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2. Temporal evolution of new T1-weighted hypo-intense lesions and central brain atrophy in patients with a first clinical demyelinating event treated with subcutaneous interferon β-1a

Author

H. Vrenken, M. Battaglini, M. L. de Vos, G. J. Nagtegaal, B. C. A. Teixeira, A. Seitzinger, D. Jack, M. P. Sormani, B. M. J. Uitdehaag, A. Versteeg, G. Comi, L. Kappos, N. De Stefano, F. Barkhof, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neuroinfection & -inflammation, Neurology, CCA - Cancer Treatment and quality of life, CCA - Imaging and biomarkers, and Plastic and Reconstructive Surgery and Hand Surgery

Subjects
Neurology, Neurology (clinical)
Abstract

Objective Evaluate the effect of subcutaneous interferon β-1a (sc IFN β-1a) versus placebo on the evolution of T1-weighted MRI lesions and central brain atrophy in in patients with a first clinical demyelinating event (FCDE). Methods Post hoc analysis of baseline-to-24 month MRI data from patients with an FCDE who received sc IFN β-1a 44 μg once- (qw) or three-times-weekly (tiw), or placebo, in REFLEX. Patients were grouped according to treatment regimen or conversion to clinically definite MS (CDMS) status. The intensity of new lesions on unenhanced T1-weighted images was classified as T1 iso- or hypo-intense (black holes) and percentage ventricular volume change (PVVC) was assessed throughout the study. Results In patients not converting to CDMS, sc IFN β-1a tiw or qw, versus placebo, reduced the overall number of new lesions (P P = 0.005) and new T1 iso-intense lesions (P P = 0.002) after 24 months; only sc IFN β-1a tiw was associated with fewer T1 hypo-intense lesions versus placebo (P P Conclusions In patients with an FCDE, treatment with sc IFN β-1a tiw for 24 months reduced the number of new lesions evolving into black holes.

Published
2023
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3. Facing privacy in neuroimaging: removing facial features degrades performance of image analysis methods

Author

Jette L. Frederiksen, Mike P. Wattjes, Ana Rovira, Charles R.G. Guttmann, P. C. de Witt Hamer, I. Brouwer, R.A. van Schijndel, Hugo Vrenken, Marjolein Visser, Massimo Filippi, L Kappos, Marnix G. Witte, Olga Ciccarelli, Stefan Ropele, Frederik Barkhof, A. de Sitter, Keith S. Cover, Roelant S Eijgelaar, Alzheimer’s Disease Neuroimaging Initiative, Christian Enzinger, D. M. J. Müller, de Sitter, A, Visser, M, Brouwer, I, Cover, K S, van Schijndel, R A, Eijgelaar, R S, Müller, D M J, Ropele, S, Kappos, L, Rovira, Á, Filippi, M, Enzinger, C, Frederiksen, J, Ciccarelli, O, Guttmann, C R G, Wattjes, M P, Witte, M G, de Witt Hamer, P C, Barkhof, F, Vrenken, H, MAGNIMS Study Group and Alzheimer’s Disease Neuroimaging, Initiative, Rocca, M. A., Biophotonics and Medical Imaging, LaserLaB - Biophotonics and Microscopy, Radiology and nuclear medicine, Amsterdam Neuroscience - Brain Imaging, AGEM - Endocrinology, metabolism and nutrition, APH - Aging & Later Life, APH - Health Behaviors & Chronic Diseases, Neurosurgery, and Other Research

Subjects
Male, medicine.medical_specialty, Multiple Sclerosis, Outcome measurements, Neuroimaging, 030218 nuclear medicine & medical imaging, Database, 03 medical and health sciences, Magnetic resonance imaging, 0302 clinical medicine, Alzheimer Disease, Image Interpretation, Computer-Assisted, medicine, Humans, Radiology, Nuclear Medicine and imaging, Magnetic Resonance, Ethic, Analysis method, Aged, Neuroradiology, Aged, 80 and over, Ethics, Lesion segmentation, medicine.diagnostic_test, Information Dissemination, business.industry, Outcome measures, Brain, Reproducibility of Results, General Medicine, Middle Aged, medicine.disease, Tumor Burden, Privacy, Face, Female, Radiology, Glioblastoma, business, Algorithms, Confidentiality, 030217 neurology & neurosurgery
Abstract

Background Recent studies have created awareness that facial features can be reconstructed from high-resolution MRI. Therefore, data sharing in neuroimaging requires special attention to protect participants’ privacy. Facial features removal (FFR) could alleviate these concerns. We assessed the impact of three FFR methods on subsequent automated image analysis to obtain clinically relevant outcome measurements in three clinical groups. Methods FFR was performed using QuickShear, FaceMasking, and Defacing. In 110 subjects of Alzheimer’s Disease Neuroimaging Initiative, normalized brain volumes (NBV) were measured by SIENAX. In 70 multiple sclerosis patients of the MAGNIMS Study Group, lesion volumes (WMLV) were measured by lesion prediction algorithm in lesion segmentation toolbox. In 84 glioblastoma patients of the PICTURE Study Group, tumor volumes (GBV) were measured by BraTumIA. Failed analyses on FFR-processed images were recorded. Only cases in which all image analyses completed successfully were analyzed. Differences between outcomes obtained from FFR-processed and full images were assessed, by quantifying the intra-class correlation coefficient (ICC) for absolute agreement and by testing for systematic differences using paired t tests. Results Automated analysis methods failed in 0–19% of cases in FFR-processed images versus 0–2% of cases in full images. ICC for absolute agreement ranged from 0.312 (GBV after FaceMasking) to 0.998 (WMLV after Defacing). FaceMasking yielded higher NBV (p = 0.003) and WMLV (p ≤ 0.001). GBV was lower after QuickShear and Defacing (both p Conclusions All three outcome measures were affected differently by FFR, including failure of analysis methods and both “random” variation and systematic differences. Further study is warranted to ensure high-quality neuroimaging research while protecting participants’ privacy. Key Points • Protecting participants’ privacy when sharing MRI data is important. • Impact of three facial features removal methods on subsequent analysis was assessed in three clinical groups. • Removing facial features degrades performance of image analysis methods.

Published
2019
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4. P.048 International MAGNIMS-CMSC-NAIMS consensus recommendations on the use of standardized MRI in MS

Author

A Traboulsee, M Wattjes, O Ciccarelli, D Reich, B Banwell, N de Stefano, C Enzinger, F Fazekas, M Filippi, J Frederiksen, C Gasperini, Y Hacohen, L Kappos, DK Li, K Mankad, X Montalban, S Newsome, J Oh, J Palace, M Rocca, J Sastre-Garriga, M Tintore, H Vrenken, T Yours, F Barkhof, and A Rovira

Subjects
Neurology, Neurology (clinical), General Medicine
Abstract

Background: Standardized magnetic resonance imaging (MRI) guidelines published in 2015 by the Europoean MAGNIMS group and in 2016 by the CMSC are important for the diagnosis and monitoring of patients with multiple sclerosis (MS) and for the appropriate use of MRI in routine clinical practice. Methods: Two panels of experts convened to update existing guidelines for a standardized MRI protocol. The MAGNIMS panel convened in Graz, Austria in April 2019. The CMSC NAIMS panel met separately and independently in Newark, USA in October 2019. Subsequently, the MAGNIMS, NAIMS, and CMSC working groups combined their efforts to reach an international consensus Results: The revised guidelines on MRI in MS merges recommendations from MAGNIMS, CMSC, and NAIMS to improve the use of MRI for diagnosis, prognosis and monitoring of individuals with MS. 3D acquisitions are emphasized for optimal comparison over time. Core brain sequences include a 3D-T2wFLAIR for lesion identification and monitoring treatment effectiveness. Gadolinium-based contrast is recommended for diagnostic studies and judicious use for routine monitoring of MS patients. DWI sequences are recommended for PML safety monitoring. Conclusions: The international consensus guidelines strive for global acceptance of a useful and usable standard of care for patients with MS.

Published
2021
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5. MSO907951 Supplemental Table1 - Supplemental material for The ACROSS study: Long-term efficacy of fingolimod in patients with relapsing–remitting multiple sclerosis

Author

T Derfuss, J Sastre-Garriga, X Montalban, M Rodegher, J Wuerfel, L Gaetano, D Tomic, A Azmon, C Wolf, and L Kappos

Subjects
FOS: Clinical medicine, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, MSO907951 Supplemental Table1 for The ACROSS study: Long-term efficacy of fingolimod in patients with relapsing–remitting multiple sclerosis by T Derfuss, J Sastre-Garriga, X Montalban, M Rodegher, J Wuerfel, L Gaetano, D Tomic, A Azmon, C Wolf and L Kappos in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Published
2020
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6. Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS

