Multicenter Study

. 2025 Apr 11:16:1575613.

doi: 10.3389/fimmu.2025.1575613. eCollection 2025.

Worse recovery from acute attacks and faster disability accumulation highlights the unmet need for improved treatment in patients with late-onset neuromyelitis optica spectrum disorders (COPTER-LO study)

Julian Reza Kretschmer^#¹, Daria Tkachenko^#¹, Tania Kümpfel², Joachim Havla², Daniel Engels², Friedemann Paul^{3

4}, Patrick Schindler^{3

4}, Judith Bellmann-Strobl^{3

4}, Achim Berthele⁵, Katrin Giglhuber⁵, Clarissa Zappe⁵, Luisa Klotz⁶, Lisa Revie⁶, Eva Dawin⁶, Makbule Senel⁷, Hayrettin Tumani⁷, Florian Then Bergh⁸, Clemens Warnke⁹, Markus Kraemer^{10

11}, Annette Walter¹², Antonios Bayas¹³, Uwe K Zettl¹⁴, Ann-Sophie Lauenstein¹⁵, Yavor Yalachkov¹⁶, Thorleif Etgen¹⁷, Matthias Kaste¹⁸, Felix Luessi¹⁹, Stefan Gingele¹, Sarah Passoke¹, Martin S Weber²⁰, Jörn Peter Sieb²¹, Axel Haarmann²², Patrick Oschmann²³, Veit Rothhammer²⁴, Christian Geis²⁵, Markus C Kowarik²⁶, Peter Kern²⁷, Matthias Grothe²⁸, Heike Stephanik²⁹, Klemens Angstwurm³⁰, Frank Hoffmann³¹, Ulrike Wallwitz³¹, Brigitte Wildemann³², Sven Jarius³², Jan-Patrick Stellmann^{33

34

35}, Thivya Pakeerathan³⁶, Carolin Schwake³⁶, Ilya Ayzenberg³⁶, Ingo Kleiter^{36

37}, Katinka Fischer¹¹, Orhan Aktas¹², Marius Ringelstein^{12

38}, Vivien Häußler³³, Corinna Trebst¹, Martin W Hümmert¹

Affiliations

¹ Department of Neurology, Hannover Medical School, Hannover, Germany.
² Institute of Clinical Neuroimmunology, LMU University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
³ Department of Neurology, Charite Universitätsmedizin Berlin, Berlin, Germany.
⁴ Charité Universitätsmedizin Berlin, Experimental and Clinical Research Center and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
⁵ Department of Neurology, Technical University Munich, Munich, Germany.
⁶ Department of Neurology, University of Münster, Münster, Germany.
⁷ Department of Neurology, University of Ulm, Ulm, Germany.
⁸ Department of Neurology, University of Leipzig, Leipzig, Germany.
⁹ Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁰ Department of Neurology, Alfried Krupp Hospital Essen, Essen, Germany.
¹¹ Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
¹² Department of Neurology, Herford Hospital, Herford, Germany.
¹³ Department of Neurology, Medical Faculty, University of Augsburg, Augsburg, Germany.
¹⁴ Department of Neurology, University of Rostock, Rostock, Germany.
¹⁵ Department of Neurology, DKD Helios Hospital Wiesbaden, Wiesbaden, Germany.
¹⁶ Department of Neurology, Goethe-University Frankfurt, University Medicine, Frankfurt am Main, Germany.
¹⁷ Department of Neurology, Klinikum Traunstein, Traunstein, Germany.
¹⁸ Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Sanderbusch, Germany.
¹⁹ Department of Neurology, University of Mainz, Mainz, Germany.
²⁰ Department of Neurology, University of Göttingen, Göttingen, Germany.
²¹ Department of Neurology, Helios Hanseklinikum Stralsund, Stralsund, Germany.
²² Department of Neurology, University of Würzburg, Würzburg, Germany.
²³ Department of Neurology, Klinikum Bayreuth, Bayreuth, Germany.
²⁴ Department of Neurology, FAU Erlangen-Nuremberg, Erlangen, Germany.
²⁵ Department of Neurology, University of Jena, Jena, Germany.
²⁶ Department of Neurology & Stroke and Hertie-Institute for Clinical Brain Research, Eberhard-Karls University of Tübingen, Tübingen, Germany.
²⁷ Department of Neurology, Asklepios Expert Clinic Teupitz, Teupitz, Germany.
²⁸ Department of Neurology, University of Greifswald, Greifswald, Germany.
²⁹ Department of Neurology, University of Magdeburg, Magdeburg, Germany.
³⁰ Department of Neurology, University of Regensburg, Regensburg, Germany.
³¹ Department of Neurology, Hospital Martha-Maria, Halle, Germany.
³² Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany.
³³ Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Germany.
³⁴ CEMEREM, APHM, Hôspital de la Timone, Marseille, France.
³⁵ CRMBM, Aix Marseille Univ, CNRS, Marseille, France.
³⁶ Department of Neurology, St.Josef Hospital, Ruhr University Bochum, Bochum, Germany.
³⁷ Marianne-Strauss-Klinik, Behandlungszentrum für Multiple Sklerose Kranke, Berg, Germany.
³⁸ Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

