puebla, Calle 21 Sur 1103. Puebla, PUE, México. Electronic address: [email protected]. (2)Laboratorios Clínicos de Puebla, Diaz Ordaz 808, Puebla, PUE, México; Universidad Popular Autónoma del Estado de Puebla, Calle 21 Sur 1103. Puebla, PUE, México. (3)Laboratorios Clínicos de Puebla, Diaz Ordaz 808, Puebla, PUE, México. Electronic address: [email protected]. (4)Laboratorios Clínicos de Puebla, Diaz Ordaz 808, Puebla, PUE, México; Universidad Popular Autónoma del Estado de Puebla, Calle 21 Sur 1103. Puebla, PUE, México; Centro de Hematología y Medicina Interna de Puebla, Calle 8 NB Sur 3710, Puebla, PUE, México. Electronic address: [email protected]. BACKGROUND: Dysglycemia and adiposity have been related to disability in patients with multiple sclerosis. The objective of this work was to determine the prevalence and characteristics of insulin resistance in patients with multiple sclerosis using the metabolomics Quantose score. METHODS: A total of 64 patients were accrued in the study. A blood sample was drawn to estimate the Quantose score, which is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal. RESULTS: Insulin resistance was documented in 33 out of 64 patients and it was found in association with the degree of disability and the time from diagnosis. Patients with the secondary progressive form of the disease showed the highest prevalence. CONCLUSION: Insulin resistance is frequent in patients with multiple sclerosis and might contribute to metabolic complications and general disability. Early markers of dysglycemia should be sought for in these patients to avoid additional deterioration of their quality of life. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.08.014


Proton magnetic resonance spectroscopy differentiates tumefactive demyelinating lesions from gliomas.

Ikeguchi R(1), Shimizu Y(2), Abe K(3), Shimizu S(4), Maruyama T(5), Nitta M(5), Abe K(3), Kawamata T(5), Kitagawa K(1). Author information: (1)Department of Neurology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. (2)Department of Neurology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Electronic address: [email protected]. (3)Department of Diagnostic Imaging & Nuclear Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. (4)Medical research institute, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. (5)Department of Neurosurgery, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. BACKGROUND: It is often difficult to accurately differentiate tumefactive demyelinating lesions (TDLs) from gliomas using MRI. OBJECTIVE: To investigate the utility of proton magnetic resonance spectroscopy (MRS) in differentiating TDLs from gliomas. METHODS: Cohort 1 included 6 patients with TDLs and 5 with gliomas (3 high-grade), as assessed using a 1.5T MR unit. Cohort 2 included 6 patients with TDLs and 17 patients with gliomas (8 high-grade), as assessed using a 3.0T MR unit. Single-voxel proton MRS was performed to compare the following metabolite area ratios: choline (Cho)/creatine (Cr), N-acetylaspartate (NAA)/Cr, and Cho/NAA in both cohorts. Correlations between the target-to-normal-tissue ratio (TNR) obtained using methionine-positron emission tomography (MET-PET) and each MRS metabolite ratio were examined in a subset of cohort 2 (4 patients with TDLs and 11 with gliomas). RESULTS: Mean Cho/NAA ratio was significantly higher in gliomas than in TDLs or MS in cohort 1 (p < 0.05). Mean Cho/NAA ratio was significantly higher in high-grade gliomas than in TDLs in both cohorts (ps < 0.05). In the receiver operating characteristic analysis, high-grade glioma rather than TDL was indicated when the Cho/NAA ratio was >1.72 (the area under the curve was 0.958, and the maximum sensitivity and specificity were 100% and 87%, respectively). A significant positive correlation was observed between Cho/NAA ratio and the MET-PET TNR (r2 = 0.35, p < 0.05). CONCLUSION: MRS effectively differentiates TDLs from high-grade gliomas. Therefore, the clinical use of MRS is likely to enhance patient outcomes. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.08.025


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Exploring the role of physical activity and exercise for managing vascular comorbidities in people with multiple sclerosis: A scoping review.

Ewanchuk BW(1), Gharagozloo M(2), Peelen E(3), Pilutti LA(4). Author information: (1)Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada. (2)Program of Immunology, Department of Pediatrics, CR-CHUS, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. (3)Neuroimmunology Unit, The Research Center of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada; Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada. (4)Interdisciplinary School of Health Sciences, Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1N 6N5, Canada. Electronic address: [email protected]. INTRODUCTION: Vascular comorbidities are prevalent among people with multiple sclerosis (MS) and have adverse disease-related consequences. In the general population, physical activity (PA) and exercise training have proven beneficial at all levels of vascular disease risk management. People with MS exhibit particularly low rates of PA; therefore, PA represents a modifiable health behavior for potentially managing vascular comorbidity risk in MS, and in turn, reducing disease burden. However, points of evidence justifying such an approach have yet to be summarized. OBJECTIVE: To conduct a scoping review of existing evidence linking PA and exercise training to potential modification of vascular comorbidities and related risk factors in people with MS. METHODS: We searched five electronic databases (PubMed, Ovid MEDLINE, Embase, PsycINFO, and CINAHL Plus) from inception to November 2017, for articles involving relevant vascular comorbidities (obesity, hyperlipidemia, heart disease, hypertension, and diabetes) in people with MS in conjunction with measures of PA, physical fitness, sedentary behavior, or exercise training. Studies were limited to English-language and primary research articles. Data were extracted and summarized by comorbidity type and study design (observational vs. interventional). RESULTS: Our initial search identified 1028 articles; subsequent screening resulted in 34 articles meeting the final inclusion criteria, including both observational (n = 17) and interventional (n = 17) studies. Most of the articles reported on obesity (n = 29), although evidence surrounding hyperlipidemia (n = 5), arterial function and hypertension (n = 5), and diabetes (n = 5) was also identified. Data supporting a beneficial role for PA or exercise training could be drawn from each comorbidity category. Overall, 14 of the 17 observational studies identified (82.4%) reported an association between higher levels of PA or cardiorespiratory fitness, or decreased sedentary behavior, and better function of at least one risk factor related to vascular comorbid conditions in people with MS. The efficacy of exercise training in limiting vascular comorbidity risk and burden was dependent upon intervention type and duration, with 9 of 17 interventional studies (52.9%) reporting improvement in at least one relevant measure of vascular comorbidity in participants with MS. CONCLUSIONS: Evidence points to a potential relationship between PA and exercise and risk factors related to vascular comorbidities in people with MS. PA and exercise training interventions may represent an effective therapeutic strategy for managing vascular comorbidities in people with MS, justifying further investigation. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.08.022


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Resilience and depression/anxiety symptoms in multiple sclerosis and neuromyelitis optica spectrum disorder.

Nakazawa K(1), Noda T(2), Ichikura K(3), Okamoto T(4), Takahashi Y(5), Yamamura T(6), Nakagome K(7). Author information: (1)Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Japan; Department of Neuropsychiatry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Japan. (2)Department of Psychiatry, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Japan; Integrative Brain Imaging Center, National Center of Neurology and Psychiatry, Japan; Multiple Sclerosis Center, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Japan. Electronic address: [email protected]. (3)Section of Liaison Psychiatry and Palliative Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan; Department of Health Science, School of Allied Health Sciences, Kitasato University, Japan. (4)Multiple Sclerosis Center, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Japan; Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Japan. (5)Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Japan. (6)Multiple Sclerosis Center, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Japan; Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Japan. (7)National Institute of Mental Health, National Center of Neurology and Psychiatry (NCNP), Japan. BACKGROUND: Depression and anxiety are common in multiple sclerosis (MS) and recently, studies on these symptoms in neuromyelitis optica spectrum disorder (NMOSD) are increasing. Previous studies suggest that these symptoms have negative effects on the quality of life. Resilience has garnered more interest as one of the protective factors that works to prevent psychiatric symptoms in past decades. There exist a few studies, however, regarding the effects of resilience on these psychiatric symptoms in MS/NMOSD. OBJECTIVE: The aim of this study was to clarify the relationships between resilience, psychiatric symptoms, and QOL in patients with MS/NMOSD. METHOD: Seventy-seven patients with MS/NMOSD participated in this study. They completed several questionnaires (Beck Depression Inventory-Second edition, Hospital Anxiety and Depression Scale, the Japanese version of the Resilience scale [RS], and Japanese version of Multiple Sclerosis Quality of Life-54). We also collected demographic and clinical data including age, sex, physical disability level (measured with the Expanded Disability Status Scale [EDSS]), and disease duration of the participants. RESULTS: The EDSS scores showed significant negative correlations with QOL, unlike disease duration, which did not correlate with either the psychiatric symptoms or QOL. Additionally, there was no significant correlation between RS scores and EDSS scores or disease duration. We also found that resilience showed a significant negative correlation with psychiatric symptoms, and positive correlation with QOL. CONCLUSION: These results suggest that resilience may serve to prevent or reduce depression/anxiety symptoms and maintain the QOL regardless of the physical disability level. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.08.023


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No association between socioeconomic status and risk of multiple sclerosis: A population-based incident case-control study in a developing country.

Abdollahpour I(1), Nedjat S(2), Salimi Y(3), Moradzadeh R(1), Mansournia MA(4), Sahraian MA(5), Shokoohi M(6). Author information: (1)School of Public Health, Arak University of Medical Sciences, Arak, Iran. (2)Knowledge Utilization Research Center, Tehran University of Medical Science, Tehran, Iran; Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. (3)Social Development and Health Promotion Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Epidemiology and Biostatistics, School of Public Health, Kermanshah University of Medical Sciences, Kermanshah, Iran. (4)Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. (5)MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: [email protected]. (6)Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada. BACKGROUND: Evidence on the association between socioeconomic status (SES) and multiple sclerosis (MS) is inconsistent. We examined the association of several indicators of SES with MS in an Iranian population. METHODS: We conducted a population-based incident case-control study with 547 incident cases and 1057 general population controls in Iran, 2015. Data was collected using telephone interviews and indicators of SES i.e. parental education, and household SES during adolescence using asset variables. Adjusted odds ratios (AORs) were estimated using multiple logistic regression model. RESULTS: Parental education levels were not significantly associated with MS development. Household SES during adolescence was insignificantly associated with an increased risk of MS diagnosis (P = 0.575). CONCLUSION: We did not identify an association between household SES during adolescence, parental education levels, and a subsequent risk of developing MS in an Iranian population. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.08.019


Is there an effect of dietary intake on MS-related fatigue? - A systematic literature review.

Pommerich UM, Brincks J, Christensen ME. BACKGROUND: Fatigue is considered the most common symptom of persons with multiple sclerosis MS (pwMS), occurring in up to 90% of the patients at some point with two-thirds of pwMS experience fatigue as their most disturbing symptom. Pharmacological treatment options for MS-related fatigue show only limited and contradicting results. Consequently, many pwMS search for alternative options to control the symptom. A considerable interest in dietary interventions as a means of MS symptom management has advanced in the MS community. Yet, the few empirical studies focussing on the effect of holistic dietary intake on fatigue have not been systematically examined. The aim of this review was to systematically review the effect of holistic dietary intake and the subjective perception of fatigue in adult pwMS. METHODS: Embase, Medline, Web of Science, CINAHL Complete, SPORTDiscus, PsycInfo, and Rehabilitation and Sports Medicine (Ebsco Host) databases were systematically searched to locate relevant literature. Intervention trials studying the effect of a holistic dietary regimen on the subjective perception of fatigue in a sample of adult pwMS were considered for inclusion. Risk of bias was assessed using a modified Downs and Black checklist. RESULTS: A total of four studies met the inclusion criteria: one single arm intervention pilot trial, one randomised controlled pilot trial, one double-blinded randomised trial, and one assessor-blinded randomised controlled trial. Interventions were low fat diets, a low fat, starchy plant food diet, and modified paleo diets and ranged from three to 12 months duration. Two studies supplying an adequate amount of folate and magnesium with the intervention diet reported relevant improvements in fatigue scores. CONCLUSION: Dietary intake holds the potential to lower MS-related fatigue, but solid conclusions are not possible based on the existing evidence. Sparse evidence points towards an effect of adequate magnesium and folate intake and a trend for decreased fatigue. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.08.017


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The dilemma of benign multiple sclerosis: Can we predict the risk of losing the "benign status"? A 12-year follow-up study.

Razzolini L(1), Portaccio E(2), Stromillo ML(3), Goretti B(4), Niccolai C(4), Pastò L(4), Righini I(4), Prestipino E(4), Battaglini M(3), Giorgio A(3), De Stefano N(3), Amato MP(5). Author information: (1)NEUROFARBA Department, Neuroscience Section, Florence University, Viale Piareccini 16, 50139 Florence, Italy. Electronic address: [email protected]. (2)IRCCS Don Carlo Gnocchi, Don Gnocchi Foundation, Via di Scandicci, 269, 50143, Florence, Italy. (3)Department of Neurological and Behavioral Sciences, University of Siena, Strade delle Scotte, 14, 23100 Siena, Italy. (4)NEUROFARBA Department, Neuroscience Section, Florence University, Viale Piareccini 16, 50139 Florence, Italy. (5)NEUROFARBA Department, Neuroscience Section, Florence University, Viale Piareccini 16, 50139 Florence, Italy; IRCCS Don Carlo Gnocchi, Don Gnocchi Foundation, Via di Scandicci, 269, 50143, Florence, Italy. BACKGROUND: Definition of benign multiple sclerosis (BMS) remains controversial. Moreover, a sizeable proportion of classically defined BMS patients may be no longer benign (NLB) when re-assessed in the long-term. In a previous work, we found that after a five-year follow-up, a clinical score was able to identify patients at risk of losing their benign status. OBJECTIVES: In this 12-year reappraisal of the same cohort, we aimed at assessing the predictive value of the same score in the long-term. METHODS: After a mean follow-up of 12.6 + 0.4 years, patients still having an EDSS score <3.0 were classified as "still benign" (SB), whereas patients having an EDSS score ≥3.5 were defined as NLB. The predictive value of the mentioned score was re-assessed using survival analysis. RESULTS: By the end of the follow-up, 20 (32.8%) were classified as NLB. Patients were grouped on the basis of the above mentioned score. Patients with score 2-3 were at higher risk of NLB status at the follow-up (HR = 3.5; 95%CI 1.5-8.6; p = 0.005, accuracy = 70.5%). CONCLUSIONS: In patients with established BMS, prognostic prediction of longer-term disease course remains of critical value. In this study, a clinical score was able to predict disease evolution in the long term. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.08.011


Peginterferon beta-1a for the treatment of relapsing multiple sclerosis: A case series.

Hendin BA(1). Author information: (1)University of Arizona Medical School, Tucson, AZ, USA. Electronic address: [email protected]. Interferon beta therapies have been effective in the treatment of relapsing forms of multiple sclerosis for over 2 decades. These therapies have varying routes and schedules of administration but broadly similar clinical and radiologic efficacy. The most commonly reported adverse effects are flu-like symptoms and injection site reactions. The most recent addition to the class is peginterferon beta-1a, which is administered subcutaneously every 2 weeks. Although clinically stable patients with multiple sclerosis may switch between platform therapies (such as interferons) based on tolerability or personal preference, few studies have explored the outcomes of switching. Herein I present 3 cases of patients who either initiated therapy with peginterferon beta-1a or switched from another interferon and had positive outcomes. With appropriate patient education and expectation setting regarding potential flu-like symptoms and injection-site reactions, peginterferon beta-1a may be a beneficial alternative for patients who prefer less frequent injections. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.08.012


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Promising effect of rapamycin on multiple sclerosis.

Bagherpour B(1), Salehi M(2), Jafari R(3), Bagheri A(4), Kiani-Esfahani A(5), Edalati M(6), Kardi MT(7), Shaygannejad V(8). Author information: (1)Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Gastrointestinal and Hepatobiliary Diseases Research Center, Poursina Hakim Research Institute for Health Care Development, Isfahan, Iran. (2)Cellular, Molecular and Genetics Research Center, Isfahan, Iran; Departments of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. (3)Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. (4)Department of Radiation Technology, Paramedical Sciences Faculty, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (5)Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, Isfahan, Iran. (6)Department of Pathology, Isfahan University of Medical Sciences, Isfahan, Iran. (7)Department of Biology, University of Isfahan, Isfahan, Iran. (8)Isfahan Neurosciences Research Centre, Alzahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: [email protected]. The routine therapies for relapsing-remitting multiple sclerosis (RRMS) are common disease-modifying medications, yet are not effective in all patients. The aim of the present clinical trial was to evaluate the therapeutic effects of rapamycin on the clinical and radiological aspects, regulatory T cells proliferation and FOXP3 and GARP gene expression in the patients with RRMS. In this study, eight patients with RRMS were chosen and included in the trial. Patients received rapamycin (Rapacan, Biocon, India) for six months. Magnetic resonance imaging (MRI) of the patients' brain was taken before and after the therapy. Patients' expanded disability status scale (EDSS), and FoxP3 and GARP gene expression, and Treg cell proliferation were also been evaluated. All the patients had some degrees of significant reduction in mean plaque area size (P = 0.012, Z = -2.520), and minimum and maximum size of the plaques (P = 0.012, Z = -2.521). EDSS of 50% of patients was decreased after the treatment, yet it was not significant (P = 0.059, Z = -1.89). The expression rate of FOXP3 (P = 0.003) and GARP genes in Tregs increased after the therapy. We found a promising response to rapamycin among our cases with minor side effects and it may be considered as a therapeutic option of this disease. Copyright © 2018. Published by Elsevier B.V. DOI: 10.1016/j.msard.2018.08.009


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Multiple sclerosis and neuromyelitis optica spectrum disorders in Malaysia: A comparison in different ethnic groups.

Viswanathan S(1), Rose N(2), Arip M(3), Chai CH(4), Law WC(4), Sim R(4), Ong MC(5). Author information: (1)Department of Neurology, Kuala Lumpur Hospital, Kuala Lumpur, Ministry of Health of Malaysia. Electronic address: [email protected]. (2)Department of Radiology, Kuala Lumpur Hospital, Kuala Lumpur, Ministry of Health of Malaysia. (3)Department of Immunology, Medical Research Institute, Kuala Lumpur, Ministry of Health of Malaysia. (4)Department of Neurology, Sarawak General Hospital, Kuching, Sarawak, Ministry of Health of Malaysia. (5)Department of Medicine, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Ministry of Health of Malaysia. We performed a retrospective observational analytical study looking at the frequencies and characteristics of multiple sclerosis(MS) and neuromyelitis optica spectrum disorders(NMOSD) in consecutive patients with idiopathic inflammatory demyelinating disease (IIDDs) attending three centers (2009-2017). Of 523 patients with IIDDs, there were 173 patients with NMOSD and 230 patients with MS. The percentage of NMOSD: IIDDs was 33%. The percentage of NMOSD:Total MS and NMOSD cohort was 43%. Of 141 seropositive NMOSD patients, 134(95%) were from the three main ethnic groups. The percentage of seropositive NMOSD to IIDDs and to combined MS and NMOSD was 26.9% and 35% respectively. Ratios of MS to NMOSD were nearly equal at 1.3 to 1.0, reinforcing the high ratio of NMOSD to MS in Asia. Nearly half of the Chinese cohort were seropositive ie; 71/141 (50%) with the remainder being Malays; 56/141 (39.7%) and Indians; 7/141 (5%). Amongst the other indigenous groups seropositivity was seen in 2 each of Iban, Bajau, Kadazan descent as well as one of Bidayuh origin. Comparatively, seropositivity in NMOSD is commoner amongst the Chinese compared to the Malays (p ≤ 0.005) and Indians, p ≤ 0.05 with ratios as high as 10:1. In the MS group of 230 subjects, 123(53.5%) were Malays (ratio of MS:NMOSD of 2:1), 41(17.8%) were Chinese, (ratio of MS:NMOSD of 0.5:1.0) and 54 (23.5%)were Indians (ratios of MS:NMOSD of 5:1 amongst the Indians). The remainder from East Malaysia were made up of 2 each of Kadazans, Ibans and Bajaus including 3 each of Bidayuh and Eurasian descent. Comparatively, in the NMOSD and MS cohorts a female preponderance was noted more so amongst Chinese NMOSD patients, with rare familial occurrence in both but more in Malay MS/NMOSD patients. This study also highlighted some of the inter-ethnic differences in presentation of MS and NMOSD amongst the 3 main ethnic races in Malaysia and confirms indigenous races having MS/NMOSD which needs further research. It also reviewed current literature on similar inter-ethnic differences world wide. To conclude, MS and NMOSD are the commonest demyelinating diseases seen in Malaysia with interesting inter-ethnic differences and similarities. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.msard.2018.07.003

286. N Engl J Med. 2018 Sep 13;379(11):1085-1086. doi: 10.1056/NEJMe1810019.

Therapy in Multiple Sclerosis - Coming of Age.

Antel J(1). Author information: (1)From the Montreal Neurological Institute, McGill University, Montreal. Comment on N Engl J Med. 2018 Sep 13;379(11):1017-1027. DOI: 10.1056/NEJMe1810019


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287. N Engl J Med. 2018 Sep 13;379(11):1017-1027. doi: 10.1056/NEJMoa1800149.

Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis.

Chitnis T(1), Arnold DL(1), Banwell B(1), Brück W(1), Ghezzi A(1), Giovannoni G(1), Greenberg B(1), Krupp L(1), Rostásy K(1), Tardieu M(1), Waubant E(1), Wolinsky JS(1), Bar-Or A(1), Stites T(1), Chen Y(1), Putzki N(1), Merschhemke M(1), Gärtner J(1); PARADIGMS Study Group. Collaborators: Kornberg A, Bajer-Kornek B, Likhachev S, Pereira Gomes Neto A, Diniz D, Paz J, Alvarenga R, Bojinova-Tchamova V, Mah J, Venkateswaran S, Hafner K, Gross-Paju K, Brochet B, Cheuret E, Rivier F, Deiva K, Milh M, Blaschek A, Trollmann R, Korinthenberg R, Luecke T, Ziemssen T, Pozzilli C, Patti F, Comi G, Marfia GA, Grimaldi LME, Trojano M, Zaffaroni M, Capra R, Brescia Morra V, Rozentals G, Laurynaitiene J, Vaiciene-Magistris N, Castro Farfan F, Quinones S, Steinborn B, Ujma-Czapska B, Stasiolek M, Jasinski M, Craiu D, Boyko A, Kairbekova E, Khabirov F, Kuzenkova L, Malkova N, Nikolic D, Jancic J, Gebauer-Bukurov K, Payerova J, Gascon Jiménez F, Izquierdo Ayuso G, Mendibe Bilbao M, Hintzen R, Fernandez Sanchez VE, Meca Lallana V, Montalban Gairin X, Nordborg K, Anlar B, Yalcinkaya C, Gucuyener K, Terzi M, Ozakbas S, Yilmaz U, Makedonska I, Prokopenko K, Tantsura L, Moskovko S, Kobys T, Muratova T, Nehrych T, Prykhodko T, Hemingway C, Wassmer E, Shetty J, Desai J, Waldman A, Chinea Martinez A, Ness J, Rammohan K, Lloyd M, Williams M, Ayala R, Davis R, Bhise V. Author information: (1)From the Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital, Boston (T.C.); Montreal Neurological Institute, McGill University, and NeuroRx Research - both in Montreal (D.L.A.); Children's Hospital of Philadelphia (B.B.) and the Center for Neuroinflammation and Experimental Neurotherapeutics and the Department of Neurology (A.B.-O.), Perelman School of Medicine, University of Pennsylvania - all in Philadelphia; the Department of Neuropathology (W.B.) and the Department of Pediatrics and Adolescent Medicine, German Center for Multiple Sclerosis in Childhood and Adolescence (J.G.), University Medical Center Göttingen, Göttingen, and the Division of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln (K.R.) - all in Germany; Gallarate Hospital, Gallarate, Italy (A.G.); Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London (G.G.); the University of Texas Southwestern Medical Center, Children's Health, Dallas (B.G.), and McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.) - both in Texas; Pediatric Multiple Sclerosis Center at NYU Langone, New York (L.K.); Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Paris (M.T.); the Department of Neurology, University of California at San Francisco, San Francisco (E.W.); Novartis Pharmaceuticals, East Hanover, NJ (T.S., Y.C., N.P.); and Novartis Pharma, Basel, Switzerland (M.M.). Comment in N Engl J Med. 2018 Sep 13;379(11):1085-1086. BACKGROUND: Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. METHODS: In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate. RESULTS: Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T2-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient). CONCLUSIONS: Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIGMS ClinicalTrials.gov number, NCT01892722 .). DOI: 10.1056/NEJMoa1800149


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288. Nat Commun. 2018 Sep 26;9(1):3930. doi: 10.1038/s41467-018-06408-6.

A scalable online tool for quantitative social network assessment reveals potentially modifiable social environmental risks.

Dhand A(1)(2), White CC(3), Johnson C(4), Xia Z(5), De Jager PL(3)(4). Author information: (1)Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA. [email protected]. (2)Network Science Institute, Northeastern University, Boston, 02115, MA, USA. [email protected]. (3)Broad Institute, Program in Medical and Population Genetics, Cambridge, 02142, MA, USA. (4)Multiple Sclerosis Center and the Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, 10032, NY, USA. (5)Department of Neurology, University of Pittsburgh, Pittsburgh, 15260, PA, USA. Social networks are conduits of support, information, and health behavior flows. Existing measures of social networks used in clinical research are typically summative scales of social support or artificially truncated networks of ≤ 5 people. Here, we introduce a quantitative social network assessment tool on a secure open-source web platform, readily deployable in large-scale clinical studies. The tool maps an individual's personal network, including specific persons, their relationships to each other, and their health habits. To demonstrate utility, we used the tool to measure the social networks of 1493 persons at risk of multiple sclerosis. We examined each person's social network in relation to self-reported neurological disability. We found that the characteristics of persons surrounding the participant, such as negative health behaviors, were strongly associated with the individual's functional disability. This quantitative assessment reveals the key elements of individuals' social environments that could be targeted in clinical trials. DOI: 10.1038/s41467-018-06408-6


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289. Nat Microbiol. 2018 Sep 10. doi: 10.1038/s41564-018-0236-1. [Epub ahead of print]

Male offspring born to mildly ZIKV-infected mice are at risk of developing neurocognitive disorders in adulthood.

Stanelle-Bertram S(1), Walendy-Gnirß K(1), Speiseder T(1), Thiele S(1), Asante IA(1), Dreier C(1), Kouassi NM(1), Preuß A(1), Pilnitz-Stolze G(1), Müller U(1), Thanisch S(1), Richter M(2), Scharrenberg R(2), Kraus V(3), Dörk R(3), Schau L(3), Herder V(4)(5), Gerhauser I(4), Pfankuche VM(4)(5), Käufer C(6), Waltl I(6), Moraes T(7), Sellau J(8), Hoenow S(8), Schmidt-Chanasit J(8)(9), Jansen S(8), Schattling B(10), Ittrich H(11), Bartsch U(12), Renné T(13), Bartenschlager R(7), Arck P(14), Cadar D(8), Friese MA(10), Vapalahti O(15), Lotter H(8), Benites S(16), Rolling L(16), Gabriel M(8), Baumgärtner W(4)(5), Morellini F(3), Hölter SM(17)(18), Amarie O(17)(18), Fuchs H(18), Hrabe de Angelis M(18)(19)(20), Löscher W(6), Calderon de Anda F(2), Gabriel G(21)(22)(23)(24). Author information: (1)Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany. (2)Neuronal Development, Center for Molecular Neurobiology Hamburg (ZNMH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (3)Research Group for Behavioral Biology, Center for Molecular Neurobiology Hamburg (ZNMH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (4)Department of Pathology, University of Veterinary Medicine, Hannover, Germany. (5)Center of Systems Neuroscience, Hannover, Germany. (6)Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany. (7)Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany. (8)Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. (9)German Centre for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany. (10)Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (11)Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (12)Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (13)Institute for Clinical and Laboratory Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (14)Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (15)University of Helsinki and Helsinki University Hospital, Helsinki, Finland. (16)Tropical Pathology and Infectious Disease Association, Cusco, Peru. (17)Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany. (18)German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany. (19)Chair of Experimental Genetics, School of Life Science Weihenstephan, Technical University of Munich, Freising, Germany. (20)German Center for Diabetes Research (DZD), Neuherberg, Germany. (21)Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany. [email protected]. (22)German Centre for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany. [email protected]. (23)Center for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany. [email protected]. (24)University of Veterinary Medicine, Hannover, Germany. [email protected]. Congenital Zika virus (ZIKV) syndrome may cause fetal microcephaly in ~1% of affected newborns. Here, we investigate whether the majority of clinically inapparent newborns might suffer from long-term health impairments not readily visible at birth. Infection of immunocompetent pregnant mice with high-dose ZIKV caused severe offspring phenotypes, such as fetal death, as expected. By contrast, low-dose (LD) maternal ZIKV infection resulted in reduced fetal birth weight but no other obvious phenotypes. Male offspring born to LD ZIKV-infected mothers had increased testosterone (TST) levels and were less likely to survive in utero infection compared to their female littermates. Males also presented an increased number of immature neurons in apical and basal hippocampal dendrites, while female offspring had immature neurons in basal dendrites only. Moreover, male offspring with high but not very high (storm) TST levels were more likely to suffer from learning and memory impairments compared to females. Future studies are required to understand the impact of TST on neuropathological and neurocognitive impairments in later life. In summary, increased sex-specific vigilance is required in countries with high ZIKV prevalence, where impaired neurodevelopment may be camouflaged by a healthy appearance at birth. DOI: 10.1038/s41564-018-0236-1


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290. Nat Neurosci. 2018 Oct;21(10):1341-1349. doi: 10.1038/s41593-018-0238-6. Epub 2018 Sep 26.

Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases.

Jucker M(1)(2), Walker LC(3). Author information: (1)Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. [email protected]. (2)German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. [email protected]. (3)Department of Neurology and Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA. [email protected]. Many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by the progressive appearance of abnormal proteinaceous assemblies in the nervous system. Studies in experimental systems indicate that the assemblies originate from the prion-like seeded aggregation of specific misfolded proteins that proliferate and amass to form the intracellular and/or extracellular lesions typical of each disorder. The host in which the proteopathic seeds arise provides the biochemical and physiological environment that either supports or restricts their emergence, proliferation, self-assembly, and spread. Multiple mechanisms influence the spatiotemporal spread of seeds and the nature of the resulting lesions, one of which is the cellular uptake, release, and transport of seeds along neural pathways and networks. The characteristics of cells and regions in the affected network govern their vulnerability and thereby influence the neuropathological and clinical attributes of the disease. The propagation of pathogenic protein assemblies within the nervous system is thus determined by the interaction of the proteopathic agent and the host milieu. DOI: 10.1038/s41593-018-0238-6


Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis.

Ellwardt E(1), Pramanik G(1)(2), Luchtman D(1), Novkovic T(3), Jubal ER(2), Vogt J(4), Arnoux I(2), Vogelaar CF(1), Mandal S(1), Schmalz M(1), Barger Z(2), de Azua IR(5), Kuhlmann T(6), Lutz B(5), Mittmann T(3), Bittner S(1), Zipp F(7), Stroh A(8). Author information: (1)Department of Neurology Focus Program Translational Neurosciences (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (2)Focus Program Translational Neurosciences & Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (3)Focus Program Translational Neurosciences & Institute of Physiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (4)Focus Program Translational Neurosciences & Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. (5)Focus Program Translational Neurosciences & Institute for Physiological Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany. (6)Institute for Neuropathology, University Hospital Münster, Münster, Germany. (7)Department of Neurology Focus Program Translational Neurosciences (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. [email protected]. (8)Focus Program Translational Neurosciences & Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. [email protected]. Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca2+ imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration. DOI: 10.1038/s41593-018-0193-2


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292. Nat Neurosci. 2018 Oct;21(10):1310-1317. doi: 10.1038/s41593-018-0240-z. Epub 2018 Sep 26.

Deconstructing and targeting the genomic architecture of human neurodegeneration.

De Jager PL(1)(2), Yang HS(3)(4), Bennett DA(5). Author information: (1)Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA. [email protected]. (2)Cell Circuits Program, Broad Institute, Cambridge, MA, USA. [email protected]. (3)Cell Circuits Program, Broad Institute, Cambridge, MA, USA. (4)Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. (5)Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA. The field of neurodegenerative disease research has seen tremendous advances over the last two decades as new technologies and analytic methods have enabled well-powered human genomic studies. Driven first by genetic studies and more recently by transcriptomic and epigenomic studies of proper size, we have uncovered a large repertoire of loci, genes, and molecular features that are implicated in discrete, syndromically defined neurodegenerative conditions, such as Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, and Parkinson's disease. As we begin to understand the impact of these genomic features in each disease, we also appreciate that many aging individuals accumulate each of these pathologies without fulfilling criteria for syndromic diagnoses, that other pathologies are common in individuals with a given diagnosis, and that there may be shared protective factors against central nervous system injury. Thus, we now need to bring these disparate observations together into a person-centered approach that considers all neurodegenerative and protective processes simultaneously to modulate the trajectory of cognitive and functional decline that comes with brain aging. DOI: 10.1038/s41593-018-0240-z

293. Nat Neurosci. 2018 Oct;21(10):1318-1331. doi: 10.1038/s41593-018-0234-x. Epub 2018 Sep 24.

The role of brain vasculature in neurodegenerative disorders.

Sweeney MD(1), Kisler K(1), Montagne A(1), Toga AW(2), Zlokovic BV(3). Author information: (1)Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. (2)Laboratory of Neuro Imaging, Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. (3)Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. [email protected]. Adequate supply of blood and structural and functional integrity of blood vessels are key to normal brain functioning. On the other hand, cerebral blood flow shortfalls and blood-brain barrier dysfunction are early findings in neurodegenerative disorders in humans and animal models. Here we first examine molecular definition of cerebral blood vessels, as well as pathways regulating cerebral blood flow and blood-brain barrier integrity. Then we examine the role of cerebral blood flow and blood-brain barrier in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. We focus on Alzheimer's disease as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders. Finally, we propose a hypothetical model of Alzheimer's disease biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and we suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders. DOI: 10.1038/s41593-018-0234-x


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CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature.

Louveau A(1)(2), Herz J(3)(4), Alme MN(3)(4)(5)(6), Salvador AF(3)(4)(7), Dong MQ(3)(4), Viar KE(3)(4), Herod SG(3)(4), Knopp J(3)(4), Setliff JC(3)(4), Lupi AL(3)(4), Da Mesquita S(3)(4), Frost EL(3)(4), Gaultier A(3)(4), Harris TH(3)(4), Cao R(8), Hu S(8), Lukens JR(3)(4), Smirnov I(3)(4), Overall CC(3)(4), Oliver G(9), Kipnis J(10)(11)(12)(13). Author information: (1)Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. [email protected]. (2)Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. [email protected]. (3)Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. (4)Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. (5)Department of Clinical Medicine, University of Bergen, Bergen, Norway. (6)Department of Neurology, Haukeland University Hospital, Bergen, Norway. (7)Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA. (8)Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA. (9)Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. (10)Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. [email protected]. (11)Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. [email protected]. (12)Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA. [email protected]. (13)Gutenberg Research Fellowship Group of Neuroimmunology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. [email protected]. Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention. DOI: 10.1038/s41593-018-0227-9

295. Nat Rev Neurol. 2018 Oct;14(10):571. doi: 10.1038/s41582-018-0069-9.

A new subtype of multiple sclerosis?

Fyfe I(1). Author information: (1)Nature Reviews Neurology, . [email protected]. DOI: 10.1038/s41582-018-0069-9


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296. Nat Rev Neurol. 2018 Oct;14(10):577-589. doi: 10.1038/s41582-018-0058-z.

Neurofilaments as biomarkers in neurological disorders.

Khalil M(1), Teunissen CE(2), Otto M(3), Piehl F(4), Sormani MP(5)(6), Gattringer T(7), Barro C(8), Kappos L(8), Comabella M(9), Fazekas F(7), Petzold A(10)(11), Blennow K(12)(13), Zetterberg H(12)(13)(14)(15), Kuhle J(16). Author information: (1)Department of Neurology, Medical University of Graz, Graz, Austria. [email protected]. (2)Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Amsterdam, Netherlands. (3)Department of Neurology, Ulm University Hospital, Ulm, Germany. (4)Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. (5)Department of Health Sciences, University of Genoa, Genoa, Italy. (6)Ospedale Policlinico San Martino IRCCS, Genoa, Italy. (7)Department of Neurology, Medical University of Graz, Graz, Austria. (8)Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, and Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland. (9)Unit of Clinical Neuroimmunology, Department of Neurology, Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain. (10)UCL Institute of Neurology, Department of Molecular Neurosciences, Moorfields Eye Hospital and The National Hospital for Neurology and Neurosurgery, London, UK. (11)Departments of Neurology, Ophthalmology and Expertise Center for Neuro-ophthalmology, Amsterdam UMC, Amsterdam, Netherlands. (12)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. (13)Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden. (14)Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK. (15)UK Dementia Research Institute at UCL, London, UK. (16)Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, and Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland. [email protected]. Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice. DOI: 10.1038/s41582-018-0058-z


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297. Nature. 2018 Sep;561(7723):331-337. doi: 10.1038/s41586-018-0499-y. Epub 2018 Sep 5.

A homing system targets therapeutic T cells to brain cancer.

Samaha H(1)(2)(3)(4), Pignata A(2)(3)(4), Fousek K(2)(3)(4)(5), Ren J(6), Lam FW(4)(7)(8), Stossi F(4)(9), Dubrulle J(4)(9), Salsman VS(2)(3)(4), Krishnan S(6), Hong SH(10), Baker ML(4)(11), Shree A(2)(3)(4), Gad AZ(1)(2)(3)(4)(5), Shum T(2)(4)(5), Fukumura D(6), Byrd TT(2)(3)(4)(5), Mukherjee M(3)(4)(12), Marrelli SP(10), Orange JS(4)(7)(12), Joseph SK(2)(3)(4), Sorensen PH(13), Taylor MD(14), Hegde M(2)(3)(4)(15)(16), Mamonkin M(2)(3)(4)(5)(17), Jain RK(6), El-Naggar S(1), Ahmed N(18)(19)(20)(21)(22)(23)(24)(25). Author information: (1)Children's Cancer Hospital Egypt-57357, Cairo, Egypt. (2)Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. (3)Texas Children's Hospital, Houston, TX, USA. (4)Baylor College of Medicine, Houston, TX, USA. (5)Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. (6)Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (7)Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. (8)Center for Translational Research on Inflammatory Diseases at the Michael E DeBakey Veterans Affairs Medical Center, Houston, Texas, USA. (9)Integrated Microscopy Core, Advanced Technology Cores, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. (10)Department of Neurology, McGovern Medical School at UT Health, Houston, TX, USA. (11)National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, TX, USA. (12)Center for Human Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. (13)Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. (14)Developmental and Stem Cell Biology Program, The Arthur and Sonia Labatt Brain Tumour Research Centre, Division of Neurosurgery, Departments of Surgery, Laboratory Medicine and Pathobiology, and of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (15)Houston Methodist Hospital, Houston, TX, USA. (16)Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. (17)Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA. (18)Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. [email protected]. (19)Texas Children's Hospital, Houston, TX, USA. [email protected]. (20)Baylor College of Medicine, Houston, TX, USA. [email protected]. (21)Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. [email protected]. (22)Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. [email protected]. (23)Houston Methodist Hospital, Houston, TX, USA. [email protected]. (24)Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. [email protected]. (25)Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA. [email protected]. Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer. DOI: 10.1038/s41586-018-0499-y


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298. Nervenarzt. 2018 Sep 27. doi: 10.1007/s00115-018-0607-0. [Epub ahead of print]

[MOG encephalomyelitis: international recommendations on diagnosis and antibody testing].

[Article in German] Jarius S(1), Paul F(2), Aktas O(3), Asgari N(4), Dale RC(5), de Seze J(6), Franciotta D(7), Fujihara K(8), Jacob A(9), Kim HJ(10), Kleiter I(11), Kümpfel T(12), Levy M(13), Palace J(14), Ruprecht K(15), Saiz A(16), Trebst C(17), Weinshenker BG(18), Wildemann B(19). Author information: (1)AG Molekulare Neuroimmunologie, Neurologische Klinik, Universitätsklinikum Heidelberg, Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120, Heidelberg, Deutschland. [email protected]. (2)Experimental and Clinical Research Center, NeuroCure Clincial Research Center, und Berliner Institut für Gesundheitsforschung, Max-Delbrück-Zentrum für Molekulare Medizin und Charité - Universitätsmedizin Berlin, Gliedkörperschaft der Freien Universität Berlin und der Humboldt-Universität zu Berlin, Berlin, Deutschland. (3)Neurologische Klinik, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland. (4)Department of Neurology, University of Southern Denmark, Odense, Dänemark. (5)Children's Hospital at Westmead, University of Sydney, Sydney, Australien. (6)Department of Neurology, Hôpital de Hautepierre, Strasbourg Cedex, Frankreich. (7)Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italien. (8)Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan. (9)The Walton Centre, Walton Centre NHS Foundation Trust, Liverpool, Großbritannien. (10)Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Südkorea. (11)Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Deutschland. (12)Institut für Klinische Neuroimmunologie, Ludwig-Maximilians-Universität, München, Deutschland. (13)Department of Neurology, Johns Hopkins Hospital, Cleveland, USA. (14)Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, Großbritannien. (15)Klinik für Neurologie mit experimenteller Neurologie, Charité - Universitätsmedizin Berlin, Gliedkörperschaft der Freien Universität Berlin und der Humboldt-Universität zu Berlin, Berlin, Deutschland. (16)Service of Neurology, Hospital Clinic, and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spanien. (17)Neurologische Klinik, Medizinische Hochschule Hannover, Hannover, Deutschland. (18)Department of Neurology, Mayo Clinic, Rochester, MN, USA. (19)AG Molekulare Neuroimmunologie, Neurologische Klinik, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Deutschland. [email protected]. Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM ("red flags") that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation, and propose for the first time diagnostic criteria for MOG-EM. DOI: 10.1007/s00115-018-0607-0


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299. Nervenarzt. 2018 Sep 13. doi: 10.1007/s00115-018-0597-y. [Epub ahead of print]

[Neuroimmunology and rheumatology: overlap and differential diagnoses].

[Article in German] Trebst C(1), Kümpfel T(2). Author information: (1)Klinik für Neurologie, Medizinische Hochschule Hannover, Hannover, Deutschland. (2)Institut für klinische Neuroimmunologie, Klinikum Großhadern, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377, München, Deutschland. [email protected]. Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are chronic inflammatory diseases of the central nervous system (CNS). They may cause inflammation in the brain, spinal cord and optic nerve. Both conditions must be differentiated from CNS manifestations of other systemic autoimmune diseases such as systemic lupus erythematosus (SLE), Sjögren's syndrome, autoinflammtory diseases and sarcoidosis, since amongst others myelitis and optic nerve inflammation may also occur in these conditions. Nevertheless, coexistence of MS or NMOSD with rheumatic disorders such as SLE or Sjögren's syndrome has also been reported especially in NMOSD. Since the therapeutic approach is different it is important to determine a clear diagnosis. In addition some drugs used in rheumatic disease such as anti-tumor necrosis factor biologics may induce inflammatory disease of the CNS and should be avoided in MS. An interdisciplinary approach between neuroimmunology and rheumatology is important for optimal care and treatment in such patients. DOI: 10.1007/s00115-018-0597-y

300. Neural Regen Res. 2018 Nov;13(11):1879-1882. doi: 10.4103/1673-5374.239434.

Cadmium-induced neurotoxicity: still much ado.

Branca JJV(1), Morucci G(1), Pacini A(1). Author information: (1)Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. Cadmium (Cd) is a highly toxic heavy metal that accumulates in living system and as such is currently one of the most important occupational and environmental pollutants. Cd reaches into the environment by anthropogenic mobilization and it is absorbed from tobacco consumption or ingestion of contaminated substances. Its extremely long biological half-life (approximately 20-30 years in humans) and low rate of excretion from the body cause cadmium storage predominantly in soft tissues (primarily, liver and kidneys) with a diversity of toxic effects such as nephrotoxicity, hepatotoxicity, endocrine and reproductive toxicities. Moreover, a Cd-dependent neurotoxicity has been also related to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and multiple sclerosis. At the cellular level, Cd affects cell proliferation, differentiation, apoptosis and other cellular activities. Among all these mechanisms, the Cd-dependent interference in DNA repair mechanisms as well as the generation of reactive oxygen species, seem to be the most important causes of its cellular toxicity. Nevertheless, there is still much to find out about its mechanisms of action and ways to reduce health risks. This article gives a brief review of the relevant mechanisms that it would be worth investigating in order to deep inside cadmium toxicity. DOI: 10.4103/1673-5374.239434 Conflict of interest statement: None


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301. Neural Regen Res. 2018 Nov;13(11):1871-1874. doi: 10.4103/1673-5374.239432.

Sequencing of high-efficacy disease-modifying therapies in multiple sclerosis: perspectives and approaches.

Grand'Maison F(1), Yeung M(2), Morrow SA(3), Lee L(4), Emond F(5), Ward BJ(6), Laneuville P(7), Schecter R(8). Author information: (1)Neuro Rive-Sud, Hôpital Charles LeMoyne, Greenfield Park, Quebec, Canada. (2)Clinical Neurosciences, Foothills Medical Centre, Calgary, Alberta, Canada. (3)London Health Sciences Center (LHSC), Western University, London, Ontario, Canada. (4)Department of Neurology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. (5)Centre Hospitalier Universitaire de Québec - hôpital de l'Enfant-Jésus, Quebec City, Quebec, Canada. (6)Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. (7)Department of Medicine, McGill University, Montreal, Quebec, Canada. (8)Novartis Pharmaceuticals Canada Inc., Dorval, Quebec, Canada. Multiple sclerosis (MS) is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting course that later transitions to secondary progressive MS. Currently available disease-modifying therapies (DMTs) for relapsing MS have been demonstrated to reduce disease activity, however most patients require a change in therapy over the course of their disease. Treatment goals include the prevention of relapses and disability accumulation and to achieve this objective requires careful planning. Sequencing of DMTs for individual patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes. DOI: 10.4103/1673-5374.239432 Conflict of interest statement: FG has disclosed that he has received grant funding from Novartis, Chugai, Opexa, Serono, Biogen, Roche, Genzyme, Abbott and Actelion. MY has disclosed that he has received consultation fees from EMD Serono, Genzyme and Novartis, and the Canadian Agency for Drugs and Technologies in Health (CADTH)/Health Canada, and research support from Biogen Idec, Genzyme, Hoffmann-La Roche, Novartis, and Teva Canada Innovation. SAM has disclosed that she has received honoraria for speaking, consulting and advisory board participation from Biogen Idec, EMD Serono, Genzyme, Novartis and Roche; she has acted as site principal investigator for clinical trials for Novartis, Genzyme and Roche; she has received investigator initiated trial funding from Genzyme. LL has disclosed that he has served on advisory boards, received honoraria, conducted clinical trials with and received research funding from Allergan, Biogen Canada, Serono Canada, Teva Neurosciences, Schering (Berlex), BioMS, Bayer Canada, Novartis Canada, Sanofi-Aventis, Genzyme Canada and Roche Canada. FE has disclosed that he has received honoraria as a speaker, consultant/advisor or received educational/CME grant or a research grant from Biogen Idec, EMD Serono, Genzyme, Novartis, Teva Innovation and Hoffman-La Roche. BJW has disclosed that he received compensation from Novartis for work related to infectious complications of DMTs. PL has disclosed that he has served as a consultant in an advisory board related to fingolimod; he has received honoraria as a speaker on the immunological effects of DMTs in MS from Novartis and Sanofi; he has also received reimbursement of travel and lodging expenses to give presentations on the immunological effects of DMTs in MS from Novartis. RS has disclosed that she is an employee of Novartis Pharmaceuticals Canada Inc


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302. Neurobiol Dis. 2018 Sep 13. pii: S0969-9961(18)30574-6. doi: 10.1016/j.nbd.2018.09.011. [Epub ahead of print]

Stem cell therapy for neurological disorders: A focus on aging.

Nguyen H(1), Zarriello S(1), Coats A(1), Nelson C(1), Kingsbury C(1), Gorsky A(1), Rajani M(1), Neal EG(1), Borlongan CV(2). Author information: (1)Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA. (2)Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA. Electronic address: [email protected]. Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy. We raise important questions to guide future research and advance novel treatment options. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1016/j.nbd.2018.09.011

303. Neurochem Res. 2018 Sep 24. doi: 10.1007/s11064-018-2648-y. [Epub ahead of print]

The Role of Calpain and Proteasomes in the Degradation of Carbonylated Neuronal Cytoskeletal Proteins in Acute Experimental Autoimmune Encephalomyelitis.

Smerjac SM(1), Zheng J(1), Hu CL(1), Bizzozero OA(2)(3). Author information: (1)Department of Cell Biology and Physiology, University of New Mexico - Health Sciences Center, Albuquerque, NM, USA. (2)Department of Cell Biology and Physiology, University of New Mexico - Health Sciences Center, Albuquerque, NM, USA. [email protected]. (3)Department of Cell Biology and Physiology, University of New Mexico School of Medicine, 1 University Of New Mexico, MSC08 4750, Albuquerque, NM, 87131, USA. [email protected]. The present study was designed to investigate the role of calpain and the proteasome in the removal of oxidized neuronal cytoskeletal proteins in myelin basic protein-induced experimental autoimmune encephalomyelitis (EAE). To this end, EAE rats received a single intrathecal injection of calpeptin or epoxomicin at the first sign of clinical disease. Forty-eight hours later, animals were sacrificed and lumbar spinal cord segments were dissected and used for biochemical analyses. The results show that calpain and proteasome activity is specifically, but partially, inhibited with calpeptin and epoxomicin, respectively. Calpain inhibition causes an increase in total protein carbonylation and in the amount of neurofilament proteins (NFPs), β-tubulin and β-actin that were spared from degradation, but no changes are seen in the oxidation of any of three NFPs. By contrast, proteasome inhibition has no effect on total protein carbonylation or cytoskeletal protein degradation but increases the amount of oxidized NFH and NFM. These results suggest that while the proteasome may contribute to removal of oxidized NFPs, calpain is the main protease involved in degradation of neuronal cytoskeleton and does not preferentially targets oxidized NFPs species in acute EAE. Different results were obtained in a cell-free system, where calpain inhibition rises the amount of oxidized NFH, and proteasome inhibition fails to change the oxidation state of the NFPs. The later finding suggests that the preferential degradation of oxidized NFH and NFM in vivo by the proteasome occurs via the 26S and not the 20S particle. DOI: 10.1007/s11064-018-2648-y


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304. Neurodegener Dis Manag. 2018 Sep 14. doi: 10.2217/nmt-2018-0032. [Epub ahead of print]

Identifying a new subtype of multiple sclerosis.

Trapp BD(1), Ontaneda D(2). Author information: (1)Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. (2)Medicine Institute, Mellen Center for Treatment & Research in Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. Dr Bruce Trapp and Dr Daniel Ontaneda speak to Laura Dormer, Commissioning Editor: Bruce D Trapp, PhD, is a Chair of the Department of Neurosciences at the Lerner Research Institute, Cleveland Clinic (OH, USA) and Professor of Molecular Medicine at Case Western Reserve University (OH, USA). Dr Trapp received his PhD from Loyola University Stritch School of Medicine in Chicago (IL, USA). Dr Trapp's research investigates the cause of neurological disability in multiple sclerosis patients, cellular mechanism of brain repair in neurodegenerative diseases and the molecular biology of myelination in the central and peripheral nervous systems. Daniel Ontaneda, MD, is a staff neurologist at the Cleveland Clinic Mellen Center for Multiple Sclerosis. Dr Ontaneda earned his MD from the Universidad Católica del Ecuador and MSc in clinical research from Case Western Reserve University. He completed a postdoctoral fellowship at Baylor College of Medicine, followed by neurology and neuroimmunology training at the Cleveland Clinic. His specialties include acute disseminated encephalomyelitis, Devic's disease (neuromyelitis optica), multiple sclerosis, neuroimmunology, optic neuritis and transverse myelitis. DOI: 10.2217/nmt-2018-0032

305. Neurodegener Dis Manag. 2018 Oct;8(5):323-335. doi: 10.2217/nmt-2018-0011. Epub 2018 Sep 18.

The role of optical coherence tomography and infrared oculography in assessing the visual pathway and CNS in multiple sclerosis.

Coric D(1), Nij Bijvank JA(1)(2), van Rijn LJ(2), Petzold A(1)(3), Balk LJ(1). Author information: (1)Department of Neurology, Amsterdam Neuroscience, VU University Medical Centre, Amsterdam, The Netherlands. (2)Department of Ophthalmology, VU University Medical Centre, Amsterdam, The Netherlands. (3)Moorfields Eye Hospital & The National Hospital for Neurology & Neurosurgery, London, UK. In this review, a current overview is provided of how optical coherence tomography and infrared oculography can aid in assessing the visual system and CNS in multiple sclerosis (MS). Both afferent and efferent visual disorders are common in MS and visual complaints can have a tremendous impact on daily functioning. Optical coherence tomography and infrared oculography can detect and quantify visual disorders with high accuracy, but could also serve as quantitative markers for inflammation, neurodegeneration and network changes including cognitive decline in MS patients. The assessment of the efferent and afferent visual pathways is relevant for monitoring and predicting the disease course, but is also potentially valuable as an outcome measure in therapeutic trials. DOI: 10.2217/nmt-2018-0011

306. Neurodegener Dis Manag. 2018 Oct;8(5):315-322. doi: 10.2217/nmt-2018-0016. Epub 2018 Sep 18.

Naturally occurring change in Multiple Sclerosis Walking Scale-12 scores over time in multiple sclerosis.

Motl RW(1), Sandroff BM(1), McAuley E(2). Author information: (1)Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, USA 35294. (2)Department of Kinesiology & Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, USA 61801. AIM: This study examined the trajectory and pattern of naturally occurring change in perceived walking impairment over a 30-month period in relapsing-remitting multiple sclerosis (RRMS). PATIENTS & METHODS: Two hundred and sixty-nine persons with RRMS completed the 12-item Multiple Sclerosis Walking Scale (MSWS-12) every 6 months over a 30-month period. Data were analyzed using latent growth curve modeling and latent class growth curve modeling. RESULTS: Latent growth curve modeling demonstrated that a linear trajectory adequately described the group-level pattern of change in MSWS-12 scores over time. Latent class growth curve modeling supported a three-class model for describing the heterogeneity of changes in MSWS-12 scores over time. CONCLUSION: Walking impairment does change over time in RRMS, and this can be described by three patterns of change trajectories that differed based on initial status of walking impairment. DOI: 10.2217/nmt-2018-0016


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307. Neuroimage Clin. 2018 Sep 4;20:724-730. doi: 10.1016/j.nicl.2018.09.002. [Epub ahead of print]

Characterization of relapsing-remitting multiple sclerosis patients using support vector machine classifications of functional and diffusion MRI data.