Author

Caroline Lavie, Fabien Rollot, Françoise Durand-Dubief, Romain Marignier, Iuliana Ionescu, Romain Casey, Thibault Moreau, Patricia Tourniaire, Michael Hutchinson, Marie Béatrice D’Hooghe, David-Axel Laplaud, Pierre Clavelou, Jérôme De Sèze, Marc Debouverie, David Brassat, Jean Pelletier, Christine Lebrun-Frenay, Emmanuelle Le Page, Giovanni Castelnovo, Eric Berger, Patrick Hautecoeur, Olivier Heinzlef, Luca Durelli, Marinella Clerico, Maria Trojano, Francesco Patti, Sandra Vukusic, A. Alpérovitch, H. Carton, M.B. d’Hooghe, O. Hommes, M. Hutchinson, P. Adeleine, A. Biron, P. Cortinovis-Tourniaire, J. Grimaud, M. Hours, T. Moreau, S. Vukusic, C. Confavreux, G. Chauplannaz, D. Latombe, M. Clanet, G. Lau, L. Rumbach, J.Y. Goas, F. Rouhart, A. Mazingue, E. Roullet, M. Madigand, P. Hautecoeur, P. Brunet, G. Edan, C. Allaire, G. Riffault, J. Leche, T. Benoit, C. Simonin, F. Ziegler, J.C. Baron, Y. Rivrain, R. Dumas, D. Loche, J.C. Bourrin, B. Huttin, B. Delisse, I. Gibert, C. Boulay, M. Verceletto, G. Durand, G. Bonneviot, R. Gil, M.A. Hedreville, C. Belair, R.J. Poitevin, J.L. Devoize, P. Wyremblewski, F. Delestre, A. Setiey, G. Comi, M. Filippi, A. Ghezzi, V. Martinelli, P. Rossi, M. Zaffaroni, M.R. Tola, M.P. Amato, C. Fioretti, G. Meucci, M. Inglese, G.L. Mancardi, D. Gambi, A. Thomas, M. Cavazzuti, A. Citterio, A. Heltberg, H.J. Hansen, O. Fernandez, F. Romero, T. Arbizu, J.J. Hernandez, C. De Andres de Frutos, D. Geffner Sclarky, Y. Aladro Benito, P. Reyes Yanes, M Aguilar, J.A. Burguera, R. Yaya, W. Bonakim Dib, D. Arzua-Mouronte, C.J.M. Sindic, R. Medaer, H. Roose, K.M.J. Geens, D. Guillaume, M. Van Zandycke, J. Janssens, M. Cornette, L. Mol, F. Weilbach, P. Flachenecker, H.P. Hartung, J. Haas, I. Tendolkar, E. Sindrn, H.W. Kölmel, D. Reichel, M. Rauch, S. Preuss, S. Poser, E. Mauch, S. Strausser-Fuchs, H. Kolleger, S. Hawkins, S.J.L. Howell, J.E. Rees, A. Thompson, M. Johnson, M. Boggild, R.P. Gregory, D. Bates, I. Bone, C. Polman, S. Frequin, P. Jongen, J. Correia de Sa, M.E. Rio, S. Huber, J. Lechner-Scott, L. Kappos, I. Ionescu, C. Cornu, M. El-Etr, E.E. Baulieu, M Schumacher, D.H. Miller, M. Pugeat, C. d’Archangues, J. Conard, J. Ménard, R. Sitruk-Ware, C. Pelissier, S. Dat, J. Belaïsch-Allard, N. Athéa, D. Büschsenschutz, O. Lyon-Caen, R. Gonsette, J.P. Boissel, P. Ffrench, F. Durand-Dubief, F. Cotton, C. Pachai, L. Bracoud, G. Androdias, R. Marignier, D.A. Laplaud, S. Wiertlewski, C. Lanctin-Garcia, G. Couvreur, G. Madinier, P. Clavelou, F. Taithe, D. Aufauvre, N. Guy, A. Ferrier, J. De Sèze, N. Collongues, M. Debouverie, F. Viala, D. Brassat, A. Gerdelat-Mas, P. Henry, J. Pelletier, A. Rico-Lamy, C. Lebrun-Frenay, E. Lepage, V. Deburghraeve, G. Castelnovo, E. Berger, M. Blondiau, O. Heinzlef, M. Coustans, C. Clerc, L. Rieu, M. Lauxerois, G. Hinzelin, J.C. Ouallet, D. Minier, P. Vion, N. Gromaire-Fayolle, N. Derache, E. Thouvenot, M. Sallansonnet-Froment, P. Tourniaire, L. Toureille, F. Borgel, B. Stankoff, C. Moroianu, A.M. Guennoc, C.L. Tournier-Gervason, S. Peysson, M. Trojano, F. Patti, E. D’Amico, L. Motti, L. Durelli, A. Tavella, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Observatoire Français de la Sclérose En Plaques [Lyon] (OFSEP), Service de neurologie fonctionnelle et d'épileptologie [Hôpital Pierre Wertheimer-HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Henri Duffaut (Avignon), National MS Center Melsbroek, Vrije Universiteit Brussel [Bruxelles] (VUB), Vrije Universiteit Brussel (VUB), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Laboratoire de Neuroimagerie in Vivo (LNV), CHU Strasbourg-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Neurologie vasculaire, pathologie neuro-dégénérative et explorations fonctionnelles du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Neurologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Università degli studi di Torino = University of Turin (UNITO), University of Catania [Italy], Hospices Civils de Lyon, Departement de Neurologie (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Protéines membranaires transductrices d'énergie (PMTE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut des Géosciences de l’Environnement (IGE), Institut de Recherche pour le Développement (IRD)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherches sur les Macromolécules Végétales (CERMAV ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Environnement Ville Société (EVS), École normale supérieure - Lyon (ENS Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Solvay (France), Laboratoire des Mécanismes et Transfert en Géologie (LMTG), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Institute of Evolutionary Biology, University of Edinburgh, Université de Lille, Sciences et Technologies, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Différenciation, interaction, activation et migration des sous-populations lymphocitaires humaines, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Motricité, interactions, performance EA 4334 / Movement - Interactions - Performance (MIP), Le Mans Université (UM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR des Sciences et Techniques des Activités Physiques et Sportives (UFR STAPS), Laboratoire Ecologie Fonctionnelle et Environnement (ECOLAB), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), RMN et optique : De la mesure au biomarqueur, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Department of Neurology, CHU Lyon, Institut de Recherche de Chimie Paris (IRCP), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Hôpital de Hautepierre [Strasbourg], Laboratoire de Réactivité des Surfaces et des Interfaces (LRSI), Département de Physico-Chimie (DPC), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Empenn, Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques, European Leukodystrophies Association, PHRC National, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pierre Wertheimer, Département de Neurologie, Laboratoire de Mathématiques (LAMA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Nottingham Scientific Limited, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Turin, Università degli studi di Torino (UNITO), University of Bari Aldo Moro (UNIBA), Department of Neurosciences, Università degli studi di Catania [Catania], Centre de recherche en neurosciences de Lyon (CRNL), Neuroépidémiologie, Institut de Physique du Globe de Paris (IPGP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut de Recherche pour le Développement (IRD)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École nationale supérieure d'architecture de Lyon (ENSAL)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École Nationale des Travaux Publics de l'État (ENTPE)-Université Jean Monnet [Saint-Étienne] (UJM)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ministère de la Culture (MC), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lavie, Caroline, Rollot, Fabien, Durand-Dubief, Françoise, Marignier, Romain, Ionescu, Iuliana, Casey, Romain, Moreau, Thibault, Tourniaire, Patricia, Hutchinson, Michael, D’Hooghe, Marie Béatrice, Laplaud, David-Axel, Clavelou, Pierre, De Sèze, Jérôme, Debouverie, Marc, Brassat, David, Pelletier, Jean, Lebrun-Frenay, Christine, Le Page, Emmanuelle, Castelnovo, Giovanni, Berger, Eric, Hautecoeur, Patrick, Heinzlef, Olivier, Durelli, Luca, Clerico, Marinella, Trojano, Maria, Patti, Francesco, Vukusic, Sandra, on behalf of PRIMS and POPARTMUS, Investigator, Filippi, Massimo, Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Environnement, Ville, Société (EVS), École normale supérieure de Lyon (ENS de Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Neuroimagerie: méthodes et applications (Empenn), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Laboratoire de glaciologie et géophysique de l'environnement (LGGE), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire Motricité, Interactions, Performance, Université de Nantes (UN), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction de l'Energie Nucléaire (CEA-DEN), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service de neurologie [Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Service de Neurologie [CHU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Service de Neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Clinical sciences, Neuroprotection & Neuromodulation, and Neurology

Subjects
relapses, Neurology, [SDV]Life Sciences [q-bio], MESH: Pregnancy Complications / physiopathology, 0302 clinical medicine, MESH: Pregnancy, Anesthesia, Conduction, Recurrence, MESH: Anesthesia, Conduction / adverse effects, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, reproductive and urinary physiology, relapse, Postpartum Period, post-partum, MESH: Follow-Up Studies, MESH: Multiple Sclerosis / physiopathology, Obstetrical Analgesia, MESH: Multiple Sclerosis / chemically induced, Anesthesia, Female, pregnancy, Adult, medicine.medical_specialty, Clinical Neurology, Multiple sclerosis, MESH: Postpartum Period, 03 medical and health sciences, medicine, Humans, Multiple sclerosi, Post partum, Retrospective Studies, Pregnancy, MESH: Humans, MESH: Pregnancy Complications / chemically induced, business.industry, Neurotoxicity, MESH: Adult, MESH: Retrospective Studies, neuraxial analgesia, medicine.disease, MESH: Recurrence, Multiple sclerosis, neuraxial analgesia, post-partum, pregnancy, Pregnancy Complications, Increased risk, Neurology (clinical), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992–1995 and 2005–2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.

Published
2019
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7. Long-Term Reduction of Relapse Rate and Confirmed Disability Progression After 6 Years of Ocrelizumab Treatment in Patients with Relapsing Multiple Sclerosis

Author

Harold Koendgen, Xavier Montalban, Marianna Manfrini, Kalpesh Prajapati, Lahar R Mehta, L Kappos, Stephen L. Hauser, Gavin Giovannoni, and Jerry S. Wolinsky

Subjects
Oncology, medicine.medical_specialty, business.industry, Multiple sclerosis, medicine.medical_treatment, General Medicine, Relapse rate, medicine.disease, Term (time), Neurology, Internal medicine, Medicine, In patient, Ocrelizumab, Disability progression, Neurology (clinical), business, Reduction (orthopedic surgery), medicine.drug
Published
2020
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8. Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice

Author

Robert J. Fox, Ralf Gold, J. Theodore Phillips, Shifang Liu, L Kappos, Christian von Hehn, Catherine Miller, Karen Spach, Derrick Robertson, Jordana Campbell, Devangi Mehta, André Palma da Cunha Matta, Eris Bame, Douglas L. Arnold, Lili Yang, A Bar-Or, and Jerome Hanna

Subjects
0301 basic medicine, Adult, Male, Lymphocyte, Dimethyl Fumarate, T-Lymphocytes, CD4-CD8 Ratio, Risk Assessment, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immunophenotyping, Multiple Sclerosis, Relapsing-Remitting, Lymphopenia, medicine, Humans, Longitudinal Studies, Lymphocyte Count, Lymphocytes, Adverse effect, B-Lymphocytes, Dimethyl fumarate, business.industry, Progressive multifocal leukoencephalopathy, Multiple sclerosis, Middle Aged, medicine.disease, 3. Good health, Discontinuation, 030104 developmental biology, medicine.anatomical_structure, Cross-Sectional Studies, chemistry, Delayed-Action Preparations, Immunology, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, CD8, Immunosuppressive Agents
Abstract

