Progressive multiple sclerosis poses a considerable challenge in the evaluation of disease progression and treatment response owing to its multifaceted pathophysiology. Traditional clinical measures such as the Expanded Disability Status Scale are limited in capturing the full scope of disease and treatment effects. Advanced imaging techniques, including MRI and PET scans, have emerged as valuable tools for the assessment of neurodegenerative processes, including the respective role of adaptive and innate immunity, detailed insights into brain and spinal cord atrophy, lesion dynamics and grey matter damage. The potential of cerebrospinal fluid and blood biomarkers is increasingly recognized, with neurofilament light chain levels being a notable indicator of neuro-axonal damage. Moreover, patient-reported outcomes are crucial for reflecting the subjective experience of disease progression and treatment efficacy, covering aspects such as fatigue, cognitive function and overall quality of life. The future incorporation of digital technologies and wearable devices in research and clinical practice promises to enhance our understanding of functional impairments and disease progression. This Review offers a comprehensive examination of these diverse evaluation tools, highlighting their combined use in accurately assessing disease progression and treatment efficacy in progressive multiple sclerosis, thereby guiding more effective therapeutic strategies.

Brain and Mind Center University of Sydney Sydney Australia

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

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Germany

Department of Neurology Palacky University Olomouc Olomouc Czech Republic

Department of Neurorehabilitation Sciences Casa di Cura Igea Milan Italy

Multiple Sclerosis Center Casa di Cura Igea Milan Italy

Sorbonne Université Paris Brain Institute Institut du Cerveau et de la Moelle Épinière Centre National de la Recherche Scientifique Inserm Paris France

University of Lille Inserm U1172 Lille Neuroscience and Cognition Centre Hospitalier Universitaire de Lille Fédération Hospitalo Universitaire Precision Medicine in Psychiatry Lille France

Vita Salute San Raffaele University Milan Italy

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