Zurita M(1), Montalba C(2), Labbé T(3), Cruz JP(4), Dalboni da Rocha J(5), Tejos C(1), Ciampi E(6), Cárcamo C(7), Sitaram R(8), Uribe S(9). Author information: (1)Biomedical Imaging Center, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Electrical Engineering, School of Engineering, Pontificia Universidad Católica de Chile, Santiago, Chile. (2)Biomedical Imaging Center, Pontificia Universidad Católica de Chile, Santiago, Chile. (3)Interdisciplinary Center of Neurosciences, Pontificia Universidad Católica de Chile, Santiago, Chile. (4)Radiology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. (5)Brain and Language Lab, Department of Clinical Neuroscience, University of Geneva, Geneva, Switzerland. (6)Interdisciplinary Center of Neurosciences, Pontificia Universidad Católica de Chile, Santiago, Chile; Neurology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; Neurology, Hospital Dr. Sótero del Río, Santiago, Chile. (7)Interdisciplinary Center of Neurosciences, Pontificia Universidad Católica de Chile, Santiago, Chile; Neurology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. (8)Institute of Biological and Medical Engineering, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Psychiatry, Section of Neuroscience, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; Laboratory for Brain-Machine Interfaces and Neuromodulation, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. (9)Biomedical Imaging Center, Pontificia Universidad Católica de Chile, Santiago, Chile; Radiology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; Millennium Nucleus for Cardiovascular Magnetic Resonance, Santiago, Chile. Electronic address: [email protected]. Multiple Sclerosis patients' clinical symptoms do not correlate strongly with structural assessment done with traditional magnetic resonance images. However, its diagnosis and evaluation of the disease's progression are based on a combination of this imaging analysis complemented with clinical examination. Therefore, other biomarkers are necessary to better understand the disease. In this paper, we capitalize on machine learning techniques to classify relapsing-remitting multiple sclerosis patients and healthy volunteers based on machine learning techniques, and to identify relevant brain areas and connectivity measures for characterizing patients. To this end, we acquired magnetic resonance imaging data from relapsing-remitting multiple sclerosis patients and healthy subjects. Fractional anisotropy maps, structural and functional connectivity were extracted from the scans. Each of them were used as separate input features to construct support vector machine classifiers. A fourth input feature was created by combining structural and functional connectivity. Patients were divided in two groups according to their degree of disability and, together with the control group, three group pairs were formed for comparison. Twelve separate classifiers were built from the combination of these four input features and three group pairs. The classifiers were able to distinguish between patients and healthy subjects, reaching accuracy levels as high as 89% ± 2%. In contrast, the performance was noticeably lower when comparing the two groups of patients with different levels of disability, reaching levels below 63% ± 5%. The brain regions that contributed the most to the classification were the right occipital, left frontal orbital, medial frontal cortices and lingual gyrus. The developed classifiers based on MRI data were able to distinguish multiple sclerosis patients and healthy subjects reliably. Moreover, the resulting classification models identified brain regions, and functional and structural connections relevant for better understanding of the disease. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.nicl.2018.09.002 PMCID: PMC6148733

308. Neuroimage Clin. 2018 Aug 10;20:506-522. doi: 10.1016/j.nicl.2018.08.019. eCollection 2018.

Structural neuroimaging as clinical predictor: A review of machine learning applications.

Mateos-Pérez JM(1), Dadar M(1), Lacalle-Aurioles M(1), Iturria-Medina Y(1), Zeighami Y(1), Evans AC(1). Author information: (1)Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. In this paper, we provide an extensive overview of machine learning techniques applied to structural magnetic resonance imaging (MRI) data to obtain clinical classifiers. We specifically address practical problems commonly encountered in the literature, with the aim of helping researchers improve the application of these techniques in future works. Additionally, we survey how these algorithms are applied to a wide range of diseases and disorders (e.g. Alzheimer's disease (AD), Parkinson's disease (PD), autism, multiple sclerosis, traumatic brain injury, etc.) in order to provide a comprehensive view of the state of the art in different fields. DOI: 10.1016/j.nicl.2018.08.019 PMCID: PMC6108077


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309. Neurol Neurochir Pol. 2018 Aug 18. pii: S0028-3843(18)30179-8. doi: 10.1016/j.pjnns.2018.08.001. [Epub ahead of print]

Lymphocyte populations and their change during five-year glatiramer acetate treatment.

Pavelek Z(1), Vyšata O(2), Sobíšek L(3), Klímová B(2), Andrýs C(4), Vokurková D(4), Mazurová R(2), Štourač P(5), Vališ M(2). Author information: (1)Department of Neurology, Faculty of Medicine and University Hospital Hradec Králové, Charles University in Prague, Hradec Králové, Sokolská 581, 500 05, Czech Republic. Electronic address: [email protected]. (2)Department of Neurology, Faculty of Medicine and University Hospital Hradec Králové, Charles University in Prague, Hradec Králové, Sokolská 581, 500 05, Czech Republic. (3)Department of Statistics and Probability, University of Economics in Prague, Prague, Czech Republic. (4)Department of Clinical Immunology and Allergology, University Hospital Hradec Králové, Hradec Králové, Sokolská 581, 500 05, Czech Republic. (5)Department of Neurology, Masaryk University Brno, Jihlavská 20, 625 00, Czech Republic. BACKGROUND: The goal of this study was to determine the characteristics that are affected in patients treated with glatiramer acetate (GA). METHODS: A total of 113 patients were included in this study. Patients were treated with glatiramer acetate (subcutaneous injection, 20 mg, each day). Peripheral blood samples were obtained just prior to treatment as well as 5 years after GA treatment. All the calculations were performed with the statistical system R (r-project.org). RESULTS: After 5 years of treatment, a significant decrease was found in the absolute and relative CD3+/CD69+ counts, the absolute and relative CD69 counts, the relative CD8+/CD38+ count and the relative CD38 count. A significant increase was found in the absolute and relative CD5+/CD45RA+ counts and the absolute CD5+/CD45RO+ count after 5 years of treatment. CONCLUSION: This study presents some parameters that were affected by long-term GA treatment. Copyright © 2018 Polish Neurological Society. Published by Elsevier Sp. z o.o. All rights reserved. DOI: 10.1016/j.pjnns.2018.08.001

310. Neurol Neuroimmunol Neuroinflamm. 2018 Aug 14;5(5):e492. doi: 10.1212/NXI.0000000000000492. eCollection 2018 Sep.

Temporal visual resolution and disease severity in MS.

Ayadi N(1), Dörr J(1), Motamedi S(1), Gawlik K(1), Bellmann-Strobl J(1), Mikolajczak J(1), Brandt AU(1), Zimmermann H(1), Paul F(1). Author information: (1)Charité-Universitätsmedizin Berlin (N.A., J.D., S.M., K.G., J.B.-S., J.M., A.U.B., H.Z., F.P.), Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, NeuroCure Clinical Research Center; Neurology Department (J.D.), Multiple Sclerosis Center, Oberhavel Clinic, Henningsdorf; Experimental and Clinical Research Center (J.B.-S., F.P.), 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; and Department of Neurology (F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany. Objective: To examine temporal visual resolution assessed as critical flicker frequency (CFF) in patients with MS and to investigate associations with visual system damage and general disability and cognitive function. Methods: Thirty-nine patients with MS and 31 healthy controls (HCs) were enrolled in this cross-sectional study and underwent CFF testing, high- and low-contrast visual acuity, alertness and information processing speed using the paced auditory serial addition task (PASAT), and retinal optical coherence tomography (OCT). In patients with MS, visual evoked potentials (VEPs) and Expanded Disability Status Scale (EDSS) scores were assessed. Results: CFF in patients with MS (mean ± SD: 40.9 ± 4.4 Hz) was lower than in HCs (44.8 ± 4.4 Hz, p < 0.001). There was no significant CFF difference between eyes with and without previous optic neuritis (ON). CFF was not associated with visual acuity, VEP latency, the peripapillary retinal nerve fiber layer thickness, and the combined ganglion cell and inner plexiform layer volume. Instead, reduced CFF was associated with worse EDSS scores (r2 = 0.26, p < 0.001) and alertness (r2 = 0.42, p = 0.00042) but not with PASAT (p = 0.33). Conclusion: CFF reduction in MS occurs independently of ON and structural visual system damage. Its association with the EDSS score and alertness suggests that CFF reflects global disease processes and higher cortical processing rather than focal optic nerve or retinal damage. DOI: 10.1212/NXI.0000000000000492 PMCID: PMC6117185


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Identification of MS-specific serum miRNAs in an international multicenter study.

Regev K(1), Healy BC(1), Paul A(1), Diaz-Cruz C(1), Mazzola MA(1), Raheja R(1), Glanz BI(1), Kivisäkk P(1), Chitnis T(1), Jagodic M(1), Piehl F(1), Olsson T(1), Khademi M(1), Hauser S(1), Oksenberg J(1), Khoury SJ(1), Weiner HL(1), Gandhi R(1). Author information: (1)Partners Multiple Sclerosis Center (K.R., B.C.H., A.P., M.A.M., R.R., P.K., T.C., H.L.W., R.G.), Brigham and Women's Hospital; Department of Neurology, Harvard Medical School (B.C.H., C.D.-C., B.I.G., T.C., H.L.W, R.G.), Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital; Biostatistics Center (B.C.H.); Massachusetts General Hospital, Boston, MA; Department of Clinical Neuroscience, Neuroimmunology Unit (M.J., F.P., T.O., M.K.), Karolinska Institute, Stockholm, Sweden; Department of Neurology (S.H., J.O.), School of Medicine, University of California, San Francisco; and Nehme and Therese Tohme Multiple Sclerosis Center (S.J.K.), Faculty of Medicine, American University of Beirut Medical Center, Lebanon. Objective: To identify circulating microRNAs (miRNAs) linked to disease, disease stage, and disability in MS across cohorts. Methods: Samples were obtained from the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB, Boston, MA), EPIC (San Francisco, CA), AMIR (Beirut, Lebanon) as part of the SUMMIT consortium, and Stockholm Prospective Assessment of Multiple Sclerosis (Stockholm, Sweden) cohorts. Serum miRNA expression was measured using locked nucleic acid-based quantitative PCR. Four groups were compared: (1) MS vs healthy control (HC), (2) relapsing-remitting (RR) vs HC, (3) secondary progressive (SP) vs HC, and (4) RR vs SP. A Wilcoxon rank-sum test was used for the comparisons. The association between each miRNA and the Expanded Disability Status Scale (EDSS) score was assessed using the Spearman correlation coefficient. For each comparison, the p values were corrected for multiple comparisons using the approach of Benjamini and Hochberg to control the false discovery rate. Results: In the CLIMB cohort, 5 miRNAs (hsa-miR-484, hsa-miR-140-5p, hsa-miR-320a, hsa-miR-486-5p, and hsa-miR-320c) showed a significant difference between patients with MS and healthy individuals; among these, miR-484 remained significant after accounting for multiple comparisons (p = 0.01). When comparing RRMS with HCs, hsa-miR-484 showed a significant difference (p = 0.004) between the groups after accounting for multiple group comparisons. When SP and HC were compared, 6 miRNAs (hsa-miR-484, hsa-miR-140-5p, hsa-miR-142-5p, hsa-miR-320a, hsa-miR-320b, and hsa-miR-320c) remained significantly different after accounting for multiple comparisons. Disability correlation analysis with miRNA provided 4 miRNAs (hsa-miR-320a, hsa-miR-337-3p, hsa-miR-199a-5p, and hsa-miR-142-5p) that correlated with the EDSS during the internal reproducibility phase. Among these, hsa-miR-337-3p was the most statistically significant miRNA that negatively correlated with the EDSS in three of the MS cohorts tested. Conclusions: These findings further confirm the use of circulating serum miRNAs as biomarkers to diagnose and monitor disease status in MS. Classification of evidence: This study provides Class III evidence that levels of circulating miRNAs identify patients with MS. DOI: 10.1212/NXI.0000000000000491 PMCID: PMC6117192


Immunotherapy-responsive dorsal column myelopathy in a patient with asymptomatic celiac disease.

Bradshaw MJ(1), Yadollahikhales G(1), Venna N(1). Author information: (1)Partners Multiple Sclerosis Center (M.J.B.), Brigham and Women's Hospital; Massachusetts General Hospital (M.J.B., N.V.), Harvard Medical School, Boston, MA; and University of Illinois (G.Y.), Chicago, IL. DOI: 10.1212/NXI.0000000000000487 PMCID: PMC6117186


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313. Neurol Sci. 2018 Sep 3. doi: 10.1007/s10072-018-3551-7. [Epub ahead of print]

The direct costs of multiple sclerosis-study in the Czech Republic.

Maresova P(1), Valis M(2), Novotny M(3), Pavelek Z(2), Kuca K(4). Author information: (1)Department of Economics, Faculty of Informatics and Management, University of Hradec Králové, Hradec Kralove, Czech Republic. (2)Department of Neurology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Kralove, Czech Republic. (3)Biomedical Research Centrum, University Hospital Hradec Králové, Sokolská 581, Hradec Kralove, Czech Republic. (4)Centre of Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, Czech Republic. [email protected]. BACKGROUND: Multiple sclerosis (MS) is a progressive autoimmune disease of the central nervous system that is often disabling and for which there is currently no cure, though disease-modifying treatment is now available. The aim of this study is to describe the current values of the direct costs of multiple sclerosis (MS) in the Czech Republic. METHODS: Attention is focused on direct medical costs. The costs were monitored in the Czech Republic among 5673 patients in the period between 2011 and 2015. These costs included complex, special and targeted visits at the neurologist, blood collection and the costs of hospitalisation. The results refer to the diagnoses according to the International Statistical Classification of Diseases and Related Health Problems. The attention is focused on MS G35 (NS; brain stem; spinal cord; disseminated; generalised). RESULTS: The average total direct costs per patient per year are 4838.1 €. Not every patient has to be hospitalised during the year, and not every patient has prescribed medication. According to the above data, 12% of patients are hospitalised and 55% of patients are prescribed medication. The minimum average cost per patient without medication and hospitalisation is 54.1 €. CONCLUSION: Cost evaluation across countries is difficult due to the different evidence. If only selected direct costs considered in this study are compared, the absolute economics burden increases over time. The only statistically significant difference in the average price and the time spent is between 2012 and 2013, where the correlation value is 0.597. DOI: 10.1007/s10072-018-3551-7


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314. Neurol Sci. 2018 Sep 25. doi: 10.1007/s10072-018-3582-0. [Epub ahead of print]

Health-related quality of life in clinically isolated syndrome and risk of conversion to multiple sclerosis.

Baldin E(1), Riise T(2)(3), Mattarozzi K(4), Gajofatto A(5), Granella F(6), Leone M(7), Lugaresi A(8), Malagù S(9), Motti L(10), Neri W(11), Pesci I(12), Santangelo M(13), Scandellari C(1), Tola MR(14), Vignatelli L(1), Zenesini C(1), D'Alessandro R(15); G.E.Ro.N.I.Mu.S. study group. Author information: (1)IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. (2)Department of Global Public Health and Primary Care, Bergen University, Bergen, Norway. (3)The Norwegian Multiple Sclerosis Competence Center, Haukeland University Hospital, Bergen, Norway. (4)Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. (5)Neurology Unit B, University Hospital of Verona, Verona, Italy. (6)Department of Medicine and Surgery, University of Parma, Parma, Italy. (7)SC Neurology, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. (8)Multiple Sclerosis Center, Department of Neuroscience and Imaging, University "G. D'Annunzio", Chieti-Pescara, Italy. (9)Neurology Unit, "Bufalini" Hospital, Cesena, Italy. (10)Neurology Unit, Arcispedale S. Maria Nuova, Reggio Emilia, Italy. (11)Neurology Unit, Multiple Sclerosis Center, G.B.Morgagni-L.Pierantoni Hospital, Forlì, Italy. (12)Neurology Unit, AUSL Parma, Fidenza Hospital, Fidenza, Parma, Italy. (13)Neurology Unit, Ramazzini Hospital, Carpi, Modena, Italy. (14)Neurology Unit, Department of Neuroscience, University Hospital of Ferrara, Ferrara, Italy. (15)IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. [email protected]. BACKGROUND AND OBJECTIVES: A few studies have found that low scores on self-rated health and quality of life measures are associated with following worsening disability in multiple sclerosis (MS). We wanted to estimate the association between self-rated quality of life scores among patients with clinically isolated syndrome (CIS) and the risk of subsequent conversion to definite MS. METHODS: One hundred sixty-two patients from the GERONIMUS cohort with a symptom or sign suggestive of MS and without a definite diagnosis of MS at the time of inclusion were asked to evaluate their health-related quality of life according to MSQoL-54 scale. They were clinically assessed and mood and depression scales were applied. The association between the scores of these scales and the risk of converting to definite MS during a 5-year follow-up was estimated using the Cox- proportional hazard regression model. RESULTS: Quality of life at examination was significantly lower compared to those of an age- and sex-adjusted general Italian population. During the follow-up, 116 patients (72%) converted to definite MS. No significant predictive effects were found for the summary scales of MSQol-54 or other scales. The estimates did not change after adjusting for age, sex, BMI, education, MRI findings, Expanded Disability Status Scale (EDSS) score, and treatment at time of examination. CONCLUSION: Persons with CIS in this cohort reported reduced self-rated quality of life compared to the general population, but variation in these scores was not associated with subsequent conversion from CIS to clinical definite MS. DOI: 10.1007/s10072-018-3582-0


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315. Neurol Sci. 2018 Aug 31. doi: 10.1007/s10072-018-3550-8. [Epub ahead of print]

A randomized double-blind trial of comparative efficacy and safety of Avonex and CinnoVex for treatment of relapsing-remitting multiple sclerosis.

Pakdaman H(1), Abbasi M(1), Gharagozli K(1), Ashrafi F(1), Delavar Kasmaei H(1), Amini Harandi A(2). Author information: (1)Brain Mapping Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (2)Brain Mapping Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. [email protected]. BACKGROUND AND AIM: Interferon beta is currently the first line treatment of relapsing-remitting multiple sclerosis (RRMS). Different formulations of interferon beta are available. Avonex and CinnoVex are two interferon beta-1a being prescribed by neurologists in Iran. The aim of this study was to compare the four and half year outcome of Avonex and CinnoVex in patients with RRMS. METHODS: A total 186 of patients with definite RRMS diagnosis were followed for four and half years. Patients were randomly assigned to receive either Avonex or CinnoVex. Patients were subsequently visited every 6 months, and MRI was also undertaken prior each visit. The efficacy end points were to compare mean scores of expanded disability status scale (EDSS) and the proportion of patients with MRI and clinical activity in follow-up visits between Avonex and CinnoVex. Safety end point was to compare the percentage of adverse events between two groups. RESULTS: One hundred and eighty-two patients completed the study. The population of study experienced a steady increase in EDSS during follow-up with a mean increase of 1.03. Repeated measures ANOVA revealed no statistically significant difference between Avonex and CinnoVex (p = 0.78). The most common adverse events were headache, myalgia, fatigue, fever, flu symptoms, injection site pain, and depression. Direct comparison of each adverse events revealed no meaningful difference between two groups except for only a few adverse events. There was no statistically significant difference in MRI activity and clinical activity between two groups. CONCLUSION: Avonex and CinnoVex showed similar efficacy and safety outcome in patients with RRMS. DOI: 10.1007/s10072-018-3550-8

316. Neurol Ther. 2018 Aug 30. doi: 10.1007/s40120-018-0110-3. [Epub ahead of print]

Practical Evidence-Based Recommendations for Patients with Multiple Sclerosis Who Want to Have Children.

Fragoso YD(1), Adoni T(2), Brooks JBB(3), Finkelsztejn A(4), da Gama PD(5), Grzesiuk AK(6), Marques VD(7), Parolin MFK(8), Sato HK(9), Varela DL(10), Vasconcelos CCF(11). Author information: (1)Universidade Metropolitana de Santos, Santos, SP, Brazil. [email protected]. (2)Hospital Sirio-Libanes de Sao Paulo, São Paulo, SP, Brazil. (3)Universidade Metropolitana de Santos, Santos, SP, Brazil. (4)Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil. (5)Pontificia Universidade Católica Campus Sorocaba, Sorocaba, SP, Brazil. (6)Neurologic Clinic in Cuiaba, Cuiabá, MT, Brazil. (7)Universidade de Sao Paulo Campus Ribeirao Preto, Ribeirão Prêto, SP, Brazil. (8)Neurologic Clinic in Curitiba, Curitiba, PR, Brazil. (9)Instituto de Neurologia de Curitiba, Curitiba, PR, Brazil. (10)Servico de Neurologia e Neurocirurgia, Passo Fundo, RS, Brazil. (11)Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Multiple sclerosis (MS) management presently aims to reach a state of no (or minimal) evidence of disease activity. The development and commercialization of new drugs has led to a renewed interest in family planning, since patients with MS may face a future with reduced (or no) disease-related neurological disability. The advice of neurologists is often sought by patients who want to have children and need to know more about disease control at conception and during pregnancy and the puerperium. When MS is well controlled, the simple withdrawal of drugs for patients who intend to conceive is not an option. On the other hand, not all treatments presently recommended for MS are considered safe during conception, pregnancy and/or breastfeeding. The objective of the present study was to summarize the practical and evidence-based recommendations for family planning when our patients (women and men) have MS.Funding TEVA Pharmaceutical Brazil. DOI: 10.1007/s40120-018-0110-3


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317. Neurologist. 2018 Sep;23(5):157-159. doi: 10.1097/NRL.0000000000000192.

Wall-eyed Bilateral Internuclear Ophthalmoplegia (WEBINO) in a Patient With Idiopathic Intracranial Hypertension.

Keereman V(1), Platteau E(2), Crevits L(3), Algoed L(4). Author information: (1)Department of Neurology, Ghent University Hospital. (2)Departments of Ophthalmology. (3)Ghent University, Ghent, Belgium. (4)Neurology, AZ Maria Middelares. INTRODUCTION: Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is a variant syndrome of internuclear ophthalmoplegia, consisting of primary gaze exotropia, adduction impairment, nystagmus of the abducting eye, and vertical gaze-evoked nystagmus. It seems to be most frequently associated with multiple sclerosis, although other etiologies such as brainstem ischemia or hydrocephalus have also been described. CASE REPORT: We report the case of a 25-year-old woman who presented with subacute progressive oculomotor disturbances, resulting in the development of a WEBINO over a few days. Fundoscopy showed papilledema first in the right and afterwards also in the left eye. Brain magnetic resonance imaging was normal. Lumbar puncture demonstrated an opening pressure of 38 cm H2O, without pleiocytosis and with normal protein. As no other cause of intracranial hypertension could be identified by imaging or extensive biochemical testing, the patient was treated with acetazolamide for idiopathic intracranial hypertension. As there was further progression despite increase of acetazolamide dosing, more aggressive therapy was pursued, and a ventriculoperitoneal shunt was placed by our neurosurgeons. Clinical follow-up showed progressive recovery of normal oculomotor function and disappearance of papilledema over the course of 6 weeks. CONCLUSIONS: To our knowledge this is the first case description of a patient with WEBINO and idiopathic intracranial hypertension. The diagnosis is supported by the very high opening pressure, the absence of neuroimaging abnormalities, the papilledema, and the response to ventriculoperitoneal drainage. DOI: 10.1097/NRL.0000000000000192

318. Neurology. 2018 Sep 7. pii: 10.1212/WNL.0000000000006329. doi: 10.1212/WNL.0000000000006329. [Epub ahead of print]

Retinal vasculopathy with cerebral leukoencephalopathy (RVCL): A rare mimic of tumefactive MS.

Raynowska J(1), Miskin DP(1), Pramanik B(1), Asiry S(1), Anderson T(1), Boockvar J(1), Najjar S(1), Harel A(2). Author information: (1)From the Department of Internal Medicine (J.R.), Division of Neuro-Immunology, Department of Neurology (D.P.M., A.H.), Division of Neuroradiology, Department of Radiology (B.P.), Division of Neuropathology, Department of Pathology (S.A., T.A.), Department of Neurosurgery (J.B.), and Department of Neurology (S.N.), Lenox Hill Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, NY. (2)From the Department of Internal Medicine (J.R.), Division of Neuro-Immunology, Department of Neurology (D.P.M., A.H.), Division of Neuroradiology, Department of Radiology (B.P.), Division of Neuropathology, Department of Pathology (S.A., T.A.), Department of Neurosurgery (J.B.), and Department of Neurology (S.N.), Lenox Hill Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, NY. [email protected]. OBJECTIVE: We report a series of 2 brothers who each developed tumefactive brain lesions, initially thought to have brain tumors or tumefactive multiple sclerosis (MS), but who were ultimately diagnosed with a rare autosomal dominant condition known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL). METHODS: Case series and literature review. RESULTS: We present 2 brothers who developed tumefactive right frontal brain lesions leading to gait disturbances and cognitive changes. Both brothers also had nonspecific brain calcifications and T2-hyperintense lesions, and both had ophthalmic and liver disease of unclear etiology. The first brother had been extensively evaluated by various specialists, underwent inconclusive brain and liver biopsies, and was ultimately unsuccessfully treated for a diagnosis of tumefactive MS. The second brother also underwent unrevealing evaluation with CSF analysis and brain biopsy. Further family history revealed that the patients' father developed a tumefactive brain lesion in the 1980s and had been diagnosed with CNS vasculitis. Given the familial link, RVCL was suspected, and genetic analysis confirmed the diagnosis with a 3-prime repair exonuclease 1 (TREX1) C-terminal mutation. CONCLUSION: The presence of tumefactive brain lesions, nonspecific brain calcifications, liver disease, and retinal vasculopathy, coupled with suggestive family history, led to the RVCL diagnosis. This report contributes to the limited understanding of RVCL, which can cause brain lesions that mimic gliomas or tumefactive MS. Recognition of this entity may prevent unnecessary invasive procedures and inappropriate therapeutic interventions, and would allow for proper counseling of family members. © 2018 American Academy of Neurology. DOI: 10.1212/WNL.0000000000006329


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Pregnancy rates and outcomes in women with and without MS in the United States.

Houtchens MK(1), Edwards NC(2), Schneider G(2), Stern K(2), Phillips AL(2). Author information: (1)From the Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston; Health Services Consulting Corporation (N.C.E.), Boxborough; formerly with Boston Health Economics, Inc. (G.S.), Waltham; Boston Health Economics (K.S.), Waltham; and EMD Serono, Inc. (A.L.P.), Rockland, MA. [email protected]. (2)From the Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston; Health Services Consulting Corporation (N.C.E.), Boxborough; formerly with Boston Health Economics, Inc. (G.S.), Waltham; Boston Health Economics (K.S.), Waltham; and EMD Serono, Inc. (A.L.P.), Rockland, MA. OBJECTIVE: To compare pregnancy prevalence and complications in women with and without multiple sclerosis (MS). METHODS: This retrospective US administrative claims study used data from January 1, 2006, to June 30, 2015. All data for women with MS were included. A nationally representative 5% random sample from approximately 58 million women without MS was used to compute the dataset. Annual pregnancy rates, identified via diagnosis/procedure codes and adjusted for covariates, were estimated via logistic regression. Claims for pregnancy and labor/delivery complications were compared using propensity score matching. RESULTS: From 2006 to 2014, the adjusted proportion of women with MS and pregnancy increased from 7.91% to 9.47%; the adjusted proportion without MS and with pregnancy decreased from 8.83% to 7.75%. The difference in linear trend (0.17% increase and 0.15% decrease in per-annum pregnancy rates) was significant (t statistic = 7.8; p < 0.0001). After matching (n = 2,115 per group), a higher proportion of women with MS than without had claims for premature labor (31.4% vs 27.4%; p = 0.005), infection (13.3% vs 10.9%; p = 0.016), cardiovascular disease (3.0% vs 1.9%; p = 0.028), anemia/acquired coagulation disorders (2.5% vs 1.3%; p = 0.007), neurologic complications (1.6% vs 0.6%; p = 0.005), sexually transmitted diseases (0.4% vs 0.1%; p = 0.045), acquired fetal damage (27.8% vs 23.5%; p = 0.002), and congenital fetal malformations (13.2% vs 10.3%; p = 0.004). CONCLUSIONS: Pregnancy rates in this population of women with MS have been increasing. High rates of claims for several peripartum complications were observed in women with and those without MS. Claims data provide knowledge of interactions patients have with the health care system and are valuable initial exploratory analyses. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. DOI: 10.1212/WNL.0000000000006384


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Relapses and disease-modifying drug treatment in pregnancy and live birth in US women with MS.