ObjectiveTo assess functional changes in lymphocyte repertoire and subsequent clinical implications during delayed-release dimethyl fumarate (DMF) treatment in patients with multiple sclerosis.MethodsUsing peripheral blood from several clinical trials of DMF, immune cell subsets were quantified using flow cytometry. For some patients, lymphocyte counts were assessed after DMF discontinuation. Incidence of adverse events, including serious and opportunistic infections, was assessed.ResultsIn DMF-treated patients, absolute lymphocyte counts (ALCs) demonstrated a pattern of decline followed by stabilization, which also was reflected in the global reduction in numbers of circulating functional lymphocyte subsets. The relative frequencies of circulating memory T- and B-cell populations declined and naive cells increased. No increased incidence of serious infection or malignancy was observed for patients treated with DMF, even when stratified by ALC or T-cell subset frequencies. For patients who discontinued DMF due to lymphopenia, ALCs increased after DMF discontinuation; recovery time varied by ALC level at discontinuation. T-cell subsets closely correlated with ALCs in both longitudinal and cross-sectional analyses.ConclusionsDMF shifted the immunophenotype of circulating lymphocyte subsets. ALCs were closely correlated with CD4+ and CD8+ T-cell counts, indicating that lymphocyte subset monitoring is not required for safety vigilance. No increased risk of serious infection was observed in patients with low T-cell subset counts. Monitoring ALC remains the most effective way of identifying patients at risk of subsequently developing prolonged moderate to severe lymphopenia, a risk factor for progressive multifocal leukoencephalopathy in DMF-treated patients.Trial registration numbersEUDRA CT 2015-001973-42, NCT00168701, NCT00420212, NCT00451451, and NCT00835770.

Published
2018

9. A randomized trial of teriflunomide added to glatiramer acetate in relapsing multiple sclerosis

Author

MS Freedman, JS Wolinsky, P Truffinet, G Comi, L Kappos, AE Miller, TP Olsson, M Benamor, S Chambers, and PW O’Connor

Subjects
safety, medicine.medical_specialty, Pharmacology, Placebo, multiple sclerosis, law.invention, Disease activity, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Randomized controlled trial, law, Internal medicine, Teriflunomide, Medicine, Glatiramer acetate, Adverse effect, business.industry, Multiple sclerosis, medicine.disease, relapsing − remitting multiple sclerosis, chemistry, Tolerability, Original Article, Neurology (clinical), Randomized clinical trial, business, medicine.drug, MRI
Abstract

Background Teriflunomide is a once-daily oral immunomodulator for the treatment of relapsing−remitting MS. Objective To evaluate the safety and tolerability of teriflunomide as add-on therapy to a stable dose of glatiramer acetate (GA) in patients with relapsing forms of MS (RMS). Methods Phase II, randomized, double-blind, add-on, placebo-controlled study. The primary objective was to assess safety and tolerability; secondary objectives were to evaluate effects of treatment on disease activity assessed by MRI and relapse. Results Patients with RMS on GA ( N = 123) were randomized 1:1:1 to receive teriflunomide 14 mg ( n = 40), 7 mg ( n = 42), or placebo ( n = 41) for 24 weeks; 96 patients entered the 24-week extension, remaining on original treatment allocation. Teriflunomide was well tolerated over 48 weeks. The frequency of adverse events (AEs) was low across all groups; 5 (12.2%), 3 (7.1%), and 2 (5.0%) patients in the 14 mg, 7 mg, and placebo groups, respectively, discontinued treatment due to AEs. Teriflunomide reduced the number of T1-Gd lesions vs placebo (14 mg: 46.6% relative reduction, p = 0.1931; 7 mg: 64.0%: relative reduction, p = 0.0306). Conclusions Teriflunomide added to stable-dose GA had acceptable safety and tolerability, and reduced some MRI markers of disease activity compared with GA alone. NCT00475865 (core study); NCT00811395 (extension).

Published
2017

10. Longer-term Safety with Siponimod Treatment in Multiple Sclerosis: Pooled Analysis of Data from the Bold and Expand Trials and their Extensions

Author

Gavin Giovannoni, T. Masior, RJ Fox, Daniela Piani Meier, Davorka Tomic, L Kappos, N. Rouyrre, Patrick Vermersch, Amit Bar-Or, R. Gold, and Bruce A.C. Cree

Subjects
medicine.medical_specialty, business.industry, Multiple sclerosis, General Medicine, medicine.disease, Term (time), 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Siponimod, Physical medicine and rehabilitation, Pooled analysis, Neurology, chemistry, 030220 oncology & carcinogenesis, medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Published
2018
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11. Investigating the Effect of Teriflunomide on Diffuse Brain Tissue Damage in the Phase 3 TEMSO Study

Author

Till Sprenger, Bassem Yamout, Ernst Wilhelm Radue, Karthinathan Thangavelu, L Kappos, Alex L. Lublin, G. Comi, John A. Lincoln, Jens Wuerfel, Steve Cavalier, Christine Lebrun-Frenay, M. S. Park, and D. Chinchilla

Subjects
Pathology, medicine.medical_specialty, business.industry, Multiple sclerosis, General Medicine, Brain tissue, medicine.disease, chemistry.chemical_compound, Neurology, chemistry, Phase (matter), Teriflunomide, medicine, Neurology (clinical), business
Published
2018
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12. Sustained Reduction in Confirmed Disability Progression in Patients with Primary Progressive Multiple Sclerosis Treated with Ocrelizumab in the Open-label Extension Period of the Phase III ORATORIO trial

Author

Marianna Manfrini, Jerry S. Wolinsky, L Kappos, M. Garas, Bruno Brochet, Robert T. Naismith, Stanislas Hubeaux, Xavier Montalban, Stephen L. Hauser, Fabian Model, and Pablo Villoslada

Subjects
0301 basic medicine, medicine.medical_specialty, business.industry, Multiple sclerosis, Primary Progressive Multiple Sclerosis, General Medicine, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, Internal medicine, Medicine, Oratorio, Disability progression, In patient, Ocrelizumab, Neurology (clinical), Open label, business, 030217 neurology & neurosurgery, medicine.drug
Published
2018
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13. Impact of Gadolinium-enhancing (GD+) Lesions on No Evidence of Disease Activity (NEDA) Status in Subcutaneous Interferon Beta-1a (SC IFNβ-1a)-treated Patients

Author

G. Comi, Julie Aldridge, Kurt Marhardt, L Kappos, Mark S. Freedman, and Patricia K. Coyle

Subjects
medicine.medical_specialty, business.industry, Multiple sclerosis, Gadolinium, Interferon beta-1a, chemistry.chemical_element, General Medicine, medicine.disease, Gastroenterology, Disease activity, Neurology, chemistry, Internal medicine, medicine, Neurology (clinical), business, medicine.drug
Published
2018
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14. FV 47 Safety of ocrelizumab in multiple sclerosis: updated analysis in patients with relapsing and primary progressive multiple sclerosis

Author

Jerry S. Wolinsky, David Wormser, Ashish Pradhan, Harold Koendgen, H.-P. Hartung, John Mcnamara, Xavier Montalban, Stephen L. Hauser, Richard Hughes, and L Kappos

Subjects
medicine.medical_specialty, business.industry, Multiple sclerosis, Primary Progressive Multiple Sclerosis, medicine.disease, Sensory Systems, Neurology, Physiology (medical), Internal medicine, medicine, Ocrelizumab, In patient, Neurology (clinical), business, medicine.drug
Published
2019
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15. [Cell depletion and myoablation for neuroimmunological diseases]

Author

M, Diebold, L, Kappos, and T, Derfuss

Subjects
Immunosuppression Therapy, Evidence-Based Medicine, Multiple Sclerosis, Treatment Outcome, Neuroimmunomodulation, Hematopoietic Stem Cell Transplantation, Antibodies, Monoclonal, Humans, Combined Modality Therapy, Immunosuppressive Agents
Abstract

The treatment of autoimmune disorders of the nervous system is based on interventions for the underlying immune phenomena.To summarize concepts of cell depletion and myeloablation studied in the context of neuroimmunological disorders.Evaluation of the available literature on multiple sclerosis as the most widely studied neuroimmunological entity.Three concepts have been introduced: classical immunosuppressants, such as azathioprine, mitoxantrone and cyclophosphamide exert general lymphopenic effects and thereby moderately decrease disease activity. Myeloablative regimens combined with autologous hematopoietic stem cell transplantation have a profound and in most cases long-lasting impact on autoimmunity at the cost of potentially life-threatening side effects. Alemtuzumab (anti-CD52), rituximab and ocrelizumab (both anti-CD20) are depleting antibodies directed against certain lymphocyte subsets and substantially ameliorate disease activity in relapsing-remitting multiple sclerosis. Ocrelizumab also shows efficacy in the primary progressive form of multiple sclerosis.Most of the presented cell-depleting and myeloablative therapies are highly effective treatment options but are also accompanied by significant risks. In the context of the increasing number of alternative immunomodulatory options the indications for use should be cautiously considered.