^# Contributed equally.

PMID: 40292288
PMCID: PMC12021610
DOI: 10.3389/fimmu.2025.1575613

Multicenter Study

Worse recovery from acute attacks and faster disability accumulation highlights the unmet need for improved treatment in patients with late-onset neuromyelitis optica spectrum disorders (COPTER-LO study)

Julian Reza Kretschmer et al. Front Immunol. 2025.

. 2025 Apr 11:16:1575613.

doi: 10.3389/fimmu.2025.1575613. eCollection 2025.

Authors

Affiliations

¹ Department of Neurology, Hannover Medical School, Hannover, Germany.
² Institute of Clinical Neuroimmunology, LMU University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
³ Department of Neurology, Charite Universitätsmedizin Berlin, Berlin, Germany.
⁴ Charité Universitätsmedizin Berlin, Experimental and Clinical Research Center and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
⁵ Department of Neurology, Technical University Munich, Munich, Germany.
⁶ Department of Neurology, University of Münster, Münster, Germany.
⁷ Department of Neurology, University of Ulm, Ulm, Germany.
⁸ Department of Neurology, University of Leipzig, Leipzig, Germany.
⁹ Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁰ Department of Neurology, Alfried Krupp Hospital Essen, Essen, Germany.
¹¹ Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
¹² Department of Neurology, Herford Hospital, Herford, Germany.
¹³ Department of Neurology, Medical Faculty, University of Augsburg, Augsburg, Germany.
¹⁴ Department of Neurology, University of Rostock, Rostock, Germany.
¹⁵ Department of Neurology, DKD Helios Hospital Wiesbaden, Wiesbaden, Germany.
¹⁶ Department of Neurology, Goethe-University Frankfurt, University Medicine, Frankfurt am Main, Germany.
¹⁷ Department of Neurology, Klinikum Traunstein, Traunstein, Germany.
¹⁸ Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Sanderbusch, Germany.
¹⁹ Department of Neurology, University of Mainz, Mainz, Germany.
²⁰ Department of Neurology, University of Göttingen, Göttingen, Germany.
²¹ Department of Neurology, Helios Hanseklinikum Stralsund, Stralsund, Germany.
²² Department of Neurology, University of Würzburg, Würzburg, Germany.
²³ Department of Neurology, Klinikum Bayreuth, Bayreuth, Germany.
²⁴ Department of Neurology, FAU Erlangen-Nuremberg, Erlangen, Germany.
²⁵ Department of Neurology, University of Jena, Jena, Germany.
²⁶ Department of Neurology & Stroke and Hertie-Institute for Clinical Brain Research, Eberhard-Karls University of Tübingen, Tübingen, Germany.
²⁷ Department of Neurology, Asklepios Expert Clinic Teupitz, Teupitz, Germany.
²⁸ Department of Neurology, University of Greifswald, Greifswald, Germany.
²⁹ Department of Neurology, University of Magdeburg, Magdeburg, Germany.
³⁰ Department of Neurology, University of Regensburg, Regensburg, Germany.
³¹ Department of Neurology, Hospital Martha-Maria, Halle, Germany.
³² Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany.
³³ Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Germany.
³⁴ CEMEREM, APHM, Hôspital de la Timone, Marseille, France.
³⁵ CRMBM, Aix Marseille Univ, CNRS, Marseille, France.
³⁶ Department of Neurology, St.Josef Hospital, Ruhr University Bochum, Bochum, Germany.
³⁷ Marianne-Strauss-Klinik, Behandlungszentrum für Multiple Sklerose Kranke, Berg, Germany.
³⁸ Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

^# Contributed equally.

