Multiple sclerosis is a chronic, inflammatory, and neurodegenerative disease of the central nervous system and a major cause of neurological disability in young adults. Its prevalence and incidence are increasing, and it has been estimated at over 2.8 million cases worldwide, in addition to recent trends towards a shift in MS prevalence to older ages, with peak prevalence estimates in the sixth decade of life. Although historically the relapsing and progressive phases of the disease have been considered separate clinical entities, recent evidence of progression independent of relapse activity (PIRA) has led to a reconsideration of multiple sclerosis as a continuum, in which relapsing and progressive features variably coexist from the earliest stages of the disease, challenging the traditional view of the disease course. In this Series article, we provide an overview of how the traditional description of the clinical course of MS and epidemiological trends in Europe have evolved. For this purpose, we focus on the concept of PIRA, discussing its potential as the main mechanism by which patients acquire disability, how its definition varies between studies, and ongoing research in this field. We emphasise the importance of incorporating the assessment of hidden clinical manifestations into patient management to help uncover and quantify the PIRA phenomenon and the possible implications for future changes in the clinical classification of the disease. At the same time, we provide insights into overcoming the challenges of identifying and defining PIRA and adopting a new understanding of the clinical course of MS.

Centre of Neuroscience Department of Medicine Imperial College London London UK

Danish Multiple Sclerosis Center Department of Neurology Copenhagen University Hospital Rigshospitalet Glostrup Denmark

Department of NEUROFARBA Unviersity of Florence Florence Italy

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic

IRCCS Fondazione Don Carlo Gnocchi Florence Italy

Magendie INSERM U 1215 Université de Bordeaux 30776 Bordeaux Cedex France

Multiple Sclerosis Centre of Catalonia Department of Neurology Neuroimmunology Hospital Universitari Vall d'Hebron Universitat Autònoma de Barcelona Barcelona Spain

Section of Neurology Department of Medicine and Surgery University of Perugia Italy

Service de Neurologie et Maladies Inflammatoires du Système Nerveux Central Centre de Ressources et Compétences Sclérose en plaques CHU de Bordeaux 33076 Bordeaux Cedex France

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