Published
2016

17. Long-term Reduction in Brain MRI Disease Activity and Atrophy after 5 years of Ocrelizumab Treatment in Patients with Relapsing Multiple Sclerosis

Author

Fabian Model, Pablo Villoslada, Stephen L. Hauser, V. Levesque, A. Traboulsee, Stanislas Hubeaux, Xavier Montalban, Douglas L. Arnold, Jerry S. Wolinsky, L Kappos, Amit Bar-Or, Shibeshih Belachew, and Marianna Manfrini

Subjects
medicine.medical_specialty, business.industry, Multiple sclerosis, medicine.medical_treatment, General Medicine, medicine.disease, Gastroenterology, 030227 psychiatry, Disease activity, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Neurology, Internal medicine, medicine, Brain mri, Ocrelizumab, In patient, Neurology (clinical), business, 030217 neurology & neurosurgery, Reduction (orthopedic surgery), medicine.drug
Published
2018
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19. Classification of patients with a clinically isolated syndrome based on signs and symptoms is supported by magnetic resonance imaging results

Author

B.M.J. Uitdehaag, P. Poppe, J.M. Nielsen, Frederik Barkhof, Rupert Sandbrink, Chris H. Polman, Mark S. Freedman, L Kappos, Christoph Pohl, H.-P. Hartung, B. Moraal, Lars Bauer, and M.L. de Vos

Subjects
Adult, Male, medicine.medical_specialty, Pathology, Multiple Sclerosis, Signs and symptoms, Central nervous system disease, Degenerative disease, medicine, Humans, First episode, Clinically isolated syndrome, medicine.diagnostic_test, business.industry, Multiple sclerosis, Magnetic resonance imaging, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical neurology, Neurology, Female, Interferons, Neurology (clinical), Radiology, business
Abstract

Background Recently, a clinical classification system was described to determine whether symptoms and signs of patients presenting with a first episode suggestive of multiple sclerosis (MS) indicate the presence of monofocal or multifocal disease. Objectives To evaluate the value of this new classification system by comparing the results with those of simultaneously obtained magnetic resonance imaging (MRI) scans. Methods The 487 patients, randomised in the BENEFIT study, were centrally assessed using the new system and classified as monofocal or multifocal, based on clinical information by two neurologists masked for the MRI results. MRI analyses were performed by expert readers masked for the clinical classification. Results Patients classified as multifocal had more T2 hyperintense (median: 21 versus 15.5) and more T1 hypo-intense lesions (median: 2 versus 1) than those classified as monofocal. Patients classified at the local site as having evidence of a single clinical lesion, but reclassified centrally as having a clinical multifocal central nervous system presentation, had more T2 lesions than monofocal patients. In addition, patients with a multifocal presentation more often fulfilled the MRI criteria for dissemination in space, as incorporated in the International Panel (IP) diagnostic criteria for MS. Conclusion These data provide justification for the recently proposed clinical classification system to be used in patients who present with a first episode suggestive of MS, in that `multifocal', based on symptoms and signs, is associated with more lesions on MRI. Multiple Sclerosis 2007; 13: 717-721. http://msj.sagepub.com

Published
2007
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20. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes

Author

L, Kappos, C H, Polman, M S, Freedman, G, Edan, H P, Hartung, D H, Miller, X, Montalban, F, Barkhof, L, Bauer, P, Jakobs, C, Pohl, and R, Sandbrink

Subjects
Adult, Male, Canada, Multiple Sclerosis, Time Factors, Interferon-beta, Syndrome, Placebo Effect, Risk Assessment, Disease-Free Survival, Europe, Treatment Outcome, Double-Blind Method, Risk Factors, Prevalence, Humans, Female, Neurology (clinical), Israel, Interferon beta-1b
Abstract

To assess efficacy, safety, and tolerability of every-other-day interferon beta-1b treatment in patients with a first clinical event suggestive of multiple sclerosis (MS) (clinically isolated syndrome).We conducted a multicenter, randomized, double-blind, placebo-controlled trial. Patients with a first clinical demyelinating event and at least two clinically silent brain MRI lesions were randomized to interferon beta-1b (IFNB-1b) 250 mug subcutaneously (SC) every other day (EOD) (n = 292) or placebo (n = 176), until clinically definite MS (CDMS) was diagnosed or they had been followed for 24 months.After 2 years, 45% of placebo patients had converted to CDMS (Kaplan-Meier estimate; primary outcome measure) and 85% fulfilled the McDonald criteria (co-primary outcome measure). Overall interferon beta-1b delayed the time to diagnosis of CDMS (p0.0001) and McDonald MS (p0.00001). Hazard ratios (95% CI) were 0.50 (0.36 to 0.70) for CDMS and 0.54 (0.43 to 0.67) for McDonald MS favoring treatment with IFNB-1b. Treatment was well tolerated, as indicated by the low rate of patients dropping out of the study before CDMS was reached (6.6% overall, 7.2% in the IFNB-1b group).Interferon beta-1b 250 mug subcutaneously every other day delayed conversion to clinically definite multiple sclerosis, and should be considered as a therapeutic option in patients presenting with a first clinical event suggestive of multiple sclerosis.

Published
2006
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22. MRI metrics as surrogate endpoints for EDSS progression in SPMS patients treated with IFN -1b

Author

Massimo Filippi, Maria Pia Sormani, K. Beckmann, K Wagner, L Kappos, Paolo Bruzzi, and DH Miller

Subjects
medicine.medical_specialty, Randomization, Context (language use), Severity of Illness Index, law.invention, Central nervous system disease, Disability Evaluation, Double-Blind Method, Randomized controlled trial, law, medicine, Humans, Immunologic Factors, business.industry, Surrogate endpoint, Multiple sclerosis, Interferon beta-1a, Brain, Interferon-beta, Multiple Sclerosis, Chronic Progressive, medicine.disease, Magnetic Resonance Imaging, Surgery, Clinical trial, Treatment Outcome, Clinical Trials, Phase III as Topic, Disease Progression, Regression Analysis, Neurology (clinical), Radiology, business, Biomarkers, Follow-Up Studies, Interferon beta-1b, medicine.drug
Abstract

Background: Although metrics derived from conventional MRI (cMRI) are widely used as outcome measures in clinical trials of MS, no formal study has been performed to validate cMRI metrics as surrogate endpoints for disability progression in MS. Methods: A validation procedure was applied to the clinical and MRI data collected in the context of the European randomized, double-blind, placebo-controlled trial of interferon β-1b (IFNβ-1b) in patients with secondary progressive MS. The Prentice operational criteria were used to assess surrogacy for the number of active lesions seen on the first year T2-weighted MRI scans and the percentage T2 lesion volume change between the baseline and the first year MRI scans. The primary clinical outcome was disability at study exit (3 years), adjusted for the baseline disability. Results: The number of active T2 lesions and the T2 lesion volume percentage change over the first year of the study accounted for 57% of the treatment effect on disability progression over the entire study duration. On the contrary, the same cMRI metrics accounted for 79% of the treatment effect on the relapse rate. Conclusions: This study shows that the beneficial effect of IFNβ-1b on disability accumulation in patients with secondary progressive MS is, to a large extent, independent of the changes detected using cMRI. As a consequence, cMRI metrics should not be used as a stand-alone measure of outcome in phase III trials of IFNβ in secondary progressive MS.

Published
2003
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23. Can the Expanded Disability Status Scale be assessed by telephone?

Author

Robert W. Gibberd, Jeannette Lechner-Scott, Maria Pia Amato, C Buttinelli, M Hofman, M Versavel, Xavier Montalban, Mar Tintoré, Chris H. Polman, M. Frontoni, Maria Letizia Bartolozzi, H Ronner, Frank Dahlke, L Kappos, J F Kapp, University of Zurich, and Kappos, L

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Intraclass correlation, 610 Medicine & health, Neurological examination, Physical examination, Walking, Interviews as Topic, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, 030212 general & internal medicine, Aged, Expanded Disability Status Scale, medicine.diagnostic_test, business.industry, Telephone call, Reproducibility of Results, 11359 Institute for Regenerative Medicine (IREM), Middle Aged, Surgery, Europe, Clinical trial, 2728 Neurology (clinical), Neurology, Telephone interview, 2808 Neurology, Physical therapy, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Kappa
Abstract

Information from patients who are unable to continue their visits to a study centre may be of major importance for the interpretatio n of results in multiple sclerosis (MS) clinical trials. To validate a questionnaire based on the Expanded Disability Status Scale (EDSS), patients in five different European centres were assessed independently by pairs of trained EDSS raters, first by telepho ne interview and a few days later by standardized neurological examination. Seventy women and 40 men with an average age of 43.7 years (range 19 -74 years) were included in the study. Mean EDSS score at the last visit was 4.5 (0 -9). EDSS assessment by telepho ne was highly correlated with the EDSS determined by physical examination (Pearson’s correlation coefficient -0.95). A n intraclass correlation coefficient (IC C) of 94.8% was found for the total sample; 77.6% and 86%, respectively, for patients with EDSSB-4.5 (n -46) and \-4.5 (n -64). Kappa values for full agreement were 0.48; for variation by -0.5 steps and -1.0 steps, 0.79 and 0.90, respectively. Best agreement could be found in higher EDSS scores, where assessment by telepho ne interview might be needed most. The telepho ne questionnaire is a valid tool to assess EDSS score in cases where the patient is unable to continue visiting a study centre or in long-term follow-up of trial participants.

Published
2003
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24. Neutralizing antibodies during treatment of secondary progressive MS with interferon -1b

Author

C, Polman, L, Kappos, R, White, F, Dahlke, K, Beckmann, C, Pozzilli, A, Thompson, J, Petkau, and D, Miller

Subjects
Adult, Male, Injections, Subcutaneous, Interferon-beta, Middle Aged, Multiple Sclerosis, Chronic Progressive, Magnetic Resonance Imaging, Antibodies, Drug Administration Schedule, Cohort Studies, Disability Evaluation, Cross-Sectional Studies, Treatment Outcome, Double-Blind Method, Recurrence, Disease Progression, Humans, Immunologic Factors, Female, Serologic Tests, Longitudinal Studies, Neurology (clinical), Interferon beta-1a, Interferon beta-1b
Abstract

To investigate the relationship between neutralizing antibodies (NAB) and disease progression, relapses, and MR measures of MS.Sequential serum samples from all 718 patients of the European Study Group in Interferon beta-1b in Secondary Progressive MS were analyzed to investigate relations between NAB and disease progression, relapses, and MR measures.This study showed no attenuating effect of NAB development on progression in disability. The effects of NAB on relapse rate showed substantial variation, depending on the statistical approach and definition of positivity, though analyses comparing low- and high-NAB+ periods with NAB- periods suggested a titer-related effect. MR T2 lesion volume changes from baseline were significantly higher for NAB+ patients but remained lower than for placebo patients. A substantial proportion of NAB+ patients became NAB-. No untoward effect of NAB development on safety was observed.These results support the conclusion that even though high NAB titers appear to have impact on treatment efficacy with respect to relapses, treatment decisions should be based primarily on clinical grounds.