PMID: 40292288
PMCID: PMC12021610
DOI: 10.3389/fimmu.2025.1575613

Abstract

Objective: This study analyzed clinical characteristics, attack recovery and long-term disability accumulation in late-onset (LO ≥ 50 years at onset) versus early-onset (EO < 50 years) NMOSD.

Methods: This multicenter cohort study included demographic and clinical data from 446 NMOSD patients collected from 35 German Neuromyelitis Optica Study Group (NEMOS) centers. Time to disability milestones was estimated through Kaplan-Meier analysis and Cox proportional hazard regression models adjusted for sex, year of onset, immunotherapy exposure and antibody status. Generalized estimating equations (GEE) were used to compare attack outcomes.

Results: Of the 446 NMOSD patients analyzed (83.4% female, 85.4% AQP4-IgG-positive, median age at disease onset = 43 years), 153 had a late-onset (34.3%). AQP4-IgG+ prevalence was higher in LO- than in EO-NMOSD (94.1% vs. 80.9%, p<0.001). Optic neuritis at onset was more frequent in EO-NMOSD (27.4% vs. 42.6%, p<0.002), whereas myelitis was more common in LO-NMOSD (58.4% vs. 37.9%, p<0.001). Both groups had similar annualized attack rates (AAR, 0.51 vs. 0.54, p=0.352), but attack recovery was poorer (complete remission in 15.6% vs. 27.4%, p<0.001) and relapse-associated worsening (RAW) was higher in LO-NMOSD (RAW: 3 vs. 0.5, p<0.001). Long-term immunotherapy use was comparable. LO-NMOSD exhibited faster progression to disability endpoints (EDSS 4: HR = 2.64, 95% CI=1.81-3.84).

Interpretation: LO-NMOSD patients presented more often with myelitis, experienced worse attack outcomes and faster disability accumulation, despite comparable AAR, acute attack treatment and long-term treatment regimens. Accordingly, therapeutic strategies for attack and prophylactic treatment in LO-NMOSD have to be improved.

Keywords: NMOSD = neuromyelitis optica spectrum disorder; aging; immunoscenecence; late onset; myelitis.

Copyright © 2025 Kretschmer, Tkachenko, Kümpfel, Havla, Engels, Paul, Schindler, Bellmann-Strobl, Berthele, Giglhuber, Zappe, Klotz, Revie, Dawin, Senel, Tumani, Bergh, Warnke, Kraemer, Walter, Bayas, Zettl, Lauenstein, Yalachkov, Etgen, Kaste, Luessi, Gingele, Passoke, Weber, Sieb, Haarmann, Oschmann, Rothhammer, Geis, Kowarik, Kern, Grothe, Stephanik, Angstwurm, Hoffmann, Wallwitz, Wildemann, Jarius, Stellmann, Pakeerathan, Schwake, Ayzenberg, Kleiter, Fischer, Aktas, Ringelstein, Häußler, Trebst and Hümmert.

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Conflict of interest statement