Houtchens MK(1), Edwards NC(2), Phillips AL(2). Author information: (1)From the Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston; Health Services Consulting Corporation (N.C.E.), Boxborough; and EMD Serono, Inc. (A.L.P.), Rockland, MA. [email protected]. (2)From the Partners MS Center (M.K.H.), Brigham and Women's Hospital, Harvard Medical School, Boston; Health Services Consulting Corporation (N.C.E.), Boxborough; and EMD Serono, Inc. (A.L.P.), Rockland, MA. OBJECTIVE: To evaluate relapse rates and disease-modifying drug (DMD) treatment in US women with multiple sclerosis (MS) and a live birth. METHODS: This retrospective administrative claims database study used US commercial health plan data from women with MS and a live birth from January 1, 2006, to June 30, 2015. Relapses and DMD treatment were evaluated 1-year prepregnancy, during pregnancy, during puerperium (6 weeks postpregnancy), and 1-year postpregnancy. Relapse was defined as MS-related hospitalization, emergency room visit, or outpatient visit with corticosteroid prescription within 7 days. Generalized estimating equation models for longitudinal data tested for differences between prepregnancy vs the other time periods. RESULTS: A total of 2,158 patients were eligible. The odds of relapse declined during pregnancy (odds ratio [OR] 0.623, 95% confidence interval [CI] 0.521-0.744; p < 0.0001), increased during puerperium (OR 1.710, 95% CI 1.358-2.152; p < 0.0001), and ended at a higher level during the last 3 postpartum quarters (OR 1.216, 95% CI 1.052-1.406; p = 0.0081). The proportion of women with DMD treatment was rather low overall: approximately 20% prepregnancy, bottoming to 1.9% during the second trimester, and peaking at 25.5% 9 to 12 months postpartum. DMD treatment declined significantly during pregnancy (OR 0.171, 95% CI 0.144-0.203; p < 0.0001), remained lower during puerperium (OR 0.361, 95% CI 0.312-0.418; p < 0.0001), and ended at a higher level during the last 3 postpartum quarters (OR 1.259, 95% CI 1.156-1.371; p < 0.0001). CONCLUSIONS: The rate of MS relapse decreased during pregnancy, increased 6 months postpartum, and decreased 6 to 12 months postpartum. DMD treatment was uncommon in the year before pregnancy, further decreased immediately prepregnancy and during pregnancy, and increased postpartum. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. DOI: 10.1212/WNL.0000000000006382


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Safety and efficacy of venoplasty in MS: A randomized, double-blind, sham-controlled, phase II trial.

Traboulsee AL(1), Machan L(2), Girard JM(2), Raymond J(2), Vosoughi R(2), Hardy BW(2), Emond F(2), Gariepy JL(2), Bone JN(2), Siskin G(2), Klass D(2), Isserow S(2), Illes J(2), Sadovnick AD(2), Li DK(2). Author information: (1)From the University of British Columbia, Departments of Medicine (Neurology) (A.L.T., S.I., J.I., A.D.S.), Radiology (L.M., D.K., D.K.L.), Medical Genetics (A.D.S.), and Statistics (J.N.B.), Vancouver; Centre Hospitalier de l'Université de Montréal (J.M.G., J.R.), Hôpital Notre-Dame, Montreal; Health Sciences Centre (R.V., B.W.H.), Winnipeg; Centre Hospitalier Universitaire de Québec-Université Laval (F.E., J.-L.G.), Hôpital Enfant-Jésus, Quebec, Canada; and Albany Medical Center (G.S.), NY. [email protected]. (2)From the University of British Columbia, Departments of Medicine (Neurology) (A.L.T., S.I., J.I., A.D.S.), Radiology (L.M., D.K., D.K.L.), Medical Genetics (A.D.S.), and Statistics (J.N.B.), Vancouver; Centre Hospitalier de l'Université de Montréal (J.M.G., J.R.), Hôpital Notre-Dame, Montreal; Health Sciences Centre (R.V., B.W.H.), Winnipeg; Centre Hospitalier Universitaire de Québec-Université Laval (F.E., J.-L.G.), Hôpital Enfant-Jésus, Quebec, Canada; and Albany Medical Center (G.S.), NY. OBJECTIVE: To determine the safety and efficacy of balloon vs sham venoplasty of narrowing of the extracranial jugular and azygos veins in multiple sclerosis (MS). METHODS: Patients with relapsing or progressive MS were screened using clinical and ultrasound criteria. After confirmation of >50% narrowing by venography, participants were randomized 1:1 to receive balloon or sham venoplasty of all stenoses and were followed for 48 weeks. Participants and research staff were blinded to intervention allocation. The primary safety outcome was the number of adverse events (AEs) during 48 weeks. The primary efficacy outcome was the change from baseline to week 48 in the patient-reported outcome MS Quality of Life-54 (MSQOL-54) questionnaire. Standardized clinical and MRI outcomes were also evaluated. RESULTS: One hundred four participants were randomized (55 sham; 49 venoplasty) and 103 completed 48 weeks of follow-up. Twenty-three sham and 21 venoplasty participants reported at least 1 AE; one sham (2%) and 5 (10%) venoplasty participants had a serious AE. The mean improvement in MSQOL-54 physical score was +1.3 (sham) and +1.4 (venoplasty) (p = 0.95); MSQOL-54 mental score was +1.2 (sham) and -0.8 (venoplasty) (p = 0.55). CONCLUSIONS: Our data do not support the continued use of venoplasty of extracranial jugular and/or azygous venous narrowing to improve patient-reported outcomes, chronic MS symptoms, or the disease course of MS. CLINICALTRIALSGOV IDENTIFIER: NCT01864941. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with MS, balloon venoplasty of extracranial jugular and azygous veins is not beneficial in improving patient-reported, standardized clinical, or MRI outcomes. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. DOI: 10.1212/WNL.0000000000006423


Pregnancy in multiple sclerosis: Data from an administrative claims database.

Cavalla P(1), Gilmore W(2). Author information: (1)From the MS Center (P.C.), City of Health & Science University Hospital, Turin, Italy; and USC MS Center (W.G.), Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles. (2)From the MS Center (P.C.), City of Health & Science University Hospital, Turin, Italy; and USC MS Center (W.G.), Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles. [email protected]. DOI: 10.1212/WNL.0000000000006371


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Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD.

Shosha E(1), Dubey D(1), Palace J(1), Nakashima I(1), Jacob A(1), Fujihara K(1), Takahashi T(1), Whittam D(1), Leite MI(1), Misu T(1), Yoshiki T(1), Messina S(1), Elsone L(1), Majed M(1), Flanagan E(1), Gadoth A(1), Huebert C(1), Sagen J(1), Greenberg BM(1), Levy M(1), Banerjee A(1), Weinshenker B(1), Pittock SJ(2). Author information: (1)From the Departments of Neurology (E.S., D.D., M.M., E.F., A.G., B.W., S.J.P.), Laboratory Medicine and Pathology (M.M., E.F., A.G., S.J.P.), and Clinical Research Unit (C.H., J.S.), Mayo Clinic College of Medicine, Rochester, MN; Nuffield Department of Clinical Neurosciences (J.P., M.I.L., S.M.), Oxford; The Walton Centre (A.J., D.W., L.E.), NHS Foundation Trust, Liverpool, UK; Department of Neurology (I.N., K.F., T.T., T.M., Y.T.), Tohoku University Graduate School of Medicine, Sendai; Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine and Multiple Sclerosis and Neuromyelitis Optica Center, Southern Tohoku Research Institute for NeuroScience, Koriyama, Japan; Department of Neurology (M.L., A.B.), Johns Hopkins University, Baltimore, MD; Departments of Neurology and Neurotherapeutics (B.M.G.), UT Southwestern Medical Center, Dallas, TX; Department of Neurology (T.T.), Yonezawa National Hospital; and Department of Neurology (I.N.), Tohoku Medical and Pharmaceutical University, Sendai, Japan. (2)From the Departments of Neurology (E.S., D.D., M.M., E.F., A.G., B.W., S.J.P.), Laboratory Medicine and Pathology (M.M., E.F., A.G., S.J.P.), and Clinical Research Unit (C.H., J.S.), Mayo Clinic College of Medicine, Rochester, MN; Nuffield Department of Clinical Neurosciences (J.P., M.I.L., S.M.), Oxford; The Walton Centre (A.J., D.W., L.E.), NHS Foundation Trust, Liverpool, UK; Department of Neurology (I.N., K.F., T.T., T.M., Y.T.), Tohoku University Graduate School of Medicine, Sendai; Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine and Multiple Sclerosis and Neuromyelitis Optica Center, Southern Tohoku Research Institute for NeuroScience, Koriyama, Japan; Department of Neurology (M.L., A.B.), Johns Hopkins University, Baltimore, MD; Departments of Neurology and Neurotherapeutics (B.M.G.), UT Southwestern Medical Center, Dallas, TX; Department of Neurology (T.T.), Yonezawa National Hospital; and Department of Neurology (I.N.), Tohoku Medical and Pharmaceutical University, Sendai, Japan. [email protected]. OBJECTIVE: To define the frequency, duration, and severity of intractable nausea, vomiting, or hiccups in aquaporin-4-immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and propose diagnostic criteria and a severity scale for area postrema syndrome (APS). METHODS: An International NMOSD database was interrogated for frequency of APS. Patients with AQP4-IgG-positive NMOSD completed an APS symptom questionnaire. Nausea and vomiting severity was derived from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score. The diagnostic criteria, severity scale, and immunotherapy response was applied to a prospective validation cohort of patients from multiple centers. RESULTS: Analysis of an international database for AQP4-IgG-seropositive NMOSD (n = 430) revealed a high prevalence of isolated APS attacks (onset 7.1%-10.3%; subsequent 9.4%-14.5%) across continents. For 100 patients with 157 episodes of APS, nausea (n = 127, 81%) lasted for a median of 14 days (range 2-365), vomiting (113, 72%) with a median of 5 episodes/d (2-40) lasted 1-20 minutes, and hiccups (102, 65%) lasted a median of 14 days (2-365). Symptoms consistently and completely resolved following immunotherapy. Data were used to propose APS diagnostic criteria and repurpose PUQE score (hiccups severity grade based on symptom duration). The clinical utility was demonstrated in a prospective validation cohort. CONCLUSION: Isolated APS attacks are frequently encountered both at onset and during the NMOSD course. The diagnostic criteria proposed here will assist clinicians in recognizing APS. Diagnosis of an APS attack earlier than 48 hours is possible if a dorsal medulla lesion is detected. Accurate diagnosis and evaluation of APS attack severity will assist in outcome measurement in NMOSD clinical trials. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. DOI: 10.1212/WNL.0000000000006392


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Incidence and prevalence of MS in children: A population-based study in Ontario, Canada.

Marrie RA(1), O'Mahony J(2), Maxwell C(2), Ling V(2), Yeh EA(2), Arnold DL(2), Bar-Or A(2), Banwell B(2); Canadian Pediatric Demyelinating Disease Network. Collaborators: Wambera K, Connolly MB, Yager J, Mah JK, Sebire G, Callen D, Meaney B, Dilenge ME, Lortie A, Pohl D, Doja A, Venkateswaran S, Levin S, MacDonald EA, Meek D, Wood E, Buckley D, Awuku M, Baird JB, Bhan V. Author information: (1)From the Departments of Internal Medicine and Community Health Sciences (R.A.M.), Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg; Institute of Health Policy, Management and Evaluation (J.O.), University of Toronto, the Hospital for Sick Children; Schools of Pharmacy and Public Health and Health Systems (C.M.), University of Waterloo; Institute for Clinical Evaluative Sciences (C.M., V.L.), Toronto; Department of Pediatrics (E.A.Y.), University of Toronto; Division of Neurology, Neurosciences and Mental Health (E.A.Y.), the Hospital for Sick Children, SickKids Research Institute, Toronto; Montreal Neurological Institute (D.L.A.), McGill University, Montreal, Canada; Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology (A.B.-O.), Perelman School of Medicine (B.B.), University of Pennsylvania, Philadelphia; and Division of Child Neurology (B.B.), the Children's Hospital of Philadelphia, PA. [email protected]. (2)From the Departments of Internal Medicine and Community Health Sciences (R.A.M.), Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg; Institute of Health Policy, Management and Evaluation (J.O.), University of Toronto, the Hospital for Sick Children; Schools of Pharmacy and Public Health and Health Systems (C.M.), University of Waterloo; Institute for Clinical Evaluative Sciences (C.M., V.L.), Toronto; Department of Pediatrics (E.A.Y.), University of Toronto; Division of Neurology, Neurosciences and Mental Health (E.A.Y.), the Hospital for Sick Children, SickKids Research Institute, Toronto; Montreal Neurological Institute (D.L.A.), McGill University, Montreal, Canada; Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology (A.B.-O.), Perelman School of Medicine (B.B.), University of Pennsylvania, Philadelphia; and Division of Child Neurology (B.B.), the Children's Hospital of Philadelphia, PA. OBJECTIVE: To validate a case definition of multiple sclerosis (MS) in the pediatric population using administrative (health claims) data, and to estimate the incidence and prevalence of MS in the pediatric population for Ontario, Canada. METHODS: We used population-based administrative data to identify persons aged ≤18 years with MS. We assessed the performance of multiple administrative case definitions using a clinical reference cohort including children with MS, children with monophasic demyelinating syndromes, and healthy children; we report sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We applied 2 preferred case definitions to estimate the incidence and prevalence of MS from 2003 to 2014. RESULTS: The Canadian Chronic Disease Surveillance System definition of ≥1 hospitalization or ≥5 physician claims for MS within 2 years had a sensitivity of 81.1%, specificity of 100%, PPV of 100%, and NPV of 86%. The Marrie definition of ≥3 hospital or physician claims for MS ever had a sensitivity of 89.2%, specificity of 100%, PPV of 100%, and NPV of 91.5%. Depending on the administrative case definition used, in 2014, the annual age-standardized annual incidence of MS in the pediatric population ranged from 0.99 to 1.24 per 100,000 population, and the age-standardized prevalence ranged from 4.03 to 6.8 per 100,000 population. The prevalence of MS rose over time. CONCLUSION: Administrative data provide a feasible, valid means of estimating the incidence and prevalence of MS in the pediatric population. MS prevalence in the Ontario pediatric population is among the highest reported in pediatric populations worldwide. © 2018 American Academy of Neurology. DOI: 10.1212/WNL.0000000000006395

325. Neurology. 2018 Sep 11;91(11):538. doi: 10.1212/WNL.0000000000005929.

Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study.

[No authors listed] Erratum for Neurology. 2018 May 15;90(20):e1805-e1814. DOI: 10.1212/WNL.0000000000005929


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326. Neuromolecular Med. 2018 Sep 18. doi: 10.1007/s12017-018-8512-z. [Epub ahead of print]

The FOXP3 rs3761547 Gene Polymorphism in Multiple Sclerosis as a Male-Specific Risk Factor.

Wawrusiewicz-Kurylonek N(1)(2), Chorąży M(3), Posmyk R(4), Zajkowska O(5), Zajkowska A(3), Krętowski AJ(6)(7), Tarasiuk J(3), Kochanowicz J(3), Kułakowska A(3). Author information: (1)Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276, Białystok, Poland. [email protected]. (2)Department of Clinical Genetics, Medical University of Bialystok, Białystok, Poland. [email protected]. (3)Department of Neurology, Medical University of Bialystok, Białystok, Poland. (4)Department of Perinatology, Medical University of Bialystok, Białystok, Poland. (5)Faculty of Applied Informatics and Mathematics, Warsaw University of Life Sciences SGGW, Warsaw, Poland. (6)Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Sklodowskiej-Curie 24A, 15-276, Białystok, Poland. (7)Clinical Research Centre, Medical University of Bialystok, Białystok, Poland. The FOXP3 gene encodes a transcription factor and is predominantly expressed in the CD4+CD25+ regulatory T cells which plays a pivotal role in the maintenance of immune homeostasis. The defect of FOXP3 gene may provide a critical link between autoimmunity and immune deficiency. The purpose of our study was to evaluate the association of chosen polymorphisms of FOXP3 gene (rs3761549, rs3761548, rs3761547) with different clinical multiple sclerosis (MS) data of our relapsing-remitting groups of patients and in control group. The study was performed on a group consisting of 174 relapsing-remitting MS patients, diagnosed under 40 years of life, and 174 healthy volunteers. Genotyping was performed using a real-time PCR-based method by TaqMan Assays. Significant differences in distribution of allele C rs3761547 were found in male MS patients in comparison to the male healthy group (p = 0.046, OR 1.95, CI 95%). No association between MS and the other two polymorphisms was observed in males and females of both studied groups. Our data may suggest that FOXP3 rs3761547 gene polymorphism are related notably with the increased risk of MS development in males patients. To our knowledge this is the first study which indicates gender-specific relation between rs3761547 FOXP3 gene polymorphism and multiple sclerosis. DOI: 10.1007/s12017-018-8512-z


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327. Neuropharmacology. 2018 Aug 30;141:181-191. doi: 10.1016/j.neuropharm.2018.08.038. [Epub ahead of print]

Re-examining the potential of targeting ABHD6 in multiple sclerosis: Efficacy of systemic and peripherally restricted inhibitors in experimental autoimmune encephalomyelitis.

Manterola A(1), Bernal-Chico A(1), Cipriani R(2), Ruiz A(1), Pérez-Samartín A(1), Moreno-Rodríguez M(3), Hsu KL(4), Cravatt BF(5), Brown JM(6), Rodríguez-Puertas R(3), Matute C(7), Mato S(8). Author information: (1)Department of Neurosciences, University of the Basque Country UPV/EHU, 48940, Leioa, Spain; Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28029, Madrid, Spain. (2)Department of Neurosciences, University of the Basque Country UPV/EHU, 48940, Leioa, Spain; Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain. (3)Department of Pharmacology, University of the Basque Country UPV/EHU, 48940, Leioa, Spain. (4)Department of Chemistry, University of Virginia, 22904, Charlottesville, USA. (5)Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 92037, La Jolla, USA. (6)Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, 44195, Cleveland, USA. (7)Department of Neurosciences, University of the Basque Country UPV/EHU, 48940, Leioa, Spain; Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28029, Madrid, Spain. Electronic address: [email protected]. (8)Department of Neurosciences, University of the Basque Country UPV/EHU, 48940, Leioa, Spain; Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain; Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28029, Madrid, Spain. Electronic address: [email protected]. α/β-Hydrolase domain-containing 6 (ABHD6) contributes to the hydrolysis of the major endocannabinoid 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS) and in the periphery. ABHD6 blockade has been proposed as novel strategy to treat multiple sclerosis (MS), based on the observation that the inhibitor WWL70 exerts protective anti-inflammatory effects in experimental autoimmune encephalomyelitis (EAE). According to recent data, WWL70 exhibits off-target anti-inflammatory activity in microglial cells and the potential of ABHD6 as drug target in MS remains controversial. Here we further investigated the role of ABHD6 during autoimmune demyelination by comparing the efficacy of two novel inhibitors with different CNS permeability in vivo. Preventive treatment with the systemically active inhibitor KT182 ameliorated the neurological signs of EAE during the time-course of disease. By contrast, administration of the peripherally restricted compound KT203 was ineffective in attenuating EAE symptomatology. Both inhibitors failed to improve corticospinal tract conduction latency and to attenuate inflammation at EAE recovery phase, despite being equally active at targeting brain ABHD6. Chronic administration of KT182 was associated to a partial loss of brain CB1 receptor coupling ability, suggesting the engagement of CB1 receptor-mediated mechanisms during the EAE disease progression. In cultured neurons, KT182 attenuated NMDA-stimulated excitotoxicity and mitochondrial calcium overload. However, these protective effects were not attributable to ABHD6, as they were not mimicked by the alternative inhibitors KT203, KT195 and WWL70. These results indicate that ABHD6 blockade exerts only modest therapeutic effects against autoimmune demyelination and call into question its utility as novel drug target in MS. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.neuropharm.2018.08.038


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328. Neuropsychiatr Dis Treat. 2018 Sep 11;14:2323-2328. doi: 10.2147/NDT.S150062. eCollection 2018.

Investigation of ischemic and demyelinating lesions by cerebral vasoreactivity based on transcranial Doppler sonography: a comparative study.

Zoghi A(1), Petramfar P(2), Nikseresht A(2), Sakhaee E(1). Author information: (1)Department of Neurology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (2)Clinical Neurology Research Center, Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran, [email protected]. Purpose: Variations of cerebral blood flow in response to hypoxia and hyperoxia in different disease conditions can provide new insights into disease etiopathogenesis. This study aimed to determine the characteristics of cerebral vasoreactivity for ischemia and demyelination. Materials and methods: This case-control study included: 28 patients with lacunar infarctions verified by history, physical examination, and MRI; 28 age- and sex-matched healthy controls; 28 patients with relapsing-remitting multiple sclerosis (MS), based on McDonald criteria; and 28 age- and sex-matched healthy controls for the MS group. Transcranial Doppler sonography was undertaken in all subjects to calculate the mean flow velocity (MFV) of the right middle cerebral artery (MCA) and, after a breath-holding (BH) maneuver, the breath-holding index (BHI) was determined. Results: There was no significant difference of BHI and changes of MFV of the MCA in MS patients compared to controls (1.02 ± 0.4 vs 1.02 ± 0.3, p = 0.993; and 16.8 ± 8.1 vs 11.3 ± 10.8, p = 0.057). BHI in patients with lacunar infarctions was significantly lower (0.8 ± 0.4 vs 1.2 ± 0.3, p < 0.001) compared to controls. The BHI (p = 0.040) and variations of MFV of MCA (p = 0.007) in MS patients were significantly higher than in patients with lacunar infarctions. The vasoreactivity of demyelinating lesions was higher than that of ischemic ones. Conclusion: Therefore, cerebral vasoreactivity determined by transcranial Doppler could be utilized for differentiating demyelinating from ischemic lesions. DOI: 10.2147/NDT.S150062 PMCID: PMC6141114 Conflict of interest statement: Disclosure The authors report no conflicts of interest in this work.


Do eyes with and without optic neuritis in multiple sclerosis age equally?

Lizrova Preiningerova J(1), Grishko A(2), Sobisek L(2), Andelova M(1), Benova B(1), Kucerova K(1), Havrdova EK(1). Author information: (1)Center of Clinical Neuroscience, Department of Neurology, General University Hospital, 1st Faculty of Medicine, Charles University, Prague Czech Republic, [email protected]. (2)Department of Statistics and Probability, University of Economics, Prague, Czech Republic. Purpose: Anterior visual pathway reflects axonal loss caused by both optic neuritis (ON) and neurodegeneration in multiple sclerosis (MS). Although the axonal injury post-ON is thought to be complete by 6 months of onset, most studies using optical coherence tomography (OCT) to evaluate retinal changes as a marker of neurodegeneration exclude eyes with a history of ON or consider them separately. The objective of this study was to assess whether the eyes post-ON (>6 months) show in later years different rate of chronic retinal changes than the fellow eyes not affected by ON. Patients and methods: Fifty-six patients with MS with a history of ON in one eye (ON eyes) and no ON in the fellow (FL) eye, who were followed by OCT for >2 years, were selected from a cohort of patients with MS. Paired eye analysis was performed. Results: Mean interval post-ON at baseline was 5.65 (SD 5.05) years. Mean length of follow-up by OCT was 4.57 years. There was no statistical difference in absolute or relative thinning of retinal nerve fiber layer in peripapillary area between the ON and FL eyes. Conclusion: This study has shown that we do not need to exclude eyes with a history of ON from longitudinal studies of neurodegeneration in MS, provided that we use data outside of the frame of acute changes post-ON. Long-term changes of peripapillary retinal nerve fiber layer in ON and FL eyes are equal. DOI: 10.2147/NDT.S169638 PMCID: PMC6130290 Conflict of interest statement: Disclosure The authors report no conflicts of interest in this work.


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Neurofilament light chain as a biological marker for multiple sclerosis: a meta-analysis study.

Cai L(1), Huang J(1). Author information: (1)Department of Neurology, The First Affiliated Hospital of Nanchang University, Jiangxi, People's Republic of China, [email protected]. Purpose: There is a need for biomarkers in multiple sclerosis (MS) to make an early diagnosis and monitor its progression. This study was designed to evaluate the value of neurofilament light (NFL) chain levels as cerebrospinal fluid (CSF) or blood biomarker in patients with MS by using a quantitative meta-analysis. Methods: The PubMed, Embase, and Web of Science databases were systematically searched for relevant studies. Articles in English that evaluated the utility of NFL in CSF and blood in the diagnosis of MS were included. Data were extracted by two independent researchers. Mean (± SD) NFL concentration for MS patients and control subjects were extracted. Review Manager version 5.3 software with a continuous-variable random-effects model was used to summarize the diagnostic indexes from eligible studies. The Newcastle-Ottawa Scale was used for assessing the quality and risk of bias of included studies. In addition, subgroup analysis and meta-regression were performed to assess potential heterogeneity sources. Results: The meta-analysis included 13 articles containing results from 15 studies. A total of 10 studies measured NFL levels in CSF and five studies measured NFL levels in blood. Data were available on 795 participants in CSF and 1,856 participants in blood. Moreover, CSF NFL in MS patients was higher than that in healthy control groups (pooled standard mean difference [Std.MD]=0.88, 95% CI [0.50, 1.26], P<0.00001) and serum NFL in MS patients was higher than that in control subjects (pooled Std.MD=0.47, 95% CI [0.24, 0.71], P<0.0001). Conclusion: NFL chain has significantly increased in MS patients, which substantially strengthens the clinical evidence of the NFL in MS. The NFL may be used as a prognostic biomarker to monitor disease progression, disease activity, and treatment efficacy in the future. DOI: 10.2147/NDT.S173280 PMCID: PMC6126505 Conflict of interest statement: Disclosure The authors report no conflicts of interest in this work.

331. Neurorehabil Neural Repair. 2018 Sep 12:1545968318798938. doi: 10.1177/1545968318798938. [Epub ahead of print]

Integrative CNS Plasticity With Exercise in MS: The PRIMERS (PRocessing, Integration of Multisensory Exercise-Related Stimuli) Conceptual Framework.

Sandroff BM(1), Motl RW(1), Reed WR(1), Barbey AK(2), Benedict RHB(3), DeLuca J(4)(5). Author information: (1)1 University of Alabama at Birmingham, AL, USA. (2)2 University of Illinois at Urbana-Champaign, Urbana, IL, USA. (3)3 University at Buffalo, State University of New York, NY, USA. (4)4 Kessler Foundation, West Orange, NJ, USA. (5)5 Rutgers Medical School, Newark, NJ, USA. There is a proliferation of research examining the effects of exercise on mobility and cognition in the general population and those with neurological disorders as well as focal research examining possible neural mechanisms of such effects. However, there is seemingly a lack of focus on what it is about exercise, in particular, that drives adaptive central nervous system neuroplasticity. We propose a novel conceptual framework (ie, PRIMERS) that describes such adaptations as occurring via activity-dependent neuroplasticity based on the integrative processing of multisensory input and associated complex motor output that is required for the regulation of physiological systems during exercise behavior. This conceptual framework sets the stage for the systematic examination of the effects of exercise on brain connectivity, brain structure, and molecular/cellular mechanisms that explain improvements in mobility and cognition in the general population and persons with multiple sclerosis (MS). We argue that exercise can be viewed as an integrative, systems-wide stimulus for neurorehabilitation because impaired mobility and cognition are common and co-occurring in MS. DOI: 10.1177/1545968318798938


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332. Neurosci Biobehav Rev. 2018 Sep 3;94:126-148. doi: 10.1016/j.neubiorev.2018.08.016. [Epub ahead of print]

Cognitive-motor interference during gait in patients with Multiple Sclerosis: a mixed methods Systematic Review.

Postigo-Alonso B(1), Galvao-Carmona A(2), Benítez I(3), Conde-Gavilán C(4), Jover A(4), Molina S(4), Peña-Toledo MA(4), Agüera E(4). Author information: (1)Department of Psychology, Universidad Loyola Andalucía, Seville, Spain; Human Neuroscience Lab (HNL), Universidad Loyola Andalucía, Seville, Spain. Electronic address: [email protected]. (2)Department of Psychology, Universidad Loyola Andalucía, Seville, Spain; Human Neuroscience Lab (HNL), Universidad Loyola Andalucía, Seville, Spain; Institute of Biomedical Sciences, Universidad Autónoma de Chile, Santiago, Chile. (3)Department of Psychology, Universidad Loyola Andalucía, Seville, Spain. (4)Dementia and Multiple Sclerosis Unit, Neurology Service, Reina Sofía University Hospital, Córdoba, Spain. BACKGROUND: Cognitive-motor interference (CMI) has been proposed as a valid marker of daily life impairment in Multiple Sclerosis (MS). The heterogeneity and scarce number of studies regarding CMI in MS has hampered the synthesis of the existing evidence. The present systematic review employed a mixed methods approach with the aim of identifying and describing variables under which CMI is particularly useful to assess patients with MS. RESULTS: MS patients showed significant CMI. The motor variables that were most sensitive in detecting significant CMI were velocity (m/s), cadence (steps/min), and double support (% gait cycle), which was also specific for MS. Among the cognitive tasks, Alternate Alphabet and Serial Subtracting 7 s were sensitive, whereas Verbal Fluency were both sensitive and specific to CMI in MS. CONCLUSIONS: CMI should be assessed in MS with a standardised dual task such as the Verbal Fluency task while walking, with measurements of the double support time and the effect on the cognitive task. The clinical usefulness of CMI in the assessment of patients with MS is discussed. Copyright © 2018 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.neubiorev.2018.08.016

333. Neurosci Lett. 2018 Aug 29;685:150-154. doi: 10.1016/j.neulet.2018.08.040. [Epub ahead of print]

Effect of voluntary wheel running on neuroactive steroid levels in murine experimental autoimmune encephalomyelitis.