Published
2003
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26. Relapses in patients treated with fingolimod after previous exposure to natalizumab

Author

R. Gold, L Kappos, Arijit Sinha, P. von Rosenstiel, Frank Dahlke, Davorka Tomic, G. Comi, Comi, Giancarlo, Gold, R, Dahlke, F, Sinha, A, von Rosenstiel, P, Tomic, D, and Kappos, L.

Subjects
Adult, Male, medicine.medical_specialty, Time Factors, Post hoc, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, Internal medicine, medicine, Humans, Immunologic Factors, In patient, business.industry, Fingolimod Hydrochloride, Multiple sclerosis, Middle Aged, medicine.disease, Fingolimod, Surgery, Treatment Outcome, Neurology, Clinical Trials, Phase III as Topic, Female, Neurology (clinical), business, medicine.drug
Abstract

In post hoc analyses of an open-label, phase 3b study (FIRST), relapse rates during 4 months of fingolimod therapy were compared in patients with and without previous natalizumab exposure. Reductions in the proportion of patients experiencing relapses and annualized relapse rates (ARRs) from years 1 and 1–2 pre-study were evident between months 1 and 2 of fingolimod treatment, and were most pronounced in natalizumab-naïve patients and those who discontinued natalizumab >6 months pre-study. Patients who discontinued natalizumab 3–6 months pre-study had a peak ARR during month 1 of fingolimod treatment, followed by a decrease during months 2–4. These data indicate that fingolimod has the potential to reduce disease reactivation but that timing of treatment initiation may be critical for achieving an optimal effect.

Published
2014

28. Magnetic resonance imaging correlates of physical disability in relapse onset multiple sclerosis of long disease duration

Author

H, Kearney, M A, Rocca, P, Valsasina, L, Balk, J, Sastre-Garriga, J, Reinhardt, S, Ruggieri, A, Rovira, C, Stippich, L, Kappos, T, Sprenger, P, Tortorella, M, Rovaris, C, Gasperini, X, Montalban, J J G, Geurts, C H, Polman, F, Barkhof, M, Filippi, D R, Altmann, O, Ciccarelli, D H, Miller, D T, Chard, Anatomy and neurosciences, Neurology, Radiology and nuclear medicine, NCA - Neuroinflamation, Kearney, H, Rocca, Ma, Valsasina, P, Balk, L, Sastre Garriga, J, Reinhardt, J, Ruggieri, S, Rovira, A, Berger, C, Kappos, L, Sprenger, T, Tortorella, P, Rovaris, M, Gasperini, C, Montalban, X, Geurts, Jjg, Polman, Ch, Barkhof, F, Filippi, Massimo, Altmann, Dr, Ciccarelli, O, Miller, Dh, and Chard DT on behalf of the Magnetic Imaging in Multiple Sclerosis collaborative, Group

Subjects
Male, Brain, spinal cord, Middle Aged, Multiple Sclerosis, Chronic Progressive, multiple sclerosis, Magnetic Resonance Imaging, Research Papers, Disability Evaluation, brain lesion load, Multiple Sclerosis, Relapsing-Remitting, disability, Image Interpretation, Computer-Assisted, Humans, Female, Atrophy, MRI, Spinal Cord, Neurology (clinical), Neurology
Abstract

Background: Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease. Objectives: The Magnetic Imaging in MS (MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS. Methods: Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups). Results: In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability. Conclusions: Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.

Published
2014
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29. The effect of IFN -1b on the evolution of enhancing lesions in secondary progressive MS

Author

DH Miller, Aj Thompson, Y. Rolland, Chris H. Polman, P D Molyneux, L Kappos, F. Barkhof, C. Pozzilli, P A Brex, Dietbert Hahn, Massimo Filippi, Tarek A. Yousry, P. Smiddy, and Oili Salonen

Subjects
Adult, Male, medicine.medical_treatment, Placebo, Lesion, White matter, Central nervous system disease, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, medicine, Enhancing Lesion, Humans, 030304 developmental biology, 0303 health sciences, Chemotherapy, business.industry, Multiple sclerosis, Interferon beta-1b, Brain, Interferon-beta, Middle Aged, Multiple Sclerosis, Chronic Progressive, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Female, Neurology (clinical), medicine.symptom, Nuclear medicine, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background: After the resolution of contrast enhancement, the majority of new MS lesions become isointense with surrounding white matter on T1-weighted MRI. Less commonly, a hypointense T1 lesion develops, representing the development of more severe focal tissue damage. Interferon beta (IFNβ) reduces both the number of new enhancing lesions and the duration of contrast enhancement. Objective: To determine if IFNβ affects the degree of tissue damage within new lesions and if its effects are related to lesion size. Methods: One hundred twenty-five patients with secondary progressive MS from seven European sites were randomized to receive either IFNβ-1b or placebo. Monthly, contrast-enhanced T1-weighted MR images were acquired at baseline, at months 1 to 6, and at months 19 to 24. The size of all new enhancing lesions developing between months 1 and 6 was recorded and their appearance at follow-up documented. Results: In the first 6 months, fewer new enhancing lesions occurred in the IFNβ-1b arm. This difference was greater for small (70% decrease) than for large (46% decrease) lesions. Hypointense T1 lesions were more likely to form from large (25%) than from small (9%) enhancing lesions in both treatment arms. Patients taking IFNβ-1b developed fewer hypointense T1 lesions; however, the proportion of enhancing lesions developing into hypointense T1 lesions was similar in both arms. Conclusion: IFNβ-1b reduced the number of new enhancing lesions, with a greater effect on small lesions. However, when a new enhancing lesion did become established, treatment with IFNβ-1b did not alter its subsequent course.

Published
2001
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31. Contents Vol. 40, 2007

Author

A. Wiebel, H. Assaloni, Nora Klinkowski, M. Rufer, D. Bürgin, Soo Churl Cho, Elie Hantouche, Pieter F. A. de Nijs, Carsten Spitzer, A. Grether, A. Schwald Dillier, C. Reck, F. Resch, Harald J. Freyberger, Alexander Korte, Luigi Grassi, F. Amsler, Sanjeev Ranjan, Sylvie Lancrenon, Frank C. Verhulst, B. Steck, Sven Barnow, In Kyoon Lyoo, Thomas Fuchs, Ernst Pfeiffer, E. Moehler, Gloria Carballo García, L. Kappos, Bernd Rüdiger Brüggemann, Petra Garlipp, Ulrike Lehmkuhl, Luciana Marmai, Federico Fagioli, Jee Hyun Ha, Hans J. Grabe, W.M.A. Verhoeven, J. Kagan, H. Moergeli, R. Schneider, Corrado Barbui, Malte Stopsack, Elvira Mendoza Lara, P. Parzer, Maria Dolores Fresneda López, R. Brunner, Arthur Kaladjian, Christoph Kessler, Hyung-Jun Kim, Santosh Prabhu, Arun Kumar Gupta, Ulrich W. Preuss, Bruno Biancosino, Jean-Michel Azorin, Eric Y.H. Chen, F.M.M.A. van der Heijden, Soojeong C. Bae, Robert F. Ferdinand, Sabine C. Herpertz, Franco Benazzi, Paz López-Herrero, Hagop S. Akiskal, Harriet Salbach, G. Romer, Liliane Châtenet Duchêne, H.J.H Kuijpers, Riccardo Sabatelli, Sujin Bae, Pol A. C. van Lier, Juana Muñoz López, Su Yeon Kim, Charles Gury, L. Poustka, Minyoung Sim, S. Tuinier, C. Mueller, Prabha S. Chandra, and Hector W. H. Tsang

Subjects
Psychiatry and Mental health, Clinical Psychology, Anthropology, Psychology
Published
2007
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32. Body fluid markers to monitor multiple sclerosis: the assays and the challenges

Author

Jon D. Laman, L Kappos, E J Thompson, TNO Preventie en Gezondheid, and Immunology

Subjects
Serum, Multiple Sclerosis, T cells, Context (language use), Disease, Urine, CSF (cerebrospinal fluid), Disease activity, 03 medical and health sciences, 0302 clinical medicine, Basic research, MMP (matrix metalloproteinase), Humans, Medicine, 030212 general & internal medicine, Antibody, Monitoring, Physiologic, Body fluid, business.industry, Multiple sclerosis, Reproducibility of Results, Nitric oxide, medicine.disease, Body Fluids, Neurology, Health, Neurology (clinical), business, Neuroscience, 030217 neurology & neurosurgery, CSF - Cerebrospinal fluid
Abstract

The need for reliable markers of disease activity in multiple sclerosis (MS) to better guide basic research, diagnosis, treatment, and monitoring of therapy is well-recognized. A recent European Charcot Foundation Symposium (Body fluid markers for course and activity of disease in multiple sclerosis (Madrid, Spain, October 2-4, 1997) organized by the European Charcot Foundation and the Fundación Española de Esclerosis Múltiple (the Spanish Multiple Sclerosis Foundation) brought together experts in the field to review the state of the art for the technology measuring markers in body fluids. An array of different approaches was presented to measure a wide diversity of classic and novel marker molecules, including cytokines, adhesion molecules, myelin compounds, and free antibody light chains, in either blood, urine, or cerebrospinal fluid. Here, recent progress in these approaches is assessed in the context of distinct pathophysiological stages of the disease, the requirements which such molecules and assays should ideally meet, and the practical and conceptual challenges which they face. Recommendations for further improvements are described.

