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Background <p>Radiologically isolated syndrome (RIS) is traditionally viewed as a preclinical state. However, emerging evidence suggests it represents an active subclinical stage of the multiple sclerosis (MS) spectrum. This systematic review integrates evidence across cognitive and psychosocial domains, along with secondary neuroimaging and biomarker findings, to explore the clinical conceptualization of RIS.</p> Methods <p>Following PRISMA guidelines, a systematic search was conducted across PubMed, Cochrane Library, and ClinicalTrials.gov for studies published between January 2010 and May 2026. Eligible studies focused on cognitive performance, psychosocial measures, and biomarkers in RIS. Quality was evaluated using the ROBINS-E tool.</p> Results <p>Thirteen studies met the eligibility criteria and were included in the final synthesis. The evidence reveals that a substantial proportion of individuals with RIS exhibit cognitive impairment, with information processing speed and executive functions being the most affected domains. Psychosocial burdens, including clinical depression and pathological fatigue, are prevalent and significantly impact quality of life. Furthermore, advanced neuroimaging and molecular biomarkers confirm ongoing neurodegeneration and inflammatory activity, characterized by cortical thinning, thalamic atrophy, and elevated neurofilament levels. Despite these subclinical changes, evidence suggests that baseline cognitive performance does not consistently predict short-term clinical conversion to symptomatic MS.</p> Conclusions <p>Current evidence suggests that at least a subset of individuals with RIS may represent an active subclinical phase of MS involving measurable neuroaxonal damage and psychosocial deterioration. However, given the limited number of studies and high risk of bias, definitive conclusions remain challenging. These findings highlight the potential need for a paradigm shift in clinical management, where incorporating targeted neuropsychological assessments and sensitive biomarkers could aid in accurate disease staging and optimized risk stratification.</p>

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The multi-dimensional spectrum of radiologically isolated syndrome: a systematic review of cognitive and psychosocial evidence

  • 期刊论文

  • 发表日期：

    2026年7月19日

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  • Mao Hsien Chang,
  • Mao Chang Chang,
  • Wei Hsi Chang

摘要

Background

Radiologically isolated syndrome (RIS) is traditionally viewed as a preclinical state. However, emerging evidence suggests it represents an active subclinical stage of the multiple sclerosis (MS) spectrum. This systematic review integrates evidence across cognitive and psychosocial domains, along with secondary neuroimaging and biomarker findings, to explore the clinical conceptualization of RIS.

Methods

Following PRISMA guidelines, a systematic search was conducted across PubMed, Cochrane Library, and ClinicalTrials.gov for studies published between January 2010 and May 2026. Eligible studies focused on cognitive performance, psychosocial measures, and biomarkers in RIS. Quality was evaluated using the ROBINS-E tool.

Results

Thirteen studies met the eligibility criteria and were included in the final synthesis. The evidence reveals that a substantial proportion of individuals with RIS exhibit cognitive impairment, with information processing speed and executive functions being the most affected domains. Psychosocial burdens, including clinical depression and pathological fatigue, are prevalent and significantly impact quality of life. Furthermore, advanced neuroimaging and molecular biomarkers confirm ongoing neurodegeneration and inflammatory activity, characterized by cortical thinning, thalamic atrophy, and elevated neurofilament levels. Despite these subclinical changes, evidence suggests that baseline cognitive performance does not consistently predict short-term clinical conversion to symptomatic MS.

Conclusions

Current evidence suggests that at least a subset of individuals with RIS may represent an active subclinical phase of MS involving measurable neuroaxonal damage and psychosocial deterioration. However, given the limited number of studies and high risk of bias, definitive conclusions remain challenging. These findings highlight the potential need for a paradigm shift in clinical management, where incorporating targeted neuropsychological assessments and sensitive biomarkers could aid in accurate disease staging and optimized risk stratification.