Mifflin K(1), Baker GB(2), Kerr BJ(3). Author information: (1)Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada. Electronic address: [email protected]. (2)Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada; Department of Psychiatry (NRU), University of Alberta, Edmonton, AB, T6G 2B7, Canada. (3)Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada; Department of Pharmacology, University of Alberta, Edmonton, AB, T6E 2H7, Canada; Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, AB, T6G 2G3, Canada. Increasing evidence from both clinical and animal research has implicated changes in neuroactive steroids (rapid acting steroids that act as allosteric modulators at NMDA and/or GABA-A receptors) in multiple sclerosis. These changes have been linked to clinical differences in disease severity, prevention of disease development, as well as the disease state (relapsing vs progressive) in patients with multiple sclerosis. Previous research has also linked changes in neuroactive steroid levels to the beneficial effects of exercise in certain disorders such as traumatic brain injury and post-traumatic stress disorder. The present study therefore examined whether voluntary wheel running could modulate any of the reported changes in neuroactive steroids associated with the EAE model of multiple sclerosis. Female mice with EAE who ran were found to have significantly increased levels of brain pregnenolone compared to male EAE mice who ran. In contrast, male mice with EAE were found to have significantly higher levels of brain allopregnanolone compared to female mice with EAE regardless of exercise. Overall, these results indicate that exercise has moderate beneficial effects on brain neuroactive steroid levels in EAE. These changes may be related to other beneficial responses to exercise, such as improvements in disease severity, in EAE and/or multiple sclerosis. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.neulet.2018.08.040


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334. Neuroscience. 2018 Sep 15;391:73-80. doi: 10.1016/j.neuroscience.2018.09.007. [Epub ahead of print]

The Short-Term Effect of Slope Walking on Soleus H-Reflexes in People with Multiple Sclerosis.

Hoque MM(1), Sabatier MJ(2), Borich M(3), Kesar T(4), Backus D(5). Author information: (1)Emory University School of Medicine, Dept of Rehabilitation Medicine, 1441 Clifton Road, NE, Atlanta, GA 30322, United States. Electronic address: [email protected]. (2)Emory University School of Medicine, Dept of Rehabilitation Medicine, 1441 Clifton Road, NE, Atlanta, GA 30322, United States; Shepherd Center, 2020 Peachtree Road, NE, Atlanta, GA 30339, United States. Electronic address: [email protected]. (3)Emory University School of Medicine, Dept of Rehabilitation Medicine, 1441 Clifton Road, NE, Atlanta, GA 30322, United States. Electronic address: [email protected]. (4)Emory University School of Medicine, Dept of Rehabilitation Medicine, 1441 Clifton Road, NE, Atlanta, GA 30322, United States. Electronic address: [email protected]. (5)Emory University School of Medicine, Dept of Rehabilitation Medicine, 1441 Clifton Road, NE, Atlanta, GA 30322, United States; Shepherd Center, 2020 Peachtree Road, NE, Atlanta, GA 30339, United States. Electronic address: [email protected]. Downslope walking (DSW) causes H-reflex depression in healthy adults, and thus may hold promise for inducing spinal reflex plasticity in people with Multiple Sclerosis (PwMS). The study purpose was to test the hypothesis that DSW will cause acute depression of spinal excitability in PwMS. Soleus H-reflexes were measured in PwMS (n = 18) before and after 20 min of treadmill walking during three visits. Participants walked on a different slope each visit [level: 0% level walking (LW), upslope: +7.5% treadmill walking with an upslope (USW) or downslope: -7.5% (DSW)]. The soleus Hmax/Mmax ratio was used to measure spinal excitability. Heart rate and ratings of perceived exertion (RPE) were measured during walking. DSW induced the largest change in spinal excitability (a 26.7% reduction in soleus Hmax/Mmax (p = 0.001)), although LW also reduced Hmax/Mmax (-5.3%, p = 0.05). Heart rate (p < 0.001) was lowest for DSW, and RPE for DSW did not exceed "Fairly light". DSW evokes short-term spinal plasticity in PwMS, while requiring no greater effort than LW. Our results suggest that PwMS retain the capacity for DSW-induced short-term spinal reflex modulation previously found in healthy adults. These results may provide a foundation for further investigation of long-term effects of DSW on spinal reflex plasticity and functional ability in PwMS. Copyright © 2018. Published by Elsevier Ltd. DOI: 10.1016/j.neuroscience.2018.09.007


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335. Neurosurg Focus. 2018 Sep;45(3):E3. doi: 10.3171/2018.7.FOCUS18220.

Preoperative evaluation and surgical management of infants and toddlers with drug-resistant epilepsy.

Pindrik J(1)(2), Hoang N(2), Smith L(2), Halverson M(3), Wojnaroski M(4), McNally K(4), Gedela S(5), Ostendorf AP(5). Author information: (1)Division of Pediatric Neurosurgery, Department of Neurosurgery. (2)Department of Neurological Surgery, The Ohio State University College of Medicine; and. (3)Division of Pediatric Neuroradiology, Department of Radiology, and. (4)Section of Pediatric Psychology and Neuropsychology, Department of Pediatrics, Nationwide Children's Hospital. (5)Division of Child Neurology, Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio. OBJECTIVE Despite perioperative risks, epilepsy surgery represents a legitimate curative or palliative treatment approach for children with drug-resistant epilepsy (DRE). Several factors characterizing infants and toddlers with DRE create unique challenges regarding optimal evaluation and management. Epilepsy surgery within children < 3 years of age has received moderate attention in the literature, including mainly case series and retrospective studies. This article presents a systematic literature review and explores multidisciplinary considerations for the preoperative evaluation and surgical management of infants and toddlers with DRE. METHODS The study team conducted a systematic literature review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, targeting studies that investigated children < 3 years of age undergoing surgical treatment of DRE. Using the PubMed database, investigators selected peer-reviewed articles that reported seizure outcomes with or without developmental outcomes and/or perioperative complications. Studies were eliminated based on the following exclusion criteria: sample size < 5 patients; and inclusion of patients > 3 years of age, when demographic and outcomes data could not be separated from the cohort of patients < 3 years of age. RESULTS The study team identified 20 studies published between January 1990 and May 2017 that satisfied eligibility criteria. All selected studies represented retrospective reviews, observational studies, and uncontrolled case series. The compiled group of studies incorporated 465 patients who underwent resective or disconnective surgery (18 studies, 444 patients) or vagus nerve stimulator insertion (2 studies, 21 patients). Patient age at surgery ranged between 28 days and 36 months, with a mean of 16.8 months (1.4 years). DISCUSSION The study team provided a detailed summary of the literature review, focusing on the etiologies, preoperative evaluation, surgical treatments, seizure and developmental outcomes, and potential for functional recovery of infants and toddlers with DRE. Additionally, the authors discussed special considerations in this vulnerable age group from the perspective of multiple disciplines. CONCLUSIONS While presenting notable challenges, pediatric epilepsy surgery within infants and toddlers (children < 3 years of age) offers significant opportunities for improved seizure frequency, neuro-cognitive development, and quality of life. Successful evaluation and treatment of young children with DRE requires special consideration of multiple aspects related to neurological and physiological immaturity and surgical morbidity. DOI: 10.3171/2018.7.FOCUS18220


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336. Neurourol Urodyn. 2018 Aug 31. doi: 10.1002/nau.23804. [Epub ahead of print]

The Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ-15): Validation of the Dutch version in patients with multiple sclerosis and spinal cord injury.

Noordhoff TC(1), Scheepe JR(1), 't Hoen LA(1), Sluis TAR(2), Blok BFM(1). Author information: (1)Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands. (2)Department of Rehabilitation, Rijndam Rehabilitation, Rotterdam, The Netherlands. AIMS: The Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ-15) evaluates symptoms of sexual dysfunction in patients with multiple sclerosis (MS). The objective of this study was to provide and validate a Dutch version of the MSISQ-15 in patients with neurological disease such as MS and spinal cord injury (SCI). METHODS: The linguistic validation process of the original English MSISQ-15 into Dutch was performed according to standardized guidelines. Sexually active patients with MS or spinal cord disorders, including SCI and cauda equine syndrome, who visited a tertiary urology center or a rehabilitation center completed the MSISQ-15, Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) in women, or International Index of Erection Function (IIEF-15) in men at baseline (test) and 2 weeks later (retest). A reference group recruited from a general medical practice completed the questionnaires once. Data were analyzed for measurement properties. RESULTS: Fifty-three patients with MS, 49 patients with spinal cord disorder, and 50 references were included. Content validity was adequate. Internal consistency (Cronbach's alpha >0.8) and reproducibility (intraclass correlation coefficient >0.8) of the MSISQ-15 were excellent. Patients' MSISQ-15 scores were correlated with severity of symptoms of sexual dysfunction measured by PISQ-12 or IIEF-15 and confirmed positive rating for criterion validity. MSISQ-15 scores in patients were higher than in references (on a scale of 15-75: 38.9 ± 11.4 vs 21.1 ± 5.4; P < 0.001), indicating good construct validity. CONCLUSIONS: The Dutch MSISQ-15 is a reliable and valid measure to evaluate symptoms of sexual dysfunction in patients with MS or with SCI. © 2018 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc. DOI: 10.1002/nau.23804

337. Neurourol Urodyn. 2018 Aug 31. doi: 10.1002/nau.23774. [Epub ahead of print]

A pilot randomized-controlled trial of the urodynamic efficacy of mirabegron for patients with neurogenic lower urinary tract dysfunction.

Welk B(1), Hickling D(2), McKibbon M(3), Radomski S(4), Ethans K(5). Author information: (1)Department of Surgery and Epidemiology and Biostatistics, Western University, London, Ontario, Canada. (2)Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada. (3)St Josephs Hospital, London, Ontario, Canada. (4)Department of Surgery, University of Toronto, Toronto, Ontario, Canada. (5)Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. AIMS: To determine the effectiveness of mirabegron in patients with neurogenic lower urinary tract dysfunction. METHODS: Randomized, double-blind, placebo-controlled study. Canadian patients with spinal cord injury (SCI) or multiple sclerosis (MS) with urinary symptoms and incontinence were recruited. Patients were randomized to mirabegron 25 mg (or an identical placebo) for 2 weeks at which point a dose escalation to mirabegron 50 mg (or an identical placebo) was maintained for 8 weeks. Urodynamics were performed before and after treatment. The primary outcome measure was maximum cystometric capacity (MCC). Intention to treat analysis and ANCOVA models (with adjustment for baseline values) were used and marginal means (MM) are reported; P-value <0.05 was considered significant. RESULTS: Sixteen (9 SCI and 7 MS) patients were randomized to mirabegron and 16 (10 SCI and 6 MS) to placebo. At study completion, there was no significant difference in MCC between mirabegron and placebo (MM 305 vs 369 mL, P = 0.20). There was no significant difference in volume at first neurogenic detrusor overactivity (NDO, MM 167 vs 137 mL, P = 0.14) and peak pressure of NDO (MM 69 vs 82 cmH2 O, P = 0.25). There was no significant difference in pad weights or voiding diary parameters. There was a significantly lower symptom burden among those treated with mirabegron (total neurogenic bladder symptom score MM 29 vs 34, P = 0.047). CONCLUSIONS: Among patients with SCI or MS, we demonstrated non-significant trends towards improvement in some urodynamic parameters with mirabegron 50 mg compared to placebo, and a significantly lower neurogenic bladder symptom burden. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/nau.23774


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338. Open Ophthalmol J. 2018 Aug 31;12:247-255. doi: 10.2174/1874364101812010247. eCollection 2018.

Clinical Characteristics, Treatment Outcomes and Predictive Factors in Optic Neuritis.

Hansapinyo L(1), Vivattanaseth C(1). Author information: (1)Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand. Background: The causes, clinical presentations and treatment outcomes of optic neuritis are distinct among different populations. Early diagnosis based on clinical presentations plays an important role in treating optic neuritis patients. Objective: The study aimed to determine clinical characteristics, treatment outcomes and predictive factors of treatment outcomes in optic neuritis patients with and without demyelinating disease. Methods: A retrospective descriptive study of optic neuritis patients carried out between January 2009 and December 2016 was done. Univariate analysis and multivariate logistic regression analysis were used to evaluate the predictive factors of treatment outcomes. Results: Among 150 patients with optic neuritis, 58 patients were diagnosed with Neuromyelitis Optica Spectrum Disease (NMOSD), 23 patients were diagnosed with Multiple Sclerosis (MS) and 69 patients were idiopathic. The age at presentation in the NMOSD group was significantly younger than the MS group and the idiopathic group. The female:male ratio was significantly lower in the idiopathic group than in the NMOSD group. The initial Best Corrected Visual Activity (BCVA) of 20/20-20/60 (p = 0.001) and the idiopathic group (p =0.030) was associated with good visual outcomes. Initial BCVA of < 20/200 (p = 0.009) and the NMOSD group (p < 0.001) was associated with poor visual outcomes. Conclusion: NMOSD is a more common cause of optic neuritis than MS in Thai population. Female patients with poor initial VA, poor response to steroids treatment, and presenting recurrent attacks are highly suspicious for NMOSD. Optic neuritis without associated demyelinating disease has a better visual outcome and lower recurrence rate. DOI: 10.2174/1874364101812010247 PMCID: PMC6131319

339. Pain. 2018 Sep 3. doi: 10.1097/j.pain.0000000000001391. [Epub ahead of print]

Neuropathic Pain and Pain Interference is Linked to Alpha Band Slowing and Reduced Beta Band MEG Activity within the Dynamic Pain Connectome in Patients with Multiple Sclerosis.

Kim JA(1)(2), Bosma RL(1), Hemington KS(1)(2), Rogachov A(1)(2), Osborne NR(1)(2), Cheng JC(1)(2), Oh J(3), Crawley AP(4), Dunkley BT(5), Davis KD(1)(2)(6). Author information: (1)Division of Brain, Imaging, and Behaviour - Systems Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Canada. (2)Institute of Medical Science, University of Toronto, Toronto, Canada. (3)Division of Neurology, Department of Medicine, St. Michael's Hospital, Toronto, Canada. (4)Department of Medical Imaging, University of Toronto, Toronto, Canada. (5)Neurosciences & Mental Health Program, The Hospital for Sick Children Research Institute, Toronto, Canada. (6)Department of Surgery, University of Toronto, Toronto, Canada. Chronic pain is a common occurrence in multiple sclerosis (MS) that severely affects quality of life, but the underlying brain mechanisms related to these symptoms are unknown. Previous electroencephalography (EEG) studies have demonstrated a role of alpha and beta band power in pain processing. However, how and where these brain signals change in MS-related chronic pain is unknown. Here we used resting state magnetoencephalography (MEG) to examine regional spectral power in the dynamic pain connectome - including areas of the ascending nociceptive pathway, default mode network (DMN) and the salience network (SN) - in patients with chronic MS pain and in healthy controls. Each patient was assessed for pain, neuropathic pain, and pain interference with activities of daily living. We found that patients with MS exhibited an increase of alpha band power and a decrease of beta band power, most prominently in the thalamus and the posterior insula of the ascending nociceptive pathway and in the right temporoparietal junction of the SN. In addition, patients with mixed-neuropathic pain exhibited slowing of alpha peak power within the thalamus and the posterior insula, and in the posterior cingulate cortex of the DMN. Finally, pain interference scores in patients with mixed-neuropathic pain were strongly correlated with alpha and beta peak power in the thalamus and posterior insula. These novel findings reveal brain mechanisms of MS-related pain in the ascending nociceptive pathway, SN, and DMN, and that these spectral abnormalities reflect the impact of pain on quality of life measures. DOI: 10.1097/j.pain.0000000000001391


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340. Patient Prefer Adherence. 2018 Aug 23;12:1557-1566. doi: 10.2147/PPA.S175095. eCollection 2018.

Adherence to disease-modifying therapies in patients with multiple sclerosis.

Kołtuniuk A(1), Rosińczuk J(1). Author information: (1)Department of Nervous System Diseases, Faculty of Health Sciences, Wroclaw Medical University, Wroclaw, Poland, [email protected]. Background: Multiple sclerosis (MS) is a chronic, inflammatory progressive demyelinating disease of the central nervous system. MS is one of the main causes of disability among young adults, and its management is a serious challenge for the healthcare system. Purpose: The main purpose of this study was to examine adherence to first-line disease-modifying therapy (DMT) in MS patients using the self-report Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ). Materials and methods: The participants consisted of 226 MS patients (166 women and 60 men) who were treated with first-line immunomodulatory DMT. This study used a questionnaire designed by the authors, which contained questions about sociodemographic data, and the Polish version of the MS-TAQ. Results: The overall adherence was 76.5% according to the first criterion (missed ≥1 injection or tablet). There were no statistically significant differences due to sociodemographic variables between adherent and nonadherent patients. However, patients taking Avonex® significantly more often belonged to the adherent group (P=0.042). The most frequently mentioned reasons why nonadherent patients forget to take the drug included the following: too busy in their daily activities, indisposition to take the drug, unwillingness to take the drug, interference with daily activities, and dissatisfaction with the drug. The degree of adherence among MS patients treated with immunomodulatory drugs is high; however, some patients do not take medications regularly. Conclusion: Due to the utility of the MS-TAQ, the caregivers of MS patients are able to quickly and easily assess the occurrence of side effects, ways to cope with them, and the occurrence of barriers to taking medication. DOI: 10.2147/PPA.S175095 PMCID: PMC6112814 Conflict of interest statement: Disclosure The authors report no conflicts of interest in this work.

341. Perm J. 2018 Aug 30;22. doi: 10.7812/TPP/18-046.

Therapeutic Interferon Interchange in Relapsing Multiple Sclerosis Lowers Health Care and Pharmacy Expenditures with Comparable Safety.

Hahn N(1), Palmer KE(2), Klocke S(3), Delate T(4). Author information: (1)Clinical Pharmacy Specialist in Neurology for Kaiser Permanente Colorado, a Clinical Instructor at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences in Aurora and Clinical Affiliate Faculty at Regis University School of Pharmacy in Denver ([email protected]). (2)Clinical Pharmacy Specialist in the Anticoagulation and Anemia Service for Kaiser Permanente Colorado in Denver ([email protected]). (3)Clinical Pharmacy Specialist in Neurology for Kaiser Permanente Colorado, a Clinical Assistant Professor at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences in Aurora and Clinical Affiliate Faculty at Regis University School of Pharmacy in Denver ([email protected]). (4)Clinical Pharmacy Research Scientist in the Pharmacy Department for Kaiser Permanente Colorado and a Clinical Instructor at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences in Aurora ([email protected]). INTRODUCTION: For patients with a less-active (fewer relapses or complete recovery from relapses, less radiologic burden of disease, or no or limited disease-related disability) relapsing form of multiple sclerosis (MS), interferon (IFN) beta-1b subcutaneous is similar in efficacy to IFN beta-1a intramuscular and subcutaneous. The purpose of this study was to assess the impact of patient interchange from an IFN beta-1a to IFN beta-1b. METHODS: This was a retrospective, pre-post study of adult patients with relapsing MS who underwent interchange from an IFN beta-1a to IFN beta-1b between April 15, 2014, and April 30, 2015. Health care financial and utilization outcomes between the 6 months before and after interchange were compared, and safety outcomes after interchange were assessed. RESULTS: A total of 36 primarily white, middle-age, and female patients underwent interchange. Monthly total health care and pharmacy expenditures decreased by approximately 40% and 44%, respectively, from pre-to-post interchange (p < 0.001). Health care utilization was unchanged (p < 0.05). Seven (43.8%) patients underwent interchange back to IFN beta-1a intramuscular. No patients underwent interchange back to IFN beta-1a subcutaneous. The most common adverse effect reported after interchange was injection-site reaction. CONCLUSION: Health care expenditures decreased and adverse effects were limited among patients with MS who underwent an interchange from an IFN beta-1a to IFN beta-1b. These findings suggest that a therapeutic interchange between IFNs for patients with less-active MS disease is well tolerated. Further research is needed to determine the impact of such an interchange on disease progression. DOI: 10.7812/TPP/18-046 PMCID: PMC6131095


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342. Phlebology. 2018 Sep 14:268355518800104. doi: 10.1177/0268355518800104. [Epub ahead of print]

CCSVI, Chlamydia pneumoniae and multiple sclerosis clarification.

Thibault P(1). Author information: (1)CCSVI Diagnostic Clinic, Broadmeadow, New South Wales, Australia. DOI: 10.1177/0268355518800104

343. Phlebology. 2018 Sep 10:268355518800130. doi: 10.1177/0268355518800130. [Epub ahead of print]

Chronic cerebrospinal venous insufficiency, chlamydia and multiple sclerosis.

Lewis A(1). Author information: (1)Southern Health Care Trust, Portadown, UK. DOI: 10.1177/0268355518800130

344. Physiol Meas. 2018 Sep 12. doi: 10.1088/1361-6579/aae0eb. [Epub ahead of print]

Threshold-based fall detection using the hybrid of tri-axial accelerometer and gyroscope.

Wang FT(1), Chan HL(2), Hsu MH(3), Lin CK(3), Chao PK(4), Chang YJ(5). Author information: (1)Department of Electrical Engineering, Hwa Hsia University of Technology, New Taipei City, TAIWAN. (2)Department of Electrical Engineering, Chang Gung University, 259 Wenhwa 1st Road, Kweishan, Taoyuan, 333, TAIWAN. (3)Department of Electrical Engineering, Chang Gung University, Kwei-Shan, Taoyuan, TAIWAN. (4)Electronic Systems Research Division, National Chung-Shan Institute of Science and Technology, Taoyuan, TAIWAN. (5)School of Physical Therapy and Graduate Institute of Rehabilitation Science, Chang Gung University, Taoyuan, TAIWAN. OBJECTIVE: Falling is an important health maintenance issue for the elderly and people with movement disorders, strokes and multiple sclerosis. With the development of light, low-cost wearable technology, inertia-based fall detection has gained much attention. However, some large movements, such as jumping and postural changes, are frequently confounded with falls. For example, commonly used fall detection methods based on acceleration amplitude produce a large number of false alerts unless they are combined with post-fall posture identification. In this paper, we propose two new inertial parameters to improve the selectivity of threshold-based fall detection methods, and evaluate strategies to distinguish falls from other activities of daily life (ADLs). APPROACH: We define two new inertial parameters, acceleration cubic-product-root magnitude (ACM) and angular velocity cubic-product-root magnitude (AVCM). Along with acceleration magnitude (AM), we test threshold-based fall detection methods based on single parameters and combinations. We collected inertial data on four types of simulated falls and eight types of ADLs from a study with 15 participants wearing a chest-mounted sensor with accelerometer and gyroscope. Two public datasets, UMAFall and Cognent Labs, were also included to evaluate fall detection methods. MAIN RESULTS: We choose the detection threshold with 99% sensitivity and the best possible specificity. The hybrid of AM, ACM and AVCM method had a lower rate of misclassification than single-parameter methods. Leave-one-out cross-validation shows that the hybrid fall detection method can achieve both high specificity and high sensitivity. SIGNIFICANCE: Using multiple inertial parameters improves the specificity of fall detection. © 2018 Institute of Physics and Engineering in Medicine. DOI: 10.1088/1361-6579/aae0eb


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345. Physiother Res Int. 2018 Sep 7:e1741. doi: 10.1002/pri.1741. [Epub ahead of print]

Gait pattern changes after six-minute walk test in persons with multiple sclerosis.

Escudero-Uribe S(1), Hochsprung A(1)(2), Izquierdo-Ayuso G(2). Author information: (1)Neuro-Physiotherapy Room, Multiple Sclerosis Unit, Virgen Macarena Hospital, Seville, Spain. (2)Department of Neurology, Multiple Sclerosis Unit, Virgen Macarena Hospital, Seville, Spain. OBJECTIVE: To examine the effect of induced fatigue on spatiotemporal gait parameters in persons with multiple sclerosis (PwMS) by using 6-min walk test (6MWT). METHODS: A cross-sectional study with a control group (25 healthy persons) was performed. Fifty-six PwMS (37 female) were divided into three groups according to their level of disability, as measured by the expanded disability status scale (EDSS): mild (n = 23, EDSS = 1.0-3.5), moderate (n = 19, EDSS = 4.0-5.5), and severe (n = 12, EDSS = 6.0-6.5). Spatiotemporal gait parameters were measured by the GAITRite electronic walkway before and after 6MWT performance. In addition, to determine the level of fatigue in PwMS, the participants completed the questionnaire modified fatigue impact scale (MFIS) before performing the 6MWT. Statistical analyses were performed to compare intragroup and intergroup differences. RESULTS: Fatigue level was lower in the mild (37.6 ± 20.5) versus moderate (54.3 ± 17.2) versus severe (53.6 ± 12.9) groups (p < 0.05). Significant differences were found among all the groups in terms of the distance walked during the 6MWT (p = 0.001) and of the spatiotemporal gait parameters: gait velocity (cm/s), cadence (steps/min), and step length (cm) decreased and, on the contrary, step time (sec), stance, and double support time (% gait cycle) increased when EDSS scores were higher (p < 0.05). The percentage of change (%) in the spatiotemporal gait parameters, after 6MWT performance, was statistically significant in the moderate and severe groups: gait velocity (-8.8%, -25.9%) and step length (-6.5%, -13.4%) decreased, whereas step time (3.0%, 15.0%), double support time (8.8%, 19.1%), step time asymmetry (32.1%, 64.0%), and single support asymmetry (60.0%, 74.7%) increased (p < 0.05). CONCLUSIONS: Gait pattern worsen after performing a walking-induced fatigue test, such as 6MWT, in moderate-severe PwMS (EDSS ≥ 4.0). Identifying these gait alterations will allow physiotherapists to determine specific therapeutic objectives. Copyright © 2018 John Wiley & Sons, Ltd. DOI: 10.1002/pri.1741

346. PLoS One. 2018 Sep 19;13(9):e0202590. doi: 10.1371/journal.pone.0202590. eCollection 2018.

Therapeutic potential of extracellular vesicles derived from human mesenchymal stem cells in a model of progressive multiple sclerosis.

Laso-García F(1), Ramos-Cejudo J(1), Carrillo-Salinas FJ(2), Otero-Ortega L(1), Feliú A(2), Gómez-de Frutos M(1), Mecha M(2), Díez-Tejedor E(1), Guaza C(2), Gutiérrez-Fernández M(1). Author information: (1)Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autonomous University of Madrid, Madrid, Spain. (2)Functional and Systems Neurobiology Department, Neuroimmunology Group, Cajal Institute, Madrid, Spain. Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication and as possible therapeutic agents in inflammation-mediated demyelinating diseases, including multiple sclerosis (MS). In the present study, we investigated whether intravenously administered EVs derived from mesenchymal stem cells (MSCs) from human adipose tissue might mediate recovery in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease, a progressive model of MS. SJL/J mice were subjected to EV treatment once the disease was established. We found that intravenous EV administration improved motor deficits, reduced brain atrophy, increased cell proliferation in the subventricular zone and decreased inflammatory infiltrates in the spinal cord in mice infected with TMEV. EV treatment was also capable of modulating neuroinflammation, given glial fibrillary acidic protein and Iba-1 staining were reduced in the brain, whereas myelin protein expression was increased. Changes in the morphology of microglial cells in the spinal cord suggest that EVs also modulate the activation state of microglia. The clear reduction in plasma cytokine levels, mainly in the Th1 and Th17 phenotypes, in TMEV mice treated with EVs confirms the immunomodulatory ability of intravenous EVs. According to our results, EV administration attenuates motor deficits through immunomodulatory actions, diminishing brain atrophy and promoting remyelination. Further studies are necessary to establish EV delivery as a possible therapy for the neurodegenerative phase of MS. DOI: 10.1371/journal.pone.0202590 Conflict of interest statement: The authors have declared that no competing interests exist.


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In vivo conversion of astrocytes into oligodendrocyte lineage cells with transcription factor Sox10; Promise for myelin repair in multiple sclerosis.

