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3. Genetic associations with brain cortical thickness in multiple sclerosis

Author

Matsushita, T, Madireddy, L, Sprenger, T, Khankhanian, P, Magon, S, Naegelin, Y, Caverzasi, E, Lindberg, RLP, Kappos, L, Hauser, SL, Oksenberg, JR, Henry, R, Pelletier, D, and Baranzini, SE

Subjects
Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelinating lesions in the central nervous system. Associated neurodegenerative changes contributing to disability have been recognized even at early disease stages. Recent studies show the importance of gray matter damage for the accrual of clinical disability rather than white matter where demyelination is easily visualized by magnetic resonance imaging (MRI). The susceptibility to MS is influenced by genetic risk, but genetic factors associated with the disability are not known. We used MRI data to determine cortical thickness in 557 MS cases and 75 controls and in another cohort of 219 cases. We identified nine areas showing different thickness between cases and controls (regions of interest, ROI) (eight of them were negatively correlated with Kurtzke's expanded disability status scale, EDSS) and conducted genome-wide association studies (GWAS) in 464 and 211 cases available from the two data sets. No marker exceeded genome-wide significance in the discovery cohort. We next combined nominal statistical evidence of association with physical evidence of interaction from a curated human protein interaction network, and searched for subnetworks enriched with nominally associated genes and for commonalities between the two data sets. This network-based pathway analysis of GWAS detected gene sets involved in glutamate signaling, neural development and an adjustment of intracellular calcium concentration. We report here for the first time gene sets associated with cortical thinning of MS. These genes are potentially correlated with disability of MS. Common genetic variation is associated with cortical thickness in multiple sclerosis (MS) patients. Here we performed GWA on two independent cohorts of patients (n=675 in total). While no marker exceeded genome-wide significance, protein interaction based network analysis identified pathways involved in glutamate signaling, neural development and intracellular calcium concentration as significantly associated with cortical thickness in MS.

Published
2015

4. Radiologic MS disease activity during natalizumab treatment interruption: findings from RESTORE

Author

Kaufman, M, Cree, BAC, De Sèze, J, Fox, RJ, Gold, R, Hartung, H-P, Jeffery, D, Kappos, L, Montalbán, X, Weinstock-Guttman, B, Ticho, B, Duda, P, Pace, A, and Campagnolo, D

Subjects
Gadolinium-enhancing lesions, MRI, Multiple sclerosis, Natalizumab, Treatment interruption, Clinical Research, Clinical Trials and Supportive Activities, Cancer, Biomedical Imaging, 6.1 Pharmaceuticals, Neurology & Neurosurgery, Clinical Sciences, Neurosciences
Abstract

The objective of this study is to characterize the timing and extent of radiologic MS disease recurrence during the 24-week natalizumab treatment interruption period in RESTORE. RESTORE was a randomized, partially placebo-controlled exploratory study. Natalizumab-treated patients with no gadolinium-enhancing (Gd+) lesions at screening (n = 175) were randomized 1:1:2 to continue natalizumab (n = 45), switch to placebo (n = 42), or switch to other therapies (n = 88) for 24 weeks. MRI assessments were performed every 4 weeks. Predictors of increased numbers of Gd+ lesions during natalizumab treatment interruption were evaluated. The numbers of Gd+ lesions were compared with retrospectively collected pre-natalizumab MRI reports and data from placebo-treated patients from two historical randomized clinical trials. Gd+ lesions were detected in 0 % (0/45) of natalizumab patients, 61 % (25/41) of placebo patients, and 48 % (39/81) of other-therapies patients during the randomized treatment period. Gd+ lesions were detected starting at week 12; most were observed at week 16 or later. Thirteen percent (14/107) of patients had >5 Gd+ lesions on ≥1 (of 6) scans during the randomized treatment period versus 7 % (7/107) of patients pre-natalizumab (based on medical record of a single scan). Younger patients and those with more Gd+ lesions pre-natalizumab were more likely to have increased MRI activity. Distribution of total and persistent Gd+ lesions in RESTORE patients was similar to placebo-treated historical control patients. In most patients, recurring radiological disease activity during natalizumab interruption did not exceed pre-natalizumab levels or levels seen in historical control patients.

Published
2014

5. MS disease activity in RESTORE: A randomized 24-week natalizumab treatment interruption study

Author

Cree, Bruce, Fox, RJ, Cree, BAC, De, J, Gold, R, Hartung, HP, Jeffery, D, Kappos, L, Kaufman, M, Montalbán, X, and Weinstock-Guttman, B

Abstract

Objective: RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab. Methods: Eligible patients were relapse-free through the prior year on nat

Published
2014

7. A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility.

Author

Bush, WS, McCauley, JL, DeJager, PL, Dudek, SM, Hafler, DA, Gibson, RA, Matthews, PM, Kappos, L, Naegelin, Y, Polman, CH, Hauser, SL, Oksenberg, J, Haines, JL, Ritchie, MD, and International Multiple Sclerosis Genetics Consortium

Subjects
International Multiple Sclerosis Genetics Consortium, Cytoskeleton, Humans, Multiple Sclerosis, Disease Susceptibility, Calcium, Signal Transduction, Epistasis, Genetic, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci, Human Genome, Autoimmune Disease, Brain Disorders, Neurodegenerative, Neurosciences, Genetics, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Neurological, multiple sclerosis, knowledge-driven interaction, neurodegenerative mechanism, Immunology
Abstract

Gene-gene interactions are proposed as an important component of the genetic architecture of complex diseases, and are just beginning to be evaluated in the context of genome-wide association studies (GWAS). In addition to detecting epistasis, a benefit to interaction analysis is that it also increases power to detect weak main effects. We conducted a knowledge-driven interaction analysis of a GWAS of 931 multiple sclerosis (MS) trios to discover gene-gene interactions within established biological contexts. We identify heterogeneous signals, including a gene-gene interaction between CHRM3 (muscarinic cholinergic receptor 3) and MYLK (myosin light-chain kinase) (joint P=0.0002), an interaction between two phospholipase C-β isoforms, PLCβ1 and PLCβ4 (joint P=0.0098), and a modest interaction between ACTN1 (actinin alpha 1) and MYH9 (myosin heavy chain 9) (joint P=0.0326), all localized to calcium-signaled cytoskeletal regulation. Furthermore, we discover a main effect (joint P=5.2E-5) previously unidentified by single-locus analysis within another related gene, SCIN (scinderin), a calcium-binding cytoskeleton regulatory protein. This work illustrates that knowledge-driven interaction analysis of GWAS data is a feasible approach to identify new genetic effects. The results of this study are among the first gene-gene interactions and non-immune susceptibility loci for MS. Further, the implicated genes cluster within inter-related biological mechanisms that suggest a neurodegenerative component to MS.

Published
2011

9. Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis

Author

Diouf, I, Malpas, CB, Sharmin, S, Roos, I, Horakova, D, Havrdova, EK, Patti, F, Shaygannejad, V, Ozakbas, S, Izquierdo, G, Eichau, S, Onofrj, M, Lugaresi, A, Alroughani, R, Prat, A, Girard, M, Duquette, P, Terzi, M, Boz, C, Grand'Maison, F, Hamdy, S, Sola, P, Ferraro, D, Grammond, P, Turkoglu, R, Buzzard, K, Skibina, O, Yamout, B, Altintas, A, Gerlach, O, van Pesch, V, Blanco, Y, Maimone, D, Lechner-Scott, J, Bergamaschi, R, Karabudak, R, Iuliano, G, McGuigan, C, Cartechini, E, Barnett, M, Hughes, S, Sa, MJ, Solaro, C, Kappos, L, Ramo-Tello, C, Cristiano, E, Hodgkinson, S, Spitaleri, D, Soysal, A, Petersen, T, Slee, M, Butler, E, Granella, F, de Gans, K, McCombe, P, Ampapa, R, Van Wijmeersch, B, van der Walt, A, Butzkueven, H, Prevost, J, Sinnige, LGF, Sanchez-Menoyo, JL, Vucic, S, Laureys, G, Van Hijfte, L, Khurana, D, Macdonell, R, Gouider, R, Castillo-Trivino, T, Gray, O, Aguera-Morales, E, Al-Asmi, A, Shaw, C, Deri, N, Al-Harbi, T, Fragoso, Y, Csepany, T, Sempere, AP, Trevino-Frenk, I, Schepel, J, Moore, F, Kalincik, T, Diouf, I, Malpas, CB, Sharmin, S, Roos, I, Horakova, D, Havrdova, EK, Patti, F, Shaygannejad, V, Ozakbas, S, Izquierdo, G, Eichau, S, Onofrj, M, Lugaresi, A, Alroughani, R, Prat, A, Girard, M, Duquette, P, Terzi, M, Boz, C, Grand'Maison, F, Hamdy, S, Sola, P, Ferraro, D, Grammond, P, Turkoglu, R, Buzzard, K, Skibina, O, Yamout, B, Altintas, A, Gerlach, O, van Pesch, V, Blanco, Y, Maimone, D, Lechner-Scott, J, Bergamaschi, R, Karabudak, R, Iuliano, G, McGuigan, C, Cartechini, E, Barnett, M, Hughes, S, Sa, MJ, Solaro, C, Kappos, L, Ramo-Tello, C, Cristiano, E, Hodgkinson, S, Spitaleri, D, Soysal, A, Petersen, T, Slee, M, Butler, E, Granella, F, de Gans, K, McCombe, P, Ampapa, R, Van Wijmeersch, B, van der Walt, A, Butzkueven, H, Prevost, J, Sinnige, LGF, Sanchez-Menoyo, JL, Vucic, S, Laureys, G, Van Hijfte, L, Khurana, D, Macdonell, R, Gouider, R, Castillo-Trivino, T, Gray, O, Aguera-Morales, E, Al-Asmi, A, Shaw, C, Deri, N, Al-Harbi, T, Fragoso, Y, Csepany, T, Sempere, AP, Trevino-Frenk, I, Schepel, J, Moore, F, and Kalincik, T

Abstract

BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

Published
2023

10. Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial

Author

Diouf, I, Malpas, CB, Sharmin, S, Roos, I, Horakova, D, Kubala Havrdova, E, Patti, F, Shaygannejad, V, Ozakbas, S, Eichau, S, Onofrj, M, Lugaresi, A, Alroughani, R, Prat, A, Duquette, P, Terzi, M, Boz, C, Grand'Maison, F, Sola, P, Ferraro, D, Grammond, P, Yamout, B, Altintas, A, Gerlach, O, Lechner-Scott, J, Bergamaschi, R, Karabudak, R, Iuliano, G, McGuigan, C, Cartechini, E, Hughes, S, Sa, MJ, Solaro, C, Kappos, L, Hodgkinson, S, Slee, M, Granella, F, de Gans, K, McCombe, PA, Ampapa, R, van der Walt, A, Butzkueven, H, Sanchez-Menoyo, JL, Vucic, S, Laureys, G, Sidhom, Y, Gouider, R, Castillo-Trivino, T, Gray, O, Aguera-Morales, E, Al-Asmi, A, Shaw, C, Al-Harbi, TM, Csepany, T, Sempere, AP, Frenk, IT, Stuart, EA, Kalincik, T, Diouf, I, Malpas, CB, Sharmin, S, Roos, I, Horakova, D, Kubala Havrdova, E, Patti, F, Shaygannejad, V, Ozakbas, S, Eichau, S, Onofrj, M, Lugaresi, A, Alroughani, R, Prat, A, Duquette, P, Terzi, M, Boz, C, Grand'Maison, F, Sola, P, Ferraro, D, Grammond, P, Yamout, B, Altintas, A, Gerlach, O, Lechner-Scott, J, Bergamaschi, R, Karabudak, R, Iuliano, G, McGuigan, C, Cartechini, E, Hughes, S, Sa, MJ, Solaro, C, Kappos, L, Hodgkinson, S, Slee, M, Granella, F, de Gans, K, McCombe, PA, Ampapa, R, van der Walt, A, Butzkueven, H, Sanchez-Menoyo, JL, Vucic, S, Laureys, G, Sidhom, Y, Gouider, R, Castillo-Trivino, T, Gray, O, Aguera-Morales, E, Al-Asmi, A, Shaw, C, Al-Harbi, TM, Csepany, T, Sempere, AP, Frenk, IT, Stuart, EA, and Kalincik, T

Abstract

BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

Published
2023

11. Disability accrual in primary and secondary progressive multiple sclerosis

Author

Harding-Forrester, S, Roos, I, Nguyen, A-L, Malpas, CB, Diouf, I, Moradi, N, Sharmin, S, Izquierdo, G, Eichau, S, Patti, F, Horakova, D, Kubala Havrdova, E, Prat, A, Girard, M, Duquette, P, Maison, FG, Onofrj, M, Lugaresi, A, Grammond, P, Ozakbas, S, Amato, MP, Gerlach, O, Sola, P, Ferraro, D, Buzzard, K, Skibina, O, Lechner-Scott, J, Alroughani, R, Boz, C, Van Pesch, V, Cartechini, E, Terzi, M, Maimone, D, Ramo-Tello, C, Yamout, B, Khoury, SJ, La Spitaleri, D, Sa, MJ, Blanco, Y, Granella, F, Slee, M, Butler, E, Sidhom, Y, Gouider, R, Bergamaschi, R, Karabudak, R, Ampapa, R, Sanchez-Menoyo, JL, Prevost, J, Castillo-Trivino, T, McCombe, PA, Macdonell, R, Laureys, G, Van Hijfte, L, Oh, J, Altintas, A, de Gans, K, Turkoglu, R, van der Walt, A, Butzkueven, H, Vucic, S, Barnett, M, Cristiano, E, Hodgkinson, S, Iuliano, G, Kappos, L, Kuhle, J, Shaygannejad, V, Soysal, A, Weinstock-Guttman, B, Van Wijmeersch, B, Kalincik, T, Harding-Forrester, S, Roos, I, Nguyen, A-L, Malpas, CB, Diouf, I, Moradi, N, Sharmin, S, Izquierdo, G, Eichau, S, Patti, F, Horakova, D, Kubala Havrdova, E, Prat, A, Girard, M, Duquette, P, Maison, FG, Onofrj, M, Lugaresi, A, Grammond, P, Ozakbas, S, Amato, MP, Gerlach, O, Sola, P, Ferraro, D, Buzzard, K, Skibina, O, Lechner-Scott, J, Alroughani, R, Boz, C, Van Pesch, V, Cartechini, E, Terzi, M, Maimone, D, Ramo-Tello, C, Yamout, B, Khoury, SJ, La Spitaleri, D, Sa, MJ, Blanco, Y, Granella, F, Slee, M, Butler, E, Sidhom, Y, Gouider, R, Bergamaschi, R, Karabudak, R, Ampapa, R, Sanchez-Menoyo, JL, Prevost, J, Castillo-Trivino, T, McCombe, PA, Macdonell, R, Laureys, G, Van Hijfte, L, Oh, J, Altintas, A, de Gans, K, Turkoglu, R, van der Walt, A, Butzkueven, H, Vucic, S, Barnett, M, Cristiano, E, Hodgkinson, S, Iuliano, G, Kappos, L, Kuhle, J, Shaygannejad, V, Soysal, A, Weinstock-Guttman, B, Van Wijmeersch, B, and Kalincik, T

Abstract

Background: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. Methods: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. Results: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. Conclusions: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

Published
2023

12. Optical coherence tomography reflects clinically relevant gray matter damage in patients with multiple sclerosis

Author

Cagol, A., Fuertes, N.C., Stoessel, M., Barakovic, M., Schaedelin, S., D'Souza, M., Würfel, J., Brandt, A.U., Kappos, L., Sprenger, T., Naegelin, Y., Kuhle, J., Granziera, C., and Papadopoulou, A.

Subjects
Function and Dysfunction of the Nervous System
Abstract

BACKGROUND: Retinal degeneration leading to optical coherence tomography (OCT) changes is frequent in patients with multiple sclerosis (PwMS). OBJECTIVE: To investigate associations among OCT changes, MRI measurements of global and regional brain volume loss, and physical and cognitive impairment in PwMS. METHODS: 95 PwMS and 52 healthy controls underwent OCT and MRI examinations. Mean peripapillary retinal nerve fiber layer (pRNFL) thickness and ganglion cell/inner plexiform layer (GCIPL) volume were measured. In PwMS disability was quantified with the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Associations between OCT, MRI, and clinical measures were investigated with multivariable regression models. RESULTS: In PwMS, pRNFL and GCIPL were associated with the volume of whole brain (p

Published
2023

13. Fully Automatic Method for Reliable Spinal Cord Compartment Segmentation in Multiple Sclerosis

Author

Tsagkas, C., primary, Horvath-Huck, A., additional, Haas, T., additional, Amann, M., additional, Todea, A., additional, Altermatt, A., additional, Müller, J., additional, Cagol, A., additional, Leimbacher, M., additional, Barakovic, M., additional, Weigel, M., additional, Pezold, S., additional, Sprenger, T., additional, Kappos, L., additional, Bieri, O., additional, Granziera, C., additional, Cattin, P., additional, and Parmar, K., additional

Published
2023
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18. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis

Author

Montalban, X., Gold, R., Thompson, A. J., Otero‐Romero, S., Amato, M. P., Chandraratna, D., Clanet, M., Comi, G., Derfuss, T., Fazekas, F., Hartung, H. P., Havrdova, E., Hemmer, B., Kappos, L., Liblau, R., Lubetzki, C., Marcus, E., Miller, D. H., Olsson, T., Pilling, S., Selmaj, K., Siva, A., Sorensen, P. S., Sormani, M. P., Thalheim, C., Wiendl, H., and Zipp, F.

