Differential diagnosis of suspected multiple sclerosis: an updated consensus approach

Andrew J Solomon¹, Georgina Arrambide², Wallace J Brownlee³, Eoin P Flanagan⁴, Maria Pia Amato⁵, Lilyana Amezcua⁶, Brenda L Banwell⁷, Frederik Barkhof⁸, John R Corboy⁹, Jorge Correale¹⁰, Kazuo Fujihara¹¹, Jennifer Graves¹², Mary Pat Harnegie¹³, Bernhard Hemmer¹⁴, Jeannette Lechner-Scott¹⁵, Ruth Ann Marrie¹⁶, Scott D Newsome¹⁷, Maria A Rocca¹⁸, Walter Royal 3rd¹⁹, Emmanuelle L Waubant²⁰, Bassem Yamout²¹, Jeffrey A Cohen²²

Affiliations

¹ Department of Neurological Sciences, Larner College of Medicine at the University of Vermont, University Health Center, Burlington, VT, USA. Electronic address: andrew.solomon@uvm.edu.
² Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain.
³ National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
⁴ Departments of Neurology and Laboratory Medicine and Pathology and the Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA.
⁵ Department NEUROFARBA, University of Florence, Florence, Italy; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
⁶ Department of Neurology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
⁷ Department of Neurology, University of Pennsylvania, Division of Child Neurology, Philadelphia, PA, USA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands; Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, UK.
⁹ Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁰ Department of Neurology, Fleni Institute of Biological Chemistry and Physical Chemistry (IQUIFIB), Buenos Aires, Argentina; National Council for Scientific and Technical Research/University of Buenos Aires, Buenos Aires, Argentina.
¹¹ Department of Multiple Sclerosis Therapeutics, Fukushima Medical University School of Medicine, Koriyama, Japan; Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan.
¹² Department of Neurosciences, University of California, San Diego, CA, USA.
¹³ Cleveland Clinic Libraries, Cleveland Clinic, Cleveland, OH, USA.
¹⁴ Department of Neurology, Klinikum rechts der Isar, Medical Faculty, Technische Universität München, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
¹⁵ Department of Neurology, John Hunter Hospital, Newcastle, NSW Australia; Hunter Medical Research Institute Neurology, University of Newcastle, Newcastle, NSW, Australia.
¹⁶ Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
¹⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁸ Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
¹⁹ Department of Neurobiology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA.
²⁰ Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA, USA.
²¹ Neurology Institute, Harley Street Medical Center, Abu Dhabi, United Arab Emirates.
²² Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

PMID: 37479377
DOI: 10.1016/S1474-4422(23)00148-5

Review

Differential diagnosis of suspected multiple sclerosis: an updated consensus approach

Andrew J Solomon et al. Lancet Neurol. 2023 Aug.

. 2023 Aug;22(8):750-768.

doi: 10.1016/S1474-4422(23)00148-5.

Authors

Affiliations

¹ Department of Neurological Sciences, Larner College of Medicine at the University of Vermont, University Health Center, Burlington, VT, USA. Electronic address: andrew.solomon@uvm.edu.
² Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Universitat Autònoma de Barcelona, Barcelona, Spain.
³ National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
⁴ Departments of Neurology and Laboratory Medicine and Pathology and the Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA.
⁵ Department NEUROFARBA, University of Florence, Florence, Italy; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.
⁶ Department of Neurology, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
⁷ Department of Neurology, University of Pennsylvania, Division of Child Neurology, Philadelphia, PA, USA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands; Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, UK.
⁹ Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁰ Department of Neurology, Fleni Institute of Biological Chemistry and Physical Chemistry (IQUIFIB), Buenos Aires, Argentina; National Council for Scientific and Technical Research/University of Buenos Aires, Buenos Aires, Argentina.
¹¹ Department of Multiple Sclerosis Therapeutics, Fukushima Medical University School of Medicine, Koriyama, Japan; Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan.
¹² Department of Neurosciences, University of California, San Diego, CA, USA.
¹³ Cleveland Clinic Libraries, Cleveland Clinic, Cleveland, OH, USA.
¹⁴ Department of Neurology, Klinikum rechts der Isar, Medical Faculty, Technische Universität München, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
¹⁵ Department of Neurology, John Hunter Hospital, Newcastle, NSW Australia; Hunter Medical Research Institute Neurology, University of Newcastle, Newcastle, NSW, Australia.
¹⁶ Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
¹⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁸ Neuroimaging Research Unit, Division of Neuroscience, Neurology Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
¹⁹ Department of Neurobiology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA.
²⁰ Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA, USA.
²¹ Neurology Institute, Harley Street Medical Center, Abu Dhabi, United Arab Emirates.
²² Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

