Identifying Signs of Presymptomatic MS, Radiologically Isolated Syndrome

For people with multiple sclerosis, the goal is often to prevent the first debilitating attack.

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A new review article, published in Revue neurologique, provides a comprehensive summary of the latest insights into the management of radiologically isolated syndrome (RIS), a key presymptomatic phase of MS.1 The study highlighted the importance of early identification and intervention to potentially delay or prevent the onset of clinical symptoms.

Radiologically isolated syndrome is characterized by the incidental discovery of MS-like brain or spinal cord lesions on magnetic resonance imaging (MRI) in a person who is not experiencing any clinical symptoms. Although some people with RIS never progress to clinical MS, observational studies have shown that one-third of people with RIS experienced their first clinical attack within 5 years, with that number rising to about half within 10 years. The article was a critical step in establishing consensus guidelines for diagnosing and managing this condition. The goal was to enhance diagnostic accuracy, identify predictive biomarkers, and review the efficacy of treatment options in this asymptomatic population.

The authors detailed the updated 2023 RIS criteria, which were created to enhance diagnostic precision and avoid misdiagnosis.2 These new criteria require the presence of one T2-weighted hyperintense lesion in at least 2 of 4 specified locations (periventricular, juxtacortical/cortical, infratentorial, or spinal cord).1

Additionally, the criteria require at least 2 of the following features to demonstrate dissemination in time: a spinal cord lesion, cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCB), or a new T2 or gadolinium-enhancing lesion on a follow-up MRI. The study found that certain demographics and clinical data points were associated with an increased risk of progression, including a younger age and male sex.

To improve the ability to predict who might progress to clinical MS, the review also examined a variety of biological and imaging biomarkers. The authors noted that laboratory markers such as CSF-restricted OCBs and high levels of neurofilament light chain (NfL) in both CSF and serum were independent predictive factors for the transition to symptomatic MS. From an imaging perspective, new techniques were highlighted, including the central vein sign (CVS), which helped to differentiate RIS from other conditions. The study reported that a threshold of at least 6 CVS lesions had a high predictive value. Researchers also found that brain tissue loss, particularly in the thalamus, frequently occurred in people with RIS before any symptoms appeared.

The significance of the review for people with presymptomatic MS is profound. The authors pointed to 2 randomized trials that demonstrated the efficacy of 2 oral disease-modifying therapies (DMTs) in delaying a person’s first clinical event. A separate study on dimethyl fumarate specifically showed that the treatment preserved the integrity of the brainstem and upper cervical spinal cord in study participants. The authors said that these findings suggest that identifying and monitoring people with RIS could provide a crucial opportunity to intervene and delay or prevent the debilitating effects of MS.

"As proposed by the RIS Consortium, for individuals with RIS who are treated with DMT during the preclinical phase, it is advisable to monitor them as one would with early clinical MS, with clinical and MRI follow-ups every year. It is essential to understand that any red flags that may occur during follow-up should be noted and investigated. In the case of documented active disease under DMT, it would be rational to consider a switch to a more active treatment as recommended in early MS," they advised.

The authors advocated for a collaborative, personalized approach to care, recommending that each person with RIS be evaluated by an MS expert team to balance potential treatment benefits with any associated risks.

References

1. Lebrun-Frenay C, Cohen M, Okuda DT. Presymptomatic multiple sclerosis: insights from the radiologically isolated syndrome. Rev Neurol (Paris). Published online August 7, 2025. 2025. doi:10.1016/j.neurol.2025.06.013
2. Lebrun-Frénay C, Okuda DT, Siva A, et al. The radiologically isolated syndrome: revised diagnostic criteria. Brain. 2023;146(8):3431-3443. doi:10.1093/brain/awad073