Published
2018
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21. Multiple Sklerose und andere neuroimmunologische Erkrankungen des ZNS

Author

Gass, A., Kappos, L., Schölmerich, Jürgen, editor, Burdach, S., editor, Drexler, H., editor, Hallek, M., editor, Hiddemann, W., editor, Hörl, W.H., editor, Klein, H., editor, Landthaler, M., editor, Lenz, K., editor, Mann, K., editor, Mössner, J., editor, Müller-Ladner, U., editor, Reichen, J., editor, Schmiegel, W., editor, Schröder, J.O., editor, Seeger, W., editor, Stremmel, W., editor, Suttorp, N., editor, Weilemann, L.S., editor, and Wöhrle, J.C., editor

Published
2005
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23. Symposia

Author

Correll, Christoph, Kutcher, Stanley P., McClellan, John, Buitelaar, Jan, Pappadopulos, Elizabeth, Rothenberger, Aribert, Mattejat, Fritz, Scott, Stephen, Weisz, John, Schulz, Eberhard, Felder, Wilhelm, Fleischhaker, Christian, Böhme, R., Sixt, B., Jan van der Gaag, Rutger, Katz, Laurence Y., Cox, Brian J., Gunasekara, Shiny, Miller, Alec L., Laor, Nathaniel, Riedesser, Peter, Caffo, Ernesto, Leckman, James, Ammaniti, Massimo, Nicolais, Giampaolo, Speranza, Mario, Steiner, Hans, Delizonna, Laura, Schallauer, Astrid, Thienemann, Margo, McFarlane, Alexander C., van Hooff, Miranda, Sawyer, Michael, Cianchetti, Carlo, Gaddour, Naoufel, Sana, Mokni, Anouar, Mechri, Mondher, Letaief, Lotfi, Gaha, Härtling, Fabian, Bittner, Robert, Haenschel, Corinna, Cap, Marcus, Goncharova, Tanja, Linden, David E. J., Dittmann, Ralf, Maestele, Anneliese, Mehler, Claudia, Meyer, Eberhard, Jenner, Jack A., Boeing, Leonie, Murray, Val, Pelosi, Anthony, McCabe, Robert, Blackwood, Douglas, Wrate, Robert, Pellerano, S., Pintor, M., Mellis, G. L., Piroddi, T., Flisher, Alan, Nesa, Monique, Rooney, Rosanna, Roberts, Clare, Kane, Robert, Silburn, Sven, Pike, Lisbeth, Deaton, Helge Staby, Lustig, Stuart, Funk, Michelle, Rickards, Anne, Reddihough, Dinah, Wright-Rossi, Roslyn, Simpson, Jacqui, Seuthe, Dieter David, Vielhaber, H., Orden, Kinderklinik Dritter, Backmund, H., Gerlinghoff, M., Schwab-Stone, Mary, Jespers, Ine, Vermeiren, Robert, Ruchkin, Vladislav, Blatny, Marek, Hrdlicka, Michal, Urbanek, Tomas, Jelinek, Martin, Balastikova, Veronika, Jeammet, Philippe, Frottin, Alain, Filipovic, Andjelka, Albert, Eric, Schelotto, Dora Musetti, Knezevic, Mladen, Jovancevic, Milivoj, Hill, Jonathan, Lawlor, Maria, Kienbacher, Christian, Prause, Carolin, Stöckl, Margit, Bogyi, Gertrude, Friedrich, Max H., Klein, Michael, Kürschner, Katrin, Murray, Lynne, Leidecker, Victoria, Sharp, Helen, Luoma, Ilona, Kaukonen, Pälvi, Tamminen, Tuula, Nurcombe, Barry, Martin, Graham, McDermott, Brett, Resch, Franz, Schimmelman, Benno Graf, Edwards, Jane, McGorry, Patrick D., Lambert, Martin, Conus, Philippe, Preuss, Ulrich, Bürgin, Dieter, Strauss, Monika, Parzer, Peter, Spiel, Georg, von Korff, C., Ballin, H.-A., Gößler, R., Günter, M., Sange, G., Meng, Heiner, Koch, Eginhard, Minde, Klaus, True, Mary, Pisani, L., Oumar, F., Padilla, J., Bouville, Jean-François, Vogel, Wendy, Schmeck, Klaus, Goth, Kirstin, Purper-Ouakil, Diane, Dessons, Véronique, Doyen, Catherine, Perez-Diaz, Fernando, Mouren-Simeoni, Marie-Christine, Karwautz, Andreas, Wagner, Gudrun, Schwienbacher, Klaus, Haidvogl, Maria, Nobis, Gerald, Treasure, Janet Linda, Collier, David Andrew, Brunner, Romuald, Hueg, A., Haffner, Johann, Schmid, Marc, Goldbeck, Lutz, Nützel, Jakob, Höfling, Volkmar, Schermelleh-Engel, Karin, Moosbrugger, Helfried, Tomàs, Josep, Cornellà, Josep, Llusent, Alex, Bielsa, Anna, Belfer, Myron, Robertson, Brian, Mandlhate, Custodia, Seck, Birama, Zwirs, Barbara, Burger, Huib, Schulpen, Tom, Salman Al-Obedy, A. Karem, Romanchuk, Oleh, Namyslowska, Irena, Reigstad, Björn S., Jorgensen, Kirsti Margrethe, Matthys, Walter, Lochman, John, Zonnevylle-Bender, Marjo, van de Wiel, Nicolle, Wagner, Angela, Jennen-Steinmetz, Christine, Goepel, Christopher, van Bokhoven, Irene, van Goozen, Stephanie, Franciosi, L. Patt, Acquoy, Leode Graaf, Tischlinger, Anne, Pharm, B., Bronder, Knut Halyard, Schleimer, Kari, Walter, Joachim, Ephraime, Boia, Dmitrieva, Tatjana, Silva, Alvaro Seligman, Becker, Katja, Steinhausen, Hans-Christoph, Metzke, C. Winkler, Furtado, Erikson F., Laucht, Manfred, Bilke, Oliver, Zimmermann, Petra, Wittchen, Hans-Ulrich, Lieb, Roselind, Hannesdottir, Helga, Tyrfingsson, Thorarinn, Döpfner, Manfred, Hahlweg, Kurt, Kuschel, Annett, Bertram, Heike, Heinrichs, Nina, Freund-Braier, Inez, Brix, Gabriele, Hautmann, Christopher, Pluck, Julia, Crijnen, Alfons, van Lier, Pol, Vuijk, Patricia, Frank, Reiner, Vandvik, Inger Helene, Schäfert, Rainer, van Weel, Jeanne, Schieveld, Jan, Fegert, Jörg M., Friedrich, William, Celestin-Westreich, Smadar, Celestin, Leon Patrice, Ponjaert-Kristoffersen, Ingrid, Nagao, Keizo, Kisida, M., Shindo, E., Larsen, Helmer Baying, Helweg-Larsen, Karin, Lindauer, Ramón, Booij, Jan, Olff, Miranda, den Heeten, Gerard, Gersons, Berthold, Boer, Frits, Schoentjes, Eric, Bal, Sarah, Schulte-Markwort, Michael, Solantaus, Tytti, Toikka, Sini, Alasuutari, Maarit, Steck, Barbara, Grether, Andrea, Ehrensperger, M., Amsler, Felix, Kappos, L., Saha, Rina, Paschen, Bela, Baldus, Christiane, Haagen, Miriam, Pott, Martina, Romer, Georg, Ono, Yoshiro, Homma, H., Ishida, Y., Ide, H., Okamoto, M., Kameoka, S., Nakayama, Hiroshi, Yamamoto, A., Mukaddes, Nahit Motavalli, Tyano, Sam, Mozes, Tamar, Caplan, R., Malhotra, Savita, Ledda, Maria Giuseppina, Fratta, Al, Mannino, S., Corona, Simona, Zuddas, A., Olalla, Macarena Marin, Garcia, Ruth, Ramirez, Bernardo Perez, Campion, Ross, Hindley, Peter, Gupta, Nitin, Bhattacharaya, Anish, Kapoor, Mehak, van de Willge, G., Klemm, Silke, Smesny, S., Stockebrand, M., Grunwald, S., Juffer, Femmie, van Ijzendoorn, Marinus H., Bakermans-Kranenburg, Marian J., Ziegenhain, Ute, Derksen, B., Dreisörner, R., Gutschner, Daniel, Maldonado-Duran, Martin, Ferndndez-Criado, Manuel, Heidenreich, Felicia, Moro, Marie Rose, Millhuff, Charles, Pope, Kirby, Theisen, Frank, Himmerich, Hubertus, Kraus, T., Schuld, A., Pollmächter, T., Apter, Alan, Gothelf, D., Brand-Gothelf, A., Ratzoni, Gidi, Kikinzon, L., Weizman, A., Bloch, Yuval, Haberhausen, Michael, Müller, Daniel, Fayyad, John, Filho, Altino Bessa Marques, de Menezes, Adolfo Bezerra, Campo, John, Shafer, Sheree, Strohm, Jennifer, Lucas, Amanda, Shaeffer, David, Altman, Harold, Gelachek, Christine, Motomura, Naoyasu, Takino, Yozo, Iwakiri, Masahiro, Pössel, Patrick, Seemann, Simone, Hautzinger, Martin, Mutale, Theodore, Haase, Christian, Abidi, Majid Ali, Raheem, Shehla, Faw, Leyla, Hogue, Aaron, Liddle, Howard, Catthoor, Kirsten, Hutsebaut, Joost, Jasinski, Donald, Faries, Douglas, Moore, Rodney, Streeck-Fischer, Annette, Sannwald, Renate, Barth, Gottfried Maria, Schwarz, Christoph, Staigle, Monika, Pham, Manh-Hiep, Balanzin, Dario, Materi, Joelle, Eresund, Pia, Mokhovikov, Alexander, Stankovic, Sandra, Munir, Kerim, Erol, Nese, Çetin, Füsun Çuhadarodlu, Hassiotis, Angela, Flament, Martine, Scholz, Michael, Rix, Maud, Nestler, Franziska, Selisko, Annegret, Godart, Nathalie, Perdereau, Fabienne, Rein, Zoé, Curt, Florence, Akister, Jane, Lee, Pei-Chin Peggy, Tsai, Sho-Man Susan, Ho, Lai-Shiun, Wu, Su-Chun, Miermont, Jacques, Swenson, Joel, Teherani, Mardjane, Falissard, Bruno, Cottraux, Jean, Plück, Julia, Oades, Robert, Simons-Sprong, Mirjam, Schothorst, P. F., Swaab-Barneveld, J. T., Juran, Stephanie, Weisbrod, Matthias, Chen, Eric, Röpcke, Bernd, Popovic-Deusic, Smiljka, Poustka, Luise, Wild-Wall, Nele, Papousek, Mechthilde, Keren, Mirelle, Feldman, Ruth, Maestro, S., Chilosi, A., Pecini, C., Pfanner, L., Greenhill, Laurence, Jahnsen, K., den Berg, L. T. W. Jong-van, Zito, J. M., Posner, Kelly, Skrobala, Anne, Goldberg, Pablo, Kotler, Lisa, Findling, Robert, Bussing, Regina, Sayal, Kapil, Mitchell, Geoffrey, Huss, Michael, Högl, Barbara, Grimmlinger, Renate, Käppler, Karl Christoph, Teodoro, Maycoln M. L., Oswald, Sylvia Hiromi, Dagnoni, Janine M., Pinheiro, M. I., Heleno, C. T., Rothe-Neves, R., Haase, V. G., Prette, A. Del, Lambertucci, Marimilia Rodrigues, Rodrigues, J. L., Freitas, P. M., Lourenco, C. A. P., Carvalho, H. C. W., Baumeister, J., Weisenhorn, M., Stadelmann, S., Oswald, S. H., Ruder, H., Ruggerini, Ciro, Vicini, Stefania, Pupulin, Enrico, Guidi, Antonio, Puura, Kaija, Mäntymaa, Mirjami, von Klitzing, Kai, Rosvald, Orna, Kröber, Hans-Ludwig, Stöver, A., Proske, R., Semmelbeck, Rainer, Walther, Marc, Schmelzle, Matthias, Egli-Alge, Monika, Beckett, Richard, Gerhold, Constanze, Turkmen-Barta, Lieselotte, Chiland, Colette, Meyer-Bahlburg, Heino, Ceglie, Domenico Di, Lehmkuhl, Ulrike, Uccellini, Orlando, Bertolini, Mario, Neri, Francesca, Albanese, Delia, Bertola, Raffaella, Snoek, Maartje, Kas, Martien, Schulze, Ulrike Margarete Elisabeth, Calame, Silke, Keller, Ferdinand, Santel, Stephanie, Krauel, Kerstin, Rotte, Michael, Münte, Thomas F., van Elburg, Annemarie, Poustka, Fritz, Bölte, Sven, Feineis-Matthews, Sabine, Boite, Sven, Hubl, D., Prvulovic, D., Dierks, T., Klauck, Sabine, Moilanen, Irma, Mattila, M., Laurila, J., Jussila, K., Pyper, A., Linna, S. L., Ebeling, Hanna, Pauls, D., Korpilahti, Pirjo, Loukusa, Soile, Jansson-Verkasalo, Eira, Hebebrand, Johannes, Herpertz-Dahlmann, Beate, Hinney, Anke, Wermter, Anne-Kathrin, Friedel, Susann, Geller, Frank, Schafer, Helmut, Fernandez-Aranda, Fernando, Holliday, Joanna, Holtkamp, Kristian, Mika, C., Heer, M., Uher, Rudolf, Barbarich, Nicole, Henry, Shannan E., Bailer, Ursula, Frank, Guido, Kaye, Walter H., Wentz, Elisabet, Lacey, J. Hubert, Waller, Glenn, Rastam, Maria, Turk, Jeremy, Gillberg, Christopher, Verhulst, Frank C., Zwaanswijk, Marieke, Verhaak, Peter, Bensing, Jozien, van der Ende, Jan, Verhulst, Frank, Sourander, Andre, Santalahti, Paivi, Ford, Tamsin, Goodman, Robert, Meltzer, Howard, Seiffge-Krenke, Inge, Fritsch, Richard, Cutler, Marika, Anthony, E. James, Rydelius, Per-Anders, Castell, Rolf, Pejovic-Milovancevic, Milica, Pavlovic, Miroslav, Kalman, Noa, Linder, Muli, Luria, Ido, Levkovitz, Yechiel, Yamazaki, Kosuke, da Silva, Pedro Caldeira, Santos, Grata, Martins, Filipa, Chiu, Yen-Nan, Tsai, Wen-Jer, Gau, Shur-Fen, Tseng, Chang-Chang, Su, Shu-Chen, Croonenberghs, Jan, Brouw, Lucas, Wauters, Annick, Bruning, Nicole, Manjaly, Zina, Fink, Gereon, Aleksic, Olivera, Rudic, Nenad, Jansen, Lucres, Wied, Christine C. Gispen-De, Lahuis, Bertine, Swaab, Hanna, Pietersen, Jolijn, Gevers, Carolien, Kamp-Becker, Inge, Germerott, Isabell, Howlin, Patricia, Gaudière, Forresi, Barbara, Lepri, G., Laval, Soumaila, Wiefel, Andreas, Biringen, Z., Titze, Karl, Lenz, K., Seither, C., Witte, B., Dunitz-Scheer, Marguerite, Wilken, Markus, Krasnovsky, Alexandra, Scheer, Peter, Cordeiro, Maria, Muratori, Filippo, Felloni, B., Cesari, A., Helmig, Linda, Fonagy, Peter, Moody, Chris, Fultz, Jim, Glanzmann, René, Lutz-Latil, Nathalie, van Wyl, Agnes, Puras, Dainius, Hervds, Amaia, Tsiantis, John, Dragonas, T., Davis, H., Ispanovic, V., Paradisiotou, A., Shanini, Mimoza, Jones, Lynne, Uka, A., Rrustemi, A., von Knorring, Anne-Liis, Deboutte, Dirk, Dorhmi, Souraya, Agoub, Mohamed, Moussaoui, Driss, Battas, Omar, Halvorsen, Inger, Andersen, Anne, Heyerdahl, Sonja, Baillot, Denise, La Roche, Michele, Furino, Claudia, Buchholtz, Annick, Goldfield, Gary, Henderson, Katherine, Hagenah, Ulrich, Blume, Varinja, Flacke-Redanz, Marlene, Dahlmann, Beate Herpertz, Sallas, Angelique A., Adam, Hubertus, Ephraime, Boia, Jr., Mozambique, Goci-Uka, Aferdita, Schlüter-Müller, Susanne, Bawa, Umesh, Khalik, Fakhri, Forouher, Nima, Sadamatsu, Miyuki, Nanba, Kato, Nobumasa, Kasai, Kiyoto, Nanba, Eiji, Schmidt, Martin H., Esser, Günter, van Engeland, Herman, Willemsen-Swinkels, Sophie, Dietz, Claudine, Beernink, Anne Claire, Vidojevic, Oliver, Milacic, Ivona, Strous, Rael, Hegesh, Roni, Kertzman, Simion, Ben-Nahum, Z., Kotler, Moshe, van Daalen, Emma, Zeegers, Mijke, Pol, Hilleke Hulshoff, Williams, Charles, Sank, Jessica, Paulk, Martha, Schwarz, George, Wharton, Paul, Raleva, Marija, Paketchieva, Kamka, Filipovska, Angelina, Nix, Carole Müller, Guex, Margarita Forcada, Daigham, Abdel-Mohsen, Indredavik, Marit S., Vik, Torstein, Kulseng, Siri, Brubakk, Ann-Mari, Cuddy, Marion, Riley, Katharine, Vollmer, Brigitte, Wyatt, John, Murray, Robin, Soininen, Mika, Paavonen, E. Juulia, Fjällberg, Mika, Salmi, Juha, Fredrik, Almgvist, Aronen, Eeva T., Reis, Olaf, Bohne, Stephanie