Mokhtarzadeh Khanghahi A(1), Satarian L(1), Deng W(2), Baharvand H(1)(3), Javan M(1)(4). Author information: (1)Department of Brain Sciences and Cognition, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. (2)Institute for Pediatric Regenerative Medicine, University of California, Davis, School of Medicine, Sacramento, California, United States of America. (3)Department of Developmental Biology, University of Science and Culture, Tehran, Iran. (4)Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Recent studies demonstrate that astroglial cells can be directly converted into functional neurons or oligodendrocytes. Here, we report that a single transcription factor Sox10 could reprogram astrocytes into oligodendrocyte-like cells, in vivo. For transdifferentiation, Sox10-GFP expressing viral particles were injected into cuprizone-induced demyelinated mice brains after which we assessed for the presence of specific oligodendrocyte lineage cell markers by immunohistofluorescence (IHF). As control, another group of demyelinated mice received GFP expressing viral particles. After 3 weeks, the majority of transduced (GFP+) cells in animals which received control vector were astrocytes, while in animals which received Sox10-GFP vector, the main population of GFP+ cells were positive for oligodendrocyte lineage markers. We also extracted primary astrocytes from mouse pups and purified them. Primary astrocytes were transduced in vitro and then transplanted into demyelinated brains for later fate mapping. After three weeks, in vitro transduced and then transplanted astrocytes showed oligodendrocyte progenitor and mature oligodendrocyte markers. Further confirmation was done by transduction of astrocytes with lentiviral particles that expressed Sox10 and GFP and their culture in the oligodendrocyte progenitor medium. The induced cells expressed oligodendrocyte progenitor cells (iOPCs) markers. Our findings showed the feasibility of reprogramming of astrocytes into oligodendrocyte-like cells in vivo, by using a single transcription factor, Sox10. This finding suggested a master regulatory role for Sox10 which enabled astrocytes to change their fate to OPC-like cells and establish an oligodendroglial phenotype. We hope this approach lead to effective myelin repair in patients suffering from myelination deficit. DOI: 10.1371/journal.pone.0203785 PMCID: PMC6136770 Conflict of interest statement: The authors have declared that no competing interests exist.


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Longitudinal study of multiple sclerosis lesions using ultra-high field (7T) multiparametric MR imaging.

Chawla S(1)(2), Kister I(3), Sinnecker T(4), Wuerfel J(4), Brisset JC(1), Paul F(5)(6), Ge Y(1). Author information: (1)Center for Advanced Imaging Innovation and Research (CAI2R) and Bernard and Irene Schwartz Center for Biomedical Imaging, Departments of Radiology, New York, New York, United States of America. (2)Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. (3)Department of Neurology, New York University School of Medicine, New York, NY United States of America. (4)Medical Image Analysis Center AG, Basel, Switzerland. (5)NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. (6)Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany. Pathophysiology of multiple sclerosis (MS) lesions is dynamic and changes over time. The purpose of this exploratory study was to determine the longitudinal changes in MS lesions over time on ultra-high field MR imaging. Nine patients with MS underwent high-resolution 3D-susceptibility weighted imaging (SWI) and 2D-gradient-echo-T2*-weighted imaging on 7T MRI at baseline and after ~2.4 years of follow-up. Morphologic imaging characteristics, signal intensity patterns and quantitative susceptibility mapping (QSM) values of lesions were recorded at both time points. Lesions were classified as "iron-laden" if they demonstrated hypointense signal on T2*-weighted images and/or SWI as well as hyperintense signal on QSM. Lesions were considered "non-iron-laden" if they were hyperintense on T2*/SWI and isointense or hyperintense on QSM. Total of 162 non-iron-laden and 29 iron-laden lesions were observed at baseline. No change in baseline lesion size during follow up was recorded in 92.7%; no change in lesion-vessel relationship in 86.5%; and no change in signal intensity pattern in 96.9% of lesions. Three lesions which were non-iron-laden at baseline, exhibited iron at follow-up. In two iron-laden lesions, redistribution of iron content was observed at follow-up. Two-thirds of these iron-laden lesions showed an increase in QSM at follow-up relative to baseline, and the remaining one-third exhibited decrease in QSM. Most of the newly formed lesions (11/13, 84.6%) at follow-up were iron-laden. 7T multiparametric MRI is a useful tool for tracking the evolution of MS lesions, especially with regard to changes in iron content. DOI: 10.1371/journal.pone.0202918 PMCID: PMC6136714 Conflict of interest statement: The authors have declared that no competing interests exist.

349. Pract Neurol. 2018 Sep 22. pii: practneurol-2018-001945. doi: 10.1136/practneurol-2018-001945. [Epub ahead of print]

New MS diagnostic criteria in practice.

De Angelis F(1), Brownlee WJ(1)(2), Chard DT(1)(2), Trip SA(3)(2). Author information: (1)Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK. (2)National Hospital for Neurology and Neurosurgery, UCLH NHS Foundation Trust, London, UK. (3)Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, Faculty of Brain Sciences, UCL, London, UK [email protected]. DOI: 10.1136/practneurol-2018-001945 Conflict of interest statement: Competing interests: WJB reports personal fees from Roche and personal fees from Merck Serono, outside the submitted work. DTC has received, within the last 2 years, honoraria (paid to his employer) from Excemed for faculty-led education work, and meeting expenses from Novartis and Société des Neurosciences, outside the submitted work. SAT reports a personal fee from Roche, a personal fee and non-financial support from Novartis, a personal fee from Merck Serono, personal fees and non-financial support from Teva, and non-financial support from Biogen, all outside the submitted work.


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350. Pract Neurol. 2018 Sep 21. pii: practneurol-2018-002038. doi: 10.1136/practneurol-2018-002038. [Epub ahead of print]

Disseminated nocardiosis with cerebral and subcutaneous lesions on low-dose prednisone.

Mahajan KR(1). Author information: (1)Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH 44195, USA [email protected]. This case report is of a septuagenarian man on chronic low-dose prednisone who presented with disseminated nocardiosis (Nocardia cyriacigeorgica) that was initially mistaken for metastatic brain cancer. Neurologists should be aware of the potential for opportunistic infections with steroid use and to consider a definite tissue diagnosis with culture and histopathology prior to treatment. © Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ. DOI: 10.1136/practneurol-2018-002038 Conflict of interest statement: Competing interests: None declared.

351. Proc Natl Acad Sci U S A. 2018 Sep 25;115(39):9773-9778. doi: 10.1073/pnas.1810470115. Epub 2018 Sep 7.

Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease.

Häusler D(1), Häusser-Kinzel S(1), Feldmann L(1), Torke S(1), Lepennetier G(2), Bernard CCA(3)(4), Zamvil SS(5)(6), Brück W(1), Lehmann-Horn K(2)(7), Weber MS(8)(9). Author information: (1)Institute of Neuropathology, University Medical Center, 37099 Göttingen, Germany. (2)Department of Neurology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. (3)Monash Regenerative Medicine Institute, Monash University, 3800 Melbourne, Australia. (4)Multiple Sclerosis Research Group, Monash University, 3800 Melbourne, Australia. (5)Department of Neurology, University of California, San Francisco, CA 94158. (6)Program in Immunology, University of California, San Francisco, CA 94158. (7)Munich Cluster for Systems Neurology (SyNergy), 81675 Munich, Germany. (8)Institute of Neuropathology, University Medical Center, 37099 Göttingen, Germany; [email protected]. (9)Department of Neurology, University Medical Center, 37099 Göttingen, Germany. The anti-CD20 antibody ocrelizumab, approved for treatment of multiple sclerosis, leads to rapid elimination of B cells from the blood. The extent of B cell depletion and kinetics of their recovery in different immune compartments is largely unknown. Here, we studied how anti-CD20 treatment influences B cells in bone marrow, blood, lymph nodes, and spleen in models of experimental autoimmune encephalomyelitis (EAE). Anti-CD20 reduced mature B cells in all compartments examined, although a subpopulation of antigen-experienced B cells persisted in splenic follicles. Upon treatment cessation, CD20+ B cells simultaneously repopulated in bone marrow and spleen before their reappearance in blood. In EAE induced by native myelin oligodendrocyte glycoprotein (MOG), a model in which B cells are activated, B cell recovery was characterized by expansion of mature, differentiated cells containing a high frequency of myelin-reactive B cells with restricted B cell receptor gene diversity. Those B cells served as efficient antigen-presenting cells (APCs) for activation of myelin-specific T cells. In MOG peptide-induced EAE, a purely T cell-mediated model that does not require B cells, in contrast, reconstituting B cells exhibited a naive phenotype without efficient APC capacity. Our results demonstrate that distinct subpopulations of B cells differ in their sensitivity to anti-CD20 treatment and suggest that differentiated B cells persisting in secondary lymphoid organs contribute to the recovering B cell pool. Copyright © 2018 the Author(s). Published by PNAS. DOI: 10.1073/pnas.1810470115 Conflict of interest statement: The authors declare no conflict of interest.


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352. Proc Natl Acad Sci U S A. 2018 Sep 25;115(39):E9182-E9191. doi: 10.1073/pnas.1808648115. Epub 2018 Sep 4.

Engineered DNA plasmid reduces immunity to dystrophin while improving muscle force in a model of gene therapy of Duchenne dystrophy.

Ho PP(1), Lahey LJ(2)(3), Mourkioti F(4), Kraft PE(4), Filareto A(4), Brandt M(4), Magnusson KEG(4), Finn EE(5)(6)(7), Chamberlain JS(5)(6)(7), Robinson WH(2)(3), Blau HM(4), Steinman L(8). Author information: (1)Department of Neurology, Stanford University, Stanford, CA 94304. (2)Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94304. (3)Department of Medicine, Division of Immunology and Rheumatology, Veteran Affairs Palo Alto Health Care System, Palo Alto, CA 94304. (4)Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305. (5)Department of Neurology, Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, Seattle, WA 98195. (6)Department of Medicine, Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, Seattle, WA 98195. (7)Department of Biochemistry, Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington, Seattle, WA 98195. (8)Department of Neurology, Stanford University, Stanford, CA 94304; [email protected]. Comment in Proc Natl Acad Sci U S A. 2018 Sep 25;115(39):9652-9654. In gene therapy for Duchenne muscular dystrophy there are two potential immunological obstacles. An individual with Duchenne muscular dystrophy has a genetic mutation in dystrophin, and therefore the wild-type protein is "foreign," and thus potentially immunogenic. The adeno-associated virus serotype-6 (AAV6) vector for delivery of dystrophin is a viral-derived vector with its own inherent immunogenicity. We have developed a technology where an engineered plasmid DNA is delivered to reduce autoimmunity. We have taken this approach into humans, tolerizing to myelin proteins in multiple sclerosis and to proinsulin in type 1 diabetes. Here, we extend this technology to a model of gene therapy to reduce the immunogenicity of the AAV vector and of the wild-type protein product that is missing in the genetic disease. Following gene therapy with systemic administration of recombinant AAV6-microdystrophin to mdx/mTRG2 mice, we demonstrated the development of antibodies targeting dystrophin and AAV6 capsid in control mice. Treatment with the engineered DNA construct encoding microdystrophin markedly reduced antibody responses to dystrophin and to AAV6. Muscle force in the treated mice was also improved compared with control mice. These data highlight the potential benefits of administration of an engineered DNA plasmid encoding the delivered protein to overcome critical barriers in gene therapy to achieve optimal functional gene expression. DOI: 10.1073/pnas.1808648115 Conflict of interest statement: Conflict of interest statement: Stanford University has filed a provisional patent application on behalf of P.P.H. and L.S. claiming some of the concepts contemplated in this publication. L.S. and Reinhard Hohlfeld are coauthors on a 2017 Commentary.


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353. Psychiatry Res Neuroimaging. 2018 Sep 22;281:78-84. doi: 10.1016/j.pscychresns.2018.09.005. [Epub ahead of print]

Exploring mania-associated white matter injury by comparison with multiple sclerosis: a diffusion tensor imaging study.

Piaggio N(1), Schiavi S(2), Martino M(3), Bommarito G(1), Inglese M(4), Magioncalda P(5). Author information: (1)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Neurology, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy. (2)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Neurology, University of Genoa, Genoa, Italy. (3)IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genova, Genoa, Italy. Electronic address: [email protected]. (4)Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Neurology, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Department of Neurology, Radiology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, United States. (5)IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genova, Genoa, Italy. Bipolar disorder (BD), especially in its active phases, has shown some neuroimaging and immunological similarities with multiple sclerosis (MS). The objective of this study was to compare white matter (WM) alterations in BD patients in manic phase (M-BD) and MS patients at early stage of disease and with low lesion burden. We compared diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD) in a priori selected WM regions (i.e., corpus callosum and cingulum) betwixt 23 M-BD, 23 MS patients and 46 healthy controls. Both M-BD and MS showed WM changes in the corpus callosum, which, however, showed a greater impairment in MS patients. However, considering the different sub-regions of corpus callosum separately (i.e., genu, body, splenium), M-BD and MS presented an opposite pattern in spatial distribution of WM microstructure alterations, with a greater impairment in the anterior region in M-BD and in the posterior region in MS. Common features as well as divergent patterns in DTI changes are detected in M-BD and early MS, prompting a deeper investigation of analogies and differences in WM and immunological alterations of these disorders. Copyright © 2018 Elsevier B.V. All rights reserved. DOI: 10.1016/j.pscychresns.2018.09.005


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354. Psychopharmacology (Berl). 2018 Sep 22. doi: 10.1007/s00213-018-5037-y. [Epub ahead of print]

Probability discounting of treatment decisions in multiple sclerosis: associations with disease knowledge, neuropsychiatric status, and adherence.

Bruce JM(1)(2), Bruce AS(3)(4), Lynch S(5), Thelen J(6), Lim SL(6), Smith J(6), Catley D(3), Reed DD(7)(8), Jarmolowicz DP(7)(8). Author information: (1)Department of Psychology, University of Missouri - Kansas City, 5030 Cherry Hall, Kansas City, MO, 64110, USA. [email protected]. (2)Department of Biomedical and Health Informatics, University of Missouri - Kansas City, Kansas City, MO, USA. [email protected]. (3)Center for Healthy Lifestyles and Nutrition, Children's Mercy Hospital, Kansas City, MO, USA. (4)Department of Pediatrics, University of Kansas Medical Center, Kansas City, KS, USA. (5)Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA. (6)Department of Psychology, University of Missouri - Kansas City, 5030 Cherry Hall, Kansas City, MO, 64110, USA. (7)Department of Applied Behavior Science, University of Kansas, Lawrence, KS, USA. (8)Cofrin-Logan Center for Addiction Research and Treatment, Lawrence, KS, USA. RATIONALE: Patients weigh risks and benefits when making treatment decisions. Despite this, relatively few studies examine the behavioral patterns underpinning these decisions. Moreover, individual differences in these patterns remain largely unexplored. OBJECTIVES: The purpose of this study was to test a probability discounting model to explain the independent influences of risks and benefits when patients make hypothetical treatment decisions. Furthermore, we examine how individual differences in this probability discounting function are associated with patient demographics, clinical characteristics, disease knowledge, neuropsychiatric status, and adherence. METHODS: Two hundred eight participants with relapsing-remitting multiple sclerosis (MS) indicated their likelihood (0-100%) of taking a hypothetical medication as the probability of mild side effects (11 values from .1 to 99.9%) and reported medication efficacies (11 values from .1 to 99.9%) varied systematically. They also completed a series of questionnaires and cognitive tests. RESULTS: Individual components of medication treatment decision making were successfully described with a probability discounting model. High rates of discounting based on risks were associated with poor treatment adherence and less disease-specific knowledge. In contrast, high rates of discounting of benefits was associated with poorer cognitive functioning. Regression models indicated that risk discounting predicted unique variance in treatment adherence. CONCLUSIONS: Insights gained from the present study represent an important early step in understanding individual differences associated with medical decision making in MS. Future research may wish to use this knowledge to inform the development of empirically supported adherence interventions. DOI: 10.1007/s00213-018-5037-y

355. Qual Health Res. 2018 Sep 10:1049732318796831. doi: 10.1177/1049732318796831. [Epub ahead of print]

The Mindful Body: A Phenomenology of the Body With Multiple Sclerosis.

Meide HV(1)(2), Teunissen T(3), Collard P(2), Visse M(2), Visser LH(2)(4). Author information: (1)1 Tilburg University, Tilburg, The Netherlands. (2)2 University of Humanistic Studies, Utrecht, The Netherlands. (3)3 Amsterdam UMC, Amsterdam, The Netherlands. (4)4 Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands. For people living with multiple sclerosis (MS), one's own body may no longer be taken for granted but may become instead an insistent presence. In this article, we describe how the body experience of people with MS can reflect an ongoing oscillation between four experiential dimensions: bodily uncertainty, having a precious body, being a different body, and the mindful body. People with MS can become engaged in a mode of permanent bodily alertness and may demonstrate adaptive responses to their ill body. In contrast to many studies on health and illness, our study shows that the presence of the body may not necessarily result in alienation or discomfort. By focusing the attention on the body, a sense of well-being can be cultivated and the negative effects of MS only temporarily dominate experience. Rather than aiming at bodily dis-appearance, health care professionals should therefore consider ways to support bodily eu-appearance. DOI: 10.1177/1049732318796831


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356. Qual Life Res. 2018 Sep 20. doi: 10.1007/s11136-018-2005-2. [Epub ahead of print]

The 88-item Multiple Sclerosis Spasticity Scale: a Rasch validation of the Italian version and suggestions for refinement of the original scale.

Pellicciari L(1), Ottonello M(2), Giordano A(3), Albensi C(4), Franchignoni F(5). Author information: (1)Unit of Functional Rehabilitation, Azienda USL Toscana Centro, Via Rozzalupi, 57, 50053, Empoli, FI, Italy. [email protected]. (2)Department of Physical & Rehabilitation Medicine, ICS Maugeri SpA SB, Via Missolungi, 14, 16167, Nervi, GE, Italy. (3)Bioengineering Service, ICS Maugeri SpA SB, Via Revislate, 13, 28010, Veruno, NO, Italy. (4)Specialty School in Physical and Rehabilitation Medicine, Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Viale Montpellier, 1, 00133, Rome, Italy. (5)Department of Physical Medicine and Rehabilitation, ICS Maugeri SpA SB, Via Bernasconi 16, 20035, Lissone, MB, Italy. BACKGROUND: In multiple sclerosis (MS), the impact of spasticity on the patient's life is a key issue, and it is fundamental that existing tools measuring the patient's perspective undergo psychometric analysis and refinement to optimize confidence in their use in clinical practice and research. OBJECTIVE: We examined-by Rasch analysis (RA)-the main metric characteristics of the 88-item Multiple Sclerosis Spasticity Scale (MSSS-88) to: (i) further validate its Italian version (MSSS-88-IT), previously validated through classical test theory methods only and (ii) independently verify the measurement properties of the original scale. METHODS: MSSS-88 data from a convenience sample of 232 subjects with MS underwent RA, mainly examining item fit, reliability indices, test information function, dimensionality, local item independence, and differential item functioning (DIF). RESULTS: Most items fitted the Rasch model, but 13/88 items showed a misfit in infit and/or outfit values. Rasch reliability indices were high (> 0.80). Test information functions in most subscales showed a sharp decrease in measurement precision as the ability level departs from the quite limited central range of maximal information. The unidimensionality of each subscale was confirmed. Thirteen item pairs showed local dependency (residual correlations > 0.30) and three items presented DIF. CONCLUSION: Reliability, dimensionality and some internal construct validity characteristics of the MSSS-88-IT were confirmed. But, drawbacks of the original MSSS-88 emerged related to some item misfit, redundancy, or malfunctioning. Thus, further large independent studies are recommended, to verify the robustness of previous findings and examine the appropriateness of a few targeted item replacements. DOI: 10.1007/s11136-018-2005-2

357. Radiol Case Rep. 2018 Jun 1;13(5):1030-1035. doi: 10.1016/j.radcr.2018.04.010. eCollection 2018 Oct.

Advanced neuroimaging in Balo's concentric sclerosis: MRI, MRS, DTI, and ASL perfusion imaging over 1 year.

Yeo CJJ(1), Hutton GJ(2), Fung SH(1). Author information: (1)Houston Methodist Hospital, Texas Medical Center, Houston, TX, United States. (2)Maxine Mesinger MS Comprehensive Care Center, Neurology, Baylor College of Medicine, Houston, TX, United States. Balo concentric sclerosis (BCS) is a rare, atypical demyelinating disease, which may rapidly progress to become severe and fatal. Advanced neuroimaging has proven helpful for early diagnosis, classification, prognostication, and monitoring of progression in multiple sclerosis, but has not been fully explored in BCS. We present the case of a 27-year-old woman with BCS in whom advanced neuroimaging was used to correlate the evolution of disease with clinical findings over the course of 1 year. Magnetic resonance imaging, magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and arterial spin labeling cerebral perfusion were obtained at presentation (Day 0), and at Day 67 and Day 252. Imaging features include multilayered concentric ring lesion, reduced diffusion along the rim, hypoperfusion with possible mild central hyperperfusion, and MRS findings of increased choline, decreased N-acetylaspartate (NAA), and possible presence of lactate and/or lipid peak. DTI tractography and relative apparent diffusion coefficient analyses correlated with clinical symptoms and may help to determine extent of white matter tract injury and prognosis. DOI: 10.1016/j.radcr.2018.04.010 PMCID: PMC6137900


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358. Radiol Case Rep. 2018 Jun 1;13(5):1021-1024. doi: 10.1016/j.radcr.2018.04.006. eCollection 2018 Oct.

Bladder diverticuli following injection of onabotulinum toxin A in a patient with multiple sclerosis and autosomal dominant polycystic kidney disease.

Raza SI(1), Behzadi AH(1), Blumenfeld JD(2)(3), Girardi SK(4), Prince MR(1)(5). Author information: (1)Department of Radiology, Weill Cornell Medical College & New York Presbyterian Hospital, New York, NY, USA. (2)The Rogosin Institute, New York, NY, USA. (3)Department of Medicine, Weill Cornell Medical College, New York, NY, USA. (4)Department of Urology, North Shore University Hospital, Manhasset, New York, NY, USA. (5)Department of Radiology, Columbia University Medical Center, New York, NY, USA. Urinary incontinence due to neurogenic detrusor overactivity is common in patients with disorders of lower motor neurons controlling the bladder. Multiple sclerosis is a major cause of neurogenic detrusor overactivity, which negatively impacts quality of life. Bladder wall injection of onabotulinum toxin A can diminish spontaneous bladder contraction, urinary urgency, and urge incontinence. Herein we report a 61-year-old woman with multiple sclerosis and autosomal dominant polycystic kidney disease with bladder trabeculation developing after repeated injections of onabotulinum toxin A. DOI: 10.1016/j.radcr.2018.04.006 PMCID: PMC6137336

359. Radiol Case Rep. 2018 Sep 13;13(6):1108-1111. doi: 10.1016/j.radcr.2018.07.029. eCollection 2018 Dec.

Intermittent superior mesenteric artery syndrome in a patient with multiple sclerosis.

Young A(1), Kinnear N(1)(2), Hennessey D(3), Kanhere H(1)(2), Trochsler M(1)(2). Author information: (1)Department of Surgery, Port Augusta Hospital, 71 Hospital Rd, Port Augusta, SA 5700 Australia. (2)Department of Surgery, The Queen Elizabeth Hospital, 28 Woodville Rd, Woodville South, SA 5011 Australia. (3)Department of Urology, Belfast City Hospital, 51 Lisburn Rd, Belfast BT9 7AB, UK. A 42-year-old man with multiple sclerosis presented with recurrent vomiting, in the context of recent weight loss. Computed tomography scan of the abdomen and pelvis revealed duodenal compression by the superior mesenteric artery (SMA), consistent with intermittent SMA syndrome. Subsequent gastroscopy and barium meal follow-through showed resolution of the obstruction. SMA syndrome is rare and has not previously been reported in a patient with multiple sclerosis. We hypothesize that loss of the aortomesenteric fat pad on the background of contorted body habitus from multiple sclerosis placed the patient at risk for intermittent positional compression of his duodenum. DOI: 10.1016/j.radcr.2018.07.029 PMCID: PMC6138865


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360. Radiologe. 2018 Sep 20. doi: 10.1007/s00117-018-0453-x. [Epub ahead of print]

[Autoimmune reactions and paraneoplastic syndromes].

[Article in German] Lieb JM(1), Naumann N(2), Ahlhelm FJ(3). Author information: (1)Abteilung für diagnostische und interventionelle Neuroradiologie, Klinik für Radiologie und Nuklearmedizin, Universitätsspital Basel, Petersgraben 4, 4031, Basel, Schweiz. [email protected]. (2)asim, Universitätsspital Basel, Basel, Schweiz. (3)Abteilung für Neuroradiologie, Kantonsspital Baden, Baden, Schweiz. CLINICAL ISSUE: Autoimmune disorders of the central nervous system (CNS) are common but are also a heterogeneous group of diseases. The most common form is multiple sclerosis (MS), others are clinically isolated syndrome (CIS), acute demyelinating encephalomyelitis (ADEM) and neuromyelitis optica spectrum disorders (NMOSD). Paraneoplastic syndromes are rare and tumor-associated, they are not induced by direct invasion of tumor tissue but by tumor-associated autoantibodies mostly against specific CNS proteins, e. g. limbic encephalitis and paraneoplastic cerebellar ataxia or degeneration. DIAGNOSTICS, STANDARD RADIOLOGICAL METHODS, PERFORMANCE AND ACHIEVEMENTS: The correct diagnosis of autoimmune and paraneoplastic syndromes can still be challenging. In addition to the patient history, clinical examination and blood as well as cerebrospinal fluid (CSF) tests, magnetic resonance imaging (MRI) is gaining importance in the diagnostics. It is important not only in primary diagnostics but also in follow-up and therapy monitoring, especially in MS with specific therapies to detect therapy complications, such as progressive multifocal leukoencephalopathy as early as possible. In paraneoplastic syndromes MRI can also be an important component in the diagnostics but can also initially be negative and typical signal changes become visible only in follow-up scans. PRACTICAL RECOMMENDATIONS: In paraneoplastic syndromes the correct diagnosis is based on laboratory tests for specific autoantibodies in serum and CSF. TREATMENT: The treatment of autoimmune and paraneoplastic disorders of the CNS ranges from steroids and immunosuppressive agents to plasmapheresis, depending on the specific disorder. DOI: 10.1007/s00117-018-0453-x

361. Rheumatol Int. 2018 Sep 11. doi: 10.1007/s00296-018-4156-4. [Epub ahead of print]

High burden of skin sclerosis is associated with severe organ involvement in patients with systemic sclerosis and systemic sclerosis overlap syndrome.

Wannarong T(1), Muangchan C(2). Author information: (1)Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. (2)Division of Rheumatology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. [email protected]. The objective of this study is to investigate the impact of skin sclerosis burden on an internal organ involvement over a 1-year period, as measured by time-adjusted accrual-modified Rodnan skin score (TA-mRSS), and to evaluate association between TA-mRSS patterns and laboratory tests in patients with systemic sclerosis (SSc). This prospective study was conducted at Siriraj Hospital (Bangkok, Thailand) during the November 2013-November 2016. SSc patients by ACR/EULAR 2013 or ACR 1980 criteria were eligible. TA-mRSS was classified as low, intermediate, or high, and then compared between groups. Correlation between the arithmetic mean of laboratory tests and TA-mRSS was assessed by multiple linear regression analysis. A total of 118 patients, with 81.4% women, median (IQR) age 49.8 (43.8, 55.1) years, disease duration from onset of non-Raynaud symptoms to first visit of 3.3 (1, 6.8) years, 78% dcSSc, and 75.3% anti-Scl-70 positivity, were analyzed. TA-mRSS over 1 year ranged from 0 to 37.44. The high skin sclerosis burden group had a median TA-mRSS > 7.26 (> 67th percentile). Patients with high TA-mRSS were dcSSc, high initial and average mRSS, and had tendon friction rub, digital ischemic complications, usual interstitial pneumonia, diastolic dysfunction, gastrointestinal dysmotility, and low serum albumin. In multiple linear regression analysis, the arithmetic mean of hemoglobin (B = - 1.007, 95% CI - 1.779 to - 0.236), erythrocyte sedimentation rate (B = - 0.078, 95% CI - 0.126 to - 0.029), serum glutamic oxaloacetic transaminase (B = 0.073, 95% CI 0.026-0.12), creatine phosphokinase (B = 0.012, 95% CI 0.003-0.021), and albumin (B = - 4.117, 95% CI - 6.958 to - 1.276) were associated with TA-mRSS. This study found a higher cumulative course of mRSS over a 1-year period to be significantly associated with severe internal organ involvement. DOI: 10.1007/s00296-018-4156-4


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362. Rom J Morphol Embryol. 2018;59(2):591-594.

