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

Overview

The MYTH-MS study is a multicenter prospective study investigating the occurrence of clinical relapses in patients with relapsing-remitting multiple sclerosis (RRMS) in the absence of radiological activity on MRI. While MS relapses are typically associated with gadolinium-enhancing lesions on MRI, some patients present with acute neurological symptoms without radiological correlates, referred to as acute clinical events with stable MRI (ACES). The frequency, mechanisms, and clinical relevance of these events remain unclear due to limitations in previous studies. The primary objective is to determine the proportion of RRMS patients experiencing a relapse without gadolinium-enhancing lesions on early brain and spinal MRI. Secondary objectives include identifying clinical, radiological, biological, and psychological predictors, assessing neurologists' diagnostic accuracy, and evaluating clinical outcomes such as disability, cognition, and quality of life over a 6-month follow-up. A total of 136 patients with recent neurological exacerbations will be included. Each participant will undergo clinical assessment, cognitive and psychological evaluation, and early MRI, with follow-up at 6 months. An ancillary study will explore blood biomarkers (NfL, GFAP, and circulating DNA) to help differentiate true inflammatory relapses from ACES. This study aims to improve the understanding and diagnosis of MS exacerbations and to optimize patient management by reducing misdiagnosis and unnecessary treatments.

Detailed description

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.

Interventions

• Other Early Cerebro-spinal MRI
  A standardized MRI of the brain and spinal cord with gadolinium injection. Performed very early during an acute neurological exacerbation, specifically between Day 0 and Day 6 (J0 to J6). To detect the presence or absence of gadolinium-enhancing lesions, which is the study's primary endpoint. Includes Susceptibility Weighted Imaging (SWI) to look for paramagnetic rim lesions and post-gadolinium FLAIR sequences to detect leptomeningeal enhancement.
• Diagnostic test Biomarker Assessment
  Routine blood and urine tests, including CRP, blood count, and urinalysis (leukocytes, nitrites) to rule out infections that could cause a pseudo-relapse. Ancillary Study Biomarkers: For consenting patients, blood samples are collected to measure specific molecular markers: NfL (Neurofilaments): A marker of axonal damage. GFAP (Glial Fibrillary Acidic Protein): A marker of astrocytic activation. cfDNA (Cell-free DNA): Used to assess cellular stress or death
• Diagnostic test Clinical and Neuropsychological Evaluations
  Standardized Scales: * EDSS (Expanded Disability Status Scale): Used to measure the degree of neurological disability at inclusion and at the 6-month follow-up. * SDMT (Symbol Digit Modalities Test) and CSCT (Computerized Speed Cognitive Test): Used to assess cognitive processing speed. Functional Disorder Screening: A specific clinical examination is conducted to identify positive signs of Functional Neurological Disorders (FND/TNF), which may mimic a relapse.

Primary outcome measures

• Proportion of RRMS Patients with Absence or Presence of Gadolinium-Enhancing Lesion(s) on Brain and Spinal Cord MRI [Time frame: performed between Day 0 and Day 6]

Eligibility criteria

Inclusion criteria

• Adult aged 18 to 70 years.
• Relapsing-Remitting Multiple Sclerosis according to the McDonald 2024 criteria.
• Patient receiving disease-modifying therapy (DMT) for multiple sclerosis.
• Most recent EDSS score between 0 and 7.0, dating back less than 1 year.
• Patient presenting with a neurological exacerbation lasting more than 24 hours and less than 7 days (excluding fatigue and pain alone).
• Patient capable of understanding the objectives and risks associated with the study and who has provided informed consent.
• Patient affiliated with or a beneficiary of a social security health insurance scheme.

Exclusion criteria

• Primary progressive or secondary progressive multiple sclerosis.
• Diagnosis of chronic psychotic disorder.
• Infection within the past week.
• Body temperature > 38.5°C at V0 (baseline visit).
• Corticosteroid bolus or plasma exchange in the month preceding inclusion.
• Chronic treatment with corticosteroids or immunosuppressants for another pathology.
• Contraindication to MRI or gadolinium.
• Uncontrolled cardiac, renal, or hepatic pathology.
• Patient participating in another interventional study or still within an exclusion period.
• Pregnant or breastfeeding woman.
• Severe claustrophobia.
• Patient deprived of liberty (e.g., incarcerated).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Diagnostic

Study locations

France · 8 centers

• Hospices Civils de Colmar — Colmar
• CHU de Dijon Bourgogne — Dijon
• Centre Hospitalier de Haguenau — Haguenau
• Chr Metz-Thionville — Metz
• Grpe Hosp Region Mulhouse & Sud Alsace — Mulhouse
• CHU de Nancy — Nancy
• Chu Reims — Reims
• Hôpitaux Universitaires de Strasbourg — Strasbourg

Identifiers

NCT: NCT07545889 · RC25_0053

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