P., Kraenz, Susanne, Ahn, Dong-Hyun, Kim, Tae-Ho, Choi, Jun-Ho, Kim, Yun-Young, Begovac, Ivan, Skocic, Milena, Rudan, Vlasta, Filipovic, Oleg, Wolanczyk, Tomasz, Brynska, Anita, Wojtowicz, Stanislaw, Celia, Salvador, Aerts, Cisca, Cleve, Elisabeth, Hartmann, Hellmut, Kühle, Hans-Jürgen, Heidorn, Fridjof, Zeyer, Solveigh, Fuentes, Joaquin, Martin, Andrés, Sukhodolsky, Denis G., Kaltiala-Heino, Riittakerttu, Rimpelä, Matti, Andershed, Henrik, O’Donnell, Deborah, Pearce, Michelle, Burgin, Dieter, Becker, Andreas, Hagenberg, Nicola, Berking, Matthias, Roessner, Veit, Hanssen-Bauer, Ketil, Aalen, Odd, Junglas, Jürgen, Huh, Yoon-Seok, Kim, Yun Young, Oh, Kyung-Ja, Wang, Kai, Tarren-Sweeney, Michael, Leiblum, D. M., Kühl, Renate, Nötzel, Cornelia, Pfeiffer, Ernst, Lenz, Klaus, Rosling, Agneta, Poller, Marianne, Cross, Donna, Klabin, Simone, Kaplan, Diana, Mickel, Lars, Lehmkuhl, Gerd, Möckel, Regina, Leor, Shani, Frisch, Leor, Frisch, Amos, Weizman, Abraham, Zanozin, Andrey, Jamart, Sylvie, Hayez, Jean-Yves, Leor, Agnes, Ahle, Maria Elisabeth, Amitay, Galit Ben, Kosov, Irene, Reiss, Ahuva, Tamar, Moses, Smedje, Hans, Allik, Hiie, Steyaert, Jean, Castermans, Dries, Creemers, John, Kaczynska-Haladyj, Koenraad Devriendt Marta, Ballabriga, Maria Claustre Jané, Judez, Joaquima, Pelaez, Empar, Sole, Pilar, Rodriguez, Lidia, Palmen, Saskia, Kemner, Chantal, Schnack, Hugo, Kahn, Rene, Fabrizi, Anna, Gabriel, Levi, Mercadante, Marcos, Ramos, Sergiode Paula, Rosario-Campos, Maria Concecao, Rutter, Michael, Collishaw, Stephan, Maughan, Barbara, Pickles, Andrew, Messer, Julie, Caspi, Avshalom, Moffitt, Terrie, Kreppner, Jana, Borge, Anne Inger H., Luthar, Suniya, Hamarman, Stephanie, Ulger, C., Fossella, J., Brimacombe, M., Dermody, J., Stein, Mark, Waldman, L. D., Sarampote, C., Robb, A., Cook, E. H., Kirley, Aiveen, Lowe, N., Hawi, Z., Mullins, C., Daly, G., Waldman, I., McCarro, M., O’Donell, van der Meulen, Emma, Bakker, S. C., Pauls, D. L., Sinke, R. J., Polanczyk, Guilherme, Zeni, C., Genro, J. P., Roman, Tatiana, Hutz, Mara, Schaff, Christa, Haemmerle, Patrick, Sontag, Harald, Vetro, Agnes, Gadoros, Julia, Roosen-Runge, Gotthard, Hattab, Jocelyn, Hummel, Peter, Braun-Lewensohn, Orna, Schechter, Daniel, Zeanah, Charles, Myers, Michael, Liebowitz, Michael, Davies, Mark, Soong, Wei-Tsuen, James, Deborah, Sofroniou, Nick, Gegelashvili, Marine, Parikh, Umesh, Kane, John M., Malhotra, Anil K., Shah, Manoj, Pleak, Richard R., Hizami, Ronen, Michelson, David, Danckaerts, Marina, Zuddas, Alessandro, Zhang, Shuyu, Hazell, Philip, Zeiner, P., Johnson, M., Häßler, Frank, Suyash, Prasad, Sonuga-Barke, Edmund, Poole, Lynne, Mares, Sarah, Jureidini, Jon, Steel, Zachary, Newman, Louise, Lucas, Torsten, Paulus, Stephanie, Aßhauer, Martin, Miller, Birgit, Björn, Gunilla Jarkman, Bodén, Christina, Gustafsson, Per, Ivkic, Viola Povse, Tenjovic, Lazar, Jelena, Radosavljev, Deusic, Smiljka Popovic, Graham, Philip, Klasen, Henrikje, Tan, Jacinta, Hope, Tony, Stewart, Anne, Fitzpatrick, Raymond, Kölch, Michael, Diaz-Caneja, Angeles, Johnson, Sonia, Dippold, Ines, Keller, Katja Wiethoffi Ferdinand, Bailey, Sue, Whittle, Nathan, Hennighausen, Klaus, Kohls, Gregor, Maas, Verena, Rinker, Tanja, Zachau, Swantje, Christmann, Gabriele, Jaremkiewicz, Anna, Schecker, Michael, von Suchodoletz, Waldemar, Uwer, Ruth, Albrecht, Ronald, Glass, Lisa, Csépe, Valéria, Honbology, Ferenc, Rago, Anett, Mészdros, Eva, Schwartz, Richard G., Shafer, Valerie L., Green, Jonathan, Jacobs, C., Kroll, L., Briskman, J., Dunn, G., Beecham, J., Tobias, B., Baird, L., Ogden, Terje, Fitzgerald, Michael, Bellgrove, Mark, Gill, Michael, Robertson, Ian H., McArdle, Paul, Burke, Amanda, Hong, K. Michael, Hoven, Christina, Wasserman, Danuta, Braun, Katharina, Bock, Jórg, Helmecke, Carina, Gruß, Michael, Poeggel, Gerd, Marsden, Charles, Muchimapura, S., Pardon, M.-C., Bianchi, M., Feldon, Joram, Rüedi-Bettschen, Daniela, Dettling, Andrea C., Pryce, Christopher R., Clement, Hans-Willi, Sommer, O., Pschibul, A., Rombach, C., Gerlach, M., Mehler-Wex, Claudia, Zeiske, S., Grünblatt, E., Gille, G., Rausch, D., Gerlach, Manfred, El-Din, Amira Seif, Kadri, Nadia, Andaloussi, Houda Hjiej, Chihabeddine, Khadija, Almaqrami, Mohammed, von Gontard, Alexander, Okuno, M., Quaschner, Kurt, Bilenberg, Niels, Obel, Carsten, Henriksen, Tine Brink, Hedegaard, Morten, Secher, Niels Jurgen, Olsen, Jorn, Fonseca, Antonio, Koch, Isabelle Nathalie, Bite, Ieva, Cohen, Phyllis, Russell, Katrin, Broyden, Nichaela, Lancaster, Gillian, Eichhorn, Christina, Tiedtke, Karola, Feldman, Ronald, Warnke, Andreas, Scheuerpflug, Peter, Vetter, V., Bartling, Jürgen, Konrad, Kerstin, Neufang, Susanne, Hanisch, Charlotte, Fink, Gereon R., Durston, Sarah, Davidson, Matthew C., Tottenham, Nim, Spicer, Julie, Galvan, Adriana, Horvitz, John, Fossella, John A., Watts, Richard, Casey, B. J., Brandeis, Daniel, Fallgatter, Andreas J., Ehlis, Ann-Christine, Seifert, Jürgen, Strik, W. K., Zillessen, K. E., Herrmann, Martin J., Schulte-Körne, Gerd, Lyytinen, Heikki, Guttorm, Tomi, Poikkeus, Anna-Maija, Eklund, Kenneth M., Lyytinen, Paula, Torppa, Minna, Laakso, M.-L., Leskinen, E., Tolvanen, A., Paracchini, Silvia, Schumacher, J., König, I. R., Libertus, Claudia, Griesemann, Heide, Kleensang, A., Ziegler, A., Propping, P., Näthen, M., Wolmer, Leo, Zagout, Iyad, Galili-Weisstub, Esti, Fisch, Gene, Swillen, Ann, Vogels, Annick, Freitag, Christine, Bouville, Jean-Francois, Atlanti-Duault, Laetitia, Baubet, Thierry, Osrow, Robyn, Leplomb, Marie-Madeleine, Marchandy, Yves, Bennabi, Malika, Halpern, Ricardo, Monteiro, Odon, Durkin, Abbey-Robin, Haapanen, Rudy, Bauer, Susanne, Friedrich, Max, Stadler, Christina, Sterzer, Philipp, Kleinschmidt, Andreas, Nowraty, Irene, Müller, W. E., Knölker, Ulrich, Schmid, Gabriele, Berndt, Swantje, Behn, B., Puls, Jan Hendrik, Stevens, Luc, Jungmann, Joachim, Juretic, Zoran, Ercegovic, Nela, Schepker, Renate, Çuhadaroglu-Çetin, Füsun, Herhaus, G., Melfsen, S., Cheng, Daomeng, Harder, Donald, Laws, Harry, Nakane, Yoshibumi, Takeshita, Kenzo, Naruse, Hiroshi, Zhu, Yan, Liu, Jun, Du, Yasong, Sikorski, John, Hamerlynck, Sannie, Hart, Lisettet, Nauta-Janssen, Lucres, Chitsabesan, Prathiba, Nguyen, Hien, Simeon, Jovan, Cuzner, Cathy, Schachter, Howard, Martins, Ana Soledade, Kieling, Chirstian, Comassetto, Julia, Goncalves, Renata, Oswald, Silvia, Buchmann, Johannes, Kirschner, J., Garvey, M., Moll, Gunther, Heinrich, Hartmut, Malhotra, Sameer, Poulakis, Zeffie, Menahem, Sam, Sauer, Karin, Samia, Tilouch, Rimeh, Hannachi, Sonia, Missaoui, Allodi, Mara Westling, Biscaldi, Monica, Wagner, Bettina, Uchida, Chiyoko, Jozefiak, Thomas, Penge, Roberta, Biaggini, Valentina Ivancich, Fischbein, Siv, Joukamaa, Matti, Taanila, Anja, Veijola, Juha, Karvonen, Juha T., Miettunen, Jouko, Llaberia, Edelmira Domenech, Domenech, Teresa Corbella, Ballabriga, Maria Claustre Jane, Sanz, Josepa Canals, Esparo, Griselda, Sola, Sergi Ballespi, Liu, Xuejun, Kano, Yukiko, Ohta, Masataka, Nagai, Yoko, Arai, Takashi, Linyan, Su, Bridge, Jeff, Birmaher, Boris, Di Lorenzo, Carlo, Iyengar, Satish, Brent, David, Blanz, Bernhard, Weninger, Laura, Libal, Gerhard, Skrabal, Anna, Bowden, Michael, Cooper, Howard, Simonsen, Inger, Bechstrom, Carl, Medby, Mette, Erkolahti, Ritva, Klosinski, Gunther, Oba, Mihoko, Murase, Satomi, Murakami, Takashi, Takai, Jiro, Kaneko, Hitoshi, Honjo, Shuji, Rickards, Katrina, Weber, Annhild, Karle, Michael, Lazartigues, Alain, Planche, Pascale, Lemonnier, Eric, Pavuluri, Mani, Schenkel, Lindsay, Shaw, Ryan, Sweeny, John, Rigon, Giancarlo, Costa, Stefano, Mancaruso, Alessandra, Mansi, Roberta, Poggioli, Daniele Giovanni, Chiodo, Simona, Radobuljac, Maja, Groleger, Urban, Ovsenik, Nada, Tomori, Martina, Haas, Barbara, Denoix, Susanne, Kimmig, Franz, Weinhardt, Marc, Schmitz, Günter, Filschke, Berit, Fliegauf, Conny, Kim, Ji-Hae, Krischer, Maya, Stone, Michael H., Sevecke, Kathrin, Doepfner, Manfred, König, Cornelia, Grasmann, Dörte, Schlander, Michael, Ralston, Stephen, Pereira, R. Rodrigues, Brussel, W., Vlasveld, L., Tuynman-Qua, H. G., Lorenzo, M. J., Tauscher-Wisniewski, R., Palazzi, Stefano, Guaia, Ettore, Kolakowski, Artur, Pisula, Agnieszka, Wilens, Timothy, Banaschewski, Tobias, Uebel, Henrik, Albrecht, Björn, Robatzek, Monika, Migliaccio-Walle, Kristen, Caro, Jaime, Allen, Albert J., Sangal, R. Bart, Owens, Judith, Kelsey, Douglas, Sutton, Virginia, Schuh, Kory, Bahadir, Aliye Tugba, Yaman, Zeynep, Arman, Ayse Rodopman, Kuscu, Kemal, Yazgan, Yanki, Berkem, Meral, Feldman, Peter, Denai, Milton, Simpson, Alexander, Kratochvil, Christopher, Newcorn, Jeffrey, Biederman, Joseph, Gelowitz, Douglas, Thomason, Christine, Gao, Haitao, Bijttebier, Patricia, Decoene, Steff, Niklaus, Pia, Duits, Nils, Auer, Ulrich, Schnoor, Kathleen, Schläfke, Detlef, Çetin, Füsun Çuhadaroälu, Harper, Gordon, Hamdan, Sami, El-Haib, Muhammed, Canat, Saynur, Halfon, Olivier, Bolognini, Monique, Plancherel, B., Phan, Olivier, Corcos, Maurice, Cardinaux, Jean-René, Magistretti, Pierre J., Pierrehumbert, Blaise, Koskinen, Minna, Engqvist, Ulf, Allin, Matthew, Rifkin, Larry, Lancaster, Sandra, Borghini, Ayala, Jaugey, Laure, Forcada-Guex, Margarita, Jaunin, Lyne, Müller-Nix, Carole, Ansermet, François, Simoes, Mariada Conceicao Taborda, Lima, Luiza Nobre, Dias, Mariada Luz Vale, Siefen, Rainer Georg, Como, Ariel, Alikaj, Valbona, Tomori, Sonila, Capozzi, Flavia, Romano, Angela, Roello, Mara, Piperno, Francesca, Mann, Mali A., Stösser, Dieter, Barth, Gottfried, Pimenov, Alina, Schwab, Jenny, Bingöl, Hülya, Barbe, Rémy, Elkshishy, Heba, Jovanovic, Ana, Lakic, Aneta, Milovanovic, Vesna, Vukasinovic, Milorad, Bridge, Jeffrey, Kolko, David, Brent, David A., Gilson, Kathryn, Montague, Roslyn, Shochet, Ian, Marques, Cristina Maria Ribeiro, Cepeda, Teresa, Ligges, Carolin, Ligges, Marc, Huonker, Ralph, Leppänen, Paavo, Guttorm, Torni K., Hämäläinen, Jarmo, Puolakanaho, Anne, Plume, Ellen, König, Inke R., Deimel, Wolfgang, Nöthen, Markus M., Propping, Peter, Kleensang, André, Müller-Myhsok, Bertram, Ziegler, Andreas, Hong, Sung-Do David, Gao, Xueping, Li, Xuerong, Lee, Soyoung Irene, Kim, Eui-Jung, Cho, In-Hee, Kim, Ji-Hoon, Park, Se-Hyun, Choi, J-Wook, Heger, Steffen, Schreiner, Andreas, Rettig, Klaus, Medori, Rossella, Gustafsson, Peik, Hansson, Kjell, Eidevall, Lena, Thernlund, Gunilla, Heiser, Philip, Dempfle, A., Smidt, Judith, Grabarkiewicz, Justyna, Kiefl, Hans, Hemminger, U., Saar, K., Swanson, James, Volkov, Nora D., Gupta, S., Williams, L., Agler, D., Wasdell, M., Wigal, S., Martins, Silvia, Tramontina, Silza, Eizirik, Mariana, Vitiello, Benedetto, Clevenger, Walter, Faraone, Stephen, McGough, James, McCracken, James, Rohde, Luis Augusto, Greenhill, Larry, Leary, Michael, Larsson, Bo, Gunning, W. Boudewijn, Villat, Jean-Marie, O’Connell, Redmond, Bellgrove, Mark A., Dockree, Paul, Traube, Raymond, Braunschweig, Mary, Chabanier, Jacques, De Leo, Germana, Ibanez, Margerita, Mikolajaks, Olivette, Ropstad, Ida, Young, J. Gerald, Aiello, Rachele, Porcari, Viviana, Salatiello, Maria Patrizia, Lo Bue, Anna, Dell’Oglio, Valentina, Cardella, Rosaria, Chifari, Sabrina, Undheim, Anne Mari, Su, Linyan, Luo, Xuerong, Barton, Joanne, Baying, Lioba, Rellum, Thomas, Duezel, Emrah, Hinrichs, Hermann, Bartel, Christoph, Linde, Iris, Friederichs, E., Bangs, Mark, Remschmidt, Helmut, Doreleijers, Theodore, Rebernig, Elisabeth, Camerini, Giovanni Battista, Otero, Soraya, Rivas, Ana, Pombo, Guadalupe, Yeghiyan, Maruke, Kachatur, Gasparyan, Danileyan, Arman, Ivarsson, Tord, Valderhaug, Robert, Walitza, Susanne, Wewetzer, Christoph, Barth, Nikolaus, Hahn, F., Asbahr, Fernando, Castillo, Ana Regina, Ito, Ligia, Latorre, Mariado Rosario, Moreira, Michelle, Lotufo-Neto, Francisco, Symann, Sophie, Charlier, Dominique, Plattner, Belinda, Schallauer, Astrid Elisabeth, Mohler, Beat, Staub, P., Müller, Carsten, Oelkers-Ax, Rieke, Fischer, Jochen, Hermanns, Uta, Nickel, Anne, Bolay, Hans Volker, Cherro-Aguerre, Miguel, Sorensen, Merete Juul, Nissen, Judith Becker, Mors, Ole, Thomsen, Per Hove, Sund, Anne Mari, Drugli, May Britt, Wichstrom, Lars, Schwannauer, Matthias, Taylor, Emily, Wrate, Rob, Martin, Matthias, Larsson, Jan-Olov, Larsson, Henrik, Lichtenstein, Paul, Ludolph, Andrea G., Mottaghy, Felix, Kraemer, Susanne, Claus, Dieter, Krause, Bernhard, Fegert, Jbrg M., Hurtig, Tuula, Malakhova, Anna, Maniadaki, Katerina, Kakouros, Efthymios, Jensen, Peter, Garcia, Joe Albert, Glied, Sherry, Crowe, Maura, Foster, E. Michael, Golse, Bernard, Junghanß, Jenny, Salin, Aino-Maija, Rytölä, Päivi, Hiltunen, Pauliina, Remschmidt, Helmut, editor, and Belfer, Myron L., editor