JK: received institutional research support from NEMOS e. V.; DT: has no conflict of interest to declare; TK: received speaker honoraria and/or personal fees for advisory boards from Novartis Pharma, Roche Pharma, Alexion/Astra Zeneca, Horizon Therapeutics/Amgen, Merck, Chugai Pharma, and Biogen, the institution she works for received compensation for serving as a member of a steering committee from Roche, is a site principal investigator in several randomized clinical trials (Novartis Pharma, Roche Pharma, BMS, and Sanofi Genzyme) and in a randomized clinical trial supported by the BMBf (funding code: 01GM1908E), the institution received compensation for clinical trials, all outside the present work. JH: reports a grant for OCT research from the Friedrich-Baur-Stiftung Horizon, Roche, and Merck, personal fees and nonfinancial support from Merck, Alexion, Novartis, Roche, Celgene, Biogen, Bayer, and Horizon, nonfinancial support from the Sumaira-Foundation and Guthy-Jackson Charitable Foundation, all outside the submitted work; DE: received speaker honoraria from Alexion and Horizon/Amgen. FP: receives honoraria for lecturing and travel expenses from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe, Celgene, and support for attending meetings from Alexion, research funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche, Parexel, and Almirall, serves on advisory boards and steering committees for Celgene, Roche, UCB, and Merck, associate editor of Neurology, Neuroimmunology & Neuroinflammation, academic editor for PLoS ONE. PS: received travel reimbursement from UCB. JB-S: received research support from NEMOS e.V. and Bayer AG, personal compensation from Alexion, speaking honoraria and travel grants from Bayer Healthcare, Horizon, Novartis, and Sanofi-Aventis/Genzyme, compensation for serving on a scientific advisory board of Roche and Merck, all unrelated to the presented work. AcB: receives funding from the Innovationsausschuss of the German Federal Joint Committee (G-BA; project NUTSEN, grant 01VSF23040), and from the German Federal Ministry of Education and Research (BMBF; project MIDIA-Hub, grant 01ZZ2102B), consulting and/or speaker fees from Alexion, Argenx, Biogen, Horizon/Amgen, Merck, Novartis, Roche, and Sandoz/Hexal, the institution received compensation for clinical trials from Alexion, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. KG: reports no disclosures relevant to the manuscript. CZ: reports no disclosures relevant to the manuscript. LK: received compensation for serving on Scientific Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Genzyme, Horizon, Janssen, Merck Serono, Novartis, Roche, and Viatris, speaker honoraria and travel support from Argenx, Bayer, Biogen, Bristol-Myers Squibb, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera, and Teva, receives research support from the German Research Foundation, the IZKF Münster, IMF Münster, Biogen, Immunic AG, Novartis, and Merck Serono. LR: reports no disclosures relevant to the manuscript. ED: reports no disclosures relevant to the manuscript. MS: received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Horizon, Roche, and Sanofi Genzyme. HT: received consulting and/or speaker honoraria and/or travel support from Alexion, Bayer, Biogen, Bristol‐Myers Squibb/Celgene, Diamed, Fresenius, Fujirebio, GlaxoSmithKline, Horizon, Janssen‐Cilag, Merck, Novartis, Roche, Sanofi‐Genzyme, Siemens, Teva, and Viatris; FT: reports no disclosures relevant to the manuscript. CW: received institutional support from Novartis, Biogen, Alexion, Janssen, Merck, and Roche. MK: received honoraria for teaching activities from Chugai Pharma and Roche Pharma; AW: reports no disclosures relevant to the manuscript. AnB: received personal compensation from Merck, Biogen, Novartis, TEVA, Roche, Sanofi/Genzyme, Celgene/Bristol Myers Squibb, Janssen, Sandoz/HEXAL, Alexion, Horizon, Argenx, grants for congress travel and participation from Biogen, TEVA, Novartis, Sanofi/Genzyme, Merck Serono, Celgene, Janssen, and Roche, none related to this study, UZ: received speaking fees, travel support, and/or financial support for research activities from Alexion, Almirall, Bayer, Biogen, Bristol Myers Squibb, Janssen, Merck Serono, Novartis, Octapharm, Roche, Sanofi Genzyme, Teva, as well as EU, BMBF, BMWi, and DFG, none resulted in a conflict of interest. AL: has received speaker honoraria from Novartis and Roche, as well as compensation for serving on an advisory board of Teva. YY: has been supported by travel grants from Novartis and Sanofi Genzyme, received an honorarium for active participation in an advisory board by Sanofi Genzyme, and speaking honoraria by Roche and Sanofi Genzyme, none related to this study; FL: received consultancy fees from Roche and support with travel cost from Teva Pharma. SG: reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft, and Hannover Biomedical Research School (HBRS), consulting and/or speaker honoraria from Alexion, Alnylam Pharmaceuticals, AstraZeneca, GSK, Pfizer, and Merck, all outside the submitted work. MS: received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer, and Genzyme. AH: received travel funding, consulting, and/or speaker honoraria from Alexion, Argenx, and Horizon, none related to this manuscript. PO: has received research support as well as lecture fees and travel expenses from Alexion, Bayer Health Care, Biogen, Janssen, Merck Serono, Novartis, Pfizer, Roche, Sanofi Genzyme, TEVA, Lilly, and Anavex; VR: was funded by an ERC Starting Grant provided by the European Research Council, a Heisenberg fellowship, as well as research grants provided by the German Research Foundation and BMBF (Bundesministerium für Bildung und Forschung), has served on advisory boards and received speaker fees from Alexion, Bayer, Biogen, Bristol Myers Squibb, Hexal, Merck, Novartis, Roche, and Sanofi. CG: received speaker honoraria from Argenx, Roche, Alexion, and served as a consultant and participated in advisory boards of Argenx, Roche, Alexion, and Sobi. MK: has served on advisory boards and received speaker fees/travel grants from Merck, Sanofi-Genzyme, Novartis, Biogen, Janssen, Alexion, Celgene/Bristol-Myers Squibb, and Roche, has received research grants from Merck, Roche, Novartis, Janssen, Sanofi-Genzyme, and Celgene/Bristol-Myers Squibb; KA: received speaker honoraria from Biogen Idec, travel grants (until 2014) from Alexion, Bayer Schering, Biogen Idec, Merck Serono, Novartis, and Teva, nonpersonal study compensation from Alexion, Bayer Schering, Biogen, Merck Serono, Novartis, and Roche, none related to this study. FH: reports consulting and/or speaking fees (Alexion, Bayer, Biogen, CSL Behring, DIAMED Medizintechnik, Grifols, Ipsen, Janssen, Merck, Novartis, Roche, Sanofi, and Teva) and grant/research support (Bayer, Biogen, Merck, Novartis). BW: received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, the Dietmar Hopp Foundation, and the Klaus Tschira Foundation, received grants and personal fees from Merck Serono, Sanofi Genzyme, and Novartis Pharmaceuticals, received personal fees from Alexion, Bayer, Biogen, INSTAND, and Roche. IA: received consulting and/or speaker fees and travel support from Roche, Alexion, Sanofi Genzyme, BMS, Horizon, and Merck, received research support from Chugai, Diamed, and Roche, none related to this manuscript. IK: has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Almirall, Bayer, Biogen, GlaxoSmithKline, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai, and Sanofi, received speaking honoraria from Roche, unrelated to this study. OA: has received personal fees from Alexion, Bayer Healthcare, Biogen, Celgene, Merck Serono, MedImmune, Novartis, Roche, Teva, and Zambon, outside of the submitted work. MR: received speaker honoraria from Novartis, Bayer Vital GmbH, Roche, Alexion, Horizon, and Ipsen, travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, Alexion, Horizon, and Merck, none related to this study. VH: reports funding from NEMOS e.V., independent of this project. CT: has received honoraria for consultation and expert testimony from Alexion Pharma Germany GmbH and Roche Pharma GmbH, none of this interfered with the current report. MH: received institutional research support from Myelitis e.V., German Federal Joint Committee/Innovation Fund, and NEMOS e.V., speaker honoraria from selpers OG, AMGEN/Horizon, and Alexion, travel grants from Alexion, compensation for serving on an advisory board from Alexion, Roche, and UCB, none of this interfered with the current manuscript. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