PMID: 37479377
DOI: 10.1016/S1474-4422(23)00148-5

Abstract

Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.

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Conflict of interest statement

Declaration of interests AJS reports grant funding from National Institute of Neurological Disorders and Stroke, National Institutes of Health, and Bristol Myers Squibb; contracted research with Sanofi, Biogen, Novartis, Actelion, and Genentec; personal compensation for consulting from EMD Serono and Octave Bioscience; payment or honoraria for lectures from EMD Serono; expert testimony from The Jacob D Fuchsberg Law Firm and Koskoff Koskoff & Bieder; participation on a Data Safety Monitoring Board for Patient Centered Research Institute and Yale University; participation on an advisory board for Genentech, Biogen, Alexion, Celgene, Greenwich Biosciences, TG Therapeutics, and Horizon Therapeutics. AJS is also content Chair for the American Academy of Neurology Institute Multiple Sclerosis Quality Measure Development Work Group and Section Editor for Multiple Sclerosis and Related Disorders. GA reports a grant from FIS PI19/01590 from Instituto de Salud Carlos III, Spain; personal compensation for consulting from Sanofi; payment or honoraria for lectures from Merck, Roche, and Novartis; support for attending meetings or travel from Merck, Novartis, European Committee for Treatment and Research in Multiple Sclerosis, and European Academy of Neurology; participation on a Data Safety Monitoring Board or Advisory Board for Merck, Roche, Horizon Therapeutics. GA is editor for Europe of Multiple Sclerosis Journal—Experimental, Translational and Clinical. GA is also executive committee member of International Women in Multiple Sclerosis network and steering committee member of European Biomarkers in Multiple Sclerosis consortium. WJB reports personal compensation for consulting from Biogen, Jannsen, Merck, Novartis, Roche, Sanofi, and Viatris; and payment or honoraria for lectures from Biogen, Jannsen, Merck, Novartis and Roche. EPF reports grant funding from the National Institutes of Health; personal compensation for consulting from Alexion, Genentech, UCB, and Horizon Therapeutics; and payment or honoraria for lectures from Pharmacy Times. EPF also served as site primary investigator in a randomised clinical trial on inebilizumab in neuromyelitis optica spectrum disorder sponsored by Medimmune/Viela-Bio/Horizon Therapeutics. EPF is also employed at the Mayo Clinic where commercial MOG-IgG, aquaporin-4-IgG and other antibodies are tested but does not receive any royalties from this testing. MPA reports grants or contracts with Biogen, Merck, Sanofi, Genzyme, Roche, Novartis, and Celgene/Bristol Myers Squibb; payment or honoraria for lectures from Biogen, Merck, Sanofi, Genzyme, Roche, Novartis, and Celgene/Bristol Myers Squibb; and participation on a Data Safety Monitoring Board or Advisory Board for Biogen, Merck, Sanofi, Genzyme, Roche, Novartis, and Celgene/Bristol Myers Squibb. BLB reports a grant from the National Multiple Sclerosis Society; personal compensation for consulting from Roche, Sanofi, Novartis, and UCB; and serves on the American Academy of Neurology Board of Directors and the International Medical and Scientific Advisory Board for the Multiple Sclerosis International Federation (MSIF). FB reports a grant from EU-IMI; personal compensation for consulting from Merck, Biogen, Roche, Combinostics, and IXICO; participation on a Data Safety Monitoring Board or Advisory Board for Prothena and EISAI; and stock options for QSA LTD. QSA is a contract research organization that provides imaging analysis services to the pharmaceutical industry. FB notes that his work with QSA has no relationship with his work as a diagnostic neuroradiologist nor with the content of the Personal View. JRC reports grants or contracts from the National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, EMD Serono, and Med Day; payment or honoraria for lectures from ECTRIMS European Charcot Foundation, Emory University, University of Chicago, MS XChange, and The Ohio State University. JRC also reports expert testimony for Mylan; participation on a Data Safety Monitoring