Published
2004
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25. Artificial intelligence extension of the OSCAR-IB criteria

Author

Petzold, A., Albrecht, P., Balcer, L., Bekkers, E., Brandt, A. U., Calabresi, P. A., Deborah, O. G., Graves, J. S., Green, A., Keane, P. A., Nij Bijvank, J. A., Sander, J. W., Paul, F., Saidha, S., Villoslada, P., Wagner, S. K., Yeh, E. A., Aktas, O., Antel, J., Asgari, N., Audo, I., Avasarala, J., Avril, D., Bagnato, F. R., Banwell, B., Bar-Or, A., Behbehani, R., Manterola, A. B., Bennett, J., Benson, L., Bernard, J., Bremond-Gignac, D., Britze, J., Burton, J., Calkwood, J., Carroll, W., Chandratheva, A., Cohen, J., Comi, G., Cordano, C., Costa, S., Costello, F., Courtney, A., Cruz-Herranz, A., Cutter, G., Crabb, D., Delott, L., De Seze, J., Diem, R., Dollfuss, H., El Ayoubi, N. K., Fasser, C., Finke, C., Fischer, D., Fitzgerald, K., Fonseca, P., Frederiksen, J. L., Frohman, E., Frohman, T., Fujihara, K., Cuellar, I. G., Galetta, S., Garcia-Martin, E., Giovannoni, G., Glebauskiene, B., Suarez, I. G., Jensen, G. P., Hamann, S., Hartung, H. -P., Havla, J., Hemmer, B., Huang, S. -C., Imitola, J., Jasinskas, V., Jiang, H., Kafieh, R., Kappos, L., Kardon, R., Keegan, D., Kildebeck, E., Kim, U. S., Klistorner, S., Knier, B., Kolbe, S., Korn, T., Krupp, L., Lagreze, W., Leocani, L., Levin, N., Liskova, P., Preiningerova, J. L., Lorenz, B., May, E., Miller, D., Mikolajczak, J., Said, S. M., Montalban, X., Morrow, M., Mowry, E., Murta, J., Navas, C., Nolan, R., Nowomiejska, K., Oertel, F. C., Oh, J., Oreja-Guevara, C., Orssaud, C., Osborne, B., Outteryck, O., Paiva, C., Palace, J., Papadopoulou, A., Patsopoulos, N., Pontikos, N., Preising, M., Prince, J., Reich, D., Rejdak, R., Ringelstein, M., Rodriguez de Antonio, L., Sahel, J. -A., Sanchez-Dalmau, B., Sastre-Garriga, J., Schippling, S., Schuman, J., Shindler, K., Shin, R., Shuey, N., Soelberg, K., Specovius, S., Suppiej, A., Thompson, A., Toosy, A., Torres, R., Touitou, V., Trauzettel-Klosinski, S., van der Walt, A., Vermersch, P., Vidal-Jordana, A., Waldman, A. T., Waters, C., Wheeler, R., White, O., Wilhelm, H., Winges, K. M., Wiegerinck, N., Wiehe, L., Wisnewski, T., Wong, S., Wurfel, J., Yaghi, S., You, Y., Yu, Z., Yu-Wai-Man, P., Zemaitien≐, R., Zimmermann, H., Albrecht P., Petzold A., Balcer, L., Bekkers, E., Brandt, A. U., Calabresi, P. A., Deborah, O. G., Graves, J. S., Green, A., Keane, P. A., Nij Bijvank, J. A., Sander, J. W., Paul, F., Saidha, S., Villoslada, P., Wagner, S. K., Yeh, E. A., Aktas, O., Antel, J., Asgari, N., Audo, I., Avasarala, J., Avril, D., Bagnato, F. R., Banwell, B., Bar-Or, A., Behbehani, R., Manterola, A. B., Bennett, J., Benson, L., Bernard, J., Bremond-Gignac, D., Britze, J., Burton, J., Calkwood, J., Carroll, W., Chandratheva, A., Cohen, J., Comi, G., Cordano, C., Costa, S., Costello, F., Courtney, A., Cruz-Herranz, A., Cutter, G., Crabb, D., Delott, L., De Seze, J., Diem, R., Dollfuss, H., El Ayoubi, N. K., Fasser, C., Finke, C., Fischer, D., Fitzgerald, K., Fonseca, P., Frederiksen, J. L., Frohman, E., Frohman, T., Fujihara, K., Cuellar, I. G., Galetta, S., Garcia-Martin, E., Giovannoni, G., Glebauskiene, B., Suarez, I. G., P. , Jensen, G., Hamann, S., Hartung, H. -P., Havla, J., Hemmer, B., Huang, S. -C., Imitola, J., Jasinskas, V., Jiang, H., Kafieh, R., Kappos, L., Kardon, R., Keegan, D., Kildebeck, E., Kim, U. S., Klistorner, S., Knier, B., Kolbe, S., Korn, T., Krupp, L., Lagreze, W., Leocani, L., Levin, N., Liskova, P., Preiningerova, J. L., Lorenz, B., May, E., Miller, D., Mikolajczak, J., Said, S. M., Montalban, X., Morrow, M., Mowry, E., Murta, J., Navas, C., Nolan, R., Nowomiejska, K., Oertel, F. C., Oh, J., Oreja-Guevara, C., Orssaud, C., Osborne, B., Outteryck, O., Paiva, C., Palace, J., Papadopoulou, A., Patsopoulos, N., Pontikos, N., Preising, M., Prince, J., Reich, D., Rejdak, R., Ringelstein, M., Rodriguez de Antonio, L., Sahel, J. -A., Sanchez-Dalmau, B., Sastre-Garriga, J., Schippling, S., Schuman, J., Shindler, K., Shin, R., Shuey, N., Soelberg, K., Specovius, S., Suppiej, A., Thompson, A., Toosy, A., Torres, R., Touitou, V., Trauzettel-Klosinski, S., van der Walt, A., Vermersch, P., Vidal-Jordana, A., Waldman, A. T., Waters, C., Wheeler, R., White, O., Wilhelm, H., Winges, K. M., Wiegerinck, N., Wiehe, L., Wisnewski, T., Wong, S., Wurfel, J., Yaghi, S., You, Y., Yu, Z., Yu-Wai-Man, P., Zemaitien≐, R., and Zimmermann, H.

Subjects
0301 basic medicine, Big Data, medicine.medical_specialty, Neurology, media_common.quotation_subject, Big data, MEDLINE, Reviews, Socio-culturale, Neurosciences. Biological psychiatry. Neuropsychiatry, Review, Public domain, Retina, Cohort Studies, 03 medical and health sciences, Annotation, 0302 clinical medicine, Artificial Intelligence, medicine, Humans, Quality (business), RC346-429, Tomography, media_common, Image pattern recognition, business.industry, General Neuroscience, Nervous System Diseases, Tomography, Optical Coherence, Algorithms, 030104 developmental biology, Optical Coherence, Imaging technology, RC0321, Neurology. Diseases of the nervous system, Neurology (clinical), Artificial intelligence, sense organs, business, 030217 neurology & neurosurgery, RC321-571
Abstract

Artificial intelligence (AI)‐based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human‐led validated consensus quality control criteria (OSCAR‐IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI‐based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five‐point expansion of the OSCAR‐IB criteria to embrace AI (OSCAR‐AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.

Published
2021

26. Confirmed disability progression as a marker of permanent disability in multiple sclerosis.

Author

Sharmin S., Bovis F., Malpas C., Horakova D., Havrdova E., Izquierdo G., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., Terzi M., Gerlach O., Alroughani R., Boz C., Shaygannejad V., van Pesch V., Cartechini E., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Iuliano G., Granella F., Van Wijmeersch B., Spitaleri D., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J., Soysal A., Vucic S., Petersen T., de Gans K., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Cristiano E., Castillo-Trivino T., Saladino M., Barnett M., Moore F., Rozsa C., Yamout B., Skibina O., van der Walt A., Buzzard K., Gray O., Hughes S., Sempere A.P., Singhal B., Fragoso Y., Shaw C., Kermode A., Taylor B., Simo M., Shuey N., Al-Harbi T., Macdonell R., Dominguez J.A., Csepany T., Sirbu C., Sormani M.P., Butzkueven H., Kalincik T., Sharmin S., Bovis F., Malpas C., Horakova D., Havrdova E., Izquierdo G., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., Terzi M., Gerlach O., Alroughani R., Boz C., Shaygannejad V., van Pesch V., Cartechini E., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Iuliano G., Granella F., Van Wijmeersch B., Spitaleri D., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J., Soysal A., Vucic S., Petersen T., de Gans K., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Cristiano E., Castillo-Trivino T., Saladino M., Barnett M., Moore F., Rozsa C., Yamout B., Skibina O., van der Walt A., Buzzard K., Gray O., Hughes S., Sempere A.P., Singhal B., Fragoso Y., Shaw C., Kermode A., Taylor B., Simo M., Shuey N., Al-Harbi T., Macdonell R., Dominguez J.A., Csepany T., Sirbu C., Sormani M.P., Butzkueven H., and Kalincik T.

Abstract

Background and purpose: The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Method(s): In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Result(s): The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score >1.5). Conclusion(s): Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual.Copyright © 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behal

Published
2022

27. Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis.

Author

Roos I., Malpas C., Leray E., Casey R., Horakova D., Havrdova E.K., Debouverie M., Patti F., De Seze J., Izquierdo G., Eichau S., Edan G., Prat A., Girard M., Ozakbas S., Grammond P., Zephir H., Ciron J., Maillart E., Moreau T., Amato M.P., Labauge P., Alroughani R., Buzzard K., Skibina O., Terzi M., Laplaud D.A., Berger E., Grand'Maison F., Lebrun-Frenay C., Cartechini E., Boz C., Lechner-Scott J., Clavelou P., Stankoff B., Prevost J., Kappos L., Pelletier J., Shaygannejad V., Yamout B.I., Khoury S.J., Gerlach O., Spitaleri D.L.A., Van Pesch V., Gout O., Turkoglu R., Heinzlef O., Thouvenot E., McCombe P.A., Soysal A., Bourre B., Slee M., Castillo-Trivino T., Bakchine S., Ampapa R., Butler E.G., Wahab A., Macdonell R.A., Aguera-Morales E., Cabre P., Ben N.H., Van der Walt A., Laureys G., Van Hijfte L., Ramo-Tello C.M., Maubeuge N., Hodgkinson S., Sanchez-Menoyo J.L., Barnett M.H., Labeyrie C., Vucic S., Sidhom Y., Gouider R., Csepany T., Sotoca J., de Gans K., Al-Asmi A., Fragoso Y.D., Vukusic S., Butzkueven H., Kalincik T., Roos I., Malpas C., Leray E., Casey R., Horakova D., Havrdova E.K., Debouverie M., Patti F., De Seze J., Izquierdo G., Eichau S., Edan G., Prat A., Girard M., Ozakbas S., Grammond P., Zephir H., Ciron J., Maillart E., Moreau T., Amato M.P., Labauge P., Alroughani R., Buzzard K., Skibina O., Terzi M., Laplaud D.A., Berger E., Grand'Maison F., Lebrun-Frenay C., Cartechini E., Boz C., Lechner-Scott J., Clavelou P., Stankoff B., Prevost J., Kappos L., Pelletier J., Shaygannejad V., Yamout B.I., Khoury S.J., Gerlach O., Spitaleri D.L.A., Van Pesch V., Gout O., Turkoglu R., Heinzlef O., Thouvenot E., McCombe P.A., Soysal A., Bourre B., Slee M., Castillo-Trivino T., Bakchine S., Ampapa R., Butler E.G., Wahab A., Macdonell R.A., Aguera-Morales E., Cabre P., Ben N.H., Van der Walt A., Laureys G., Van Hijfte L., Ramo-Tello C.M., Maubeuge N., Hodgkinson S., Sanchez-Menoyo J.L., Barnett M.H., Labeyrie C., Vucic S., Sidhom Y., Gouider R., Csepany T., Sotoca J., de Gans K., Al-Asmi A., Fragoso Y.D., Vukusic S., Butzkueven H., and Kalincik T.

