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Original research
Primary lateral sclerosis: consensus diagnostic criteria
  1. Martin R Turner1,
  2. Richard J Barohn2,
  3. Philippe Corcia3,
  4. John K Fink4,
  5. Matthew B Harms5,
  6. Matthew C Kiernan6,7,
  7. John Ravits8,
  8. Vincenzo Silani9,10,
  9. Zachary Simmons11,
  10. Jeffrey Statland2,
  11. Leonard H van den Berg12,
  12. Delegates of the 2nd International PLS Conference,
  13. Hiroshi Mitsumoto5
    1. 1 Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK
    2. 2 Department of Neurology, The University of Kansas Medical Center, Kansas City, Kansas, USA
    3. 3 ALS Centre, Department of Neurology, CHRU Bretonneau, Tours, France
    4. 4 Neurology, University of Michigan, Ann Arbor, Michigan, USA
    5. 5 Neurology, Columbia University College of Physicians and Surgeons, New York City, New York, USA
    6. 6 Bushell Chair of Neurology, Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia
    7. 7 Neurology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
    8. 8 Neurosciences, University of California San Diego, La Jolla, California, USA
    9. 9 Department of Neurology & Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milano, Italy
    10. 10 Department of Pathophysiology & Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milano, Italy
    11. 11 Neurology, Penn State Health Milton S Hershey Medical Center, Hershey, Pennsylvania, USA
    12. 12 Neurology, University Medical Center Utrecht, Utrecht, The Netherlands
    1. Correspondence to Professor Martin R Turner, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK; martin.turner{at}ndcn.ox.ac.uk

    Abstract

    Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after exclusion of structural, neurodegenerative and metabolic mimics. Differentiation of PLS from upper motor neuron-predominant forms of amyotrophic lateral sclerosis remains a significant challenge in the early symptomatic phase of both disorders, with ongoing debate as to whether they form a clinical and histopathological continuum. Current diagnostic criteria for PLS may be a barrier to therapeutic development, requiring long delays between symptom onset and formal diagnosis. While new technologies sensitive to both upper and lower motor neuron involvement may ultimately resolve controversies in the diagnosis of PLS, we present updated consensus diagnostic criteria with the aim of reducing diagnostic delay, optimising therapeutic trial design and catalysing the development of disease-modifying therapy.

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    This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

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    Footnotes

    • Twitter @jnnp_bmj

    • Collaborators The following delegates of the 2nd International PLS Conference (3 May 2019, Pennsylvania, USA) contributed to these consensus criteria: Senda Ajroud-Driss, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Jinsy A. Andrews, Director of Neuromuscular Clinical Trials, Columbia University Irving Medical Center, New York, NY, USA. Suma Babu, Sean M. Healey & AMG Center for ALS, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Peter Bede, Associate Professor, Computational Neuroimaging Group, Trinity College Dublin, Ireland. Michael Benatar, Professor of Neurology and Public Health Sciences, Chief, Neuromuscular Division Executive Director, The ALS Center, Department of Neurology, Miami, FL, USA. Sheena Chew, Massachusetts General Hospital, Boston, MA, USA. Robin Conwit, Program Director, Division of Clinical Research, NINDS, NIH, Bethesda, MD, USA. Merit Cudkowicz, Neurologist, Clinical Researcher, Professor of Neurology, Chief, Neurology Department, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. Mamede de Carvalho, Faculdade de Medicina-IMM, Universidade de Lisboa, Department of Neurosciences, Hospital de Santa Maria-CHULN, Lisbon, Portugal. Vivian E. Drory, Head of Neuromuscular Diseases Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. Lauren Elman, Associate Professor of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA, USA. J. Americo M. Fernandes, Associate Professor, University of Nebraska Medical Center, Omaha, NE, USA. Dominic Ferrey, Department of Neurosciences, University of California at San Diego, La Jolla, CA, USA. Eoin Finegan, Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Ireland. Mary Kay Floeter, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. Christina N. Fournier, Department of Neurology, Emory University, Atlanta, GA, USA. Raghav Govindarajan, Associate Professor, University of Missouri, Columbia, MO, USA. Volkan Granit, Department of Neurology, Neuromuscular Division, University of Miami, Miller School of Medicine, Miami, FL, USA. Orla Hardiman, Clinical Professor Neurology, Consultant Neurologist at the National Neuroscience Centre, Director of the National ALS Clinic & Irish ALS Research Group, Trinity Institute of Neuroscience, Trinity College Dublin, Ireland. Ghazala Hayat, Professor of Neurology, St. Louis University, St. Louis, MO, USA. Terry D. Heiman-Patterson, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA. Annemarie Hübers, Service de Neurologie, Hôpitaux Universitaires de Genève, Switzerland. Edward D. Huey, Associate Professor of Psychiatry and Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA. Omar Jawdat, Assistant Professor of Neurology, Director, ALS Clinic, University of Kansas Medical Center, Kansas City, KS, USA. Osamu Kano, Professor and Chairman, Division of Neurology, Department of Internal Medicine, Toho University Faculty of Medicine, Tokyo, Japan. Yaz Y. Kisanuki, Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Dale Lange, Chair, Department of Neurology; Neurologist-in-Chief, Hospital for Special Surgery; Professor of Neurology

