Multicenter Prospective Study Analyzing the Occurrence of Multiple Sclerosis Relapses Without Radiological Evidence: Myth or Reality?

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by relapses corresponding to episodes of new or worsening neurological symptoms. These relapses are typically associated with focal inflammatory activity detectable on magnetic resonance imaging (MRI) as gadolinium-enhancing lesions. However, in clinical practice, a subset of patients presents with symptoms suggestive of relapse without corresponding radiological findings, referred to as acute clinical events with stable MRI (ACES). The clinical significance, underlying mechanisms, and frequency of these events remain uncertain. The MYTH-MS study is a multicenter, prospective cohort study designed to determine the proportion of patients with relapsing-remitting MS (RRMS) who experience a clinical relapse without gadolinium-enhancing lesions on early brain and spinal MRI. The study also aims to better characterize these events by identifying associated clinical, radiological, biological, and psychological factors. Eligible participants are adults with RRMS presenting with recent neurological worsening suggestive of a relapse. At inclusion, patients will undergo standardized clinical evaluation, including neurological examination, disability assessment, cognitive testing, and patient-reported outcomes related to quality of life and psychological status. An early brain and spinal MRI with gadolinium injection will be performed within a defined time window following symptom onset. The study will also assess the diagnostic performance of neurologists by comparing their clinical judgment regarding the presence of radiological activity and the likelihood of a true relapse versus a pseudo-relapse, along with their level of diagnostic confidence. Participants will be followed for six months to evaluate clinical outcomes, including disability progression, cognitive performance, quality of life, and psychological parameters, and to assess the impact of relapse treatment according to MRI findings. An ancillary biological study will be conducted to evaluate circulating biomarkers of neuronal and glial injury (e.g., neurofilament light chain \[NfL\], glial fibrillary acidic protein \[GFAP\], and circulating cell-free DNA). These biomarkers will be analyzed at baseline and follow-up to explore their potential role in distinguishing inflammatory relapses from ACES. By providing a comprehensive characterization of MS exacerbations with and without radiological activity, this study aims to improve diagnostic accuracy, reduce uncertainty in clinical decision-making, and optimize therapeutic strategies in patients with RRMS.