Abstract

OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHOD(S): This was a retrospective cohort study from two large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12-months were included in the analysis. The primary study outcome was annualised relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULT(S): 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for seven therapies. Annualised rates of relapse (ARR) started to increase 2-months after natalizumab cessation (month 2-4 ARR, 95% confidence interval): 0.47, 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89), and stabilised faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01-0.29). Magnitude of disease reactivation for other therapies was low, but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were higher relapse rate in the year before cessation, female sex, younger age and higher EDSS. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95%CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). CONCLUSION(S): The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different t

Published
2022

28. Multiple Sclerosis Relapses Following Cessation of Fingolimod

Author

Malpas, CB, Roos, I, Sharmin, S, Buzzard, K, Skibina, O, Butzkueven, H, Kappos, L, Patti, F, Alroughani, R, Horakova, D, Havrdova, EK, Izquierdo, G, Eichau, S, Hodgkinson, S, Grammond, P, Lechner-Scott, J, Kalincik, T, Malpas, CB, Roos, I, Sharmin, S, Buzzard, K, Skibina, O, Butzkueven, H, Kappos, L, Patti, F, Alroughani, R, Horakova, D, Havrdova, EK, Izquierdo, G, Eichau, S, Hodgkinson, S, Grammond, P, Lechner-Scott, J, and Kalincik, T

Abstract

BACKGROUND: There is growing interest in the issue of disease reactivation in multiple sclerosis following fingolimod cessation. Relatively little is known about modifiers of the risk of post-cessation relapse, including the delay to commencement of new therapy and prior disease activity. OBJECTIVE: We aimed to determine the rate of relapse following cessation of fingolimod and to identify predictors of relapse following cessation. METHODS: Data were extracted from the MSBase registry in March 2019. Inclusion criteria were (a) clinically definite relapsing multiple sclerosis, (b) treatment with fingolimod for ≥ 12 months, (c) follow-up after cessation for ≥ 12 months, and (d) at least one Expanded Disability Status Scale score recorded in the 12 months before cessation. RESULTS: A total of 685 patients were identified who met criteria. The mean annualised relapse rate was 1.71 (95% CI 1.59, 1.85) in the year prior to fingolimod, 0.50 (95% CI 0.44, 0.55) on fingolimod and 0.43 (95% CI 0.38, 0.49) after fingolimod. Of these, 218 (32%) patients experienced a relapse in the first 12 months. Predictors of a higher relapse rate in the first year were: younger age at fingolimod cessation, higher relapse rate in the year prior to cessation, delaying commencement of new therapy and switching to low-efficacy therapy. CONCLUSIONS: Disease reactivation following fingolimod cessation is more common in younger patients, those with greater disease activity prior to cessation and in those who switch to a low-efficacy therapy.

Published
2022

29. Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry

Author

Butzkueven, H, Spelman, T, Horakova, D, Hughes, S, Solaro, C, Izquierdo, G, Kubala Havrdova, E, Grand'Maison, F, Prat, A, Girard, M, Hupperts, R, Onofrj, M, Lugaresi, A, Taylor, B, Giovannoni, G, Kappos, L, Hauser, SL, Montalban, X, Craveiro, L, Freitas, R, Model, F, Overell, J, Muros-Le Rouzic, E, Sauter, A, Wang, Q, Wormser, D, Wolinsky, JS, Butzkueven, H, Spelman, T, Horakova, D, Hughes, S, Solaro, C, Izquierdo, G, Kubala Havrdova, E, Grand'Maison, F, Prat, A, Girard, M, Hupperts, R, Onofrj, M, Lugaresi, A, Taylor, B, Giovannoni, G, Kappos, L, Hauser, SL, Montalban, X, Craveiro, L, Freitas, R, Model, F, Overell, J, Muros-Le Rouzic, E, Sauter, A, Wang, Q, Wormser, D, and Wolinsky, JS

Abstract

BACKGROUND AND PURPOSE: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662). METHODS: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0-6.5) were investigated in ORATORIO and MSBase. RESULTS: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31-0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: -4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years. CONCLUSIONS: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence.

Published
2022

30. Confirmed disability progression as a marker of permanent disability in multiple sclerosis

Author

Sharmin, S., Bovis, F., Malpas, C., Horakova, D., Havrdova, E.K., Izquierdo, G., Eichau, S., Trojano, M., Prat, A., Girard, M., Duquette, P., Onofrj, M., Lugaresi, A., Grand'Maison, F., Grammond, P., Sola, P., Ferraro, D., Terzi, M., Gerlach, O., Alroughani, R., Boz, C., Shaygannejad, V., van Pesch, V., Cartechini, E., Kappos, L., Lechner‐Scott, J., Bergamaschi, R., Turkoglu, R., Solaro, C., Iuliano, G., Granella, F., Van Wijmeersch, B., Spitaleri, D., Slee, M., McCombe, P., Prevost, J., Ampapa, R., Ozakbas, S., Sanchez‐Menoyo, J.L., Soysal, A., Vucic, S., Petersen, T., de Gans, K., Butler, E., Hodgkinson, S., Sidhom, Y., Gouider, R., Cristiano, E., Castillo‐Triviño, T., Saladino, M.L., Barnett, M., Moore, F., Rozsa, C., Yamout, B., Skibina, O., van der Walt, A., Buzzard, K., Gray, O., Hughes, S., Sempere, A.P., Singhal, B., Fragoso, Y., Shaw, C., Kermode, A., Taylor, B., Simo, M., Shuey, N., Al‐Harbi, T., Macdonell, R., Dominguez, J.A., Csepany, T., Sirbu, C.A., Sormani, M.P., Butzkueven, H., Kalincik, T., Sharmin, S., Bovis, F., Malpas, C., Horakova, D., Havrdova, E.K., Izquierdo, G., Eichau, S., Trojano, M., Prat, A., Girard, M., Duquette, P., Onofrj, M., Lugaresi, A., Grand'Maison, F., Grammond, P., Sola, P., Ferraro, D., Terzi, M., Gerlach, O., Alroughani, R., Boz, C., Shaygannejad, V., van Pesch, V., Cartechini, E., Kappos, L., Lechner‐Scott, J., Bergamaschi, R., Turkoglu, R., Solaro, C., Iuliano, G., Granella, F., Van Wijmeersch, B., Spitaleri, D., Slee, M., McCombe, P., Prevost, J., Ampapa, R., Ozakbas, S., Sanchez‐Menoyo, J.L., Soysal, A., Vucic, S., Petersen, T., de Gans, K., Butler, E., Hodgkinson, S., Sidhom, Y., Gouider, R., Cristiano, E., Castillo‐Triviño, T., Saladino, M.L., Barnett, M., Moore, F., Rozsa, C., Yamout, B., Skibina, O., van der Walt, A., Buzzard, K., Gray, O., Hughes, S., Sempere, A.P., Singhal, B., Fragoso, Y., Shaw, C., Kermode, A., Taylor, B., Simo, M., Shuey, N., Al‐Harbi, T., Macdonell, R., Dominguez, J.A., Csepany, T., Sirbu, C.A., Sormani, M.P., Butzkueven, H., and Kalincik, T.

Abstract

Background and purpose The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Methods In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Results The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29–0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score ˃1.5). Conclusions Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual.

Published
2022

31. Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis

Author

Roos, I, Malpas, C, Leray, E, Casey, R, Horakova, D, Havrdova, EK, Debouverie, M, Patti, F, De Seze, J, Izquierdo, G, Eichau, S, Edan, G, Prat, A, Girard, M, Ozakbas, S, Grammond, P, Zephir, H, Ciron, J, Maillart, E, Moreau, T, Amato, MP, Labauge, P, Alroughani, R, Buzzard, K, Skibina, O, Terzi, M, Laplaud, DA, Berger, E, Grand'Maison, F, Lebrun-Frenay, C, Cartechini, E, Boz, C, Lechner-Scott, J, Clavelou, P, Stankoff, B, Prevost, J, Kappos, L, Pelletier, J, Shaygannejad, V, Yamout, B, Khoury, SJ, Gerlach, O, Spitaleri, DLA, Van Pesch, V, Gout, O, Turkoglu, R, Heinzlef, O, Thouvenot, E, McCombe, PA, Soysal, A, Bourre, B, Slee, M, Castillo-Trivino, T, Bakchine, S, Ampapa, R, Butler, EG, Wahab, A, Macdonell, RA, Aguera-Morales, E, Cabre, P, Ben, NH, Van der Walt, A, Laureys, G, Van Hijfte, L, Ramo-Tello, CM, Maubeuge, N, Hodgkinson, S, Sanchez-Menoyo, JL, Barnett, MH, Labeyrie, C, Vucic, S, Sidhom, Y, Gouider, R, Csepany, T, Sotoca, J, de Gans, K, Al-Asmi, A, Fragoso, YD, Vukusic, S, Butzkueven, H, Kalincik, T, Roos, I, Malpas, C, Leray, E, Casey, R, Horakova, D, Havrdova, EK, Debouverie, M, Patti, F, De Seze, J, Izquierdo, G, Eichau, S, Edan, G, Prat, A, Girard, M, Ozakbas, S, Grammond, P, Zephir, H, Ciron, J, Maillart, E, Moreau, T, Amato, MP, Labauge, P, Alroughani, R, Buzzard, K, Skibina, O, Terzi, M, Laplaud, DA, Berger, E, Grand'Maison, F, Lebrun-Frenay, C, Cartechini, E, Boz, C, Lechner-Scott, J, Clavelou, P, Stankoff, B, Prevost, J, Kappos, L, Pelletier, J, Shaygannejad, V, Yamout, B, Khoury, SJ, Gerlach, O, Spitaleri, DLA, Van Pesch, V, Gout, O, Turkoglu, R, Heinzlef, O, Thouvenot, E, McCombe, PA, Soysal, A, Bourre, B, Slee, M, Castillo-Trivino, T, Bakchine, S, Ampapa, R, Butler, EG, Wahab, A, Macdonell, RA, Aguera-Morales, E, Cabre, P, Ben, NH, Van der Walt, A, Laureys, G, Van Hijfte, L, Ramo-Tello, CM, Maubeuge, N, Hodgkinson, S, Sanchez-Menoyo, JL, Barnett, MH, Labeyrie, C, Vucic, S, Sidhom, Y, Gouider, R, Csepany, T, Sotoca, J, de Gans, K, Al-Asmi, A, Fragoso, YD, Vukusic, S, Butzkueven, H, and Kalincik, T

Abstract

BACKGROUND AND OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHODS: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULTS: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). DISCUSSION: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued di

Published
2022

32. Multiple Sclerosis Severity Score (MSSS) improves the accuracy of individualized prediction in MS

Author

Kalincik, T, Kister, I, Bacon, TE, Malpas, CB, Sharmin, S, Horakova, D, Kubala-Havrdova, E, Patti, F, Izquierdo, G, Eichau, S, Ozakbas, S, Onofrj, M, Lugaresi, A, Prat, A, Girard, M, Duquette, P, Grammond, P, Sola, P, Ferraro, D, Alroughani, R, Terzi, M, Boz, C, Grand'Maison, F, Bergamaschi, R, Gerlach, O, Sa, MJ, Kappos, L, Cartechini, E, Lechner-Scott, J, van Pesch, V, Shaygannejad, V, Granella, F, Spitaleri, D, Iuliano, G, Maimone, D, Prevost, J, Soysal, A, Turkoglu, R, Ampapa, R, Butzkueven, H, Cutter, G, Kalincik, T, Kister, I, Bacon, TE, Malpas, CB, Sharmin, S, Horakova, D, Kubala-Havrdova, E, Patti, F, Izquierdo, G, Eichau, S, Ozakbas, S, Onofrj, M, Lugaresi, A, Prat, A, Girard, M, Duquette, P, Grammond, P, Sola, P, Ferraro, D, Alroughani, R, Terzi, M, Boz, C, Grand'Maison, F, Bergamaschi, R, Gerlach, O, Sa, MJ, Kappos, L, Cartechini, E, Lechner-Scott, J, van Pesch, V, Shaygannejad, V, Granella, F, Spitaleri, D, Iuliano, G, Maimone, D, Prevost, J, Soysal, A, Turkoglu, R, Ampapa, R, Butzkueven, H, and Cutter, G

Abstract

BACKGROUND: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. OBJECTIVE: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. METHODS: The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients' demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. RESULTS: A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. CONCLUSION: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.

Published
2022

35. A multicentric investigation of the diagnostic accuracy of cortical lesions and central vein sign in multiple sclerosis

Author

Cagol, A., Cortese, R., Barakovic, M., Schaedelin, S., Ruberte, E., Absinta, M., Barkhof, F., Calabrese, M., Marco Castellaro, Ciccarelli, O., Cocozza, S., Stefano, N., Enzinger, C., Filippi, M., Jurynczyk, M., Maggi, P., Mahmoudi, N., Montalban, X., Palace, J., Pontillo, G., Rocca, M. A., Ropele, S., Rovira, A., Schoonheim, M. M., Sowa, P., Strijbis, E., Wattjes, M. P., Wuerfel, J., Kappos, L., and Granziera, C.

Published
2022

36. Longitudinal machine learning modeling of MS patient trajectories improves predictions of disability progression (vol 208, 106180, 2021)

Author

De Brouwer, E, Becker, T, Moreau, Y, Havrdova, EK, Trojano, M, Eichau, S, Ozakbas, S, Onofrj, M, Grammond, P, Kuhle, J, Kappos, L, Sola, P, Cartechini, E, Lechner-Scott, J, Alroughani, R, Gerlach, O, Kalincik, T, Granella, F, Grand'Maison, F, Bergamaschi, R, Sa, MJ, Van Wijmeersch, B, Soysal, A, Sanchez-Menoyo, JL, Solaro, C, Boz, C, Iuliano, G, Buzzard, K, Aguera-Morales, E, Terzi, M, Trivio, TC, Spitaleri, D, Van Pesch, V, Shaygannejad, V, Moore, F, Oreja-Guevara, C, Maimone, D, Gouider, R, Csepany, T, Ramo-Tello, C, and Peeters, L

Published
2022

38. Prognostic biomarkers in primary progressive multiple sclerosis: Validating and scrutinizing multimodal evoked potentials

Author

Hardmeier, M., Schlaeger, R., Lascano, A. M., Toffolet, L., Schindler, C., Gobbi, C., Lalive, P., Kuhle, J., Kappos, L., and Fuhr, P.

Subjects
Disability Evaluation, Multiple Sclerosis, Neurology, Physiology (medical), Disease Progression, Humans, Neurology (clinical), Multiple Sclerosis, Chronic Progressive, Prognosis, Evoked Potentials, Sensory Systems, Biomarkers
Abstract

OBJECTIVE: To validate the prognostic value of multimodal evoked potentials (mmEP) in primary progressive multiple sclerosis (PPMS) and to determine the most predictive EP-modalities. METHODS: Thirty-nine patients with PPMS (expanded disability status scale (EDSS): 2.0-6.5; mean clinical follow-up: 2.8 years) had visual (VEP), upper and lower limb somatosensory (SEP) and motor EP (MEP) at baseline. Quantitative EP-scores for single (qVEP, qSEP, qMEP) and combined modalities were correlated to EDSS and compared to previously published data of 21 PPMS patients. Predictors of EDSS-change were analyzed in pooled data by linear regression. RESULTS: Samples were comparable. Except qVEP, all EP-scores were correlated to EDSS at baseline (Rho: 0.45-0.69; p < 0.01) and follow-up (Rho: 0.59-0.80; p < 0.001). Combined EP-modalities significantly predicted EDSS-change (R(2)adj: 0.24), while EDSS and age did not. Tibial qSEP (R(2)adj: 0.22) and qMEP (R(2)adj: 0.26) were the best single modality predictors, outperformed by their combination (R(2)adj: 0.32). CONCLUSIONS: Quantitative EP-scores predict up to 32% of EDSS-change over three years. Modalities representing motor and long tract function carry the main prognostic information. SIGNIFICANCE: Replication of previous results corroborates the use of mmEP as a prognostic biomarker candidate in PPMS.

Published
2021

40. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis

Author

Montalban, X., Hauser, S. L., Kappos, L., Arnold, D. L., Bar‑or, A., Comi, G., de Seze, J., Giovannoni, G., Hartung, H. -P., Hemmer, B., Lublin, F., Rammohan, K. W., Selmaj, K., Traboulsee, A., Sauter, A., Masterman, D., Fontoura, P., Belachew, S., Garren, H., Mairon, N., Chin, P., Wolinsky, J. S., Uccelli, A, for the ORATORIO Clinical Investigators, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Neurowetenschappen, Institut Català de la Salut, [Montalban X] Hospital Universitari Vall d’Hebron, Barcelona, Spain. [Hauser SL] University of California, San Francisco, United States. [Kappos L] University Hospital Basel, Basel, Switzerland. [Arnold DL, Bar-Or A] McGill University, Montreal, Canada. [Comi G] University Vita-Salute San Raffaele, Milan, Italy., Hospital Universitari Vall d'Hebron, CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, CHU Strasbourg, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Montalban, X., Hauser, S. L., Kappos, L., Arnold, D. L., Bar or, A., Comi, Giancarlo, De Seze, J., Giovannoni, G., Hartung, H. . P., Hemmer, B., Lublin, F., Rammohan, K. W., Selmaj, K., Traboulsee, A., Sauter, A., Masterman, D., Fontoura, P., Belachew, S., Garren, H., Mairon, N., Chin, P., and Wolinsky, J. S.

