Developed through a collaborative effort by Paradigms members, the article offers a practical guide to a simple three-step approach to help identify and confirm disease progression early.
Authors
Bart Van Wijmeersch, Celia Oreja-Guevara, Melinda Magyari, Laura Airas, Andrew Chan, Florian Deisenhammer, Nikolaos Grigoriadis, Hans-Peter Hartung, Maura Pugliatti, Patrick Vermersch, Tjalf Ziemssen, Jelena Drulovic, Mona Marwan Alkhawajah, Magd Zakaria, Veronica Popescu & Carlo Pozzilli
Author information
Author notes
- Bart Van Wijmeersch, Celia Oreja-Guevara and Carlo Pozzilli contributed equally.
Authors and Affiliations
- University MS Centre, Hasselt-Pelt, BelgiumBart Van Wijmeersch
- Noorderhart Hospitals, Rehabilitation & MS, Pelt, BelgiumBart Van Wijmeersch & Veronica Popescu
- Department of Neurology, Hospital Clínico Universitario San Carlos IdISSC, Madrid, SpainCelia Oreja-Guevara
- Department of Medicine, Faculty of Medicine, Complutense University of Madrid, Madrid, SpainCelia Oreja-Guevara
- Department of Neurology, The Danish Multiple Sclerosis Registry, Copenhagen University Hospital – Rigshospitalet, Glostrup, DenmarkMelinda Magyari
- Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital – Rigshospitalet, Glostrup, DenmarkMelinda Magyari
- Institute for Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkMelinda Magyari
- University of Turku and Turku University Hospital, Turku, FinlandLaura Airas
- Department of Neurology, Inselspital, University Hospital Bern, Bern University, Bern, SwitzerlandAndrew Chan
- Department of Neurology, Medical University of Innsbruck, Innsbruck, AustriaFlorian Deisenhammer
- Multiple Sclerosis Center, Second Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, GreeceNikolaos Grigoriadis
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, GermanyHans-Peter Hartung
- Brain and Mind Center, University of Sydney, Sydney, NSW, AustraliaHans-Peter Hartung
- Department of Neurology, Palacky University Olomouc, Olomouc, CzechiaHans-Peter Hartung
- Department of Neurosciences and Rehabilitation, University of Ferrara, Ferrara, ItalyMaura Pugliatti
- University of Lille, Inserm U1172, Lille Neuroscience & Cognition, Centre Hospitalier Universitaire de Lille, Fédération Hospitalo-Universitaire Precision Medicine in Psychiatry, Lille, FrancePatrick Vermersch
- Center of Clinical Neuroscience, Department of Neurology, Faculty of Medicine, University Hospital Carl Gustav Carus and Centre for Tactile Internet With Human-in-the-Loop (CeTI), TU Dresden, Dresden, GermanyTjalf Ziemssen
- Clinic of Neurology, University Clinical Center of Serbia, Belgrade, SerbiaJelena Drulovic
- Neuroscience Centre of Excellence , King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi ArabiaMona Marwan Alkhawajah
- College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi ArabiaMona Marwan Alkhawajah
- Department of Neurology, Ain Shams University, Cairo, EgyptMagd Zakaria
- Faculty of Medicine and Life Sciences, UHasselt, Diepenbeek, BelgiumVeronica Popescu
- Department of Human Neurosciences, Sapienza University, Rome, ItalyCarlo Pozzilli
Contributions
Bart Van Wijmeersch, Celia Oreja-Guevara, and Carlo Pozzilli: conceptualized and directed the writing of the paper, revised the manuscript critically for intellectual content, and read and approved the final manuscript. Melinda Magyari, Laura Airas, Andrew Chan, Florian Deisenhammer, Nikolaos Grigoriadis, Hans-Peter Hartung, Maura Pugliatti, Patrick Vermersch, Tjalf Ziemssen, Jelena Drulovic, Mona Marwan Alkhawajah, Magd Zakaria, and Veronica Popescu: revised the manuscript critically for intellectual content and read and approved the final manuscript.
Corresponding author
Correspondence to Bart Van Wijmeersch.
Abstract
Background
People with MS (pwMS) often experience disability progression even when disease-modifying therapies effectively suppress relapses, a phenomenon known as progression independent of relapse activity (PIRA). Characterizing these patients in clinical practice is challenging because existing PIRA definitions rely mainly on the EDSS, which is biased towards ambulation and does not capture the gradual accumulation of symptoms in other clinical areas.
Methods
The recommendations were developed by a panel of experts over several meetings, supported by the ParadigMS Foundation. The guide was built by considering the objectives of both neurologists and patients, then using clinical experience and literature to select the most relevant parameters for identifying disability progression in routine practice.
Results
A three-step approach is proposed: (1) identify pwMS at risk through a detailed history and risk factors (age, sex, smoking, comorbidities), (2) assess progression with as many tools as feasible (motor, cognitive and patient-reported tests, MRI, serum biomarkers, OCT, evoked potentials), and (3) confirm progression and consider treatment changes. A flowchart and a practical checklist are provided.
Conclusions
This guidance can help neurologists detect subtle disability progression early, irrespective of age, EDSS or disease duration, and could support personalized treatment, particularly as new disability-targeting therapies become available. Some cut-offs have not been validated for MS and the checklist items are not weighted, so further research is needed.
Keywords:
Multiple sclerosis; Disability progression; PIRA; Smouldering disease.
Publication History:
Received 06 August 2026; Revised 03 October 2026; Accepted 05 October 2026; Published 03 November 2026; Version of record 03 November 2026.
DOI: https://doi.org/10.1007/s00415-026-14212-2 .Also available on Journal of Neurology vol. 273
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