Board or Advisory Board for Bristol Myers Squibb; and serves as Medical Director of Rocky Mountain Multiple sclerosis Center. JC reports grants or contracts from Biogen and Merck; payment or honoraria for lectures from Biogen, Merck, Sanofi, Bristol Myers Squibb, Novartis, Roche, and Jansen; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Novartis. KF reports grants from Ministry of Education, Culture, Sports, Science and Technology of Japan, and from Ministry of Health, Welfare and Labor of Japan. KF also reports personal compensation for consulting from Merck Biopharma, Japan Tobacco, and Abbvie; payment or honoraria for lectures and presentations from Biogen, Eisai, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon, Therapeutics, Teijin, Asahi Kasei Medical, Merck, and Takeda; participation on an Advisory Board for Biogen, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon Therapeutics, and UCB. KF serves as President of Pan-Asian Committee for Treatment and Research in Multiple Sclerosis, President of the Japanese Society of Neuroimmunology, Board Member of Japan Multiple Sclerosis Society and European Charcot Foundation, and Committee and Board member Executive Committee, International Medical and Scientific Board, MSIF. BH reports support from the European Union, Bundesministerium für Bildung und Forschung, and Deutsche Forschungsgemeinschaft; personal compensation for consulting from Sandoz and Biocom; patents for antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis (2012) and genetic determinants of neutralizing antibodies to interferon (filed 2010); and participation on a Data Safety Monitoring Board for TG Therapeutics and Polpharma and an Advisory Board for Novartis. RAM reports grants or contracts from Biogen Idec and Roche. SDN reports grants or contracts from Biogen, Roche, Genentech, National Multiple Sclerosis Society, Department of Defense, and Patient Centered Outcomes Research Institute; personal compensation for consulting from Biogen, Roche, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Novartis, and Horizon Therapeutics; and participation on a Data Safety Monitoring Board or Advisory Board for MedDay Pharmaceuticals. SDN also reports support from the Stiff Person Syndrome Research Foundation. MAR reports grants or contracts from Multiple Sclerosis Society of Canada and Fondazione Italiana Sclerosi Multipla; personal compensation for consulting from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, and Roche; payment or honoraria for lectures from Bayer, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Merck Healthcare Germany, Merck Serono SpA, Novartis, Roche, and Teva. MAR also serves as Associate Editor for Multiple Sclerosis and Related Disorders. BY serves on the MSIF scientific advisory board and as President of MENACTRIMS. BY also reports personal compensation for consulting from Merck, Biogen, Novartis, Roche, Sanofi, and Bayer. JAC reports personal compensation for consulting from Biogen, Convelo, EMD Serono, Gossamer Bio, and PSI; serves as President of the Americas Committee on Treatment and Research in Multiple Sclerosis; and receives personal compensation for working as the Editor of Multiple Sclerosis Journal. All other authors declare no competing interests.

Comment in

Commentary: Solomon AJ et al. Differential diagnosis of suspected multiple sclerosis: An updated consensus approach. Lancet Neurol 2023; 22(8): 750-768.
Cohen JA. Cohen JA. Mult Scler. 2023 Aug;29(9):1047-1048. doi: 10.1177/13524585231188097. Epub 2023 Jul 20. Mult Scler. 2023. PMID: 37470270 No abstract available.
Navigating the challenges of diagnosing multiple sclerosis.
Chitnis T. Chitnis T. Lancet Neurol. 2023 Aug;22(8):649-651. doi: 10.1016/S1474-4422(23)00243-0. Lancet Neurol. 2023. PMID: 37479366 No abstract available.

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Differential diagnosis of suspected multiple sclerosis: an updated consensus approach

Affiliations

Differential diagnosis of suspected multiple sclerosis: an updated consensus approach

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Abstract

Conflict of interest statement

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