      Weill Cornell Medicine; New York, NY, USA. Ian Mackenzie, Professor, Neuropathology, Department of Pathology and Laboratory Medicine University of British Columbia, Vancouver, Canada. David Marren, Spastic Paraplegia Foundation Mitsuya Morita Associate Professor, Chief of Rehabilitation Center, Jichi Medical University, Tochigi, Japan. Jennifer Murphy, University of California, San Francisco, CA, USA. Sharon Nations, Professor, Department of Neurology and Neurotherapeutics, University of Texas Medical Center, Dallas, TX, USA. Björn Oskarsson, Associate Professor of Neurology, Jacksonville, Director ALS Center of Excellence, Mayo Clinic, Jacksonville, FL, USA. Sabrina Paganoni, Healey Center for ALS, Massachusetts General Hospital, Boston, MA, USA. Erik P. Pioro, Director, Section of ALS & Related Disorders, Professor of Neurology Department of Neurology, Cleveland Clinic, Cleveland, OH, USA. Seth L. Pullman, Columbia University, NY, USA. Kourosh Rezania, Department of Neurology, University of Chicago, Illinois, USA. Guy Rouleau, Director, Montreal Neurological Institute and Hospital, Chair, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. Stephen Scelsa, Site Medical Director, Department of Neurology, Mount Sinai Downtown and Mount Sinai Beth Israel; Director of the ALS Center, Mount Sinai Downtown Union Square; Professor of Neurology, the Icahn School of Medicine, New York, NY, USA. Nailah Siddique, Neurogenomics Lab, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Juan Solano, Neuromuscular Disorders Research Group, Universidad de Antioquia, Medellín, Colombia Marka van Blitterswijk Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. David Walk, Professor, Department of Neurology, University of Minnesota, Minneapolis, MN, USA. James Wymer, University of Florida, Gainesville, FL, USA. Cuiping Zhao, Department of Neurology, Qilu Hospital, Shandong University, China.

    • Contributors MRT drafted the manuscript, revised and synthesised the final version and is the guarantor. RJB co-drafted the EMG section and provided intellectual content and revisions to the overall manuscript. PC drafted table 2 and provided intellectual content and revisions to the overall manuscript. JKF provided intellectual content and revisions to the overall manuscript. MBH provided intellectual content and revisions to the overall manuscript. MCK provided intellectual content and revisions to the overall manuscript. JR provided intellectual content and revisions to the overall manuscript. VS drafted table 3 and provided intellectual content and revisions to the overall manuscript. ZS provided intellectual content and revisions to the overall manuscript. JS co-drafted the EMG section and provided intellectual content and revisions to the overall manuscript. LHvdB provided intellectual content and revisions to the overall manuscript. HM conceived the article and provided intellectual content and revisions to the overall manuscript.

    • Funding MRT is supported by the Motor Neurone Disease Association. MCK was supported by the National Health and Medical Research Council of Australia Program Grant (#1132524), Partnership Project (1153439) and Practitioner Fellowship (1156093). VS was supported by the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and E-Rare Joint Transnational Call. ZS received funding from Cytokinetics, Biohaven & Biogen. HM received funding from CDC, MDA, SPF, Cytokinetics and Tsumura.

    • Competing interests MRT is on the Scientific Advisory Board for Orphazyme, has been a paid consultant for Genentech Inc. (2017) and anonymous clients separately through GLG Consulting on the topic of ALS diagnosis, management and biomarker development. He received neurofilament assay kits in-kind from Euroimmun UK (2018).PC has reveived honoraria from Biogen & Cytokinetics. ZS has received honoraria from Wiley, Cytokinetics & Biohaven. HM is on the Advisory Board of Mitsubishi-Tanabe & Biohaven.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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