Diagnostic challenges in a patient with calciphylaxia - a case report.

Bojincă VC(1), Bojincă M, Iosif CI, Bălănescu ŞM, Bălănescu AR. Author information: (1)Department of Internal Medicine and Rheumatology, "Dr. Ion Cantacuzino" Hospital, Bucharest, Romania; [email protected]. Calciphylaxis is a condition with unclear etiopathogeny with vascular calcifications and thrombotic occlusion that lead to necrotic lesions. It is usually described in patients with end-stage renal disease (ESRD), but also in other conditions. The mortality rate is high, due to sepsis and internal organ failure. We present the case of a patient with multiple comorbidities (ESRD, diabetes, hypertension, Mönckeberg's sclerosis) with problems of differential diagnostic due to the necrotic lesions that mislead initially to systemic lupus erythematosus (SLE) with necrotizing vasculitis.

363. Schizophr Bull. 2018 Sep 3. doi: 10.1093/schbul/sby130. [Epub ahead of print]

Burden for Parents of Patients With Schizophrenia-A Nationwide Comparative Study of Parents of Offspring With Rheumatoid Arthritis, Multiple Sclerosis, Epilepsy, and Healthy Controls.

Mittendorfer-Rutz E(1), Rahman S(1), Tanskanen A(1)(2)(3), Majak M(4), Mehtälä J(4), Hoti F(4), Jedenius E(5), Enkusson D(5), Leval A(6), Sermon J(7), Taipale H(1)(8), Tiihonen J(1)(2). Author information: (1)Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden. (2)Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland. (3)The Impact Assessment Unit, National Institute for Health and Welfare, Helsinki, Finland. (4)EPID Research Oy, Espoo, Finland. (5)Janssen Cilag, Sweden. (6)Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. (7)Janssen Cilag, Beerse, Belgium. (8)School of Pharmacy, University of Eastern Finland, Kuopio, Finland. Background: The study aimed to (1) compare the risk of health care use, adverse health status, and work productivity loss of parents of patients with schizophrenia to parents of patients with multiple sclerosis (MS), rheumatoid arthritis (RA), epilepsy, and healthy controls; and (2) evaluate such outcome measures while considering disease severity of schizophrenia. Methods: Based on linkage of Swedish registers, at least one parent was included (n = 18215) of patients with schizophrenia (information 2006-2013, n = 10883). Similarly, parental information was linked to patients with MS, RA, epilepsy, and matched healthy controls, comprising 11292, 15516, 34715, and 18408 parents, respectively. Disease severity of schizophrenia was analyzed. Different regression models yielding odds ratios (OR), hazard ratios (HR), or relative risks (RR) with 95% confidence intervals (CI) were run. Results: Psychiatric health care use, mainly due to anxiety and affective disorders, showed a strongly increasing trend for parents of patients with schizophrenia throughout the observation period. During the follow-up, these parents had an up to 2.7 times higher risk of specialized psychiatric health care and receipt of social welfare benefits than other parents. Parents of the moderately severely ill patients with schizophrenia had higher risk estimates for psychiatric health care (RR: 1.12; 95% CI: 1.07-1.17) compared with parents of least severely ill patients. Conclusions: Parents of patients with schizophrenia have a considerably higher risk of psychiatric health care and social welfare benefit receipt than other parents. Psychiatric health care use worsens over time and with increasing disease severity of the offspring. DOI: 10.1093/schbul/sby130


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364. Sci Rep. 2018 Sep 7;8(1):13437. doi: 10.1038/s41598-018-31542-y.

Neuronal microRNA regulation in Experimental Autoimmune Encephalomyelitis.

Juźwik CA(1), Drake S(1), Lécuyer MA(2), Johnson RM(3), Morquette B(1), Zhang Y(1), Charabati M(2), Sagan SM(4), Bar-Or A(1)(5), Prat A(2), Fournier AE(6). Author information: (1)McGill University, Montréal Neurological Institute, Montréal, QC, H3A 2B4, Canada. (2)Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, QC, H2X 0A9, Canada. (3)McGill University, Goodman Cancer Research Centre, Montréal, H3A 1A3, Canada. (4)McGill University, Departments of Microbiology & Immunology and Biochemistry, Montréal, QC, H3G 0B1, Canada. (5)Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. (6)McGill University, Montréal Neurological Institute, Montréal, QC, H3A 2B4, Canada. [email protected]. Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease but the molecular mechanisms underlying neurodegenerative aspects of the disease are poorly understood. microRNAs (miRNAs) are powerful regulators of gene expression that regulate numerous mRNAs simultaneously and can thus regulate programs of gene expression. Here, we describe miRNA expression in neurons captured from mice subjected to experimental autoimmune encephalomyelitis (EAE), a model of central nervous system (CNS) inflammation. Lumbar motor neurons and retinal neurons were laser captured from EAE mice and miRNA expression was assessed by next-generation sequencing and validated by qPCR. We describe 14 miRNAs that are differentially regulated in both neuronal subtypes and determine putative mRNA targets though in silico analysis. Several upregulated neuronal miRNAs are predicted to target pathways that could mediate repair and regeneration during EAE. This work identifies miRNAs that are affected by inflammation and suggests novel candidates that may be targeted to improve neuroprotection in the context of pathological inflammation. DOI: 10.1038/s41598-018-31542-y PMCID: PMC6128870

365. Sci Rep. 2018 Sep 27;8(1):14473. doi: 10.1038/s41598-018-32832-1.

Identification of Peptide Mimotope Ligands for Natalizumab.

Ruff LE(1), Pfeilsticker JA(1), Johnsen NE(1), Nocchi S(1), Messmer BT(2). Author information: (1)Abreos Biosciences, 3550 General Atomics Ct, Bldg G02, Rm 137, San Diego, CA, 92121, USA. (2)Abreos Biosciences, 3550 General Atomics Ct, Bldg G02, Rm 137, San Diego, CA, 92121, USA. [email protected]. Mimotope peptides selected from combinatorial peptide libraries can be used as capture reagents for immunoassay detection of therapeutic monoclonal antibodies (mAbs). We report the use of phage display libraries to identify peptide ligands (VeritopesTM) that bind natalizumab, a therapeutic mAb indicated for use in multiple sclerosis. PKNPSKF is identified as a novel natalizumab-binding motif, and peptides containing this motif demonstrated utility as capture reagents in enzyme-linked immunosorbent assays (ELISAs). A peptide containing the identified motif was shown to be competitive with the natural ligand (α4-integrin) and a neutralizing anti-idiotype antibody for natalizumab binding, indicating that VeritopesTM act as surrogate ligands that bind the antigen binding site of natalizumab. Affinity maturation further confirmed the motif sequence and yielded peptides with greater apparent affinity by ELISA. VeritopesTM are promising assay reagents for therapeutic drug level monitoring. DOI: 10.1038/s41598-018-32832-1


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366. Sci Rep. 2018 Sep 21;8(1):14223. doi: 10.1038/s41598-018-31773-z.

Misfolded SOD1 pathology in sporadic Amyotrophic Lateral Sclerosis.

Paré B(1)(2), Lehmann M(3), Beaudin M(4), Nordström U(3), Saikali S(5), Julien JP(6)(7), Gilthorpe JD(3), Marklund SL(8), Cashman NR(9), Andersen PM(3), Forsberg K(10), Dupré N(4), Gould P(5), Brännström T(10), Gros-Louis F(11)(12). Author information: (1)Laval University Experimental Organogenesis Research Center/LOEX, Division of Regenerative Medicine, CHU de Québec Research Center - Enfant-Jésus Hospital, Québec, Canada. (2)Department of Surgery, Faculty of Medicine, Laval University, Québec, Canada. (3)Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden. (4)Neuroscience Division of the CHU de Québec and Department of Medicine of the Faculty of Medicine, Laval University, Québec, QC, Canada. (5)Department of Medical Biology, Division of Anatomic Pathology and Neuropathology, CHU de Québec, Hôpital de l'Enfant-Jésus, Québec, Canada. (6)Department of Psychiatry and Neuroscience, Laval University, Québec City, Québec, Canada. (7)Centre de Recherche CERVO, Québec City, Québec, Canada. (8)Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden. (9)Department of Medicine (Neurology), Brain Research Center, University of British Columbia, Vancouver, BC, Canada. (10)Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden. (11)Laval University Experimental Organogenesis Research Center/LOEX, Division of Regenerative Medicine, CHU de Québec Research Center - Enfant-Jésus Hospital, Québec, Canada. [email protected]. (12)Department of Surgery, Faculty of Medicine, Laval University, Québec, Canada. [email protected]. Aggregation of mutant superoxide dismutase 1 (SOD1) is a pathological hallmark of a subset of familial ALS patients. However, the possible role of misfolded wild type SOD1 in human ALS is highly debated. To ascertain whether or not misfolded SOD1 is a common pathological feature in non-SOD1 ALS, we performed a blinded histological and biochemical analysis of post mortem brain and spinal cord tissues from 19 sporadic ALS, compared with a SOD1 A4V patient as well as Alzheimer's disease (AD) and non-neurological controls. Multiple conformation- or misfolded-specific antibodies for human SOD1 were compared. These were generated independently by different research groups and were compared using standardized conditions. Five different misSOD1 staining patterns were found consistently in tissue sections from SALS cases and the SOD1 A4V patient, but were essentially absent in AD and non-neurological controls. We have established clear experimental protocols and provide specific guidelines for working, with conformational/misfolded SOD1-specific antibodies. Adherence to these guidelines will aid in the comparison of the results of future studies and better interpretation of staining patterns. This blinded, standardized and unbiased approach provides further support for a possible pathological role of misSOD1 in SALS. DOI: 10.1038/s41598-018-31773-z


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367. Sci Rep. 2018 Sep 19;8(1):14040. doi: 10.1038/s41598-018-32326-0.

N-Phenylquinazolin-2-amine Yhhu4952 as a novel promotor for oligodendrocyte differentiation and myelination.

Yu X(1)(2), Cheng G(3), Zhang L(1)(2), Zhang Y(1)(2), Wang Q(1)(2), Zhao M(1)(2), Zeng L(1)(2), Hu Y(4), Feng L(5)(6). Author information: (1)CAS Key Laboratory of Receptor Research and Department of Neuropharmacology,Shanghai Institute of Materia Medica, 555 Zu Chongzhi Road, Shanghai, 201203, China. (2)University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. (3)College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. (4)College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. [email protected]. (5)CAS Key Laboratory of Receptor Research and Department of Neuropharmacology,Shanghai Institute of Materia Medica, 555 Zu Chongzhi Road, Shanghai, 201203, China. [email protected]. (6)University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. [email protected]. Oligodendrocytes are a type of glial cells that ensheath multiple neuronal axons and form myelin. Under pathological conditions, such as multiple sclerosis (MS), inflammatory damage to myelin and oligodendrocytes leads to demyelination. Although the demyelinated regions can partially resolve functional deficits through remyelination, however, as the disease progresses, remyelination typically becomes incomplete and ultimately fails. One possible explanation for this failure is the activation of the Notch pathway in MS lesions, which impedes oligodendrocyte precursor cells (OPCs) at maturation. This leads to a potential target for remyelination. Here, we have identified a compound Yhhu4952 that promoted the maturation of cultured OPCs in a dose-dependent and time-dependent manner. Neonatal rats showed a significant increase in the expression of myelin basic protein (MBP) and the prevalence of mature oligodendrocytes in the corpus callosum after Yhhu4952 treatment. The compound was also effective in promoting remyelination in cuprizone-induced demyelination model and improving severity scores in experimental autoimmune encephalomyelitis (EAE) model. Mechanism studies revealed that Yhhu4952 promotes OPC differentiation through the inhibition of the Jagged1-Notch1 pathway. These findings suggest Yhhu4952 is potentially useful for proceeding oligodendrocyte differentiation and remyelination. DOI: 10.1038/s41598-018-32326-0 PMCID: PMC6145871


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368. Sci Rep. 2018 Sep 12;8(1):13650. doi: 10.1038/s41598-018-31911-7.

Objective Evaluation of Multiple Sclerosis Lesion Segmentation using a Data Management and Processing Infrastructure.

Commowick O(1), Istace A(2), Kain M(3), Laurent B(4), Leray F(3), Simon M(3), Pop SC(5), Girard P(5), Améli R(2), Ferré JC(3)(6), Kerbrat A(3)(7), Tourdias T(8), Cervenansky F(5), Glatard T(9), Beaumont J(3), Doyle S(10), Forbes F(10)(11), Knight J(12), Khademi A(13), Mahbod A(14), Wang C(14), McKinley R(15), Wagner F(15), Muschelli J(16), Sweeney E(16), Roura E(17), Lladó X(17), Santos MM(18), Santos WP(19), Silva-Filho AG(18), Tomas-Fernandez X(20), Urien H(21), Bloch I(21), Valverde S(17), Cabezas M(17), Vera-Olmos FJ(22), Malpica N(22), Guttmann C(23), Vukusic S(2), Edan G(3)(7), Dojat M(24), Styner M(25), Warfield SK(20), Cotton F(2), Barillot C(3). Author information: (1)VISAGES: INSERM U1228 - CNRS UMR6074 - Inria, University of Rennes I, Rennes, France. [email protected]. (2)Department of Radiology, Lyon Sud Hospital, Hospices Civils de Lyon, Lyon, France. (3)VISAGES: INSERM U1228 - CNRS UMR6074 - Inria, University of Rennes I, Rennes, France. (4)LaTIM, INSERM, UMR 1101, University of Brest, IBSAM, Brest, France. (5)Univ Lyon, INSA-Lyon, Université Claude Bernard Lyon 1, UJM-Saint Etienne, CNRS, Inserm, CREATIS UMR 5220, U1206, F-69621, Lyon, France. (6)CHU Rennes, Department of Neuroradiology, F-35033, Rennes, France. (7)CHU Rennes, Department of Neurology, F-35033, Rennes, France. (8)CHU de Bordeaux, Service de Neuro-Imagerie, Bordeaux, France. (9)Department of Computer Science and Software Engineering, Concordia University, Montreal, Canada. (10)Pixyl Medical, Grenoble, France. (11)Inria Grenoble Rhône-Alpes, Grenoble, France. (12)Image Analysis in Medicine Lab, School of Engineering, University of Guelph, Guelph, Canada. (13)Image Analysis in Medicine Lab (IAMLAB), Ryerson University, Toronto, Canada. (14)School of Technology and Health, KTH Royal Institute of Technology, Stockholm, Sweden. (15)Department of Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Bern, Switzerland. (16)Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. (17)Research institute of Computer Vision and Robotics (VICOROB), University of Girona, Girona, Spain. (18)Centro de Informática, Universidade Federal de Pernambuco, Pernambuco, Brazil. (19)Depto. de Eng. Biomédica, Universidade Federal de Pernambuco, Pernambuco, Brazil. (20)Computational Radiology Laboratory, Department of Radiology, Children's Hospital, 300 Longwood Avenue, Boston, MA, USA. (21)LTCI, Télécom ParisTech, Université Paris-Saclay, Paris, France. (22)Medical Image Analysis Lab, Universidad Rey Juan Carlos, Madrid, Spain. (23)Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA. (24)Inserm U1216, University Grenoble Alpes, CHU Grenoble, GIN, Grenoble, France. (25)Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA. We present a study of multiple sclerosis segmentation algorithms conducted at the international MICCAI 2016 challenge. This challenge was operated using a new open-science computing infrastructure. This allowed for the automatic and independent evaluation of a large range of algorithms in a fair and completely automatic manner. This computing infrastructure was used to evaluate thirteen methods of MS lesions segmentation, exploring a broad range of state-of-theart algorithms, against a high-quality database of 53 MS cases coming from four centers following a common definition of the acquisition protocol. Each case was annotated manually by an unprecedented number of seven different experts. Results of the challenge highlighted that automatic algorithms, including the recent machine learning methods (random forests, deep learning, …), are still trailing human expertise on both detection and delineation criteria. In addition, we demonstrate that computing a statistically robust consensus of the algorithms performs closer to human expertise on one score (segmentation) although still trailing on detection scores. DOI: 10.1038/s41598-018-31911-7 PMCID: PMC6135867


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369. Sci Rep. 2018 Sep 11;8(1):13628. doi: 10.1038/s41598-018-31957-7.

Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis.

Williams SK(1), Fairless R(2), Maier O(3), Liermann PC(2), Pichi K(2), Fischer R(3), Eisel ULM(4), Kontermann R(3), Herrmann A(5), Weksler B(6), Romero N(7), Couraud PO(8), Pfizenmaier K(3), Diem R(2). Author information: (1)Department of Neurology, University Clinic Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. [email protected]. (2)Department of Neurology, University Clinic Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. (3)Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany. (4)Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Science, Faculty of Science and Engineering, University of Groningen, P.O. Box 11103, NL-9700, CC, Groningen, The Netherlands. (5)Baliopharm AG, Eulerstr. 55, CH-4051, Basel, Switzerland. (6)Weill Medical College of Cornell University, New York, NY, USA. (7)Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, MK7 6AA, UK. (8)INSERM, U1016, Institut Cochin, Paris, France. Tumour necrosis factor (TNF) signalling is mediated via two receptors, TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2), which work antithetically to balance CNS immune responses involved in autoimmune diseases such as multiple sclerosis. To determine the therapeutic potential of selectively inhibiting TNFR1 in mice with experimental autoimmune encephalomyelitis, we used chimeric human/mouse TNFR1 knock-in mice allowing the evaluation of antagonistic anti-human TNFR1 antibody efficacy. Treatment of mice after onset of disease with ATROSAB resulted in a robust amelioration of disease severity, correlating with reduced central nervous system immune cell infiltration. Long-term efficacy of treatment was achieved by treatment with the parental mouse anti-human TNFR1 antibody, H398, and extended by subsequent re-treatment of mice following relapse. Our data support the hypothesis that anti-TNFR1 therapy restricts immune cell infiltration across the blood-brain barrier through the down-regulation of TNF-induced adhesion molecules, rather than altering immune cell composition or activity. Collectively, we demonstrate the potential for anti-human TNFR1 therapies to effectively modulate immune responses in autoimmune disease. DOI: 10.1038/s41598-018-31957-7 PMCID: PMC6133964

370. Semin Speech Lang. 2018 Sep 25. doi: 10.1055/s-0038-1669992. [Epub ahead of print]

"Augmentative and Alternative Communication (AAC) Will Give You a Voice": Key Practices in AAC Assessment and Intervention as Described by Persons with Amyotrophic Lateral Sclerosis.

McNaughton D(1), Giambalvo F(2), Kohler K(1), Nazareth G(3), Caron J(2), Fager S(4). Author information: (1)Department of Educational Psychology, Counseling, and Special Education, Pennsylvania State University, University Park, Pennsylvania. (2)Department of Communication Sciences and Disorders, Pennsylvania State University, University Park, Pennsylvania. (3)X-Biomedical, Wayne, Pennsylvania. (4)Communication Center of Excellence, Institute for Rehabilitation Science and Engineering, Madonna Rehabilitation Hospital, Lincoln, Nebraska. The purpose of this study was to describe the perceptions of persons with amyotrophic lateral sclerosis (pALS) who use augmentative and alternative communication (AAC) with the AAC assessment and intervention process. Twenty-one pALS with complex communication needs participated in a multipart survey (and follow-up e-mails) to provide information on their experiences with AAC assessment and intervention. A majority of the participants agreed with the importance of three key AAC intervention principles: appropriate staging of the timing of assessment and intervention activities, inclusion of communication partners, and the use of multiple modalities and strategies as communication supports. Most participants reported that their assessment and intervention experiences included at least some aspect of these three key practices. The results of this study suggest that the identified best practices in AAC should be reviewed and implemented on an individualized basis for pALS with complex communication needs. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. DOI: 10.1055/s-0038-1669992 Conflict of interest statement: Disclosure The authors report no conflicts of interest in this work.


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371. Surg Neurol Int. 2018 Aug 14;9:166. doi: 10.4103/sni.sni_147_18. eCollection 2018.

Intraspinal calcinosis mimicking intervertebral disc extrusion: A clinical and surgical case report.

Maraković J(1)(2), Marinović T(1)(2), Jeleč V(1)(2), Dlaka D(1), Muller D(3), Blažević A(1), Raguž M(1). Author information: (1)Department of Neurosurgery, Dubrava University Hospital, Zagreb, Croatia. (2)Department of Surgery and Neurosurgery, School of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia. (3)Department of Pathology and Cytology, Dubrava University Hospital, Zagreb, Croatia. Background: Subcutaneous calcinosis is a well-recognized manifestation of systemic sclerosis that usually involves multiple pressure points and may also be found in the paraspinal or intraspinal regions. In this case, intraspinal calcinosis uniquely led to a severe neurological deficit. Case Description: A patient with severe systemic sclerosis/calcinosis exhibited left greater than right lower extremity radiculopathy attributed to intraspinal left-sided L4-L5 calcinosis. On examination, the patient exhibited bilateral positive Lasegue signs, distal lower extremity weakness (left greater than right), and bilaterally decreased Achilles responses. When the magnetic resonance imaging (MRI) revealed a significant intracanalicular mass on the left side at the L4-L5 level, the patient underwent a left-sided L4-L5 decompressive laminectomy. The MRI scan 5 years later revealed no recurrence of the calcinosis, and the patient had no residual neurological deficit. Conclusions: Spinal calcinosis rarely involves the lumbar spinal canal. Here, a patient with a large left-sided L4-L5 focus of intraspinal calcinosis, mimicking a disc herniation, required a laminectomy to resect the lesion. Lumbar calcinosis should be radiologically evaluated utilizing using X-ray, MRI, and computed tomography studies to adequately document the pathology. Patients, when symptomatic, may require surgical decompression and excision of these lesions. DOI: 10.4103/sni.sni_147_18 PMCID: PMC6108162 Conflict of interest statement: There are no conflicts of interest.

372. Ther Adv Neurol Disord. 2018 Sep 14;11:1756286418799864. doi: 10.1177/1756286418799864. eCollection 2018.

Neurological complications of immune checkpoint inhibitors: what happens when you 'take the brakes off' the immune system.

Dalakas MC(1). Author information: (1)Chief Neuromuscular Division, Thomas Jefferson University, Philadelphia, PA Chief, Neuroimmunology Unit, Department of Pathophysiology, National and Kapodistrian University of Athens Medical School, Athens, Greece. Patients with advanced malignancies treated with immune checkpoint inhibitors are at increased risk for developing immune-related neurological complications. It is a phenomenon of immunological twist when immunotherapy against co-stimulatory molecules activates previously normal T cells to kill tumor cells but, in so doing, the T cells become unrestrained, triggering other autoimmune diseases for which conventional immunotherapy is needed. The most common autoimmune neurological diseases, usually occurring within 2-12 weeks after immune checkpoint inhibitor initiation, include: inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculoneuropathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. The neurological events can evolve rapidly, necessitating the need for vigilance at all stages of treatment, even after completion, because early immunotherapeutic interventions are effective. The review addresses these complications and the applied therapies, discusses immune pathomechanisms including triggering preexisting autoimmunity, highlights the distinction between paraneoplastic and autoimmune etiologies, and identifies uncertainties regarding risk factors, use of immune checkpoint inhibitors in patients with known immune diseases or restarting therapy after a neurological event. Although the autoimmune neurological complications are not very common, their incidence will likely increase as the use of immune checkpoint inhibitors in metastatic cancer is growing rapidly. DOI: 10.1177/1756286418799864 PMCID: PMC6144585 Conflict of interest statement: Conflict of interest statement: The author declares that there is no conflict of interest.


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Short-term disability progression in two multiethnic multiple sclerosis centers in the treatment era.

Kister I(1), Bacon TE(2), Cutter GR(3). Author information: (1)Department of Neurology, NYU Multiple Sclerosis Care Center, NYU School of Medicine, 240 East 38th St, 18th floor, New York, NY 10026, USA. (2)Department of Neurology, NYU Multiple Sclerosis Care Center, NYU School of Medicine, New York, NY, USA. (3)Department of Biostatistics, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA. Background: Short-term disease progression is well documented in clinical trials, but there are limited published data on disease course in real-life practice. Methods: Patient-derived Multiple Sclerosis Severity Score (PMSSS), a disease severity rank score, was computed at each visit for consecutive MS patients attending two large, ethnically diverse MS centers in New York metropolitan area. Disability was assessed via Patient-Determined Disease Steps (PDDS). Clinicians recorded disease subtype and relapse status at each visit, but did not rate disability. PMSSS change from the first to the last visit was calculated for the cohort as a whole and for subgroups of interest. Multivariable regression models were constructed for predicting final PMSSS based on readily available predictor variables collected at the initial visit and relapse history during follow up. Results: A total of 1740 consecutive patients from New York University (n = 1079) and Barnabas (n = 661) MS Care Centers were included. During follow up (mean 2.4 ± 0.82 years, range 1-4 years), mean PDDS score increased from 1.9 ± 2.2 to 2.3 ± 2.2 (p < 0.0001), while PMSSS remained roughly unchanged (initial PMSSS = 3.71 ± 2.73, last PMSSS = 3.81 ± 2.76, paired t test, p = 0.28). The only major predictor of final PMSSS was the initial PMSSS. Demographic variables (age, sex, race) or relapse status did not predict final severity score. Conclusions: Baseline disability in two MS clinics was much lower than in the reference population from which PMSSS was derived. We observed no discernable slowing of disability accumulation during the short-term follow up in our cohort compared with the reference cohort. Overwhelmingly the most important predictor of final disease severity rank score was the initial disease severity rank score. DOI: 10.1177/1756286418793613 PMCID: PMC6134488 Conflict of interest statement: Conflict of interest statement: This study was supported by an investigator-initiated grant from Sanofi Genzyme. IK has served on advisory boards for Biogen and Genentech and received research support for investigator-initiated grants from Sanofi Genzyme, Biogen, EMD Serono, National MS Society and Guthy Jackson Charitable Foundation. TEB has nothing to disclose. GC has served on data and safety monitoring boards for AMO Pharmaceuticals, Apotek, Horizon Pharmaceuticals, Merck, Merck/Pfizer, Modigenetech/Prolor, Neurim, Opko Biologics, Reata Pharmaceuticals, Receptos/Celgene, Sanofi, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), and NICHD (OPRU oversight committee); has received compensation for consulting or advisory boards from Argenix, Atara Biotherapeutics, Biogen, Bioeq GmBH, the Consortium of MS Centers (grant), Sanofi Genzyme, Genentech, Innate Therapeutics, Klein-Buendel Incorporated, MedDay, Medim-mune, Novartis, Opexa Therapeutics, Roche, Savara Inc., Somahlution, Teva Pharmaceuticals, TG Therapeutics, and Transparency Life Sciences; and is president of Pythagoras, Inc., a private consulting company.


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Comparable efficacy and safety of dimethyl fumarate and teriflunomide treatment in Relapsing-Remitting Multiple Sclerosis: an Italian real-word multicenter experience.

