Multicenter Prospective Study Analyzing the Occurrence of Multiple Sclerosis Relapses Without Radiological Evidence: Myth or Reality? (MYTH-MS)

April 15, 2026 updated by: University Hospital, Strasbourg, France

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

136

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • France
      • Colmar, France, 68024
      • Dijon, France, 21079
      • Haguenau, France, 67504
      • Metz, France, 57085
      • Mulhouse, France, 68051
        • Grpe Hosp Region Mulhouse & Sud Alsace
        • Contact:
      • Nancy, France, 54035
        • CHU de Nancy
        • Contact:
      • Reims, France, 51092
      • Strasbourg, France, 67098

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: RRMS Patients with Acute Neurological Exacerbations
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

Other Names:
  • biological markers
  • NfL, GFAP, and cfDNA
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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

This measure evaluates the frequency of "Acute Clinical Events with Stable MRI" (ACES). Participants undergo a standardized MRI of the brain and spinal cord using gadolinium contrast medium within a strict window of 0 to 6 days following the onset of a suspected neurological relapse.

The primary finding is defined as the absence of any gadolinium-enhancing lesions (which indicate active inflammation) despite the presence of clinical symptoms. Data is reported as the percentage of the total cohort meeting these criteria, assessed through a centralized radiological review using a standardized reading grid. This allows for a precise characterization of clinical relapses that lack immediate radiological confirmation.
performed between Day 0 and Day 6

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Strasbourg, France

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2026

Primary Completion (Estimated)

September 7, 2029

Study Completion (Estimated)

May 1, 2030

Study Registration Dates

First Submitted

April 15, 2026

First Submitted That Met QC Criteria

April 15, 2026

First Posted (Actual)

April 22, 2026

Study Record Updates

Last Update Posted (Actual)

April 22, 2026

Last Update Submitted That Met QC Criteria

April 15, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RC25_0053

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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