Published
1998
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33. Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS)

Author

L Kappos, Xiangyi Meng, Jean Pelletier, H.-P. Hartung, Augusto Grinspan, P. von Rosenstiel, J. A. Cohen, G. Comi, Ron Hashmonay, Bhupendra Khatri, F. Barkhof, Radiology and nuclear medicine, and NCA - neurodegeneration

Subjects
medicine.medical_specialty, business.industry, Multiple sclerosis, Therapeutic effect, Placebo-controlled study, General Medicine, medicine.disease, Fingolimod, Discontinuation, Surgery, Neurology, Interferon, Internal medicine, medicine, Neurology (clinical), Glatiramer acetate, Adverse effect, business, medicine.drug
Abstract

Background Fingolimod demonstrated superior efficacy compared with interferon β-1a intramuscular in relapsing multiple sclerosis. The impact of treatment history on fingolimod efficacy is unknown. Objectives This post-hoc analysis of phase 3 TRANSFORMS data compared the efficacy and safety of fingolimod and interferon β-1a intramuscular among patient subgroups defined by prior treatment history. Methods Annualized relapse rate and safety of once-daily oral fingolimod 0.5mg, 1.25mg, or once-weekly interferon β-1a 30μg intramuscular for 12 months were analyzed in 1292 patients with relapsing multiple sclerosis according to prior disease-modifying therapy, reason for prior disease-modifying therapy discontinuation (adverse events or unsatisfactory therapeutic effect), and prior disease-modifying therapy duration. Results Compared with interferon β-1a intramuscular, fingolimod 0.5mg significantly reduced annualized relapse rate in patients who were treatment naive, received prior interferon-β treatment, discontinued prior disease-modifying therapy for unsatisfactory therapeutic effect, or had prior disease-modifying therapy duration of ≥1 year ( P≤ 0.05, all comparisons). Similar trends were observed in patients with prior glatiramer acetate treatment. Significant reductions were also seen with fingolimod 1.25mg for treatment-naive and prior interferon-β-treated patients. Conclusions This analysis demonstrates superiority of fingolimod over interferon β-1a intramuscular regardless of prior (interferon-β) treatment and prior treatment efficacy and duration. ClinicalTrials.gov identifier: NCT00340834.

Published
2013
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34. Klinische Grundlagen der Multiplen Sklerose

Author

L. Kappos and Ö. Yaldizli

Abstract

Die Multiple Sklerose (MS) ist seit uber 200 Jahren als eigenstandiges Krankheitsbild bekannt. Die Ursache der Erkrankung ist bis heute ungeklart. Es ist eine autoimmun bedingte chronisch-entzundliche Erkrankung von Gehirn und Ruckenmark (zentrales Nervensystem, ZNS) und betrifft weltweit vermutlich ca. 2,5 Millionen Menschen. Die Diagnose trifft die Menschen meist im jungen Erwachsenenalter, mit Auswirkungen auf Familie und Beruf. Viele Patienten und Angehorige reagieren bei der Erstdiagnose schockiert, haben Angst, fuhlen sich unsicher und hoffnungslos. Die Physiotherapie ist eine der wichtigsten Saulen in der Betreuung und Behandlung von MS-Patienten. Dieses Kapitel soll einen Uberblick uber die wichtigsten klinischen Grundlagen der MS liefern.

Published
2011
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35. Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients

Author

M Hochberger, L Kappos, J Sidney, Luciano Adorini, E D Albert, Alessandro Sette, Carla Oseroff, A Valli, and G Miescher

Subjects
Adult, Male, Multiple Sclerosis, T-Lymphocytes, T cell, Molecular Sequence Data, Peptide, Human leukocyte antigen, Epitope, Cell Line, HLA-DQ Antigens, medicine, Humans, Amino Acid Sequence, Peptide sequence, Alleles, HLA-DR Antigen, Aged, chemistry.chemical_classification, biology, HLA-DQ Antigen, Immunodominant Epitopes, Histocompatibility Antigens Class II, Myelin Basic Protein, HLA-DR Antigens, General Medicine, Middle Aged, Virology, Molecular biology, Peptide Fragments, Myelin basic protein, medicine.anatomical_structure, chemistry, biology.protein, Female, Research Article
Abstract

Multiple sclerosis (MS) is an autoimmune disease in which myelin proteins have been implicated as autoantigens recognized by pathogenic autoreactive T cells. To study the relationship between human myelin basic protein (hMBP) and HLA alleles associated to MS susceptibility, such as DRB1*1501, the binding of synthetic peptides spanning the entire hMBP sequence to 10 purified HLA-DR molecules was determined. All the hMBP peptides tested showed binding affinity for at least one of the DR molecules analyzed, but three hMBP peptides, included in sequences 13-32, 84-103, and 144-163 were found capable of binding to three or more DR molecules. The hMBP peptide 84-103 was the most degenerate in binding, in that it bound to 9 out of 10 DR molecules tested. Interestingly, it bound with highest affinity to DRB1*1501 molecules. To correlate the binding pattern of hMBP peptides to HLA class II molecules with their recognition by T cells, 61 hMBP-specific T cell lines (TCL) were established from the peripheral blood of 20 MS patients, who were homozygous, heterozygous, or negative for DRB1*1501. Analysis of hMBP epitopes recognized by these TCL and their HLA restriction demonstrated a very good correlation between binding data and T cell proliferation to hMBP peptides. Although virtually all hMBP peptides tested could be recognized by at least one TCL from MS patients, three immunodominant T cell epitopes were apparent among the TCL examined, corresponding exactly to the hMBP peptides capable of binding to several DR molecules. No major difference could be detected in the recognition of immunodominant hMBP peptides by TCL from DRB1*1501 positive or negative MS patients. These results have implications for the role of hMBP as relevant autoantigen, and of DRB1*1501 as susceptibility allele in MS.

Published
1993
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36. Four-year Expanded Disability Status Scale (EDSS) outcomes in patients treated with fingolimod in the Phase 3 and extension trial program

Author

S. Casiano, Shannon Ritter, Bruce A.C. Cree, Philipp von Rosenstiel, L Kappos, Daniela Piani Meier, and Peter Chin

Subjects
medicine.medical_specialty, Percentile, Expanded Disability Status Scale, business.industry, General Medicine, Fingolimod, Objective assessment, Neurology, Internal medicine, Physical therapy, Medicine, In patient, Neurology (clinical), business, medicine.drug
Abstract

Background/objective Assessment of long-term disability status is important for characterizing the benefit-risk profile of disease modifying MS therapies, although a lack of control group and selective drop-outs may produce bias. Here we explored longitudinal Expanded Disability Status Scale (EDSS) outcomes in fingolimod treated patients in the FREEDOMS, FREEDOMS 2 and TRANSFORMS Phase 3 and extension trials. Design/methods EDSS data from patients initiating fingolimod in Phase 3 or extension were pooled for post-hoc analysis. Kaplan–Meier (KM) estimates of proportions not reaching EDSS 4, 6 and 7 were calculated from start of fingolimod 0.5 mg or any dose (all-FTY). Proportions with EDSS score less than or equal to the baseline score at start of fingolimod (FTY-BL), and decreased compared to FTY-BL, after 24, 36 and 48 months were analyzed descriptively. Results The pooled 0.5 mg/all-FTY (N=1641/3283) cohorts had median (25th, 75th percentile) treatment exposures of 967/918 (556/1343, 482/1325) days. KM estimates of proportions not reaching EDSS 4, 6 and 7, were 71.3%, 87.8% and 96.7% for 0.5 mg and 69.5%, 87.0% and 96.3% for all-FTY. At months 24 (N=1324/2580), 36 (N=909/1727) and 48 (N=587/1110), the proportions with EDSS score less than or equal to FTY-BL were, 67.9%, 64.7% and 66.8% for 0.5 mg and 69.0%, 66.4% and 66.2% for all-FTY. Of these, EDSS was improved at months 24, 36 and 48 compared to FTY-BL in 15.7%, 17.4% and 17.4% for 0.5 mg and 17.5%, 18.7% and 18.5% for all-FTY. Conclusion Most Phase 3 and extension trial patients treated with fingolimod in either dose for up to 4.9 years remained free of the need for walking assistance. Approximately two-thirds of fingolimod patients continuing on treatment had the same or better EDSS score after 2, 3 and 4 years of treatment, while 16–18% had improved scores. Absence of a control group and selective drop-outs may bias these results.

Published
2014
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37. Phase 2 BOLD extension study efficacy results for siponimod (BAF312) in patients with relapsing-remitting multiple sclerosis

Author

Bernhard Hemmer, Olaf Stüve, K. Selmaj, D. K. B. Li, Peter Rieckmann, Mark S. Freedman, Xavier Montalban, Tjalf Ziemssen, H.-P. Hartung, and L Kappos

Subjects
medicine.medical_specialty, Core (anatomy), medicine.diagnostic_test, business.industry, Multiple sclerosis, Magnetic resonance imaging, General Medicine, Lesion Number, medicine.disease, Placebo, Confidence interval, Surgery, Lesion, chemistry.chemical_compound, Siponimod, Neurology, chemistry, Internal medicine, medicine, Neurology (clinical), medicine.symptom, business
Abstract

Background/objectives In the adaptive dose-ranging, 6- or 3-month BOLD study in patients with relapsing-remitting multiple sclerosis, once-daily siponimod (BAF312) showed dose-dependent reduction of combined unique active lesion number and annualized relapse rate (ARR); near-maximal effects were observed at 2 mg. Here, we report the efficacy findings of first 12 months of the extension (representing >18 or 15 months of total treatment). Design/methods Patients either continued on siponimod doses assigned in the core phase or were re-randomized from placebo to siponimod 10, 2, 1.25, 0.5 and 0.25 mg: 33, 29, 43, 29 and 50 patients comprised each dose group, respectively. Patients had >7 days (washout time) study drug interruption between core and extension phases to enable siponimod dose titration from 0.25 mg over the first 10 days. Magnetic resonance imaging (MRI) was performed at extension baseline, month 6 and month 12. Results 263/297 (88.6%) patients completed the core study; 184 of these (62.0%) entered the extension. The following data pertain to patients taking 10, 2, 1.25, 0.5 and 0.25 mg, respectively. 27, 25, 37, 24 and 37 patients had a 12-month MRI, and mean gadolinium-enhancing lesion numbers at extension month 12 were: 0.1, 0.5, 0.1, 0.6, 0.8 (compared with 1.7, 1.4, 1.8, 3.1, 1.3 at core study baseline, and 1.7 in placebo at month 6). Mean numbers of new/enlarged T2 lesions at extension month 12 were 0.4, 0.6, 0.2, 1.7 and 1.7, and ARRs were 0.27 (95% confidence interval, 0.14–0.52), 0.18 (0.08–0.42), 0.13 (0.06–0.28), 0.34 (0.18–0.64) and 0.33 (0.20–0.54). No new safety issues were observed. Conclusion Over the 12-month extension, MRI-assessed inflammatory lesion activity and ARRs remained low, particularly in the 1.25, 2 and 10 mg treatment groups, with no new safety concerns.