D'Amico E(1), Zanghì A(1), Callari G(2), Borriello G(3), Gallo A(4), Graziano G(5), Valentino P(6), Buccafusca M(7), Cottone S(8), Salemi G(9), Ragonese P(9), Bossio RB(10), Docimo R(4), Grimaldi LME(2), Pozzilli C(3), Tedeschi G(4), Zappia M(1), Patti F(11). Author information: (1)Department G.F. Ingrassia, Multiple Sclerosis Center, University of Catania, Italy. (2)Institute Foundation G. Giglio, Cefalù, Italy. (3)S. Andrea Hospital, Sapienza Rome University, Rome, Italy. (4)I Neurologic Clinic, Federico II University of Naples, Italy. (5)Giovanni Paolo II, IRCCS Cancer Institute, Bari, Italy. (6)Azienda Ospedaliera Universitaria Mater Domini, Catanzaro, Italy. (7)Azienda Ospedaliera Universitaria G. Martino, Messina, Italy. (8)Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy. (9)Policlinico Paolo Giaccone, Palermo, Italy. (10)Azienda Sanitaria Provinciale di Cosenza, U. O. di Neurologia, Cosenza, Italy. (11)Department G. Ingrassia, Policlinico G. Rodolico, V. Santa Sofia 78, 95123, Catania, Italy. Background: The aim of the study was to evaluate the achievement of 'no evidence of disease activity' (NEDA) over a 12-month period in a large multicenter population with relapsing remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) and teriflunomide (TRF) using a propensity-score adjustment. Methods: A time-to-event method was used to determine the percentages of patients with RRMS (pwRRMS) in both groups achieving NEDA 3 (no relapses, no 12-week confirmed disability progression, and no new T2/gadolinium-enhancing brain lesions). We described the safety profile of the investigated drugs. Results: Of the 587 pwRRMS treated with DMF and the 316 pwRRMS treated with TRF, 468 pwRRMS were successfully paired by propensity score: 234 on DMF and 234 on TRF. The percentages of pwRRMS who achieved NEDA 3 were 80.3% in the DMF group and 77.2% in the TRF group. Serious adverse events occurred in four (1.9%) pwRRMS on DMF and in three (1.3%) pwRRMS on TRF. Conclusions: DMF and TRF significantly impacted RRMS disease activity in our study. Serious safety concerns were recorded in less than 2% of the studied population. DOI: 10.1177/1756286418796404 PMCID: PMC6131312 Conflict of interest statement: Conflict of interest statement: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ED, GC, GB, AG, and MB received personal fees from Biogen and Sanofi. ED, GC, GB, AG, PV, and MB received travel funding from Bayer Biogen and Merck. AZ received travel funding from Bayer Schering and Sanofi Genzyme outside the submitted work. PV received personal fees from Biogen, Sanofi, Novartis, and Roche. SC and GS received personal fees for speaking activities from Bayer Biogen, Merck, Novartis, and Teva. PR received travel expenses or honoraria for consultancy from Merck Serono, Biogen idec, Novartis, Sanofi Genzyme, and Teva. RBB served on the advisory board for Almirall and received grants for congress participation from Sanofi and Merck. LMEG and CP served on advisory boards for Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi, and Teva. LMEG and CP also received personal fees for speaking activities at congresses or sponsored symposia. GT, MZ, and FP served on advisory boards for Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi, Teva, and Almirall. GT, MZ, and FP also received personal fees for speaking activities at congresses or sponsored symposia.


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375. Ther Adv Neurol Disord. 2018 Aug 28;11:1756286418795085. doi: 10.1177/1756286418795085. eCollection 2018.

Peginterferon β-1a every 2 weeks increased achievement of no evidence of disease activity over 4 years in the ADVANCE and ATTAIN studies in patients with relapsing-remitting multiple sclerosis.

Arnold DL(1), Shang S(2), Dong Q(2), Meergans M(3), Naylor ML(4). Author information: (1)Montreal Neurological Institute, McGill University, and NeuroRx Research, Montreal, QC, Canada. (2)Biogen, Cambridge, MA, USA. (3)Biogen, Zug, Switzerland. (4)Biogen, 225 Binney St., Cambridge, MA 02142, USA. Background: No evidence of disease activity (NEDA) is a composite measurement, incorporating clinical and magnetic resonance imaging (MRI) elements of disease activity to sensitively evaluate the therapeutic efficacy of treatments for relapsing-remitting multiple sclerosis (RRMS). Objective: To assess the NEDA status of patients treated with peginterferon β-1a in the ADVANCE and ATTAIN studies and explore its predictive value on longer-term clinical outcomes. Methods: ATTAIN was a 2-year extension of the pivotal 2-year ADVANCE study of peginterferon β-1a for RRMS. Achievement of clinical NEDA, MRI NEDA, or overall NEDA was calculated cumulatively and by year over 4 years. Clinical outcomes during ATTAIN were analyzed based on NEDA status at the end of ADVANCE. Results: Significantly more patients treated with peginterferon β-1a every 2 weeks than every 4 weeks achieved clinical NEDA (60.6% versus 50.6%, p = 0.0063) and MRI NEDA (28.3% versus 15.8%, p = 0.0005) through year 4 and overall NEDA through year 3 (20.9% versus 13.9%, p = 0.0160). Over 4 years, 15.8% of patients in the every 2 weeks group and 10.7% of patients in the every 4 weeks group maintained overall NEDA (p = 0.0584). Achievement of clinical NEDA, MRI NEDA, or overall NEDA in ADVANCE was predictive of annualized relapse rate in ATTAIN; achievement of clinical NEDA in ADVANCE was also predictive of NEDA achievement and confirmed disability worsening in ATTAIN. Conclusions: Peginterferon β-1a every 2 weeks is associated with higher levels of NEDA compared with placebo in year 1 or peginterferon β-1a every 4 weeks in years 2-4. Overall NEDA within the first 2 years of treatment may be prognostic of long-term clinical outcomes.Clinicaltrials.gov: NCT01332019. DOI: 10.1177/1756286418795085 PMCID: PMC6113732 Conflict of interest statement: Conflict of interest statement: DA: had an equity interest in NeuroRx during the conduct of the study and has received personal fees from Acorda, Biogen, EMD Serono, Genentech, Genzyme, Hoffman–La Roche, Innate Immunotherapy, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi, and Teva, and grants from Biogen and Novartis. SS, QD: full-time employees and stockholders of Biogen at the time of the analysis. MM, MLN: full-time employees and stockholders of Biogen.


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376. Ther Adv Neurol Disord. 2018 Aug 28;11:1756286418791143. doi: 10.1177/1756286418791143. eCollection 2018.

Long-term outcomes of peginterferon beta-1a in multiple sclerosis: results from the ADVANCE extension study, ATTAIN.

Newsome SD(1), Scott TF(2), Arnold DL(3), Nelles G(4), Hung S(5), Cui Y(5), Shang S(5), Naylor ML(6), Kremenchutzky M(7). Author information: (1)Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2)Department of Neurology, Allegheny General Hospital, Pittsburgh, PA, USA. (3)Montreal Neurological Institute, McGill University, and NeuroRx Research, Montreal, QC, Canada. (4)Neurology, NeuroMed Campus Hohenlind, Cologne, Germany. (5)Biogen, Cambridge, MA, USA (during completion of work). (6)Biogen, 225 Binney Street, Cambridge, MA 02142, USA. (7)Department of Clinical Neurological Sciences, University of Western Ontario, and London Health Science Centre, London, ON, Canada. Background: ADVANCE was a phase III trial of the efficacy and safety of subcutaneous peginterferon beta-1a 125 µg every 2 or 4 weeks in patients with relapsing-remitting multiple sclerosis (RRMS). ATTAIN was a 2-year extension study of ADVANCE. The aim was to evaluate the long-term safety, tolerability, and efficacy of peginterferon beta-1a 125 µg every 2 or 4 weeks in ATTAIN. Methods: ADVANCE dosing schedules were maintained in ATTAIN, except that every-4-weeks dosing patients were switched to every-2-weeks dosing after conversion of the study to an open-label protocol. ATTAIN was considered complete when the last patient completed the 96-week extension study. Primary endpoints included adverse event (AE) and serious AE (SAE) incidence. Secondary endpoints included relapse, magnetic resonance imaging, and disability outcomes. Results: Of the 1512 patients randomized in ADVANCE, 1076 (71%) continued treatment in ATTAIN; of these, 842 (78%) completed the open-label extension study. During ATTAIN, 478 patients (87%) in the every-2-weeks group and 471 patients (89%) in the every-4-weeks group experienced an AE; SAEs were reported in 90 patients (16%) in the every-2-weeks group and 113 patients (21%) in the every-4-weeks group. The most frequent AEs reported were injection site reactions and flu-like symptoms, both of which numerically decreased over time. Peginterferon beta-1a every 2 weeks versus every 4 weeks significantly reduced the adjusted annualized relapse rate over 6 years (0.188 versus 0.263, p = 0.0052) and the risk of relapse over 5 years (36% versus 49%, p = 0.0018). Fewer new T1, new/newly enlarging T2, and gadolinium-enhancing magnetic resonance imaging lesions were observed with every-2-weeks dosing than every-4-weeks dosing over 4 years. Conclusions: Results from the ADVANCE extension study, ATTAIN, confirm the favorable long-term safety and tolerability profile of peginterferon beta-1a in patients with RRMS and provide additional evidence for the clinical and radiological benefits associated with this therapy. DOI: 10.1177/1756286418791143 PMCID: PMC6113734 Conflict of interest statement: Conflict of interest statement: SDN has received research support (paid directly to institution) from Biogen, Genentech, the National MS Society, and Novartis, and has participated in scientific advisory boards for Biogen and Genentech. TFS has received research support from Biogen and Novartis and has received honoraria for participation in scientific advisory boards and speaking from Acorda Therapeutics, Biogen, Genentech, Genzyme, Novartis, and Teva Neurosciences. DLA reports an equity interest in NeuroRx during the conduct of the study and personal fees from Acorda, Biogen, EMD Serono, Genentech, Genzyme, Hoffman-La Roche, Innate Immunotherapy, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi-Aventis, and Teva outside the submitted work, as well as grants from Biogen and Novartis. GN has participated in scientific advisory boards for Bayer HealthCare, Biogen, Genzyme, and Merck, and received personal compensation for speaking activities from Bayer HealthCare, Biogen, Genzyme, Merck, Novartis, and Teva. SH, YC, and SS were full-time employees of Biogen and holders of Biogen stock and/or stock options at the time of the analysis. MLN is a full-time employee of Biogen and holder of Biogen stock and/or stock options. MK has received research grants, research support, and personal compensation for consulting or speaking activities from Biogen, the Canadian Institute of Health Research, Genzyme, the MS Society of Canada, Novartis, Sanofi, Teva, and Wellesley Therapeutics. MK’s institution has received research grants from Biogen and the Canadian Institute of Health Research and research support from the Chapman Chair in MS Clinical Research at London Health Sciences Centre.


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377. Theranostics. 2018 Aug 7;8(16):4477-4490. doi: 10.7150/thno.26249. eCollection 2018.

Integration of magnetic resonance imaging and protein and metabolite CSF measurements to enable early diagnosis of secondary progressive multiple sclerosis.

Herman S(1)(2), Khoonsari PE(1), Tolf A(3), Steinmetz J(4), Zetterberg H(5)(6)(7)(8), Åkerfeldt T(1), Jakobsson PJ(4), Larsson A(1), Spjuth O(2), Burman J(3), Kultima K(1). Author information: (1)Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sweden. (2)Department of Pharmaceutical Biosciences, Uppsala University, Sweden. (3)Department of Neuroscience, Uppsala University, Sweden. (4)Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. (5)Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. (6)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. (7)UCL Institute of Neurology, Queen Square, London, United Kingdom. (8)UK Dementia Research Institute at UCL, London, United Kingdom. Molecular networks in neurological diseases are complex. Despite this fact, contemporary biomarkers are in most cases interpreted in isolation, leading to a significant loss of information and power. We present an analytical approach to scrutinize and combine information from biomarkers originating from multiple sources with the aim of discovering a condensed set of biomarkers that in combination could distinguish the progressive degenerative phenotype of multiple sclerosis (SPMS) from the relapsing-remitting phenotype (RRMS). Methods: Clinical and magnetic resonance imaging (MRI) data were integrated with data from protein and metabolite measurements of cerebrospinal fluid, and a method was developed to sift through all the variables to establish a small set of highly informative measurements. This prospective study included 16 SPMS patients, 30 RRMS patients and 10 controls. Protein concentrations were quantitated with multiplexed fluorescent bead-based immunoassays and ELISA. The metabolome was recorded using liquid chromatography-mass spectrometry. Clinical follow-up data of the SPMS patients were used to assess disease progression and development of disability. Results: Eleven variables were in combination able to distinguish SPMS from RRMS patients with high confidence superior to any single measurement. The identified variables consisted of three MRI variables: the size of the spinal cord and the third ventricle and the total number of T1 hypointense lesions; six proteins: galectin-9, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor alpha (TGF-α), tumor necrosis factor alpha (TNF-α), soluble CD40L (sCD40L) and platelet-derived growth factor AA (PDGF-AA); and two metabolites: 20β-dihydrocortisol (20β-DHF) and indolepyruvate. The proteins myelin basic protein (MBP) and macrophage-derived chemokine (MDC), as well as the metabolites 20β-DHF and 5,6-dihydroxyprostaglandin F1a (5,6-DH-PGF1), were identified as potential biomarkers of disability progression. Conclusion: Our study demonstrates, in a limited but well-defined and data-rich cohort, the importance and value of combining multiple biomarkers to aid diagnostics and track disease progression. DOI: 10.7150/thno.26249 PMCID: PMC6134925 Conflict of interest statement: Competing Interests: The authors have declared that no competing interest exists.


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378. Top Companion Anim Med. 2018 Jun;33(2):49-57. doi: 10.1053/j.tcam.2018.04.002. Epub 2018 May 16.

Veterinary Neurologic Rehabilitation: The Rationale for a Comprehensive Approach.

Frank LR(1), Roynard PFP(2). Author information: (1)Physical Rehabilitation and Acupuncture Service, Long Island Veterinary Specialists, Plainview, NY, USA. (2)Neurology/Neurosurgery Department, Long Island Veterinary Specialists, Plainview, NY, USA; Fipapharm, Mont-Saint-Aignan, France. Electronic address: [email protected]. The increase in client willingness to pursue surgical procedures, the heightened perceived value of veterinary patients, and the desire to provide comprehensive medical care have driven the recent demand of using an integrative treatment approach in veterinary rehabilitation. Physical therapy following neurologic injury has been the standard of care in human medicine for decades, whereas similar rehabilitation techniques have only recently been adapted and utilized in veterinary medicine. Spinal cord injury is the most common neurologic disease currently addressed by veterinary rehabilitation specialists and will be the primary focus of this review; however, research in other neurologic conditions will also be discussed. Of particular interest, to clients and veterinarians are techniques and modalities used to promote functional recovery after neurologic injury, which can mean the difference between life and death for many veterinary patients. The trend in human neurologic rehabilitation, often regardless of etiology, is a multimodal approach to therapy. Evidence supports faster and improved recoveries in people after neurologic injury using a combination of rehabilitation techniques. Although the primary neurological disorders researched tend to be spinal cord injury, peripheral neuropathies, allodynia, multiple sclerosis, and strokes-many correlations can be made to common veterinary neurological disorders. Such comprehensive protocols entail gait training activities in combination with neuromuscular electrical stimulation and directed exercises. Additionally, pain-relieving and functional benefits are bolstered when acupuncture is used in addition to rehabilitation. Studies, both laboratory and clinical, support the use of acupuncture in the management of neurologic conditions in small animals, specifically in cases of intervertebral disc disease, other myelopathies, and neuropathic pain conditions. Acupuncture's ability to promote analgesia, stimulate trophic factors, and decrease inflammation, including neuroinflammation, make it an alluring adjunct therapy after neurologic injury. Although there is limited research in veterinary medicine on physical techniques that expedite recovery after neurologic injury, there are sparse publications on clinical veterinary research suggesting the benefits of acupuncture, rehabilitation, and LASER in dogs with intervertebral disk disease. Accordingly, due to the relative lack of evidence-based studies in veterinary neurologic rehabilitation, much of the data available is human or laboratory-animal based, however, evidence supports the utilization of an early, comprehensive treatment protocol for optimal neurologic recovery. The rationale for why an integrative approach is critical will be detailed in this review; in addition, literature on specific physical rehabilitation techniques that have evidence of improved recoveries after neurologic injury, will be addressed. Copyright © 2018 Elsevier Inc. All rights reserved. DOI: 10.1053/j.tcam.2018.04.002


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379. Toxins (Basel). 2018 Sep 11;10(9). pii: E367. doi: 10.3390/toxins10090367.

Impacts of Indoxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120.

Liu WC(1)(2), Tomino Y(3), Lu KC(4). Author information: (1)Division of Nephrology, Department of Internal Medicine, Tungs' Taichung Metro Harbor Hospital, Taichung City 435, Taiwan. [email protected]. (2)Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 106, Taiwan. [email protected]. (3)Asian Pacific Renal Research Promotion Office, Medical Corporation SHOWAKAI, Tokyo 160-0023, Japan. [email protected]. (4)Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 243, Taiwan. [email protected]. Uremic toxins, such as indoxyl sulfate (IS) and p-cresol, or p-cresyl sulfate (PCS), are markedly accumulated in the organs of chronic kidney disease (CKD) patients. These toxins can induce inflammatory reactions and enhance oxidative stress, prompting glomerular sclerosis and interstitial fibrosis, to aggravate the decline of renal function. Consequently, uremic toxins play an important role in the worsening of renal and cardiovascular functions. Furthermore, they destroy the quantity and quality of bone. Oral sorbent AST-120 reduces serum levels of uremic toxins in CKD patients by adsorbing the precursors of IS and PCS generated by amino acid metabolism in the intestine. Accordingly, AST-120 decreases the serum IS levels and reduces the production of reactive oxygen species by endothelial cells, to impede the subsequent oxidative stress. This slows the progression of cardiovascular and renal diseases and improves bone metabolism in CKD patients. Although large-scale studies showed no obvious benefits from adding AST-120 to the standard therapy for CKD patients, subsequent sporadic studies may support its use. This article summarizes the mechanisms of the uremic toxins, IS, and PCS, and discusses the multiple effects of AST-120 in CKD patients. DOI: 10.3390/toxins10090367

380. Urology. 2018 Sep 26. pii: S0090-4295(18)31000-8. doi: 10.1016/j.urology.2018.09.014. [Epub ahead of print]

Assessment of renal deterioration and associated risk factors in patients with multiple sclerosis.

Shakir NA(1), Satyanarayan A(1), Eastman J(1), Greenberg BM(2), Lemack GE(3). Author information: (1)Department of Urology, University of Texas Southwestern Medical Center. (2)Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center. (3)Department of Urology, University of Texas Southwestern Medical Center; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center. Electronic address: [email protected]. OBJECTIVE: To evaluate predictors of renal deterioration (RD) in patients with multiple sclerosis (MS) at a tertiary referral center. METHODS: We reviewed adult patients with MS presenting for evaluation of lower urinary tract symptoms, with baseline UDS and either serum creatinine (SCr) or renal ultrasound (RUS), from a prospectively maintained database, and excluded patients with abnormal renal function. RD was defined as doubled SCr, new hydronephrosis, or renal atrophy on follow-up US. Demographic and UDS parameters were evaluated in multivariable models of RD. RESULTS: From 1999-2016, 660 patients were evaluated, and 355 met criteria with median followup of 79 months. SCr doubled in 8 patients, 4 had decline by RUS, and 1 by both (3%). Overall, 46 patients met less strict criteria of decrease in estimated glomerular filtration rate (eGFR) by ≥30%. Using the less rigid criterion, detrusor overactivity (DO) remained associated with RD on multivariable analysis. 11/355 patients had RD by either imaging or doubled Cr, with which only history of diabetes mellitus and nephrolithiasis were associated. CONCLUSIONS: By strict criteria, the rate of RD in patients with NGB due to MS was low (3%) at intermediate-term followup and was not associated with UDS parameters. Using more liberal criteria, DO was associated with deterioration, suggesting that study of the impact of more aggressive control of DO in this population may be warranted. Copyright © 2018. Published by Elsevier Inc. DOI: 10.1016/j.urology.2018.09.014


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381. Value Health. 2018 Sep;21(9):1083-1089. doi: 10.1016/j.jval.2017.10.025. Epub 2018 Jan 8.

Cost Sharing of Disease-Modifying Treatments (DMTs) as Policy Lever to Improve DMTs' Access in Multiple Sclerosis.

Shao H(1), Stoecker C(1), Monnette AM(1), Shi L(2). Author information: (1)Department of Global Health Management and Policy, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA. (2)Department of Global Health Management and Policy, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA. Electronic address: [email protected]. OBJECTIVES: To understand the nonlinear relationship between out-of-pocket (OOP) payments and disease-modifying treatment (DMT) use and adherence, primarily to pinpoint the threshold at which the use of DMTs becomes price sensitive. METHODS: Individuals with more than two multiple sclerosis (MS) diagnoses (International Classification of Diseases, Ninth Revision code 340) were identified from the MarketScan database (2006-2009). Heterogeneity in treatment was normalized by calculating an annual OOP payment as the average OOP payment for purchasing a fixed basket of DMTs at the insurance plan level. A local linear regression with a model-based recursive partitioning algorithm was applied to explore the relationship between OOP and consequently lower DMT use and adherence as measured by days covered by DMT. RESULTS: We identified the inflection points in annual OOP payments as $442 for DMT use and $890 for DMT adherence. For patients with annual OOP payments of more than $442, a $100-increase in OOP payment was associated with a decline of 0.6% in DMT use; for annual OOP payments of more than $890, a $100-increase in OOP payment was associated with two fewer days of DMT treatments. CONCLUSIONS: Although the use of DMTs and DMT adherence appeared unassociated with OOP payment below $442 and $890, respectively, an excessive OOP payment was a barrier to DMT access. This information can inform maximum monthly and yearly payment caps when designing valued-based insurance plans. Copyright © 2018 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.jval.2017.10.025


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382. Viruses. 2018 Aug 30;10(9). pii: E466. doi: 10.3390/v10090466.

BK Polyomavirus MicroRNA Levels in Exosomes Are Modulated by Non-Coding Control Region Activity and Down-Regulate Viral Replication When Delivered to Non-Infected Cells Prior to Infection.

Martelli F(1), Wu Z(2), Delbue S(3), Weissbach FH(4), Giulioli MC(5), Ferrante P(6), Hirsch HH(7)(8), Giannecchini S(9). Author information: (1)Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy. [email protected]. (2)Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, CH-4003 Basel, Switzerland. [email protected]. (3)Department of Biomedical, Surgical and Dental Sciences, University of Milan, I-20100 Milano, Italy. [email protected]. (4)Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, CH-4003 Basel, Switzerland. [email protected]. (5)Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy. [email protected]. (6)Department of Biomedical, Surgical and Dental Sciences, University of Milan, I-20100 Milano, Italy. [email protected]. (7)Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, CH-4003 Basel, Switzerland. [email protected]. (8)Infectious Diseases & Hospital Epidemiology, University Hospital Basel, CH-4003 Basel, Switzerland. [email protected]. (9)Department of Experimental and Clinical Medicine, University of Florence, I-50134 Florence, Italy. [email protected]. In immunosuppressed patients, BKPyV-variants emerge carrying rearranged non-coding control-regions (rr-NCCRs) that increase early viral gene region (EVGR) expression and replication capacity. BKPyV also encodes microRNAs, which have been reported to downregulate EVGR-encoded large T-antigen transcripts, to decrease viral replication in infected cells and to be secreted in exosomes. To investigate the interplay of NCCR and microRNAs, we compared archetype- and rr-NCCR-BKPyV infection in cell culture. We found that laboratory and clinical rr-NCCR-BKPyV-strains show higher replication rates but significantly lower microRNA levels than archetype virus intracellularly and in exosomes. To investigate whether rr-NCCR or increased EVGR activity modulated microRNA levels, we examined the (sp1-4)NCCR-BKPyV, which has an archetype NCCR-architecture but shows increased EVGR expression due to point mutations inactivating one Sp1 binding site. We found that microRNA levels following (sp1-4)NCCR-BKPyV infection were as low as in rr-NCCR-variants. Thus, NCCR rearrangements are not required for lower miRNA levels. Accordingly, Sp1 siRNA knock-down decreased microRNA levels in archetype BKPyV infection but had no effect on (sp1-4)- or rr-NCCR-BKPyV. However, rr-NCCR-BKPyV replication was downregulated by exosome preparations carrying BKPyV-microRNA prior to infection. To explore the potential relevance in humans, urine samples from 12 natalizumab-treated multiple sclerosis patients were analysed. In 7 patients, rr-NCCR-BKPyV were detected showing high urine BKPyV loads but low microRNAs levels, whereas the opposite was seen in 5 patients with archetype BKPyV. We discuss the results in a dynamic model of BKPyV replication according to NCCR activity and exosome regulation, which integrates immune selection pressure, spread to new host cells and rr-NCCR emergence. DOI: 10.3390/v10090466


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383. Wiad Lek. 2018;71(5):1056-1060.

[Paroxysmal dyskinesias - disorder categories, their causes and treatment].

[Article in Polish] Gontarz M(1), Papuć E(1), Rejdak K(1). Author information: (1)Klinika Neurologii Spsk4 W Lublinie, Lublin, Polska. Paroxysmal dyskinesias refer to category of abnormal involuntary movements, such as chorea, dystonia, athetosis, ballism or their various configurations. Depending on the type of seizure, sudden movement, stress, emotions, coffee or alcohol may be the trigger factors. Acute seizures are characterized by short duration and are self-limitated. Patients present correct portray of movements between seizures. Intact consciousness during seizure is the invariable characteristic of all paroxysmal dyskinesias. The intent of this work is to systematize knowledge about paroxysmal dyskinesias. This research includes synthetic information developed based on specialistic literature cencerned with paroxysmal movement disorders. The authors focused primarily on characteristics of the most important issues in this area, into which types of disorders, their causes and treament as well as psychopathology aspect having crucial influence on patients' life comfort were included. The essence of three categories of seizures were put across more extesively: paroxysmal kinesigenic dyskinesia, proxysmal non-kinesigenic dyskinesia and paroxysmal exercise-induced dyskinesia. Primary dyskinesias with genetic basis and secondary to other diseases, such as multiple sclerosis were distinguished. Modes of pharmacological treatment with antiepileptic drug and benzodiazepines were described. Special concern was put on holistic approach to problem of diagnosis and treatment of analyzed movement disorders.

384. Xenobiotica. 2018 Sep 20:1-54. doi: 10.1080/00498254.2018.1525508. [Epub ahead of print]

Absorption, Disposition and Metabolic Pathway of Amiselimod (MT-1303) in Healthy Volunteers in a Mass Balance Study. Kifuji T(1), Inoue S(1), Furukawa M(1), Madera BP(2), Goto T(3), Kumagai H(3), Mair SJ(4), Kawaguchi A(1).

Author information: (1)a Data Science Department, Sohyaku Innovative Research Division , Mitsubishi Tanabe Pharma Corporation , Tokyo , Japan. (2)b Mitsubishi Tanabe Pharma Europe Ltd , Dashwood House, 69 Old Broad Street , London , EC2M 1QS , UK. (3)c DMPK Research Laboratories Sohyaku Innovative Research Division , Mitsubishi Tanabe Pharma Corporation , Yokohama , Kanagawa , Japan. (4)d Quotient Sciences , Mere Way, Ruddington Fields, Ruddington , Nottingham , NG11 6JS , UK. 1. The absorption, metabolism and excretion of MT-1303 were investigated in healthy male subjects after a single oral dose of 0.4 mg [14C]-MT-1303 (ClinicalTrials.gov NCT02293967). 2. The MT-1303 concentration in the plasma reached a maximum at 12 h after administration. Thereafter, the concentration declined with a half-life of 451 h. At the final assessment on Day 57, 91.16% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 35.32% and 55.84%, respectively. 3. The most abundant metabolite in plasma was MT-1303-P, which accounted for 42.6% of the area under the plasma concentration-time curve (AUC) of the total radioactivity. The major component excreted in urine was Human Urine (HU)4 (3066434), accounting for 28.1% of radioactivity in the sample (4.05% of the dose), whereas MT-1303 was a major component in the faeces, accounting for 89.8% of radioactivity in the sample (25.49% of the dose) up to 240 h after administration. 4. This study indicates multiple metabolic pathways are involved in the elimination of MT-1303 from the human body and the excretion of MT-1303 and MT-1303-P via kidney is low. Therefore, MT-1303 is unlikely to cause conspicuous drug interactions or alter pharmacokinetics in patients with renal impairment. DOI: 10.1080/00498254.2018.1525508

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Langjährige Erfahrungbei der Betreuung von Betaferon®-Patienten

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Literatur-Dauerrecherche Multiple Sklerose Ausgabe ... · Die Literatur-Dauerrecherche finden Sie zum Download auch auf unserer Internetseite ... The effectiveness of exercise interventions