Subjects
Male, 0301 basic medicine, Intention to Treat Analysi, T-Lymphocytes, Esclerosi múltiple, enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes desmielinizantes del SNC::esclerosis múltiple::esclerosis múltiple crónica progresiva [ENFERMEDADES], Other subheadings::Other subheadings::/drug therapy [Other subheadings], DOUBLE-BLIND, chemistry.chemical_compound, 0302 clinical medicine, DEMYELINATION, Monoclonal, Clinical endpoint, aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos monoclonales::anticuerpos monoclonales humanizados [COMPUESTOS QUÍMICOS Y DROGAS], Infusions, Intravenou, Other subheadings::/therapeutic use [Other subheadings], Otros calificadores::Otros calificadores::/inmunología [Otros calificadores], Humanized, Otros calificadores::Otros calificadores::/tratamiento farmacológico [Otros calificadores], MULTICENTER TRIAL, Enfermedades del Sistema Nervioso::Enfermedades Autoinmunes del Sistema Nervioso::Enfermedades Autoinmunes Desmielinizantes SNC::Esclerosis Múltiple::Esclerosis Múltiple Crónica Progresiva [ENFERMEDADES], DAMAGE, B-Lymphocytes, Medicine (all), Hazard ratio, B-Lymphocyte, Brain, General Medicine, Multiple Sclerosis, Chronic Progressive, Middle Aged, Magnetic Resonance Imaging, Intention to Treat Analysis, 3. Good health, Chronic Progressive, Disease Progression, Female, Intravenous, Human, medicine.drug, Adult, Infusions, medicine.medical_specialty, Multiple Sclerosis, Adolescent, CANCER-RISK, Antibodies, Monoclonal, Humanized, Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies, Monoclonal::Antibodies, Monoclonal, Humanized [CHEMICALS AND DRUGS], Placebo, Antibodies, Young Adult, 03 medical and health sciences, Double-Blind Method, Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis::Multiple Sclerosis, Chronic Progressive [DISEASES], Other subheadings::Other subheadings::/immunology [Other subheadings], Multicenter trial, Internal medicine, medicine, Humans, CD20, Lymphocyte Count, Antigens, Intention-to-treat analysis, Otros calificadores::/uso terapéutico [Otros calificadores], business.industry, Multiple sclerosis, Antigens, CD20, medicine.disease, Infusions, Intravenous, Surgery, PATHOLOGY, 030104 developmental biology, Siponimod, T-Lymphocyte, ANTIBODY, chemistry, Ocrelizumab, Medicaments immunosupressors, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

Ocrelizumab; Placebo; Multiple sclerosis Ocrelizumab; Placebo; Esclerosi múltiple Ocrelizumab; Placebo; Esclerosis múltiple BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P