**Figure 1**
Recovery data after attack and attack treatment. Shown are the percentage of attack recovery after all attacks **(A)**, attack at onset **(B)**, isolated myelitis **(C)**, isolated optic neuritis **(D)**, IVMP therapy only **(E)**, apheresis therapy only **(F)** and after combined IVMP and apheresis therapy **(G)**. Percentages may not add exactly to 100% because of rounding.

**Figure 2**
Time from disease onset to EDSS ≥4, 6 and 8, categorized by age at disease onset. Years from disease onset to EDSS ≥4 **(A)**, 6 **(B)**, 8 **(C)**. All three Kaplan-meier survival curves demonstrate significant faster EDSS progression in LO-NMOSD. Disability values were included if collected at regular follow-up, attack-independent and confirmed in a subsequent visit (C: medians could not be calculated, log rank p=0.016).

See this image and copyright information in PMC

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Worse recovery from acute attacks and faster disability accumulation highlights the unmet need for improved treatment in patients with late-onset neuromyelitis optica spectrum disorders (COPTER-LO study)

Affiliations

Worse recovery from acute attacks and faster disability accumulation highlights the unmet need for improved treatment in patients with late-onset neuromyelitis optica spectrum disorders (COPTER-LO study)

Authors

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Abstract

Conflict of interest statement

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