Published
2014
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40. Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis

Author

Ernst Wilhelm, Radue, William, H. Stuart, Peter, A. Calabresi, Christian, Confavreux, Steven, L. Galetta, Richard, A. Rudick, Fred, D. Lublin, Bianca, Weinstock Guttman, Daniel, R. Wynn, Elizabeth, Fisher, Athina, Papadopoulou, Frances, Lynn, Michael, A. Panzara, Alfred, W. Sandrock, For, the SENTINEL Investigators including F. Fazekas, Enzinger, C., Seifert, T., Storch, M., Strasser Fuchs, S., Berger, T., Dilitz, E., Egg, R., Deisenhammer, F., Decoo, D, Lampaert, J., Bartholome, E., Bier, J., Stenager, E., Rasmussen, M., Binzer, M., Shorsh, K., Christensen, M., Ravnborg, M., Soelberg Sørensen, P., Blinkenberg, M., Petersen, B., Hansen, H. J., Bech, E., Petersen, T., Kirkegaard, M., Finland:, J. Eralinna, Ruutiainen, J., Soilu Hänninen, M., Säkö, E., Laaksonen, M., Reunanen, M., Remes, A., Keskinarkaus, I., Moreau, T., Noblet, M., Rouaud, O., Couvreur, G., Edan, G., Lepage, E., Drapier, S., De Burghgraeve, V., Yaouanq, J., Merienne, M., Cahagne, V., Gout, O., Deschamps, R., Le Canuet, P., Moulignier, A., Vermersch, P., De Seze, J., Stojkovic, T., Griffié, G., Engles, Ferriby, D., Debouverie, M., Pittion Vouyouvitch, S., Lacour, J. C., Pelletier, J., Feuillet, L., Suchet, L., Dalecky, A., Tammam, D., Lubetzki, C., Youssov, K., Mrejen, S., Charles, P., Yaici, S., Clavelou, P., Aufauvre, D., Renouil Guy, N., Cesaro, P., Degos, F., Benisty, S., Rumbach, L., Decavel, P., Confavreux, C., Blanc, S., Aubertin, P., Riche, G., Brochet, B., Ouallet, J. C., Anne, O., Menck, S., Grupe, Guttman, Lensch, E., Fucik, E., Heitmann, S., Hartung, H. P., Schröter, M., Kurz, F. M. W., Heidenreich, F., Trebst, C., Pul, R., Hohlfeld, R., Krumbholz, M., Pellkofer, H., Haas, J., Segert, A., Meyer, R., Anagnostou, P., Kabus, C., Poehlau, D., Schneider, K., Hoffmann, V., Zettl, U., Steinhagen, V., Adler, S., Steinbrecher E. Rothenfusser Körber, A. Steinbrecher E. Rothenfusser Körber, Zellner, Baum, K., Günther, A., Bläsing, H., Stoll, G., Gold, R., Bayas, A., Kleinschnitz, C., Limmroth, V., Katsarava, Z., Kastrup, O., Haller, P., Stoeve, S., Höbel, D., Oschmann, P., Voigt, K., Burger, C. V., Israel:, O. Abramsky, Karusiss, D., Achiron, A., Kishner, I., Stern, Y., Sarove Pinhas, I., Dolev, M., Magalashvili, D., Pozzili, : C., Lenzi, D., Scontrini, A., Millefiorini, E., Buttinelli, C., Gallo, P., Ranzato, F., Tiberio, M., Perini, P., Laroni, Alice, Marrosu, M., Cocco P. Marchi, E. Cocco P. Marchi, Spinicci, G., Massole, S., Mascia, M., Floris, G., Trojano, M., Bellacosa, A., Paolicelli, D., Bosco Zimatore, G., Simone, I. L., Giorelli, M., Di Monte, E., Mancardi, GIOVANNI LUIGI, Pizzorno, M., Murialdo, A., Narciso, E., Capello, A., Comi, G., Martinelli, V., Rodegher, M., Esposito, F., Colombo, B., Rossi, P., Polman, C. H., Jasperse, M. M. S., Zwemmer, J. N. P., Nielsen, J., Kragt, J. J., Jongen, P. J. H., De Smet, E., Tacken, H., Frequin, S. T. F. M., Siegers, H. P., Mauser, H. W., Fernandez Fernandez, O., León, A., Romero, F., Alonso, A., Tamayo, J., Montalban, X., Nos, C., Pelayo, R., Tellez, N., Rio, J., Tintore, M., Arbizu, T., Romero, L., Moral, E., Martinez, S., Switzerland:, L. Kappos, Achtnichts, L., Wilmes, S., Turkey:, R. Karabudak, Kurne, A., Erdem, S., Siva, A., Saip, S., Altintas, A., Atamer, A., Eraksoy, M., Bilgili, F., Topcular, B., Giovannoni, G., Lim, E. T., Lava, N., Murnane, M., Dentinger, M., Zimmerman, E., Reiss, M., Gupta, V., Scott, T., Brillman, J., Kunschner, L., Wright, D., Perel, A., Babu, A., Rivera, V., Killian, J., Hutton, G., Lai, E., Picone, M., Cadivid, D., Kamin, S., Shanawani, M., Gauthier, S., Morgan, A., Buckle, G., Margolin, D., Weinstock Guttman, B., Kwen, P. L., Garg, N., Munschauer, F., Khatri, B., Rassouli, M., Saxena, V., Ahmed, A., Turner, A., Fox, E., Couch, C., Tyler, R., Horvit, A., Fodor, P., Humphries, S., Wynn, D., Nagar, C., O'Brien, D., Allen, N., Turel, A., Friedenberg, S., Carlson, J., Hosey, J., Crayton, H., Richert, J., Tornatore, C., Sirdofsky, M., Greenstein, J., Shpigel, Y., Mandel, S., Adbelhak, T., Schmerler, M., Zadikoff, C., Rorick, M., Reed, R., Elias, S., Feit, H., Angus, E., Sripathi, N., Herbert, J., Kiprovski, K., Qu, X., Del Bene, M., Mattson, D., Hingtgen, C., Fleck, J., Horak, H., Javerbaum, J., Elmore, R., Garcia, E., Tasch, E., Gruener, G., Celesia, G., Chawla, J., Miller, A., Drexler, E., Keilson, M., Wolintz, R., Drasby, E., Muscat, P., Belden, J., Sullivan, R., Cohen, J., Stone, L., Marrie, R. A., Fox, R., Hughes, B., Babikian, P., Jacoby, M., Doro, J., Puricelli, M., Rossman, H., Boudoris, W., Belkin, M., Pierce, R., Eggenberger, E., Birbeck, G., Martin, J., Kaufman, D., Stuart, W., English, J. B., Stuart, D. S., Gilbert, R. W., Kaufman, M., Putman, S., Diedrich, A., Follmer, R., Pelletier, D., Waubant, E., Cree, B., Genain, C., Goodin, D., Guarnaccia, J., Patwa, H., Rizo, M., Kitaj, M., Blevins, J., Smith, T., Mcgee, F., Honeycutt, W., Brown, M., Isa, A., Nieves Quinones, D., Krupp, L., Smiroldo, J., Zarif, M., Perkins, C., Sumner, A., Fisher, A., Gutierrez, Jacoby, R., Svoboda, S., Dorn, D., Groeschel, A., Steingo, B., Kishner, R., Cohen, B., Melen, O., Simuni, T., Zee, P., Cohan, S., Yerby, M., Hendin, B., Levine, T., Tamm, H., Travis, L. H., Freedman, S. M., Tim, R., Ferrell, W., Stefoski, D., Stevens, S., Katsamakis, G., Topel, J., Ko, M., Gelber, D., Fortin, C., Green, B., Logan, W., Carpenter, D., Temple, L., Sadiq, S., Sylvester, A., Sim, G., Mihai, C., Vertino, M., Jubelt, B., Mejico, L., Phillips, J. T., Martin, A., Heitzman, D., Greenfield, C. F., Riskind, P., Cabo, A., Paskavitz, J., Moonis, M., Bashir J. Brockington, K. Bashir J. Brockington, Nicholas, A., Slaughter, R., Archer S. Harik, R. Archer S. Harik, Haddad, N., Pippenger, M. A., Van den Noort, S., Thai, G., Olek, M., Demetriou, M., Shin, R., Calabresi, P., Rus, H., Bever, C., Johnson, K., Sheremata, W., Delgado, S., Sherbert, R., Herndon, R., Uschmann, H., Chandler, A., Markowitz, C., Jacobs, D., Balcer, L., Mitchell, G., Chakravorty, S., Heyman, R., Stauber, Z., Goodman, A., Segal, B., Schwid, S., Samkoff, L., Levin, M., Jacewicz, M., Menkes, D., Pulsinelli, W., Frohman, E., Racke, M., Hawker, K., Ulrich, R., Panitch, H., Hamill, R., Tandon, R., Dulaney, E., Simnad, V., Miller, J., Wooten, G. F., Harrison, M., Bowen, J., Doherty, M., Wundes, A., Garden, G. A., Distad, J., Kachuck, N., Berkovich, R., Burnett, M., Sahai, S., Bandari, D., Weiner, L., Storey, J. R., Beesley, B., Hart, D., Moses, H., Sriram, S., Fang, J., O'Duffy, A., Kita, M., Taylor, L., Elliott, M., Roberts, J., Jeffery, D., Maxwell, S., Lefkowitz, D., Kumar, S., Sinclair, M., Neurology, and NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases

Subjects
Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Relapsing-Remitting, Placebo, Antibodies, Monoclonal, Humanized, Gastroenterology, Antibodies, Central nervous system disease, Pharmacotherapy, Natalizumab, Multiple Sclerosis, Relapsing-Remitting, pathology/therapy, Drug Therapy, Internal medicine, Monoclonal, Medicine, Humans, Immunologic Factors, Humanized, medicine.diagnostic_test, business.industry, Multiple sclerosis, Patient Selection, Interferon beta-1a, Antibodies, Monoclonal, Brain, Magnetic resonance imaging, Interferon-beta, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Surgery, Treatment Outcome, Neurology, therapeutic use, Combination, Drug Therapy, Combination, pathology, Female, Neurology (clinical), Adolescent, Adult, Antibodies, Humanized, Antibodies, therapeutic use, Brain, pathology, Drug Therapy, Combination, Female, Humans, Immunologic Factors, therapeutic use, Interferon-beta, therapeutic use, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, pathology/therapy, Patient Selection, Treatment Outcome, business, medicine.drug
Abstract

The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNbeta-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg (n=589) or placebo (n=582) intravenously every 4 weeks plus IFNbeta-1a 30 microg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNbeta-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNbeta-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNbeta-1a and increased in those receiving IFNbeta-1a alone (-277.5mm(3) versus 525.6mm(3); p0.001). Compared with IFNbeta-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3mm(3) versus 2210.5mm(3); p0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; p0.001), and a slower rate of brain atrophy during the second year of therapy (-0.31% versus -0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNbeta-1a alone.

Published
2010
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41. Expression of the B cell-associated tyrosine kinase gene Lyn in primary neuroblastoma tumours and its modulation during the differentiation of neuroblastoma cell lines

Author

L Kappos, Wolfgang Bielke, Andrew Ziemieki, and Guido C. Miescher

Subjects
Transcription, Genetic, Cellular differentiation, Molecular Sequence Data, Drug Resistance, Biophysics, Retinoic acid, Biology, environment and public health, Biochemistry, Gene Expression Regulation, Enzymologic, Neuroblastoma, chemistry.chemical_compound, LYN, Sequence Homology, Nucleic Acid, hemic and lymphatic diseases, Gene expression, Tumor Cells, Cultured, medicine, Humans, Amino Acid Sequence, RNA, Messenger, RNA, Neoplasm, Molecular Biology, B cell, B-Lymphocytes, Base Sequence, Cell Differentiation, hemic and immune systems, Cell Biology, Protein-Tyrosine Kinases, medicine.disease, Clone Cells, Gene Expression Regulation, Neoplastic, enzymes and coenzymes (carbohydrates), src-Family Kinases, medicine.anatomical_structure, Oligodeoxyribonucleotides, chemistry, Cancer research, biological phenomena, cell phenomena, and immunity, Clone (B-cell biology), Tyrosine kinase, Signal Transduction
Abstract

The src-related intracellular protein tyrosine kinase Lyn is a signal transducing molecule for surface immunoglobulin M and is expressed predominantly in hemopoietic cells. We report here the expression of the lyn gene in human neuroblastoma. In surgical tumour samples lyn transcripts were found preferentially at early stages whereas they were barely detectable in highly malignant tumours. In a cloned human neuroblastoma cell line, Be(2)C, lyn mRNA levels increased during neuronal differentiation induced by retinoic acid. Lyn mRNA levels were undetectable and did not respond to retinoic acid in a glial-type neuroblastoma clone, SH-EP. Retinoic acid-induced glial differentiation was associated with a reduction of lyn transcripts in a clonal I-type neuroblastoma cell line, SH-IN, which shares properties of both neuronal- and glial-type clones. Like pp60c-src Lyn may be involved in a signalling pathway of neuroblasts committed to neuronal differentiation.

Published
1992
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42. Black holes in multiple sclerosis: definition, evolution, and clinical correlations

Author

M A, Sahraian, E-W, Radue, S, Haller, and L, Kappos

Subjects
Multiple Sclerosis, Adjuvants, Immunologic, Brain, Humans, Interferon-beta, Interferons, Magnetic Resonance Imaging
Abstract

Magnetic resonance imaging (MRI) is a sensitive paraclinical test for diagnosis and assessment of disease progression in multiple sclerosis (MS) and is often used to evaluate therapeutic efficacy. The formation of new T2-hyperintense MRI lesions is commonly used to measure disease activity, but lacks specificity because edema, inflammation, gliosis, and axonal loss all contribute to T2 lesion formation. As the role of neurodegeneration in the pathophysiology of MS has become more prominent, the formation and evolution of chronic or persistent Tl-hypointense lesions (black holes) have been used as markers of axonal loss and neuronal destruction to measure disease activity. Despite the use of various detection methods, including advanced imaging techniques such as magnetization transfer imaging and magnetic resonance spectroscopy, correlation of persistent black holes with clinical outcomes in patients with MS remains uncertain. Furthermore, although axonal loss and neuronal tissue destruction are known to contribute to irreversible disability in patients with MS, there are limited data on the effect of therapy on longitudinal change in Tl-hypointense lesion volume. Measurement of black holes in clinical studies may elucidate the underlying pathophysiology of MS and may be an additional method of evaluating therapeutic efficacy.

Published
2009

47. [Cerebral and spinal MRI examination in patients with clinically isolated syndrome and definite multiple sclerosis]

Author

M, Sailer, F, Fazekas, A, Gass, L, Kappos, E-W, Radue, P, Rieckmann, K, Toyka, H, Wiendl, and M, Bendszus

Subjects
Diagnosis, Differential, Multiple Sclerosis, Brain, Contrast Media, Humans, Magnetic Resonance Imaging, Spine
Abstract

Magnetic resonance imaging (MRI) has become a valuable tool for diagnosing and monitoring multiple sclerosis (MS). The high sensitivity for the detection of hyperintense lesions in T 2-weighted scans contributes substantially to diagnosis. The initial lesion number or lesion volume stands for an increased probability of further accumulation of lesion burden, an earlier conversion to clinically definite MS and progression of disability in the next 5 - 15 years. This diagnostic and prognostic information gained from MRI early in the disease course lead in 2001 to a revision of the diagnostic criteria.For the first time MRI criteria were defined in addition to the clinical and paraclinical criteria using the clinical terms for dissemination with respect to space and time. In particular, the defined MRI criteria are based on lesion number and location, the appearance of new lesions and lesion enhancement using contrast agent.Reliable detection and description of older and new lesions in the disease course by MRI represents subclinical disease activity which can substitute the clinical confirmation of a relapse leading to an earlier diagnosis. This places importance on the assessment of the subclinical disease activity in sequential MR scans requiring a standardized and reproducible approach to minimize variability despite different MR scanners.This review provides an updated proposal for the approach and management of cranial and spinal MR scans in patients with MS. We describe the influence of variables which cannot be standardized (scanner, field strength, manufacturer and software) and outline potential pitfalls of clinical MR imaging in MS resulting from a non-standardized approach. This updated proposal for slice positioning, sequences and documentation is a result of a consensus process targeting systematic and standardized use in clinical MR evaluations of MS.

Published
2008

48. [Stress-related vertical double vision and ptosis]

Author

A M, Palmowski-Wolfe, L, Kappos, J, Müller-Brand, C, Buitrago-Tellez, and A, Merlo

Subjects
Adult, Diagnosis, Differential, Muscle Weakness, Diplopia, Meningeal Neoplasms, Blepharoptosis, Humans, Female, Meningioma, Stress, Psychological
Abstract

A 43-year-old patient presented to our department because her left eyelid had exhibited drooping to varying extents for 2-3 months. Furthermore, in extreme positions or after rapid eye movement, she perceived diplopic images and was sensitive to light. The diagnosis of sphenoid meningioma was reached. Subsequently two rounds of radiopeptide therapy with (90)Y-DOTATOC (somatostatin analog) were administered within 3 months. This treatment approach led to a reduction of tumor volume in our patient as well as clinical improvement followed by stabilization.

Published
2008

49. Individual assessment of chronic brain tissue changes in MRI – the role of focal lesions for brain atrophy development. A Voxel-Guided Morphometry study

Author

J Hirsch, M. Kraemer, V. Hömberg, T. Schormann, L Kappos, A. Dabringhaus, K.M. Stephan, and Achim Gass

Subjects
Pathology, medicine.medical_specialty, Atrophy, Voxel, business.industry, Physiology (medical), medicine, Neurology (clinical), Brain tissue, medicine.disease, computer.software_genre, business, computer
Published
2008
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50. ['Numb chin syndrome': first presenting syndrome of multiple sclerosis?]

Author

A, Oestmann, L, Achtnichts, L, Kappos, A, Gass, and Y, Naegelin

Subjects
Adult, Chin, Multiple Sclerosis, Brain, Interferon-beta, Syndrome, Magnetic Resonance Imaging, Lip, Diagnosis, Differential, Hypesthesia, Immunoglobulin G, Humans, Immunologic Factors, Female, Trigeminal Nerve
Abstract

A 34-year-old previously healthy woman presented with a five-day history of subacute onset of a numb chin. Examination on admission revealed isolated hypesthesia on the left side of the chin and lower lip.Brain magnetic resonance imaging (MRI) demonstrated a lesion involving the pontine trigeminal fibers and multiple periventricular T2-hyperintense white matter lesions suggestive of inflammatory /demyelinating disease. Cerebrospinal fluid analysis revealed oligoclonal IgG bands (only in cerebrospinal fluid) and an increased IgG index. A follow-up MRI after four months demonstrated new supratentorial brain lesions, confirming a syndrome, highly suggestive of multiple sclerosis as the likely underlying diagnosis. TREATMENT AND FOLLOW-UP: The facial sensory disturbance resolved spontaneously. Prophylactic treatment with interferon-beta was started.The numb chin syndrome may be the initial presentation of a clinically isolated syndrome suggestive of multiple sclerosis. Prophylactic immunomodulatory treatment may be started after the suspicion of inflammatory/demyelinating activity is confirmed.

Published
2008

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