Published
2017

41. Ofatumumab versus Teriflunomide in Multiple Sclerosis

Author

Hauser S. L., Bar-Or A., Cohen J. A., Comi G., Correale J., Coyle P. K., Cross A. H., de Seze J., Leppert D., Montalban X., Selmaj K., Wiendl H., Kerloeguen C., Willi R., Li B., Kakarieka A., Tomic D., Goodyear A., Pingili R., Haring D. A., Ramanathan K., Merschhemke M., Kappos L., Stephen L Hauser, Ludwig Kappos, Amit Bar-Or, Jeffrey A Cohen, Giancarlo Comi, Jorge Correale, Patricia K Coyle, Anne Cross, Jerome de Seze, Xavier Montalban, Krzysztof Selmaj, Heinz Wiendl, Stephen C Reingold, Garry R Cutter, Thomas Doerner, Hans-Peter Hartung, Per Soelberg Sørensen, Israel Steiner, Jerry S Wolinsky, Carlos Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana Liwacki, Jeannette Lechner-Scott, John Parratt, Suzanne Hodgkinson, Eva-Maria Maida, Fritz Leutmezer, Barbara Willekens, Bart Van Wijmeersch, Guy Laureys, Jo Caekebeke, Karine Geens, Ludo Vanopdenbosch, Olivier Deryck, Valerie Delvaux, Vincent Van Pesch, Ivan Milanov, Ivaylo Tarnev, Lyubomir Haralanov, Maria Manova Slavova, Penko Shotekov, Francois Emond, Francois Grandmaison, Francois Jacques, Liesly Lee, Marie Sarah Gagne Brosseau, Mark Freedman, Martin Cloutier, Robert Carruthers, Sarah Morrow, Yves Lapierre, Anton Vladic, Hana Bokun, Igor Antoncic, Marija Bosnjak Pasic, Mario Habek, Silva Butkovic Soldo, Vladimira Vuletic, Alena Martinkova, Eva Meluzinova, Ivana Stetkarova, Jan Mares, Jolana Markova, Marta Vachova, Martin Valis, Michaela Tyblova, Michal Dufek, Ondrej Skoda, Pavel Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina Svendsen, Mads Ravnborg, Peter Vestergaard Rasmussen, Katrin Gross-Paju, Sulev Haldre, Juha Pekka Eralinna, Marja-Liisa Sumelahti, Bruno Brochet, Celine Louapre, Christine Lebrun-Frenay, David Axel Laplaud, Gilles Edan, Giovanni Castelnovo, Marc Debouverie, Patrick Vermersch, Pierre Clavelou, Pierre Labauge, Achim Berthele, Aiden Haghikia, Anselm Kornhuber, Arnfin Bergmann, Benedikt Frank, Birte Elias-Hamp, Bjoern Tackenberg, Brigitte Wildemann, Erik Strauss, Eugen Schlegel, Florian Then Bergh, Gereon Nelles, Hayrettin Tumani, Karl-Otto Sigel, Martin Stangel, Matthias Boehringer, Olaf Martin Hoffmann, Patrick Oschmann, Reinhard Hohlfeld, Silke Walter, Sylvia Menck, Till Sprenger, Tjalf Ziemssen, Veit Ulrich Becker, Vera Straeten, Konstantinos Kilidireas, Konstantinos Voumvourakis, Nikolaos Fakas, Nikolaos Grigoriadis, Agnes Koves, Csilla Rozsa, Krisztina Kovacs, Laszlo Vecsei, Satori Maria, Zita Biro, Anshu Rohatgi, Dheeraj Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha Pandit, Meena Angamuthu Kanikannan, Pahari Ghosh, Rahul Chakor, Rahul Kulkarni, Roopkumar Gursahani, Sangeeta Ravat, Srinivasa Rangasetty, Suresh Kumar, Alla Shifrin, Arnon Karni, Radi Shahien, Ron Milo, Antonio Uccelli, Carlo Pozzilli, Francesco Sacca, Giacomo Lus, Girolama Alessandra Marfia, Laura Brambilla, Marco Salvetti, Massimo Filippi, Mauro Zaffaroni, Paolo Gallo, Silvia Rossi, Simona Bonavita, Valeria Studer, Andrejs Millers, Guntis Karelis, Jolanta Kalnina, Dalia Mickeviciene, Rasa Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs Wokke, Bob W Van Oosten, Peter Van Domburg, Raymond Hupperts, Rogier Q Hintzen, Astrid Edland, Cesar Castaneda, Julio Perez, Martin Gavidia, Andrzej Wiak, Bartosz Karaszewski, Elzbieta Jasinska, Halina Bartosik Psujek, Iwona Jastrzebska, Jaroslaw Slawek, Maciej Maciejowski, Miroslaw Dziki, Monika Adamczyk Sowa, Robert Bonek, Waldemar Fryze, Ana Martins Da Silva, Angela Timoteo, Antonio Vasco Salgado, Carlos Capela, Carlos Veira, Filipe Correia, Joao Cerqueira, Joao De Sa, Livia De Sousa, Raquel Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon Kurca, Georgi Krastev, Miroslav Brozman, Peter Koleda, Peter Turcani, Peter Valkovic, Viera Hancinova, Vladimir Donath, Chris Retief, Michael Isaacs, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik Piehl, Jan Lycke, Chiara Zecca, Tobias Derfuss, Thy-Sheng Lin, Somsak Tiamkao, Ayse Nur Yuceyar, Aysun Soysal, Belgin Petek Balci, Cavit Boz, Husnu Efendi, Murat Terzi, Serhan Sevim, Serkan Ozakbas, Andrew Gale, Ben Turner, David Barnes, David Paling, Eli Silber, James Overell, Matthew Craner, Aaron Carlson, Adam Wolff, Adaeze Onuoha, Adnan Subei, Ahmad Ata, Aimee Borazanci, Akram Dastagir, Alberto Vasquez, Alison Brooke Allen, Andrew P Keegan, Angel Carrasco, Angel R Chinea Martinez, Ann Bass, Annette Okai, April Erwin, Ariel Antezana-Antezana, Barbara Green, Bharathy E Sundaram, Bhupendra Khatri, Bhupesh Dihenia, Bogdan Gheorghiu, Brian Costell, Brian Steingo, Bruce L Hughes, Carrie M Hersh, Christopher Laganke, Christopher Luzzio, Corey Ford, Craig Edward Herrman, Craig Senzon, Cynthia Huffman, Daniel R Wynn, David D O Bear, David Lesch, David H Mattson, David Weisman, Deborah A Burke, Dennis W Dietrich, Deren Huang, Derrick Robertson, Djamchid Lotfi, Don Joseph Alfonso, Dusan Stefoski, Edward J Fox, Emily Pharr, Enrique Alvarez, Evanthia Bernitsas, Faria Amjad, Gabriel Pardo, Geoffrey Eubank, Gerald Mcintosh, Giles F Crowell, Hemanth Rao, J Michael Hemphill, Jack H Florin, Jacqueline Nicholas, James Napier, James Scott, Jason M Silversteen, Javier Vasallo, Jean-Raphael Schneider, Jeanette Wendt, Jeffrey Cohen, Jeffrey Gross, Jeffrey Groves, Jeffrey Kaplan, Jessica Stulc, Joanna A Cooper, John Foley, John Scagnelli, Jonathan C Calkwood, Jose Pizarro Otero, Jose Rafecas, Joshua Katz, Juliette S Saad, Katherine Standley, Keith Edwards, Kenneth Sharlin, Khurram Bashir, Kimberly Wagner, Kore Liow, Larry Lee Blankenship Jr, Laszlo Mate, Liliana Montoya, Lon D Lynn, Mark Agius, Mark Cascione, Mark Allan Goldstein, Mark Janicki, Martin R Bialow, Mary Denise Hughes, Matthew J Baker, Michelle Apperson, Michelle B Kuczma, M Mateo Paz Soldan, Mirela Cerghet, Nathaniel Robb Whaley, Paul K Winner, Pavle Repovic, Praful Kelkar, Romero Rekha Pillai, Ricardo Ayala, Richard Sater, Randall Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert Naismith, Ronald S Murray, Samuel Hunter, Sara Qureshi, Sharon Lynch, Sibyl Wray, Silvia R Delgado, Stacy Donlon, Stanley Cohan, Stanya Smith, Stuart James Shafer, Susan Azalone, Susan Hibbs, Tamara A Miller, Thomas Giancarlo, Troy Desai, Varun K Saxena, Virginia Simnad, William David Honeycutt, William Logan, William E McElveen, William Wagner, University of California [San Francisco] (UCSF), University of California, Perelman School of Medicine, University of Pennsylvania [Philadelphia], Cleveland Clinic, IRCCS Ospedale San Raffaele [Milan, Italy], Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia [Buenos Aires] (FLENI), FLENI, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, University Hospital Basel [Basel], Vall d'Hebron University Hospital [Barcelona], University of Warmia and Mazury [Olsztyn], University of Münster, Novartis Pharma S.A.S., Novartis Pharmaceuticals, University of Basel (Unibas), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Willekens, Barbara, ASCLEPIOS I and ASCLEPIOS II Trial Groups, Hauser, S. L., Bar-Or, A., Cohen, J. A., Comi, G., Correale, J., Coyle, P. K., Cross, A. H., de Seze, J., Leppert, D., Montalban, X., Selmaj, K., Wiendl, H., Kerloeguen, C., Willi, R., Li, B., Kakarieka, A., Tomic, D., Goodyear, A., Pingili, R., Haring, D. A., Ramanathan, K., Merschhemke, M., Kappos, L., Asclepios, I and ASCLEPIOS II Trial Group, Filippi, M, L Hauser, Stephen, Kappos, Ludwig, Bar-Or, Amit, A Cohen, Jeffrey, Comi, Giancarlo, Correale, Jorge, K Coyle, Patricia, Cross, Anne, de Seze, Jerome, Montalban, Xavier, Selmaj, Krzysztof, Wiendl, Heinz, C Reingold, Stephen, R Cutter, Garry, Doerner, Thoma, Hartung, Hans-Peter, Soelberg Sørensen, Per, Steiner, Israel, S Wolinsky, Jerry, Ballario, Carlo, Calvo Vildoso, Christian, Gustavo Jose, Jorge, Haydee Deri, Norma, Liwacki, Susana, Lechner-Scott, Jeannette, Parratt, John, Hodgkinson, Suzanne, Maida, Eva-Maria, Leutmezer, Fritz, Van Wijmeersch, Bart, Laureys, Guy, Caekebeke, Jo, Geens, Karine, Vanopdenbosch, Ludo, Deryck, Olivier, Delvaux, Valerie, Van Pesch, Vincent, Milanov, Ivan, Tarnev, Ivaylo, Haralanov, Lyubomir, Manova Slavova, Maria, Shotekov, Penko, Emond, Francoi, Grandmaison, Francoi, Jacques, Francoi, Lee, Liesly, Sarah Gagne Brosseau, Marie, Freedman, Mark, Cloutier, Martin, Carruthers, Robert, Morrow, Sarah, Lapierre, Yve, Vladic, Anton, Bokun, Hana, Antoncic, Igor, Bosnjak Pasic, Marija, Habek, Mario, Butkovic Soldo, Silva, Vuletic, Vladimira, Martinkova, Alena, Meluzinova, Eva, Stetkarova, Ivana, Mares, Jan, Markova, Jolana, Vachova, Marta, Valis, Martin, Tyblova, Michaela, Dufek, Michal, Skoda, Ondrej, Hradilek, Pavel, Voldsgaard Jensen, Ana, Hvilsted Nielsen, Helle, Svendsen, Kristina, Ravnborg, Mad, Vestergaard Rasmussen, Peter, Gross-Paju, Katrin, Haldre, Sulev, Pekka Eralinna, Juha, Sumelahti, Marja-Liisa, Brochet, Bruno, Louapre, Celine, Lebrun-Frenay, Christine, Axel Laplaud, David, Edan, Gille, Castelnovo, Giovanni, Debouverie, Marc, Vermersch, Patrick, Clavelou, Pierre, Labauge, Pierre, Berthele, Achim, Haghikia, Aiden, Kornhuber, Anselm, Bergmann, Arnfin, Frank, Benedikt, Elias-Hamp, Birte, Tackenberg, Bjoern, Wildemann, Brigitte, Strauss, Erik, Schlegel, Eugen, Then Bergh, Florian, Nelles, Gereon, Tumani, Hayrettin, Sigel, Karl-Otto, Stangel, Martin, Boehringer, Matthia, Martin Hoffmann, Olaf, Oschmann, Patrick, Hohlfeld, Reinhard, Walter, Silke, Menck, Sylvia, Sprenger, Till, Ziemssen, Tjalf, Ulrich Becker, Veit, Straeten, Vera, Kilidireas, Konstantino, Voumvourakis, Konstantino, Fakas, Nikolao, Grigoriadis, Nikolao, Koves, Agne, Rozsa, Csilla, Kovacs, Krisztina, Vecsei, Laszlo, Maria, Satori, Biro, Zita, Rohatgi, Anshu, Khurana, Dheeraj, Durai Pandian, Jeyaraj, Dev Mukherji, Joy, Pandit, Lekha, Angamuthu Kanikannan, Meena, Ghosh, Pahari, Chakor, Rahul, Kulkarni, Rahul, Gursahani, Roopkumar, Ravat, Sangeeta, Rangasetty, Srinivasa, Kumar, Suresh, Shifrin, Alla, Karni, Arnon, Shahien, Radi, Milo, Ron, Uccelli, Antonio, Pozzilli, Carlo, Sacca, Francesco, Lus, Giacomo, Alessandra Marfia, Girolama, Brambilla, Laura, Salvetti, Marco, Filippi, Massimo, Zaffaroni, Mauro, Gallo, Paolo, Rossi, Silvia, Bonavita, Simona, Studer, Valeria, Millers, Andrej, Karelis, Gunti, Kalnina, Jolanta, Mickeviciene, Dalia, Kizlaitiene, Rasa, Carbajal Ramirez, Angelica, Jose Lopez Prieto, Juan, Wokke, Beatrij, W Van Oosten, Bob, Van Domburg, Peter, Hupperts, Raymond, Q Hintzen, Rogier, Edland, Astrid, Castaneda, Cesar, Perez, Julio, Gavidia, Martin, Wiak, Andrzej, Karaszewski, Bartosz, Jasinska, Elzbieta, Bartosik Psujek, Halina, Jastrzebska, Iwona, Slawek, Jaroslaw, Maciejowski, Maciej, Dziki, Miroslaw, Adamczyk Sowa, Monika, Bonek, Robert, Fryze, Waldemar, Martins Da Silva, Ana, Timoteo, Angela, Vasco Salgado, Antonio, Capela, Carlo, Veira, Carlo, Correia, Filipe, Cerqueira, Joao, De Sa, Joao, De Sousa, Livia, Gouveia, Raquel, Sergeevna Agafina, Alina, Naumovna Belova, Anna, Viktorovich Sazonov, Deni, Pokhabov, Dmitry, Igorevna Kairbekova, Ekaterina, Gennadievna Arefieva, Elena, Axatovich Khabirov, Farit, Vyacheslavovich Litvinenko, Igor, Stolyarov, Igor, Aleksandrovna Sokolova, Irina, Ivanovna Volkova, Larisa, Vafaevna Davydovskaya, Maria, Nikolaevna Zaharova, Maria, Alekseevna Malkova, Nadezhda, Agafonovna Totolyan, Natalia, Vasilievich Dorogov, Nikolay, Anatolievna Sivertseva, Stella, Kurca, Egon, Krastev, Georgi, Brozman, Miroslav, Koleda, Peter, Turcani, Peter, Valkovic, Peter, Hancinova, Viera, Donath, Vladimir, Retief, Chri, Isaacs, Michael, Saiz Hinarejos, Albert, Rodriguez Antigüedad, Alfredo, Casanova Estruch, Bonaventura, Oreja-Guevara, Celia, Reig Rosello, Gemma, Carlos Alvarez Cermeño, Jose, Martinez Rodriguez, Jose, Meca Lallana, Jose, Antonio Garcia Merino, Juan, Forero Diaz, Lucia, Costa Frossard Franca, Lucienne, Querol Gutierrez, Lui, Ramio Torrenta, Llui, Serrano Castro, Pedro, Arroyo Gonzalez, Rafael, Eichau Madueño, Sara, Martinez Yelamos, Sergio, Castillo Trivino, Tamara, Meca Lallana, Virgina, Montalban Gairin, Xaviere, Piehl, Fredrik, Lycke, Jan, Zecca, Chiara, Derfuss, Tobia, Lin, Thy-Sheng, Tiamkao, Somsak, Nur Yuceyar, Ayse, Soysal, Aysun, Petek Balci, Belgin, Boz, Cavit, Efendi, Husnu, Terzi, Murat, Sevim, Serhan, Ozakbas, Serkan, Gale, Andrew, Turner, Ben, Barnes, David, Paling, David, Silber, Eli, Overell, Jame, Craner, Matthew, Carlson, Aaron, Wolff, Adam, Onuoha, Adaeze, Subei, Adnan, Ata, Ahmad, Borazanci, Aimee, Dastagir, Akram, Vasquez, Alberto, Brooke Allen, Alison, P Keegan, Andrew, Carrasco, Angel, R Chinea Martinez, Angel, Bass, Ann, Okai, Annette, Erwin, April, Antezana-Antezana, Ariel, Green, Barbara, E Sundaram, Bharathy, Khatri, Bhupendra, Dihenia, Bhupesh, Gheorghiu, Bogdan, Costell, Brian, Steingo, Brian, L Hughes, Bruce, M Hersh, Carrie, Laganke, Christopher, Luzzio, Christopher, Ford, Corey, Edward Herrman, Craig, Senzon, Craig, Huffman, Cynthia, R Wynn, Daniel, O Bear, David D, Lesch, David, H Mattson, David, Weisman, David, A Burke, Deborah, W Dietrich, Denni, Huang, Deren, Robertson, Derrick, Lotfi, Djamchid, Joseph Alfonso, Don, Stefoski, Dusan, J Fox, Edward, Pharr, Emily, Alvarez, Enrique, Bernitsas, Evanthia, Amjad, Faria, Pardo, Gabriel, Eubank, Geoffrey, Mcintosh, Gerald, F Crowell, Gile, Rao, Hemanth, Michael Hemphill, J, H Florin, Jack, Nicholas, Jacqueline, Napier, Jame, Scott, Jame, M Silversteen, Jason, Vasallo, Javier, Schneider, Jean-Raphael, Wendt, Jeanette, Cohen, Jeffrey, Gross, Jeffrey, Groves, Jeffrey, Kaplan, Jeffrey, Stulc, Jessica, A Cooper, Joanna, Foley, John, Scagnelli, John, C Calkwood, Jonathan, Pizarro Otero, Jose, Rafecas, Jose, Katz, Joshua, S Saad, Juliette, Standley, Katherine, Edwards, Keith, Sharlin, Kenneth, Bashir, Khurram, Wagner, Kimberly, Liow, Kore, Lee Blankenship Jr, Larry, Mate, Laszlo, Montoya, Liliana, D Lynn, Lon, Agius, Mark, Cascione, Mark, Allan Goldstein, Mark, Janicki, Mark, R Bialow, Martin, Denise Hughes, Mary, J Baker, Matthew, Apperson, Michelle, B Kuczma, Michelle, Mateo Paz Soldan, M, Cerghet, Mirela, Robb Whaley, Nathaniel, K Winner, Paul, Repovic, Pavle, Kelkar, Praful, Rekha Pillai, Romero, Ayala, Ricardo, Sater, Richard, Trudell, Randall, Fairborn Armstrong, Robert, Thomas Nahouraii, Robert, Naismith, Robert, S Murray, Ronald, Hunter, Samuel, Qureshi, Sara, Lynch, Sharon, Wray, Sibyl, R Delgado, Silvia, Donlon, Stacy, Cohan, Stanley, Smith, Stanya, James Shafer, Stuart, Azalone, Susan, Hibbs, Susan, A Miller, Tamara, Giancarlo, Thoma, Desai, Troy, K Saxena, Varun, Simnad, Virginia, David Honeycutt, William, Logan, William, E McElveen, William, Wagner, William, Stephen, L Hauser, Ludwig, Kappo, Amit, Bar-Or, Jeffrey, A Cohen, Giancarlo, Comi, Jorge, Correale, Patricia, K Coyle, Anne, Cro, Jerome de Seze, Xavier, Montalban, Krzysztof, Selmaj, Heinz, Wiendl, Stephen, C Reingold, Garry, R Cutter, Thomas, Doerner, Hans-Peter, Hartung, Per Soelberg Sørensen, Israel, Steiner, Jerry, S Wolinsky, Carlos, Ballario, Christian Calvo Vildoso, Jorge Gustavo Jose, Norma Haydee Deri, Susana, Liwacki, Jeannette, Lechner-Scott, John, Parratt, Suzanne, Hodgkinson, Eva-Maria, Maida, Fritz, Leutmezer, Barbara, Willeken, Bart Van Wijmeersch, Guy, Laurey, Karine, Geen, Ludo, Vanopdenbosch, Olivier, Deryck, Valerie, Delvaux, Vincent Van Pesch, Ivan, Milanov, Ivaylo, Tarnev, Lyubomir, Haralanov, Maria Manova Slavova, Penko, Shotekov, Francois, Emond, Francois, Grandmaison, Francois, Jacque, Liesly, Lee, Marie Sarah Gagne Brosseau, Mark, Freedman, Martin, Cloutier, Robert, Carruther, Sarah, Morrow, Yves, Lapierre, Anton, Vladic, Hana, Bokun, Igor, Antoncic, Marija Bosnjak Pasic, Mario, Habek, Silva Butkovic Soldo, Vladimira, Vuletic, Alena, Martinkova, Eva, Meluzinova, Ivana, Stetkarova, Jan, Mare, Jolana, Markova, Marta, Vachova, Martin, Vali, Michaela, Tyblova, Michal, Dufek, Ondrej, Skoda, Pavel, Hradilek, Ana Voldsgaard Jensen, Helle Hvilsted Nielsen, Kristina, Svendsen, Mads, Ravnborg, Peter Vestergaard Rasmussen, Katrin, Gross-Paju, Sulev, Haldre, Juha Pekka Eralinna, Marja-Liisa, Sumelahti, Bruno, Brochet, Celine, Louapre, Christine, Lebrun-Frenay, David Axel Laplaud, Gilles, Edan, Giovanni, Castelnovo, Marc, Debouverie, Patrick, Vermersch, Pierre, Clavelou, Pierre, Labauge, Achim, Berthele, Aiden, Haghikia, Anselm, Kornhuber, Arnfin, Bergmann, Benedikt, Frank, Birte, Elias-Hamp, Bjoern, Tackenberg, Brigitte, Wildemann, Erik, Strau, Eugen, Schlegel, Florian Then Bergh, Gereon, Nelle, Hayrettin, Tumani, Karl-Otto, Sigel, Martin, Stangel, Matthias, Boehringer, Olaf Martin Hoffmann, Patrick, Oschmann, Reinhard, Hohlfeld, Silke, Walter, Sylvia, Menck, Till, Sprenger, Tjalf, Ziemssen, Veit Ulrich Becker, Vera, Straeten, Konstantinos, Kilidirea, Konstantinos, Voumvouraki, Nikolaos, Faka, Nikolaos, Grigoriadi, Agnes, Kove, Csilla, Rozsa, Krisztina, Kovac, Laszlo, Vecsei, Satori, Maria, Zita, Biro, Anshu, Rohatgi, Dheeraj, Khurana, Jeyaraj Durai Pandian, Joy Dev Mukherji, Lekha, Pandit, Meena Angamuthu Kanikannan, Pahari, Ghosh, Rahul, Chakor, Rahul, Kulkarni, Roopkumar, Gursahani, Sangeeta, Ravat, Srinivasa, Rangasetty, Suresh, Kumar, Alla, Shifrin, Arnon, Karni, Radi, Shahien, Ron, Milo, Antonio, Uccelli, Carlo, Pozzilli, Sacca', Francesco, Giacomo, Lu, Girolama Alessandra Marfia, Laura, Brambilla, Marco, Salvetti, Massimo, Filippi, Mauro, Zaffaroni, Paolo, Gallo, Silvia, Rossi, Simona, Bonavita, Valeria, Studer, Andrejs, Miller, Guntis, Kareli, Jolanta, Kalnina, Dalia, Mickeviciene, Rasa, Kizlaitiene, Angelica Carbajal Ramirez, Juan Jose Lopez Prieto, Beatrijs, Wokke, Bob, W Van Oosten, Peter Van Domburg, Raymond, Huppert, Rogier, Q Hintzen, Astrid, Edland, Cesar, Castaneda, Julio, Perez, Martin, Gavidia, Andrzej, Wiak, Bartosz, Karaszewski, Elzbieta, Jasinska, Halina Bartosik Psujek, Iwona, Jastrzebska, Jaroslaw, Slawek, Maciej, Maciejowski, Miroslaw, Dziki, Monika Adamczyk Sowa, Robert, Bonek, Waldemar, Fryze, Ana Martins Da Silva, Angela, Timoteo, Antonio Vasco Salgado, Carlos, Capela, Carlos, Veira, Filipe, Correia, Joao, Cerqueira, Joao De Sa, Livia De Sousa, Raquel, Gouveia, Alina Sergeevna Agafina, Anna Naumovna Belova, Denis Viktorovich Sazonov, Dmitry, Pokhabov, Ekaterina Igorevna Kairbekova, Elena Gennadievna Arefieva, Farit Axatovich Khabirov, Igor Vyacheslavovich Litvinenko, Igor, Stolyarov, Irina Aleksandrovna Sokolova, Larisa Ivanovna Volkova, Maria Vafaevna Davydovskaya, Maria Nikolaevna Zaharova, Nadezhda Alekseevna Malkova, Natalia Agafonovna Totolyan, Nikolay Vasilievich Dorogov, Stella Anatolievna Sivertseva, Egon, Kurca, Georgi, Krastev, Miroslav, Brozman, Peter, Koleda, Peter, Turcani, Peter, Valkovic, Viera, Hancinova, Vladimir, Donath, Chris, Retief, Michael, Isaac, Albert Saiz Hinarejos, Alfredo Rodriguez Antigüedad, Bonaventura Casanova Estruch, Celia, Oreja-Guevara, Gemma Reig Rosello, Jose Carlos Alvarez Cermeño, Jose Martinez Rodriguez, Jose Meca Lallana, Juan Antonio Garcia Merino, Lucia Forero Diaz, Lucienne Costa Frossard Franca, Luis Querol Gutierrez, Lluis Ramio Torrenta, Pedro Serrano Castro, Rafael Arroyo Gonzalez, Sara Eichau Madueño, Sergio Martinez Yelamos, Tamara Castillo Trivino, Virgina Meca Lallana, Xaviere Montalban Gairin, Fredrik, Piehl, Jan, Lycke, Chiara, Zecca, Tobias, Derfu, Thy-Sheng, Lin, Somsak, Tiamkao, Ayse Nur Yuceyar, Aysun, Soysal, Belgin Petek Balci, Cavit, Boz, Husnu, Efendi, Murat, Terzi, Serhan, Sevim, Serkan, Ozakba, Andrew, Gale, Ben, Turner, David, Barne, David, Paling, Eli, Silber, James, Overell, Matthew, Craner, Aaron, Carlson, Adam, Wolff, Adaeze, Onuoha, Adnan, Subei, Ahmad, Ata, Aimee, Borazanci, Akram, Dastagir, Alberto, Vasquez, Alison Brooke Allen, Andrew, P Keegan, Angel, Carrasco, Angel, R Chinea Martinez, Ann, Ba, Annette, Okai, April, Erwin, Ariel, Antezana-Antezana, Barbara, Green, Bharathy, E Sundaram, Bhupendra, Khatri, Bhupesh, Dihenia, Bogdan, Gheorghiu, Brian, Costell, Brian, Steingo, Bruce, L Hughe, Carrie, M Hersh, Christopher, Laganke, Christopher, Luzzio, Corey, Ford, Craig Edward Herrman, Craig, Senzon, Cynthia, Huffman, Daniel, R Wynn, David D, O Bear, David, Lesch, David, H Mattson, David, Weisman, Deborah, A Burke, Dennis, W Dietrich, Deren, Huang, Derrick, Robertson, Djamchid, Lotfi, Don Joseph Alfonso, Dusan, Stefoski, Edward, J Fox, Emily, Pharr, Enrique, Alvarez, Evanthia, Bernitsa, Faria, Amjad, Gabriel, Pardo, Geoffrey, Eubank, Gerald, Mcintosh, Giles, F Crowell, Hemanth, Rao, J Michael Hemphill, Jack, H Florin, Jacqueline, Nichola, James, Napier, James, Scott, Jason, M Silversteen, Javier, Vasallo, Jean-Raphael, Schneider, Jeanette, Wendt, Jeffrey, Cohen, Jeffrey, Gro, Jeffrey, Grove, Jeffrey, Kaplan, Jessica, Stulc, Joanna, A Cooper, John, Foley, John, Scagnelli, Jonathan, C Calkwood, Jose Pizarro Otero, Jose, Rafeca, Joshua, Katz, Juliette, S Saad, Katherine, Standley, Keith, Edward, Kenneth, Sharlin, Khurram, Bashir, Kimberly, Wagner, Kore, Liow, Larry Lee Blankenship Jr, Laszlo, Mate, Liliana, Montoya, Lon, D Lynn, Mark, Agiu, Mark, Cascione, Mark Allan Goldstein, Mark, Janicki, Martin, R Bialow, Mary Denise Hughes, Matthew, J Baker, Michelle, Apperson, Michelle, B Kuczma, M Mateo Paz Soldan, Mirela, Cerghet, Nathaniel Robb Whaley, Paul, K Winner, Pavle, Repovic, Praful, Kelkar, Romero Rekha Pillai, Ricardo, Ayala, Richard, Sater, Randall, Trudell, Robert Fairborn Armstrong, Robert Thomas Nahouraii, Robert, Naismith, Ronald, S Murray, Samuel, Hunter, Sara, Qureshi, Sharon, Lynch, Sibyl, Wray, Silvia, R Delgado, Stacy, Donlon, Stanley, Cohan, Stanya, Smith, Stuart James Shafer, Susan, Azalone, Susan, Hibb, Tamara, A Miller, Thomas, Giancarlo, Troy, Desai, Varun, K Saxena, Virginia, Simnad, William David Honeycutt, William, Logan, William, E McElveen, William, Wagner, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Herrada, Anthony, and UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire

