Early Disease-Modifying Treatments for Presymptomatic Multiple Sclerosis

Abstract

Radiologically isolated syndrome (RIS) is the earliest stage in the disease continuum of multiple sclerosis (MS). RIS is discovered incidentally in individuals who are asymptomatic but have typical lesions in the brain and/or spinal cord suggestive of demyelination. The 2009 and revised 2023 RIS criteria were developed for diagnosis. Presymptomatic individuals who fulfill the 2009 RIS criteria by having 3-4 of 4 dissemination in space McDonald 2005 MS criteria are still diagnosed with RIS using the revised 2023 RIS criteria. In presymptomatic individuals who do not fulfill the 2009 RIS criteria, the revised 2023 RIS criteria target to secure an accurate and timely diagnosis: In addition to (a) having one lesion in two of four locations (periventricular, juxtacortical/cortical, infratentorial, spinal cord), (b) two of three features (spinal cord lesion, cerebrospinal fluid (CSF)-restricted oligoclonal bands, and new T2 or gadolinium-enhancing lesion) should be fulfilled. Among laboratory biomarkers, CSF kappa-free light chain can also increase diagnostic accuracy. Once the diagnosis is confirmed, the established risk factors, including demographics, imaging, and laboratory biomarkers, should be evaluated for symptomatic MS transition and prognosis. Younger age, male sex, increased neurofilament-light chain, CSF abnormality, and the presence of infratentorial, spinal cord, or gadolinium-enhancing lesions on imaging are the main risk factors for transition to symptomatic MS. Two randomized clinical trials showed significant efficacy of disease-modifying treatments in delaying or preventing the development of the first clinical event in RIS. However, because some individuals remain as RIS, it is crucial to identify the individuals with a higher number of risk factors to optimize disease outcomes by early intervention while minimizing adverse events. Discussing each RIS case with an expert MS team is recommended because there is still a lack of clinical guidelines to improve care, counseling, and surveillance.

Figure 1.. Practical diagnosis and management considerations in individuals with RIS.

A diagnostic algorithm with a clinical follow-up recommendation, and when to consider treatment in individuals with RIS are illustrated. Both validated and updated diagnostic criteria for RIS, as well as natural history studies with prognostic determinants for RIS and the clinical trials in RIS are utilized to reflect our practical use of the knowledge in clinical practice. The following references have been utilized to construct the figure: * Lebrun-Frenay C, et al. The radiologically isolated syndrome: revised diagnostic criteria. Brain. 2023. ** Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005. ^† Okuda DT, et al. Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS One. 2014 and Lebrun-Frenay C, et al. Radiologically Isolated Syndrome: 10-Year Risk Estimate of a Clinical Event. Ann Neurol. 2020, ^†† Okuda DT, et al. Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome. Ann Neurol. 2023 and Lebrun-Frenay C, et al. Teriflunomide and Time to Clinical Multiple Sclerosis in Patients With Radiologically Isolated Syndrome: The TERIS Randomized Clinical Trial. JAMA Neurol. 2023. DMT= Disease modifying therapies; Gd= Gadolinium; MRI= magnetic resonance image; RIS= radiologically isolated syndrome

Figure 2.. Example MRI of RIS.

A–C Brain T2 FLAIR images display multiple subcortical and periventricular hyperintense lesions. The sagittal view clearly shows several lesions oriented perpendicular to the ventricles (A, B axial, C sagittal). D Brain T1 MPRAGE image displays multiple T1 hypointense “black hole” lesions consistent with axonal loss. E, F Cervical spinal cord T2 images display a dorsal spinal cord lesion at the C2 level (E sagittal, F axial). This individual fulfilled the 2023 RIS criteria and had multiple risk factors for transition to symptomatic MS (younger age, spinal cord lesion on the index scan and CSF-restricted oligoclonal bands). Therefore, she was started on an MS disease-modifying therapy, dimethyl fumarate, and has been stable. CSF= cerebrospinal fluid, FLAIR= fluid attenuated inversion recovery, MRI= magnetic resonance image, MPRAGE= magnetization prepared rapid gradient echo, RIS= radiologically isolated syndrome