Subjects
Male, MESH: Multiple Sclerosis, Relapsing-Remitting, T-Lymphocytes, Hydroxybutyrates, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Pharmacology, Relapsing-Remitting, MESH: Magnetic Resonance Imaging, chemistry.chemical_compound, 0302 clinical medicine, Teriflunomide, Monoclonal, MESH: Double-Blind Method, 030212 general & internal medicine, Humanized, MESH: Toluidines, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Subcutaneous, B-Lymphocyte, Brain, General Medicine, Magnetic Resonance Imaging, MESH: Crotonates, Crotonates, Pyrimidine metabolism, Disease Progression, Female, MESH: Disease Progression, Antibody, Human, Adult, Multiple Sclerosis, Toluidines, medicine.drug_class, Injections, Subcutaneous, Injections, Subcutaneou, Monoclonal antibody, Ofatumumab, Settore MED/26, Antibodies, Monoclonal, Humanized, Crotonate, Antibodies, Injections, 03 medical and health sciences, MESH: Brain, Multiple Sclerosis, Relapsing-Remitting, Double-Blind Method, MESH: B-Lymphocytes, Nitriles, medicine, Humans, MESH: Kaplan-Meier Estimate, MESH: Humans, business.industry, Multiple sclerosis, MESH: Injections, Subcutaneous, MESH: Adult, medicine.disease, MESH: Male, MESH: T-Lymphocytes, T-Lymphocyte, Multicenter study, chemistry, MESH: Antibodies, Monoclonal, Humanized, biology.protein, Human medicine, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P

Published
2020

42. Evaluation of the Central Vein Sign as a Diagnostic Imaging Biomarker in Multiple Sclerosis

Author

Sinnecker T., Clarke M. A., Meier D., Enzinger C., Calabrese M., De Stefano N., Pitiot A., Giorgio A., Schoonheim M. M., Paul F., Pawlak M. A., Schmidt R., Kappos L., Montalban X., Rovira A., Evangelou N., Wuerfel J., MAGNIMS Study Group, Filippi M, Rocca M. A., Anatomy and neurosciences, Amsterdam Neuroscience - Neuroinfection & -inflammation, Sinnecker, T., Clarke, M. A., Meier, D., Enzinger, C., Calabrese, M., De Stefano, N., Pitiot, A., Giorgio, A., Schoonheim, M. M., Paul, F., Pawlak, M. A., Schmidt, R., Kappos, L., Montalban, X., Rovira, A., Evangelou, N., Wuerfel, J., MAGNIMS Study, Group, Filippi, M, and Rocca, M. A.

Subjects
Central Nervous System, Male, Imaging biomarker, diagnosis, Cluster Headache, Relapsing-Remitting, multiple sclerosis, 0302 clinical medicine, 80 and over, 030212 general & internal medicine, Aged, 80 and over, Clinically isolated syndrome, medicine.diagnostic_test, Lupus Vasculitis, Central Nervous System, Neuromyelitis Optica, Brain, Middle Aged, Magnetic Resonance Imaging, medicine.anatomical_structure, Biomarker (medicine), biomarker, Female, Radiology, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Migraine Disorders, Lupus Vasculitis, Sensitivity and Specificity, Lesion, Young Adult, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, central vein sign, clinical 3T magnetic resonance imaging, medicine, Humans, Vein, Aged, Expanded Disability Status Scale, business.industry, Multiple sclerosis, Correction, Magnetic resonance imaging, Case-Control Studies, Cerebral Veins, Cross-Sectional Studies, Demyelinating Diseases, Multiple Sclerosis, medicine.disease, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Importance: The central vein sign has been proposed as a specific imaging biomarker for distinguishing between multiple sclerosis (MS) and not MS, mainly based on findings from ultrahigh-field magnetic resonance imaging (MRI) studies. The diagnostic value of the central vein sign in a multicenter setting with a variety of clinical 3 tesla (T) MRI protocols, however, remains unknown.Objective: To evaluate the sensitivity and specificity of various central vein sign lesion criteria for differentiating MS from non-MS conditions using 3T brain MRI with various commonly used pulse sequences.Design, Setting, and Participants: This large multicenter, cross-sectional study enrolled participants (n = 648) of ongoing observational studies and patients included in neuroimaging research databases of 8 neuroimaging centers in Europe. Patient enrollment and MRI data collection were performed between January 1, 2010, and November 30, 2016. Data analysis was conducted between January 1, 2016, and April 30, 2018. Investigators were blinded to participant diagnosis by a novel blinding procedure.Main Outcomes and Measures: Occurrence of central vein sign was detected on 3T T2*-weighted or susceptibility-weighted imaging. Sensitivity and specificity were assessed for these MRI sequences and for different central vein sign lesion criteria, which were defined by the proportion of lesions with central vein sign or by absolute numbers of lesions with central vein sign.Results: A total of 606 participants were included in the study after exclusion of 42 participants. Among the 606 participants, 413 (68.2%) were women. Patients with clinically isolated syndrome and relapsing-remitting MS (RRMS) included 235 women (66.6%) and had a median (range) age of 37 (14.7-61.4) years, a median (range) disease duration of 2 (0-33) years, and a median (range) Expanded Disability Status Scale score of 1.5 (0-6.5). Patients without MS included 178 women (70.4%) and had a median (range) age of 54 (18-83) years. A total of 4447 lesions were analyzed in a total of 487 patients: 690 lesions in 98 participants with clinically isolated syndrome, 2815 lesions in 225 participants with RRMS, 54 lesions in 13 participants with neuromyelitis optica spectrum disorder, 54 lesions in 14 participants with systemic lupus erythematosus, 121 lesions in 29 participants with migraine or cluster headache, 240 lesions in 20 participants with diabetes, and 473 lesions in 88 participants with other types of small-vessel disease. The sensitivity was 68.1% and specificity was 82.9% for distinguishing MS from not MS using a 35% central vein sign proportion threshold. The 3 central vein sign lesion criteria had a sensitivity of 61.9% and specificity of 89.0%. Sensitivity was higher when an optimized T2*-weighted sequence was used.Conclusions and Relevance: In this study, use of the central vein sign at 3T MRI yielded a high specificity and a moderate sensitivity in differentiating MS from not MS; international, multicenter studies may be needed to ascertain whether the central vein sign-based criteria can accurately detect MS.

Published
2019

43. Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis

Author

Maggi P, Kuhle J, Schädelin S, van der Meer F, Weigel M, Galbusera R, Mathias A, Lu PJ, Rahmanzadeh R, Benkert P, La Rosa F, Bach Cuadra M., Bach Cuadra M, Sati P, Théaudin M, Pot C, van Pesch V, Leppert D, Stadelmann C, Kappos L, Du Pasquier R, Reich DS, Absinta M, and Granziera C

Abstract

Objective:To assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage. Methods:In 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases. Results:In univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68;p< 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4;p= 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (βadd, 16.3; 95% confidence interval [CI], 4.6-28.0;p< 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; βadd, 30.4; 95% CI, 15.6-45.2;p< 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (βadd, 1.1; 95% CI, 0.3-1.9;p< 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center:p= 0.004 andp= 0.0002, respectively). Conclusion:Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.

Published
2021

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

Author

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

Published
2021
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47. Short-term adaptation to a simple motor task: A physiological process preserved in multiple sclerosis

Author

Mancini, L., Ciccarelli, O., Manfredonia, F., Thornton, J.S., Agosta, F., Barkhof, F., Beckmann, C., De Stefano, N., Enzinger, C., Fazekas, F., Filippi, M., Gass, A., Hirsch, J.G., Johansen-Berg, H., Kappos, L., Korteweg, T., Manson, S.C., Marino, S., Matthews, P.M., Montalban, X., Palace, J., Polman, C., Rocca, M., Ropele, S., Rovira, A., Wegner, C., Friston, K., Thompson, A., and Yousry, T.

Published
2009
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48. Mind the gap: from neurons to networks to outcomes in multiple sclerosis

Author

Chard, D. T., Alahmadi, A. A. S., Audoin, B., Charalambous, T., Enzinger, C., Hulst, H. E., Rocca, M. A., Rovira, A., Sastre-Garriga, J., Schoonheim, M. M., Tijms, B., Tur, C., Gandini Wheeler-Kingshott, C. A. M., Wink, A. M., Ciccarelli, O., Barkhof, F., De Stefano, N., Filippi, M., Frederiksen, J. L., Gasperini, C., Kappos, L., Palace, J., Yousry, T., Vrenken, H., University College of London [London] (UCL), Department of Diagnostic Radiology, Faculty of Applied Medical Science, King Abdulaziz University (KAU), Jeddah, 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), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Hôpital de la Timone [CHU - APHM] (TIMONE)-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)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), AP-HM, CHU Timone, Pole de Neurosciences Cliniques, Department of Neurology, Marseille, France., Department of Neurology, Research Unit for Neuronal Repair and Plasticity, Medical University of Graz, Graz, Department of Radiology, Division of Neuroradiology, Vascular and Interventional Radiology, Medical University of Graz, Graz, Department of Anatomy and Neurosciences, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Neuroimaging Research Unit and Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Universitat Autònoma de Barcelona (UAB), Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Department of Neurology, Luton and Dunstable University Hospital, Luton, Università degli Studi di Pavia = University of Pavia (UNIPV), Brain MRI 3T Research Center, IRCCS Mondino Foundation, Pavia, Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, London, Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Section of Neuroradiology, Department of Radiology Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Servei de Neurologia/Neuroimmunologia, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Institutes of Neurology and Healthcare Engineering, University College London, London, Chard, Declan T, Alahmadi, Adnan A S, Audoin, Bertrand, Charalambous, Thali, Enzinger, Christian, Hulst, Hanneke E, Rocca, Maria A, Rovira, Àlex, Sastre-Garriga, Jaume, Schoonheim, Menno M, Tijms, Betty, Tur, Carmen, Gandini Wheeler-Kingshott, Claudia A M, Wink, Alle Meije, Ciccarelli, Olga, Barkhof, Frederik, MAGNIMS Study, Group, and Filippi, Massimo

Subjects
Multiple Sclerosis, Grey matter, Network topology, 030218 nuclear medicine & medical imaging, White matter, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, medicine, Humans, Default mode network, ComputingMilieux_MISCELLANEOUS, Inflammation, Neurons, Artificial neural network, business.industry, Multiple sclerosis, [SCCO.NEUR]Cognitive science/Neuroscience, Brain, medicine.disease, medicine.anatomical_structure, Neurology (clinical), Disconnection, Alzheimer's disease, Nerve Net, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

MRI studies have provided valuable insights into the structure and function of neural networks, particularly in health and in classical neurodegenerative conditions such as Alzheimer disease. However, such work is also highly relevant in other diseases of the CNS, including multiple sclerosis (MS). In this Review, we consider the effects of MS pathology on brain networks, as assessed using MRI, and how these changes to brain networks translate into clinical impairments. We also discuss how this knowledge can inform the targeting of MS treatments and the potential future directions for research in this area. Studying MS is challenging as its pathology involves neurodegenerative and focal inflammatory elements, both of which could disrupt neural networks. The disruption of white matter tracts in MS is reflected in changes in network efficiency, an increasingly random grey matter network topology, relative cortical disconnection, and both increases and decreases in connectivity centred around hubs such as the thalamus and the default mode network. The results of initial longitudinal studies suggest that these changes evolve rather than simply increase over time and are linked with clinical features. Studies have also identified a potential role for treatments that functionally modify neural networks as opposed to altering their structure.

Published
2021

49. Cortical lesion detection using FLAWS in multiple sclerosis

Author

Muller, J., Rahmanzadeh, R., Tsagkas, C., Barakovic, M., Lu, P. -J., Yaldizli, O., Weigel, M., Beaumont, J., La Rosa, F., Cuadra, M. Bach, Kappos, L., Kuhle, J., Gambarota, G., Granziera, C., Jonchère, Laurent, University Hospital Basel [Basel], Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Laboratoire Traitement du Signal et de l'Image (LTSI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne (UNIL), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lausanne = University of Lausanne (UNIL)

Subjects
[SDV.IB] Life Sciences [q-bio]/Bioengineering, [SDV.IB]Life Sciences [q-bio]/Bioengineering, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; Meeting Abstract

Published
2021

50. Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

Author

Van Pesch V., Eichau S., Zakaria M., Onofrj M., Lugaresi A., Alroughani R., Prat A., Girard M., Duquette P., Terzi M., Boz C., Grand'Maison F., Hamdy S., Sola P., Ferraro D., Grammond P., Turkoglu R., Butzkueven H., Yamout B., Altintas A., Maimone D., Lechner-Scott J., Bergamaschi R., Karabudak R., Giuliano F., Mcguigan C., Cartechini E., Barnett M., Hughes S., Sa M., Kappos L., Ramo-Tello C., Cristiano E., Hodgkinson S., Spitaleri D., Soysal A., Petersen T., Slee M., Butler E., Granella F., Verheul F., Mccombe P., Ampapa R., Skibina O., Prevost J., Sinnige L.G.F., Sanchez-Menoyo J.L., Vucic S., Laureys G., Van Hijfte L., Khurana D., Macdonell R., Castillo-Trivino T., Gray O., Aguera E., Kister I., Shaw C., Deri N., Al-Harbi T., Fragoso Y., Csepany T., Sempere A., Kalincik T., Diouf I., Malpas C., Horakova D., Kubala Havrdova E., Patti F., Shaygannejad V., Ozakbas S., Izquierdo G., Van Pesch V., Eichau S., Zakaria M., Onofrj M., Lugaresi A., Alroughani R., Prat A., Girard M., Duquette P., Terzi M., Boz C., Grand'Maison F., Hamdy S., Sola P., Ferraro D., Grammond P., Turkoglu R., Butzkueven H., Yamout B., Altintas A., Maimone D., Lechner-Scott J., Bergamaschi R., Karabudak R., Giuliano F., Mcguigan C., Cartechini E., Barnett M., Hughes S., Sa M., Kappos L., Ramo-Tello C., Cristiano E., Hodgkinson S., Spitaleri D., Soysal A., Petersen T., Slee M., Butler E., Granella F., Verheul F., Mccombe P., Ampapa R., Skibina O., Prevost J., Sinnige L.G.F., Sanchez-Menoyo J.L., Vucic S., Laureys G., Van Hijfte L., Khurana D., Macdonell R., Castillo-Trivino T., Gray O., Aguera E., Kister I., Shaw C., Deri N., Al-Harbi T., Fragoso Y., Csepany T., Sempere A., Kalincik T., Diouf I., Malpas C., Horakova D., Kubala Havrdova E., Patti F., Shaygannejad V., Ozakbas S., and Izquierdo G.

Abstract

Background: Our current understanding of demographic and clinical modifiers of the effectiveness of multiple sclerosis (MS) therapies is limited. Objective(s): To assess whether patients' response to disease modifying therapies (DMT) in MS varies by disease activity (annualised relapse rate, presence of new MRI lesions), disability, age, MS duration or disease phenotype. Method(s): Using the international MSBase registry, we selected patients with MS followed for >=1 year, with >=3 visits, >=1 visit per year. Marginal structural models (MSMs) were used to compare the hazard ratios (HR) of 6-month confirmed worsening and improvement of disability (EDSS), and the incidence of relapses between treated and untreated periods. MSMs were continuously re-adjusted for patient age, sex, pregnancy, date, time from first symptom, prior relapse history, disability and MRI activity. Result(s): Among 23 687 patients with relapsing MS, those on DMT experienced 20% greater chance of disability improvement [HR 1.20 (95% CI 1.0-1.5)], 47% lower risk of disability worsening [HR 0.53 (0.39-0.71)] and 51% reduction in relapses [HR 0.49 (0.43-0.55)]. The effect of DMT on relapses and EDSS worsening was attenuated with longer MS duration and higher prior relapse rate. The effect of DMT on EDSS improvement and relapses was more evident in low EDSS categories. DMT was associated with 51% EDSS improvement in patients without new MRI lesions [HR 1.51 (1.00-2.28)] compared to 4% in those with MRI activity [HR 1.04 (0.88-1.24)]. Among 26329 participants with relapsing or progressive MS, DMT was associated with 25% reduction in EDSS worsening and 42% reduction in relapses in patients with relapsing MS [HR 0.75 (0.65-0.86) and HR 0.58 (CI 0.54-62), respectively], while evidence for such beneficial effects of treatment in patients with progressive MS was not found [HR 1.11 (0.91-1.46) and HR 1.16 (0.91-1.46), respectively]. Conclusion(s): DMTs are associated with reduction in relapse frequency, pro

Published
2021

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